March 2025 I Volume 7 I Issue 3

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Table of Contents
March 2025| Volume 7| Issue 3 - INDIGO

1 DNA Methylation’s Role in the Working Memory Deficits of Attention-deficit/hyperactivity disorder (ADHD)
Hibah Faisal

6 Does Fiscal Decentralization Benefit Sustainable Development? Evidence From 2020

Sebastian W. Gillmore

12 Structural And Functional Insights into EGFR And EGFRvIII Using Computational Modelling and Docking
Atreya Manaswi

16 Hydrogen Fuel Cells and Lithium-Ion Batteries For Solar Energy Balancing At Varying Climates: A Review
Bana el Ghossein

22 Forecasting Stock Market Movements with LSTM: A Case Study of Amazon and NASDAQ Performance Across Different
Economic Cycles
Raj Vansh Bollineni

28 Emerging Novel Stem Cell Therapies for Cardiovascular Diseases

Dominyka Virbickaitė

38 Promoting Female Entrepreneurship: Investigating Strategies for Japan

Elias R. Nakajo

46 The Underrepresentation of Women in the Finance Industry: Causes and Solutions

Emilie Kassis

52 Parenting Styles, ACEs, & Neurobiological Effects on Attachment Styles for High-Functioning ASD Children
Fengqi Wang

58 Effects of Obesity on Human Health and the Emerging Role of GLP-1 Based Therapies
Gauri Bansal

65 Combatting Misinformation: Divergences and Similarities Between American and Brazilian Electoral Institutions
Hugo de Cunto Bueno

71 Comprehensive Solutions to Variations of the Knight’s Tour Problem

Caleb I. Yates, Jordan Y. He, Noah J. Schmidt

82 Examining the Fast Fashion Industry and the Multifaceted Oppression of Downtown Los Angeles Garment Workers
Ileana Nguyen-Garay

87 Comparison of Classical and Hybrid Quantum Models in Secondary Structure Protein Prediction
Quaid Shubin

97 The Impacts of Artificial Intelligence on Reducing Surgical Errors in Heart Surgeries

Yonas Getenet Bekele

i © 2025 Terra Science and Education

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„ LETTER FROM THE EDITOR

This issue of IJHSR features several papers that students produced
for a scholarly event: Indigo Research's IRIS program, which immerses
high school students in online college-level seminars. IRIS culminates
in small symposia, where participating students present full-length re-
search papers before their peers and professors. The dedicated scholars
in this issue hail from both Indigo and NYAS (The New York Acad-
emy of Sciences), a prestigious global community comprising over
20,000 members, including leaders in science, industry, academia, gov-
ernment, and public policy.
All of the papers published in this issue underwent a rigorous dou-
ble-blind peer review process, facilitated by IJHSR. Following this
review, a selection of papers was accepted for further revisions, copy
editing, and publication. All accepted submissions adhered to IJHSR's
stringent quality standards, and the team responsible for organizing
IRIS had no influence over the review process. IJHSR, Indigo Re-
search, and the IRIS faculty are proud of the intellectual resilience that
all student participants brought to the review process, whether or not
their papers were accepted for this issue.

„ RESEARCH ADVISORY BOARD

Dr. Jorge Avila
Dr. Steve Bullock
Dr. Ceyhun Elgin
Dr. Siddharth Krishnan
Dr. Eric Sakk
Dr. Hamidreza Shaye
Dr. Aviezer Tucker
Dr. Abdullah Yalaman
Dr. Michellana Jester
Dallin Lowder
Collin McColl

ii
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REVIEW ARTICLE

DNA Methylation’s Role in the Working Memory Deficits of

Attention-deficit/hyperactivity disorder (ADHD)
Hibah Faisal
SICAS DHA, Phase 2 DHA, Lahore, Punjab, 54792, Pakistan; [email protected]

ABSTRACT: The addition of a mere chemical group to our DNA components can change the way our brains think and
operate. In recent years, in an attempt to unlock more truths behind the complicated Attention-deficit /hyperactivity disorder
(ADHD), research has expanded to the epigenetic factors causing it. These are factors influenced by the environment that affect
gene expression and silencing. This paper focuses on the specific influence of DNA methylation (DNAm) in causing the working
memory deficits by which ADHD is often characterized. It attempts to establish a direct correlation between the two and provide
a holistic view of potential pathways of DNAm that affect working memory. This information can be crucial in understanding the
importance of these sites as biomarkers and their utility in regulating ADHD.
KEYWORDS: Biomedical Health Sciences, Molecular Biology of Disease, Attention-deficit /hyperactivity disorder,
Epigenetics, DNA Methylation, Working Memory.

� Introduction
The question of how our environment affects us has been
vastly explored by researchers. However, the link between our
environment, genes, memory, and Attention-deficit /hyperac-
tivity disorder (ADHD) remains complicated and vague. How
does a biological process link an environmental factor to a psy-
chological one? Can a single chemical group explain this?
ADHD is one of many common neurodevelopmental disor-
Figure 1: Baddeley’s Working Memory Model. It breaks down working
ders prevalent in children, with 11.3% of children aged 12-17
memory into three core subsystems: the phonological loop, the visuospatial
being diagnosed in the United States as of 2022.¹ It is usually sketchpad, and the episodic buffer - all coordinated by the central executive.
characterized by symptoms such as inattention, hyperactivity, (Created by the author).
and impulsivity - with one evident trait being working memory
deficits.² While there are multiple models of working memory, While Figure 1 briefs us on the neurological backgrounds of
Alan Baddeley, on a basic level, defines working memory as the working memory, the answer to the previously posed question
ability to hold and manipulate information over short periods stems from the field of epigenetics. Traditional research has
of time.³ It is important for tasks such as problem-solving, de- identified genes associated with ADHD.⁵,⁶ Recent research
cision-making, and maintaining focus - overall affecting our has gone into ‘epigenetic’ factors (factors influencing gene
language, reasoning, and learning. Deficits in working mem- expression) affecting ADHD, particularly DNA Methyla-
ory have been linked to language and learning impairments, tion (DNAm) that regulates gene expression.⁷ DNAm is the
hyperactivity, and even diseases other than ADHD such as addition of a methyl group to DNA that often results in the
schizophrenia.⁴ Before we discuss these, it is important to repression of gene activity.⁸ It plays a crucial role in brain de-
understand how working memory functions and what these velopment by regulating gene expression in different cognitive
‘deficits’ look like. Building on Baddeley’s model,³ research processes. In contrast to genetic factors, epigenetic factors (like
into working memory has streamlined the functions of its DNAm) can be influenced by the environment. This alludes to
main components which can be seen in Figure 1: the central a link between genetic predisposition and environmental fac-
executive which coordinates cognitive processes, consisting of tors causing ADHD. However, the particular link of DNAm
the episodic buffer, which integrates and links information to to evident ADHD traits such as working memory is underex-
long-term memory; the phonological loop, which handles au- plored.
ditory information; and the visuospatial sketchpad, responsible Despite being a small modification, uncovering this link can
for visual and spatial data. have a significant impact. This connects back to ADHD diag-
nosis. According to a study,⁹ several difficulties come with
© 2025 Terra Science and Education 1 DOI: 10.36838/v7i3.1
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ADHD’s behavioral diagnosis right now - that only top-ti- be considered manifestations of working memory deficits
er experts can see through. The most important including which will become significant when analyzing studies done on
its nonspecific symptoms (i.e. symptoms like inattention ADHD patients later on.
etc. are common childhood behaviors), its comorbidity with
other disorders (such as speech impairments), and its vari-
ability across individuals (various mixtures of symptoms can
be present between different people with ADHD) as well as
between different stages of someone’s life. Although research
into biological pathways and the consequence diagnosis of
ADHD is undergoing, it is not yet specific enough for clin-
ical use.⁹ That is where exploring this link between DNAm
and ADHD traits becomes significant as DNAm patterns can
serve as ‘biomarkers’ - biological molecules that indicate dis-
ease or abnormality in an individual.⁹ These biomarkers can Figure 2: The Prefrontal Cortex Region is located at the front of the brain’s
help make diagnosis more specific and accurate. Specifically frontal lobe. It is essential for high-order cognitive functions such as decision-
making, attention regulation, and working memory – all involved in ADHD.
exploring working memory in relation to this is significant. (Created by the author).
Studies establish working memory as a core component in
causing functional outcomes in ADHD,¹⁰ hence this specific Going into the neurological background, studies have shown
cognitive function seems like a relevant area to focus on when
that these functions of working memory are based in the
trying to streamline a direct pathway in how DNAm results in brain’s prefrontal cortex through processes such as PET Scans,
the pathogenesis of ADHD. analyzing subjects with prefrontal damage, and tests includ-
Overall, this review aims to investigate the epigenetic mech- ing working memory-related tasks and tracking brain activity.
anisms such as DNAm that cause working memory deficits in The prefrontal cortex is a region in the frontal lobe of our
ADHD. Through synthesizing recent studies, it will aim to brains, refer to Figure 2, with a wide variety of functions - usu-
create a specific correlation between the two, exploring poten- ally related to executive function.¹¹ This fact becomes relevant
tial gene locations for DNAm in relation to working memory. as we move onto the second observation, on these working
To do this, it will first frame the cognitive functions affect- memory impairments being present in ADHD patients. Old-
ed by DNAm that are also utilized in ADHD. Then, closely er studies using neuroimaging techniques have demonstrated
examine working memory deficits in ADHD, outlining the that individuals with ADHD often exhibit reduced activity in
main genetic and environmental causes present in current re- the prefrontal cortex during tasks requiring working memory.
search. Finally, it will establish the following links between More recent studies have highlighted specific ADHD-re-
ADHD working memory deficits and DNAm: (i) DNAm lated cognitive functions that are not fully operative due to
affects dopamine regulation which disrupts working memory working memory deficits. For instance, Kofler and his team²
(ii) DNAm affects synaptic plasticity which impacts working analyzed the response of children with and without ADHD
memory function. Conclusively, the paper will discuss the im- to working memory tasks looking to test if working memory
plications of these findings for the development of biomarkers deficits resulted in organizational problems - a core symptom
and targeted therapies for ADHD. of ADHD. They concluded that impaired working memo-
� Discussion ry processes affect children’s ability to sustain attention and
Examining the Neurological Basis of Working Memory maintain consistent task engagement - overall causing organi-
Deficits in ADHD: zational problems.
Understanding the association of working memory deficits Understanding what affects the prefrontal lobe or other ar-
with ADHD relies on two observations relevant to this paper: eas associated with working memory to cause ADHD in the
(i) working memory is important for certain cognitive func- first place, recent research suggests that a mix of genetic and
tions - such as problem-solving, etc, and (ii) these cognitive environmental factors contribute. This is the idea that forms
functions are impaired in ADHD, leading to the disorder's the foundation of this paper - epigenetic factors, specifically
characteristic symptom. DNAm cause these deficits. Establishing the link between this
Referring to the first observation, our working memory and the known neurological basis of working memory deficits
affects our reasoning, comprehension, and learning. This is in ADHD, i.e. the prefrontal cortex, requires us to know more
proven by studies showing deficits in working memory being about DNAm in relation to the cognitive processes described
the cause of learning disabilities and other dysfunctions.⁴,¹⁰ above.
One study links this to errors in these individuals while ac- DNAm and Cognitive Function: Causes of DNAm, Path-
cessing phonological representations, a core pathway within ways Affected, and Link to ADHD:
the phonological loop, which is central to working memory DNAm involves the addition of a methyl group to cytosine
function.² Also, capacity limits in attentional control exacer- bases in the DNA, usually at regions called CpG sites. These
bate these issues, as individuals may struggle to prioritize or chemical modifications can act like switches, turning specific
sustain focus on auditory tasks. These limitations manifest genes on or off depending on the methylation pattern. As ex-
in difficulties with tasks requiring sustained focus. These can plained above, DNAm is an epigenetic process that responds
DOI: 10.36838/v7i3.1
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to environmental factors - directly impacting gene expression undergo DNAm changes in individuals with ADHD. Accord-
related to cognitive functions. This section will explore how ing to a study done by Tonelli on DAT1,¹⁷ DNAm changes
DNAm influences pathways involved in neurotransmitter reg- can alter the availability of dopamine in the synaptic cleft, po-
ulation and synaptic plasticity (pathways that allow neurons to tentially leading to the cognitive deficits observed in ADHD.
communicate with each other), particularly focusing on dopa- Another important factor is that dopamine has been shown
mine signaling and other neurotrophic factors. to specifically be released into the prefrontal cortex where it is
To be able to understand how DNAm affects us, it is nec- assumed to regulate neural circuits that affect certain cognitive
essary to know what causes these chemical ‘methyl’ groups to functions.¹⁵ Research has also shown that many dopamine re-
change our gene expression in the first place. Studies show that ceptors (e.g. D1) are present in the prefrontal cortex.¹⁸
during critical periods of brain development, especially prena- Secondly, DNAm has been shown to impact our neuro-
tal periods, environmental factors such as prenatal exposure to trophic signaling pathway. It can repress the expression of
toxins (e.g., tobacco smoke, heavy metals) or stress can lead to Brain-Derived Neurotrophic Factor (BDNF),¹⁹ which is
aberrant DNAm patterns.¹²,¹³ a protein that plays an important role in neural plasticity.²⁰
Going into detail, Moore explains the basic mechanisms for Neural plasticity refers to the brain's ability to adapt to vari-
DNAm,⁸ involving the addition of a methyl group to cyto- ous changes throughout our lives, the part of this affected by
sine (a base in our DNA), to form 5-methylcytosine (5mC), BDNF is synaptic plasticity - which refers to the strengthen-
as demonstrated in Figure 3 below. This suppression occurs ing and weakening of neural connections over time.²¹ Synaptic
because the methyl groups either physically block transcrip- plasticity has been shown to affect the encoding and retriev-
tion factors - proteins that activate genes - from binding to the al of memory - especially in the prefrontal cortex, impacting
DNA, or they recruit proteins that condense the DNA struc- working memory specifically.²² This shows us that these two
ture, making it less accessible for transcription. Moore explains pathways influenced by DNAm impact working memory and
that research shows methylation and demethylation occur even may relate to ADHD.
in our neurons, which are non-dividing (no change in genes Linking DNAm and Working Memory Deficits in
passed down). This suggests that methylation is about more ADHD:
than just regulating gene expression but also about adapting it So far, it has been established that (i) working memory
to external stimuli, these adaptations affect synaptic plasticity deficits are a defining feature of ADHD, affecting cognitive
and cognitive function. abilities e.g. problem-solving, decision-making, etc. (ii) DNAm
is an epigenetic process that modifies gene expression, influ-
encing cognitive functions and potentially contributing to
ADHD-related deficits and, (iii) DNAm affects genes related
to dopamine regulation (e.g., DAT1, DRD4), and the synaptic
plasticity in the neurotrophic pathway.
People with ADHD are typically associated with dopamine
imbalances due to a lack of proper dopamine regulation.¹⁶
Before, the role of dopamine in regulating neural circuits
in the prefrontal cortex, which is heavily linked to working
memory function, was established. Since dopamine is so heav-
Figure 3: Basic DNA Methylation - the addition of a methyl group to
cytosine, forming 5-methylcytosine (5mC). This modification can repress ily interlinked with both DNAm and working memory - it
gene activity by blocking transcription factor binding or recruiting proteins seems reasonable to conclude that methylation on specific do-
that compact DNA, making it less accessible. In neurons, DNAm is pamine-related genes such as DAT1, can lead to imbalances
important since it adapts gene expression in response to external stimuli,
in dopamine levels in the prefrontal cortex. This imbalance
influencing synaptic plasticity and cognitive functions. (Created by the
author). disrupts the pathways required for effective working memory,
causing the deficits observed in ADHD.
Research has identified pathways impacted by DNAm that Shang highlights that deficits might not arise only from do-
affect cognitive function. The two most relevant pathways to pamine level alterations but also from the downstream effects
ADHD that will be discussed here are (i) dopamine regulation on synaptic plasticity.²³ Since DNAm disrupts neurotrophic
and (ii) neurotrophic signaling pathway. pathways that play an important role in synaptic plasticity and
On the first point, dopamine is a neurotransmitter that reg- hence working memory, it also seems reasonable to conclude
ulates and helps modulate various cognitive functions such as that this results in the pathogenesis of the working memory
reward processing and focus.¹⁴,¹⁵ Studies show that individuals deficits seen in ADHD.
with ADHD tend to have dopamine dysfunction.¹⁶ In fact, � Conclusion
they explain that dopamine dysregulation has been linked to Conclusively, this research explores the relationship be-
the pathogenesis of ADHD. This makes sense considering tween DNAm and working memory deficits in ADHD to
the role of dopamine in modulating cognitive functions such highlight the significant role of epigenetic factors in cognitive
as focus that are affected in ADHD. Genes involved in the impairments. Epigenetic factors such as DNAm can occur in
dopamine regulation pathway, such as DAT1 (dopamine trans- pathways related to dopamine regulation and synaptic plastici-
porter) and DRD4 (dopamine receptor), have been shown to ty - this can be on, for example, dopamine receptor genes
3 DOI: 10.36838/v7i3.1
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DOI: 10.36838/v7i3.1 4
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� Author
Hibah, a senior at SICAS DHA, is drawn to the unknown in biol-
ogy, with a curiosity that might one day lead to a PhD.

5 DOI: 10.36838/v7i3.1
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RESEARCH ARTICLE

Does Fiscal Decentralization Benefit Sustainable

Development? Evidence From 2020
Sebastian W. Gillmore
Tamalpais High School, 700 Miller Ave, Mill Valley, CA, 94941, USA; [email protected]

ABSTRACT: Is fiscal federalism associated with sustainable development in countries around the world? Using the latest data
on fiscal decentralization from the IMF, we examine the relationship between fiscal decentralization and various indicators of
sustainable development across 59 diverse countries. The indicators of sustainable development include economic, educational,
environmental, health-related, and social variables. Our results suggest that the level of fiscal decentralization is significantly
associated with the economic, social, and health aspects of sustainable development, and does not correlate with the environmental
and educational categories. We also found that in many cases, fiscal revenue and expenditure decentralization have inverse effects.
Further research should be conducted to investigate the optimal level of fiscal expenditure and revenue decentralization for
each pillar of sustainability and if our results between expenditure and revenue decentralization are also present in other fields.
This research serves as a platform for future research on sustainability and fiscal decentralization through specific sustainable
development goals.
KEYWORDS: Economics, Sustainable Development, Fiscal Expenditure, Decentralization, Fiscal Revenue, Decentralization,
Fiscal Federalism.

� Introduction are being measured to inform future policy decisions. Fiscal

No country has achieved sustainable development, however, decentralization has been long researched for its impact on
there is a plethora of research on how countries should attack economic development, recently, however, there has been an
this important topic. Sustainable development is not sustain- increased interest in research on its impact on sustainable de-
ability, instead, it has been defined as “development that meets velopment. To the best of our knowledge, there has been a gap
the needs of the present without compromising the ability of in research on fiscal expenditure/revenue decentralization and
the future” by the International Institute for Sustainable De- its effect on specific metrics in the categories of sustainable
velopment. This has been quantified by creating Sustainable development goals.
Development Goals, and pillars of sustainable development, In this study, we consider how fiscal decentralization impacts
such as gender equality, no poverty, peace, justice, and strong the achievement of sustainable development goals (SDGs). We
institutions. Sustainable development has been a priority in investigate this issue to clarify which SDGs are impacted by
America for over 30 years (President's Council on Sustainable fiscal decentralization and to explore the correlation between
Development) and sustainable legislation is on the docket as fiscal decentralization and specific SDGs. A comprehensive
we continue through the 21st century. Recently, the excessive conclusion will guide future policy decisions and areas to
consumption of natural resources and the ever-widening pay subsidize as fiscal decentralization/centralization increases.
and economic support gap between richer and poorer countries Additionally, this paper provides valuable insight into what
in the aftermath of the Coronavirus Pandemic have empha- factors aren’t affected by fiscal decentralization.
sized the need for economic equality.¹ Increased research into The rest of the paper is organized as follows. Section 2 is
factors that impact sustainable development has increased be- a literature review of fiscal decentralization and sustainable
cause of these factors, as sustainable development is rooted in development. In Section 3 we present our Data and Method-
equity and equality. We have selected our 59 countries because ology, including significance tests between SDGs and fiscal
they were the most representative of all countries and had a decentralization. Section 4 contains our empirical results and
comprehensive dataset. section 5 presents our conclusions.
Fiscal decentralization, as we will calculate it in our paper � Literature Review
(through both percent expenditure and percent revenue), is Two prevailing strands of literature are pertinent to our
the amount of countries' capital/responsibility bestowed upon study. First, the economic impacts of fiscal decentralization,
a decentralized government – government vs local spending bleeding into sustainable development and the optimal level of
and government vs local revenue collection. There was a large fiscal decentralization. The next strand of literature is simply
shift to fiscal decentralization in the 1980s, transitioning the defining what sustainable development is, as this is pivotal to
responsibility of central governments to local governments understanding the paper.
across the world.² Now, the impacts of fiscal decentralization
© 2025 Terra Science and Education 6 DOI: 10.36838/v7i3.2
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The first strand of literature focuses on fiscal decentralization, and continuity.¹⁴ They found that their modified version of the
mainly the economic implications of fiscal decentralization. NSDI was more acceptable and reliable, giving a better gauge
This has been researched extensively, and both the impact on of sustainable development. In the end, sustainable develop-
countries and corporations have been analyzed. First, the im- ment has long been researched as an index, however, there is
pact of fiscal decentralization on corporations, with Pu et al. still variation between which indicators are used in each index,
concluding that fiscal decentralization leads to higher corpo- giving varied results once again. While there has been a lot
rate innovation, forwarding economic growth.³ This, however, of research on sustainability as a whole, there has been little
is not as clearly shown in the literature on fiscal decentraliza- research that compiles different explanatory variables for the
tion’s effect on countries’ economic growth. Lin & Liu found pillars of sustainable development and compares that with
that fiscal decentralization had a positive effect on econom- fiscal decentralization. For the explanatory variables for each
ic growth in China from the 1980s to 1990s.⁴ This further pillar, we will use the variables that Özgür et al. used in their
demonstrates the claim that fiscal decentralization benefits study for informality and sustainable development.¹⁵
economic growth, however, in OECD countries, it was found In sum, there has been an extensive amount of research on
that fiscal tax decentralization has an insignificant effect on fiscal decentralization and economic outcomes and even re-
economic growth. This further lends to the complexity of fis- search on fiscal decentralization and sustainable development,
cal decentralization, as different methods often yield different however, there is a gap in the literature investigating what
results.⁵ In 2003, Martinez-Vasquez & McNab published a causes the upward and downward slope of the association
paper claiming that there is still a need for more research to between fiscal decentralization and sustainable development.
decide whether fiscal decentralization is beneficial to economic We attempt to demonstrate what variables are benefited and
growth.⁶ Since then, Gemmell et al. concluded that fiscal rev- undercut by fiscal decentralization, leading to policy decisions
enue decentralization promotes economic growth while fiscal that benefit the countries that have differing levels of fiscal
expenditure decentralization hampers economic growth.⁷ The decentralization, not only contributing to the research on op-
link between economic growth and sustainable development timal levels but also showing what SDGs countries should
has been explored in a multitude of countries around the globe. subsidize for differing levels of fiscal decentralization.
In Ghana, Dick-Sagoe concluded in a literature review that � Methods
fiscal decentralization had a positive effect on Ghana’s eco- Data:
nomic growth.⁸ This was reverberated in a paper published in Our main explanatory variable of interest is fiscal decen-
the wake of fiscal decentralization in Indonesia, which found tralization. To create a benchmark for this analysis, we used
that it had beneficial economic outcomes and could provide a the revenue-centralization approach, measuring the ratio of
sustainable future for local governments in Indonesia.⁹ Finally, central government revenue to the total government revenue.
it was concluded in Russia that fiscal expenditure decentral- Central government-collected revenue is in the numerator
ization will lead to negative economic outcomes without being and total revenue collected on the denominator, this includes
paired with fiscal revenue decentralization, also finding that subnational and local governments. The second indicator is
dependence on fiscal transfers from a federal government expenditure-centralization, following the same rules as the
benefits economic growth.¹⁰ The effects of fiscal decentral- revenue approach, with the denominator and numerator be-
ization are varied across different industries, and its effects ing expenditure instead of revenue. Both series are obtained
are much more visible on a micro-scale. In summary, revenue from the International Monetary Fund’s World Development
decentralization leads to economic growth while expenditure Indicators, when data is not available there for our selected 59
decentralization does not. However, a pair of both lead to sus- countries, we default to the OECD library.¹⁶, ¹⁷ (Data provid-
tainable local governments and future success. ed from 2020/2021) Following the approach from Elgin et al.,
The second strand of literature focuses on sustainable de- we will also use the methodology of Arzaghi and Henderson.
velopment. The pillars of sustainable development have been This gives us a measure of the institutional and statutory level
placed into indices, such as the Human Development Index of fiscal federalism in a country.¹⁸,¹⁹ This measures degrees of
and the National Sustainable Development Index. These indi- decentralization instead of benchmark measures.
ces give us a sense of how sustainable development functions This is not the most common measure used in the empir-
as fiscal decentralization is changed, with studies such as Jin ical literature on the effects of fiscal decentralization. The
& Jakovljevic finding that a moderate level of fiscal decentral- fiscal expenditure approach, using a subnational expenditure
ization aids sustainable development by looking at the HDI.¹¹ approach, is also provided by the World Development Indi-
This is also reiterated by Hui & Martinez–Vazquez, who, by cators. This has been done often by researchers. (Enikolopov
using the NSDI, found the optimal level of fiscal decentral- & Zhuravskaya; Gemmell et al.; Hui & Martinez-Vasquez)²⁰,⁷
ization and also validated the hump-shaped curve created by However, there is no perfect measure, and the criticisms of
fiscal decentralization and sustainable development.¹² Olaide the GFS-based measure are plentiful among scholars. (Gov-
et al. found that there was no relationship between fiscal ernment Finance Statistics provided by the International
federalism and the NSDI, however, there was a relationship Monetary Fund)¹² There is a belief that it overstates the actual
between federalism and economic development, implying that level of expenditure decentralization. This is partly why we use
was the reason for certain policy decisions.¹³ There has also the revenue approach as well. The main issue with using any
been research into modifying the NSDI for lack of reliability other database than the GFS/WDI is that there is a lack of re-
7 DOI: 10.36838/v7i3.2
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search into non-EU countries, leading to an overrepresenta- GDP per capita (IMF), population size (IMF), urban popula-
tion of richer countries, this is the case in many studies cited tion (percentage of people that live in urban areas, WorldBank),
in Hui & Martinez-Vasquez such as Baskaran & Feld and level of democracy (Economist Intelligence Unit), corruption
Slavinskaitė.⁵,¹⁶,²¹ This leads to one-sided research that can- (0-1 with 1 being no corruption, transparency.org), rule of
not be generalized to poorer, developing countries, while the law (ourworldindata.org), and trade openness (percentage of
conclusion and policy recommendations will struggle to guide GDP, WorldBank).¹⁰,¹⁶,²²,²³ We consider these variables as
the majority of nations. Availability of data is important, and commonly used in the literature. We expect that for GDP
it is for that reason that we must push past the flaws that the per capita, urban population, level of democracy, rule of law,
GFS/WDI contains. corruption, and trade openness, there will be a positive correla-
Sustainable Development: tion with sustainable development. We expect the population
In this study, we aim to assess the empirical relationship size to have a negative correlation with sustainable develop-
between fiscal decentralization and sustainable development. ment. Trade openness is much more complex, as it reflects the
Sustainable development is difficult to measure in a few in- amount of a country's GDP that it trades every year. We ex-
dicators, which is why many researchers use indexes such as pect more trade to increase certain sustainable development
the HDI (Human Development Index) and NSDI (Nation- indicators while not affecting others. However, increased trade
al Sustainable Development Index). We have, following the may have ripple effects across different areas of sustainable
approach from Özgür et al., we grouped the sustainable devel- development. Trade openness is associated with the amount
opment indicators into 5 different categories.¹⁵ These include of women's labor force participation.²⁴ Table 1 provides the
health-related, economic, environmental, educational, and descriptive summary statistics for all of our control variables,
social variables. Each group contains several measures, pro- including log-shifted GDP per capita.
vided by the World Development Indicators from the IMF � Methodology
(2021 along with fiscal decentralization data).²² We use these Our dataset is a cross-country panel with data just from the
indicators because they let us evaluate each cornerstone of year 2020. This dataset is highly unbalanced, however, every
sustainable development. With this ability, we can find what country that we have selected has enough sustainable develop-
variables have a positive, negative, or no correlation with fiscal ment data from the year 2020 to create a comprehensive piece
decentralization, which would help us explain why the overall of data analysis. Before our regression and tests, we log shifted
indices such as the NSDI have a bell-shaped curve. GDP per capita to normalize the data. Stationary tests do not
The health-related variables include things such as life ex- apply to our dataset, because of our exclusively one-year data
pectancy, Infant mortality rate, neonatal mortality rate, and collection process. For fixed effects estimation, we estimated a
mortality under age five. They also include what percent of model like this to regress sustainable development indicators
the population is vaccinated for certain diseases and drinking on fiscal decentralization.
water/sanitation access. These variables help us gain a picture SD_Indicator = β0 + β1*FiscalDecent(i) + β2*Controls(i) +
of what life is like in these countries. ε(i) (Equation 1)
The economic variables group includes three different Here, SD_Indicator is the sustainable development out-
poverty headcount ratios and gap series, along with access to come, β0 is defined as the intercept, β1 represents the change
electricity (by percentage of population). These variables give in SD_Indicator with a 1 unit change in fiscal decentraliza-
us an understanding of how financially able the country is, and tion, FiscalDecent(i) is the measure of fiscal decentralization
if the poverty SDGs are met. for the ith observation, β2 is the coefficient for the controls in
The group of environmental variables includes CO2 emis- our model, Controls(i) is the vector of our control variables,
sions per capita, and CO2 emissions per 2021 GDP, giving and finally ε(i) is the error term. Because of the size of our data,
us a gauge of the carbon footprint in the countries. This also limiting ourselves to 59 countries in the year 2020, we only
helps us gain a view of how well these countries are abiding by have enough data to run OLS regression models. The results
the Paris 2030 agreement. of these models are presented in Table 2.
The educational variables group contains gross tertiary and Table 1: Includes descriptive summary statistics for all variables.
gross secondary schooling, giving us a comprehensive, yet brief,
understanding of education in the countries we are evaluating.
Finally, the group of social variables, including ILO pre-
dictions of female labor force participation and national
predictions of female labor force participation. This assesses
the extent to which the country has installed institutions and
programs to promote equal access for men and women in edu-
cation, health, the economy, and legal protection. These all give
us a picture of what equality exists in the countries, and how
much effort is being dedicated to achieve equality.
Control Variables:
In several of our regression models, we use control variables
other than fiscal decentralization. These variables include real

DOI: 10.36838/v7i3.2 8
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Table 2: Provides the regression model's p-values and correlation for each contrast, we found a significant negative relationship between
variable tested.
the poverty headcount at $6.85 a day, the poverty gap at $3.65
a day, and the poverty gap at $6.85 a day with fiscal expendi-
ture decentralization (more decentralization). (Table 2)
Social variables also had significant impacts on fiscal decen-
tralization. Revenue decentralization (less decentralization)
was positively associated with female labor force participation
(ILO estimate), while expenditure decentralization (more de-
centralization) showed a significant negative relationship with
female labor force participation (ILO estimate). (Table 2)
Finally, we found no significant relationships between the
educational and the environmental categories with fiscal de-
centralization. However, this makes sense as environmental
success is dependent on private industry, and education is in-
vested differently across different countries. (Table 2)
We did test for multicollinearity among all of our indepen- All of these OLS regression results are controlled for by a
dent variables. We did this through a VIF test, finding that set of 7 variables that may interfere with the achievement of
none of our independent variables had an unnaturally high sustainable development goals. All 7 of these variables, and
VIF score. This validates that our results are valid. Here is the fiscal expenditure/revenue decentralization have been tested
equation we used: for multicollinearity, finding that there were no significant is-
Y = β0 + β1 X1 + β2 X2 + ... + βk Xk + ε (Equation 2.) Where sues. Beyond economic implications, sustainability has ethical
β0 is a constant and ε is the error term. significance, particularly in protecting future generations. De-
VIF = 1 / (1 − R 2) (Equation 3.) centralized governments with strong local governments allow
This equation, which is also defined as 1/(tolerance), will countries to create tailored policies addressing specific sustain-
output a number, with < .25 and > 10 indicating high multi- ability goals and challenges.
collinearity. These results are presented in a later section. Their � Discussion
results are presented in Table 2. These findings highlight the complex relationship between
� Results fiscal decentralization and sustainable development outcomes.
Our VIF test returned above-average multicollinearity for The inverse relationship between revenue and expenditure
both corruption and the rule of law returning values of 5 and decentralization further emphasizes the need for a greater
6 respectively. While these values are higher than normal, we understanding of this relationship. Revenue decentralization
decided to leave them as control variables because they were allows local governments to generate and control financial re-
not greater than our upper bound of 10. sources, thereby fostering responsiveness to regional needs. On
Table 2 reports our benchmark estimates for all five cate- the other hand, greater centralization enables sweeping and
gories of sustainable development variables for both fiscal and coordinated federal policy, creating an equitable distribution
expenditure decentralization. A statistically significant p-value of resources, especially in sectors like healthcare. These trade-
is a < .1, and all of the p-values are presented in Table 2. The offs are evident in our results, demonstrating the need for both
variety in the 59 countries selected allows us for a nuanced a strong federal and local government. For instance, countries
analysis of how fiscal decentralization impacts sustainability like the United States have a strong decentralized government,
across different political contexts. Negative relationships show and this is reflected in their ability to create strong regional
there should be less involvement from the central government, policies. Conversely, centralized governance, seen in countries
while positive relationships show that there should be more like France, allows for sweeping national policy implementa-
involvement from the central government. We found signifi- tion, leading to very different results for different variables of
cantly positive results in the health-related variables section sustainable development.
for infant mortality, neonatal mortality, mortality under 5, and Our analysis also reveals that revenue decentralization
fiscal expenditure decentralization (less decentralization). (less decentralization) is positively associated with poverty
Additionally, there were significant negative health-related reduction (exemplified by the poverty headcount ratio and
results for infant mortality, neonatal mortality, mortality under the poverty gap). This may reflect the failure of central gov-
5, and fiscal revenue decentralization (more decentralization). ernments to distribute resources across regions to ensure that
These results show an inverse relationship between revenue disadvantaged areas gain more support. In contrast, expendi-
and expenditure decentralization, something that we did not ture decentralization (more decentralization) empowers local
hypothesize. (Table 2) governments to spend directly on specific areas, which is ben
Fiscal decentralization also showed a significant impact eficial in some instances. However, they may exacerbate in-
on variables following economic development variables. We equalities if resources are misused.
found a significant positive relationship between the poverty Beyond economic implications, sustainability has a broader
headcount ratio at $6.85 a day and the poverty gap at $6.85 a ethical significance, especially as we consider future genera-
day with fiscal revenue centralization (less decentralization). In tions. Decentralized government, with strong local institutions,
9 DOI: 10.36838/v7i3.2
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enables direct addresses with tailored policies to help sus- linearity. This dataset was also limited to data from 2020. In
tainable development. However, centralized government can the future, there should be more comprehensive datasets creat-
provide the coordination and strength to tackle large-scale ed and tested using the methodology from this paper. Finally,
issues. This is evident in health care and environmental protec- while evaluating 59 countries from around the globe, specific
tion, things that require uniform policies. The choice between case studies from countries would be beneficial to understand-
decentralization and centralization involves important trade- ing the impact of policy and their outcomes in SDGs.
offs that addict both short-term outcomes and long-term Future research could also benefit from more advanced and
sustainable success. in-depth econometric techniques, such as panel data instru-
� Conclusion mental variable regressions or case studies of more specific
Fiscal Decentralization has been shown to have a major countries across the globe. Expanding the time frame beyond
impact on economic outcomes in countries around the world. just one year could also provide more insight into this topic.
Although studies have mostly focused on its impact on eco- Furthermore, exploring and controlling how fiscal feder-
nomic outcomes, new research has begun to be produced alism affects regional inequalities may help clarify its role in
evaluating the impact of fiscal decentralization on sustainable achieving sustainable development. This paper finds the vast
development.¹¹,²² Jumping off these insights, this research pa- difference between revenue and expenditure decentralization
per analyzes fiscal expenditure and revenue decentralization’s and its effect on sustainable development variables, and it also
impact on sustainable development variables in a macro con- finds what groups of variables are not statistically affected.
text. Our empirical results show that fiscal decentralization is However, this research paper skims the surface of an issue that
significantly associated with multiple sustainable development should be investigated for its implications not only in policy
variables. Our findings suggest that decreasing fiscal revenue today, but for future endeavors as we try to build a more sus-
decentralization (higher centralization) is positively correlat- tainable world.
ed with female labor force participation (ILO estimate), the � Acknowledgments
poverty headcount ratio at $6.85 a day, and the poverty gap Thank you Dr. Ceyhun Elgin for your advice and guidance
at $6.85 a day while more centralization was negatively cor- and Dad for always being a second pair of eyes.
related with infant mortality rate, neonatal mortality rate, and � References
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� Appendix
List of 59 Countries: Albania, Armenia, Australia, Austria, Belarus,
Belgium, Bosnia and Herzegovina, Brazil, Canada, Chile, China, Co-
lombia, Costa Rica, Croatia, Czechia, El Salvador, Estonia, Finland,
Georgia, Germany, Guatemala, Hungary, Iceland, Indonesia, Isra-
el, Italy, Japan, Kazakhstan, Kenya, South Korea, Latvia, Lithuania,
Mauritius, Mexico, Moldova, Mongolia, Nepal, Netherlands, North
Macedonia, Paraguay, Peru, Portugal, Russia, Rwanda, Senegal, Ser-
bia, Somalia, South Africa, Spain, Sweden, Switzerland, Thailand,
Turkey, Uganda, Ukraine, United Arab Emirates, United Kingdom,
United States of America, Uzbekistan
� Authors
Sebastian Gillmore is a senior at Tamalpais High School with a
love for economics and business. This is his second published piece,
the first titled “I live in Northern California. Why do I have to travel
hundreds of miles to take the SAT?” published in the LA Times.
DOI: 10.36838/v7i1.2 11 DOI: 10.36838/v7i3.2
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RESEARCH ARTICLE

Structural And Functional Insights into EGFR And EGFRvIII

Using Computational Modelling and Docking
Atreya Manaswi
Orlando Science High School, 2600 Technology Dr, Orlando, FL 32804 USA; [email protected]

ABSTRACT: Glioblastoma (GBM) is the most aggressive form of adult brain cancer with a five-year survival rate of 6.9%.
Epidermal growth factor receptor (EGFR) is a major target for cancer therapeutics, particularly glioblastoma. EGFR mutations
are seen in approximately 50-60% of GBM cases. The most frequent EGFR mutation, EGFRvIII, results from a deletion of
exons 2-7 and occurs in 34-63% of GBM genetic alterations. In this work, we research the effect of the EGFRvIII mutation by
visualizing EGFR and EGFRvIII protein structures and performing molecular docking to 6 ligands. According to our analysis,
the EGFR variant III has a generally negative effect on the binding affinity of the selected ligands compared to the wild-type
EGFR structure. In addition, visualization of the structures revealed that the mutant is missing several residues of the binding
domain. Therefore, we suggest that the EGFRvIII mutation may negatively affect EGFR structure, leading to glioblastoma
proliferation.
KEYWORDS: Computational Biology and Bioinformatics, Computational Neuroscience, Glioblastoma, Epidermal growth
factor receptor, EGFRvIII.

� Introduction often limited by the emergence of resistance mechanisms.⁹,¹⁰

Glioblastoma (GBM) is the most lethal, aggressive, and The TKIs employed in this analysis were Erlotinib (Tarceva),
prevalent primary brain tumor in adults characterized by its Gefitinib (Iressa), Afatinib (Gilotrif ), Dacomitinib (Vizim-
malignancy and poor prognosis.¹ The current standard of care pro), and Osimertinib (Tagrisso). Erlotinib and Gefitinib are
for GBM–maximal surgical resection in concert with radia- examples of EGFR TKIs; both drugs are reversible inhibitors
tion therapy and chemotherapy–has not resulted in beneficial generally used in NSCLC with EGFR mutations, although
outcomes for patients with a median survival time of only 14.6 resistance may eventually build up. Afatinib is an irreversible
months.²,³ Epidermal growth factor receptor (EGFR) is a TKI that targets EGFR, HER2, and HER4, administered in
transmembrane receptor tyrosine kinase that is key in regulat- specific EGFR mutations. Dacomitinib is also irreversible and
ing cell growth, proliferation, and survival in tissues originating provides more potent EGFR inhibition, used as a first-line
from epithelia.⁴ Atypical EGFR signaling is a hallmark of var- EGFR-mutated NSCLC treatment. Osimertinib is an irre-
ious cancers, particularly glioblastoma.⁵ EGFR mutations are versible TKI of the third generation, targeting both sensitizing
expressed in approximately 50-60% of GBM patients, mak- and resistance mutations such as T790M, and is thus indicated
ing them attractive targets for therapeutic intervention.³ The in both new diagnoses and resistance.
most common EGFR mutation - EGFRvIII (also known as Understanding the structural and functional ramifications of
de2-7EGFR and ΔEGFR) - occurs due to the in-frame de- the EGFRvIII mutation remains essential. The primary objec-
letion of exons 2-7, 801 base pairs (bps), from the wild-type tive of this study was to analyze the structural differences and
(WT) EGFR coding sequence.6 The EGFR variant III muta- explain the potential functional ramifications of the mutated
tion is found in ~50% of EGFR-amplified GBM cases and is EGFRvIII structure compared to its wild-type EGFR form.
linked to increased glioma cell proliferation.⁷ The EGFRvIII We also docked EGFR and EGFRvIII to 6 ligands to com-
mutation’s role as a therapeutic target is controversial but pare binding characteristics between the structures. Molecular
its oncogenic potential has called for recent development in docking simulations work by predicting the likely orientation
mutant receptor-targeted therapeutics.⁸ These EGFR muta- of a ligand when bound to a target protein. This aids in identi-
tions are associated not only with glioblastoma but also with fying binding affinities and simulating interactions to improve
other cancers, including non-small cell lung cancer, head and therapeutic efficacy. By mapping binding sites, structural
neck cancers, and colorectal cancer. These mutations result in similarities, etc. we aimed to gain insights into the structural
the constitutive activation of the EGFR signaling pathway, determinants of drug binding and resistance. Two major pa-
contributing to tumor development and rendering tumors re- rameters have also been analyzed: SwissParam-derived binding
sistant to various therapies. The different ways in which EGFR affinity scores and Attracting Cavities scores. Binding affinity
is targeted by various TKIs influence the different treatment scores reflect alterations in the receptor-mediator interaction
options for these malignancies. Erlotinib and gefitinib, small involving EGF and therapeutic agents upon mutation and thus
molecule tyrosine kinase inhibitors (TKIs), have shown early the effects on the efficacy of targeted treatments. AC scores
promise in preclinical and clinical studies, but their efficacy is give a detailed analysis of the stability of confirmation and
© 2025 Terra Science and Education 12 DOI: 10.36838/v7i3.3
 ijhighschoolresearch.org

structural changes that may affect receptor function. Collec-

tively, these measurements give a more defined account of how
the EGFR mutations confer cancer aggressiveness and ther-
apeutic resistance. The findings of this study may inform the
development of novel therapeutic strategies that specifically
target EGFRvIII-driven GBM.
� Methods
We first determined which protein mutations influenced
glioblastoma (GBM) progression through an extensive lit-
erature review and data analysis. Genomics repositories such
as The Cancer Genome Atlas (TCGA) and cBioPortal were
utilized to identify frequently mutated genes associated with
GBM. After identifying EGFR as a focal interest, we con-
sulted various repositories to locate appropriate structures for
Figure 2: Epidermal growth factor and epidermal growth factor receptor
analysis. The WT EGFR structure (ID 1ivo)¹¹ was retrieved dimerization arm in SwissDock. Binding occurs within the amino-terminal
from the Protein Data Bank in Europe (PDBe). The EG- 622 amino acids extracellular region.
FRvIII structure (ID 8UKX)¹² was retrieved from Protein
DataBase (PDB). � Results and Discussion
The EGFR and EGFRvIII PDB files were loaded into Py- Structural Comparison of EGFR and EGFRvIII:
MOL for visualization. Subsequently, they were aligned using Visualization confirmed the EGFRvIII mutation leads to
the command [align X, Y] to compare the residues. This high- the loss of nearly the entire domain I and a portion of domain
lighted the core regions of EGFR and EGVRvIII having high II in the EGFR extracellular region. The EGFRvIII structure
structural similarity. The root mean square deviation (RMSD) was significantly smaller than EGFR due to the truncation of
was calculated to quantitatively define alignment quality. The exons 2-7. Despite this notable size difference, the structures
command employed was [rms_cur target, mobile]. showed similar alignment with several regions corresponding
Using SwissDock, 12 molecular docking simulations were (Figure 1). The MatchAlign score of 1183.500 generated by
run. 6 ligand-target simulations were performed for the PyMOL indicated high alignment but the RMSD score of
EGFR and EGFRvII each. The 6 ligands chosen consisted 15.415 suggests significant structural differences, being, on av-
of epidermal growth factor (EGF) and tyrosine kinase in- erage, the corresponding atoms in the structures are 15 Å apart
hibitors (TKIs) which are small-molecule EGFR inhibitors after alignment. Visualization of the protein structures con-
designed to block kinase activity and prevent downstream firmed these differences in conformation and visibility of the
signaling that exacerbates tumor growth. The selected ligands ligand binding site between the structural variants (Figure 2).
were Epidermal Growth Factor, Erlotinib (Tarceva), Gefitinib Additionally, the absence of a part of domain II in EGFRvIII
(Iressa), Afatinib (Gilotrif ), Dacomitinib (Vizimpro), and disrupted the dimerization arm, a key structural element in-
Osimertinib (Tagrisso). These ligands were selected due to volved in ligand-induced EGFR dimerization and subsequent
their drug-like size and structural availability. In SwissDock, activation.
the ligand and target PDB files were loaded. The search space Molecular Docking Simulations
was automatically defined and Random Initial Conditions was Molecular docking simulations were performed to charac-
set to 1. Thereafter, the Attracting Cavities (AC) (the ligand terize the interactions between EGFR, EGFRvIII, and six
binding modes in docking simulation) score and SwissParam ligands in SwissDock. The results, summarized in Table 1
scores (approximation of ligand’s binding free energy to a tar- show that EGFRvIII has consistently higher AC scores com-
get) were interpreted and statistically analyzed to determine pared to EGFR across all ligands. However, the SwissParam
differences between the binding of the ligands to the EGFR scores, which estimate binding free energy, generally favored
and EGFRvIII structures. EGFR over EGFRvIII indicating a stronger predicted bind-
ing affinity for the wild-type receptor.
Statistical Analysis:
All data were analyzed using R version 4.2.0 (R Core Team,
2021). Paired t-tests were performed to compare the AC
scores and SwissParam scores between EGFR and EGFRvIII
for each ligand. The resulting p-values were adjusted using
Bonferroni correction to account for multiple comparisons.
Statistical analysis revealed significant differences for both AC
scores (t = -9.03, p < 0.001) and SwissParam scores (t = -3.86,
p = 0.024) between EGFR and EGFRvIII across all six li-
gands, even after Bonferroni correction. These results confirm
Figure 1: Overlayed structures of EGFR and EGFRvIII in PyMOL
visualization. Key conformational differences in the extracellular domain and
that EGFRvIII leads to a significant reduction in ligand bind-
within the mutation-specific region of EGFRvIII are shown. ing affinity compared to the wild-type receptor.
13 DOI: 10.36838/v7i3.3
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Table 1: Molecular Docking Results for EGFR and EGFRvIII to 6 signaling. These properties explain why diminished binding of
Ligands.
EGF does not diminish the tumorigenic competence of EG-
FRvIII and instead renders it more aggressive and challenging
for therapeutic interventions.
Due to the heterogeneity of EGFR mutations in glioblas-
toma, targeted approaches should focus on specific molecular
anomalies driving tumor growth. Future work should address
characterizing structural and functional implications of other
common EGFR mutations for glioblastoma. While this com-
putational analysis provides promising insights, these results
should be experimentally validated by future research studies.
Additionally, further research should investigate combination
therapies that target numerous pathways.
� Discussion � Conclusion
This research investigated the structural and functional In summary, our computational study of EGFR and EG-
implications of a major oncogenic driver in glioblastoma: the FRvIII suggests that the EGFRvIII mutation drastically
EGFRvIII mutation. We used in-silico modeling and mo- changes the conformation of the receptor’s ligand-binding
lecular docking simulations to compare EGFRvIII structure domain and therefore decreases the binding of different
with that of wild-type EGFR and found critical differences ligands to the receptor. Such structural changes may be re-
in the ligand-binding region and dimerization arm of the re- lated to the malignant behavior of glioblastoma and may be
ceptor. Our structural data indicate that EGFRvIII adopts a the reason for the poor sensitivity of current EGFR-targeted
tethered-like conformation, as has been observed in the un- therapies in treating tumors with the EGFRvIII mutation.¹⁴
liganded state of wild-type EGFR.¹³ This conformation may The lowered ligand binding affinity of EGFRvIII may further
prevent ligand-induced dimerization with wild-type EGFR lead to uncontrolled cell division and tumor formation – two
and may affect its signaling and interaction in GBM. characteristics of glioblastoma. Because EGFRvIII is such a
Our docking simulations with different ligands, including significant factor in GBM progression, the creation of targeted
the natural ligand EGF and different types of TKIs, empha- drugs that block the receptor continues to be an active line of
size that EGFRvIII, in general, has lower binding affinity investigation.³
compared to the wild-type EGFR. This observation of our These results highlight the importance of individualized
structural analysis where we identified that the EGFRvIII treatment approaches targeting molecular subtypes of GBM,
mutation led to the loss of residues crucial in ligand binding. especially EGFR.² Further research should concern the pos-
The lower ligand binding affinity of EGFRvIII could interfere sibility of targeting EGFR along with EGFRvIII or other
with normal signaling by EGFR and this could partly explain signaling pathways related to glioblastoma development.
the uncontrolled cell division associated with glioblastoma. � Acknowledgments
Moreover, the modified ligand binding pocket might account The author sincerely thanks Taylor Hailstock from Emo-
for the poor response of the existing EGFR-targeted therapies ry University School of Medicine and Dr. Hamidreza Shaye
in treating glioblastoma with EGFRvIII. from Stanford University Department of Molecular and Cel-
Interestingly, docking results also revealed that EGFRvIII lular Physiology for providing guidance and technical support
can still interact with certain ligands, including EGF, despite to this research.
its impaired binding affinity. This observation is consistent � References
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active state, the EGFRvIII is, by contrast, constitutively active Growth Factor Receptor and EGFRvIII in Glioblastoma: Signal
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org/10.1126/scisignal.287re6.
FRvIII results in prolonged residence of the receptor at the cell
6. Sugawa, N.; Ekstrand, A. J.; James, C. D.; Collins, V. P. Identical S
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� Author
Atreya Manaswi is a senior at Orlando Science High School. He is
passionate about finding solutions to real-world problems using bio-
technology. He hopes to major in the biological sciences and continue
pursuing his love of research.

Data Availability Statement

The data supporting the results are available in a public repository
at: https://zenodo.org/records/13731484.

15 DOI: 10.36838/v7i3.3
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REVIEW ARTICLE

Hydrogen Fuel Cells and Lithium-Ion Batteries for Solar

Energy Balancing at Varying Climates: A Review
Bana el Ghossein
RAK Academy: Khuzam Secondary; Khuzam; Ras al Khaimah; UAE; [email protected]

ABSTRACT: The use of renewable energy has shown a drastic increase over recent years as an effort to minimize greenhouse
gas emissions from fossil fuels. Among renewable energy sources, solar energy has experienced the largest growth due to
improvements in efficiency, longevity, and reliability. However, due to the inconsistent fluctuations in solar radiation, domestic
photovoltaic (PV) cells require energy balancing for the distribution of energy during periods of inadequate solar irradiation for
self-sufficient use. This paper reviews the technical feasibility of integrating hydrogen systems, PV cells, and lithium-ion batteries
(LIB) in various climates. It also discusses the costs, efficiencies, and usage of a hybrid energy storage system. This paper compares
the performance of PV cells powering electrolyzers, batteries, and fuel cells. It evaluates the combination of H2 storage and LIB
systems for year-round energy storage solutions in different climates. Ultimately, the findings suggest that a hybrid energy storage
system combining LIBs and hydrogen systems provides an effective solution for balancing solar energy across varying climates.
KEYWORDS: Hydrogen storage system, Energy balancing, Electrolyzer, Regenerative Fuel cell, Lithium-ion battery.

� Introduction stored for extended durations without deteriorating.⁸ However,

A main contributor to achieving global decarbonization hydrogen systems are not ideal for short storage cycles due to
is renewable energy sources, which have shown significant the low chemical conversion efficiency in comparison
growth in the last several years. Solar energy has witnessed one Another method for energy balancing is batteries. Out of the
of the largest investments and growth worldwide, with a major many battery types, lead-acid and lithium-ion batteries (LIB)
increase of installments by 87% in 2023, followed by an ad- have been identified as practical methods to store electrical
ditional 29% increase in 2024.¹-³ However, this increase may energy, and they are highly suitable for integration with PV-
present challenges due to inadequate consistency of the fluctu- based systems.²,⁹ For this paper, we will be focusing on LIBs as
ations in solar irradiation, which can be categorized into three they show better performance in terms of efficiency, life cycles,
types:²,⁴,⁵ and power density compared to other batteries.² LIB have a
(a) hourly fluctuations much higher rate of efficiency and response time compared to
(b) daily fluctuations (e.g. clouding) hydrogen systems. However, the electrochemical properties of
(c) seasonal fluctuations (irradiation change dependent on LIB are temperature sensitive,¹⁰ experiencing degradation at
seasons) temperatures exceeding 45 oC and typically face daily self-dis-
It is essential to consider that the fluctuations are heavily charge issues that are unsuitable for long-term storage; hence
dependent on the geographical location of the photovoltaic they are more favorable when hourly balancing is needed.²,⁷
(PV) system. This challenge highlights the need for a sustain- A key factor to understanding what method energy stor-
able and reliable solution to balance solar energy and ensure a age systems should use is based on the energy production and
continuous electrical supply.⁶ demands of each household. While countries with abundant
Hydrogen systems are a good candidate for energy balancing, solar radiation may only require storage capacity on an hourly
as the chemical storage of hydrogen can store large amounts or daily basis for sufficient operations, northern climates with
of energy for a longer duration of time.⁵,⁷ Electricity is con- drastic seasonal changes require a capacity increase to several
verted to green hydrogen through an electrolyzer powered by weeks or months to achieve self-sufficiency.⁷,⁹ In such a case,
photovoltaic (PV) cells and stored for later use. During energy secondary batteries would be too bulky and too costly to serve
shortage periods, the hydrogen is fed to a fuel cell for the repro- the purpose.
duction of electricity, producing water and energy as their sole This paper reviews the integration of LIB and hydrogen sys-
products. The general hydrogen system comprises three main tems as a strategy for solar energy balancing. It also discusses
components: an electrolyzer for generating hydrogen, a hydro- the method of utilizing a hybrid system for optimal energy
gen tank for storing hydrogen, and a fuel cell for generating balancing throughout the year and evaluates the impacts of
electricity from the stored hydrogen.⁷ The efficiency of hydro- geographical location and climate on performance and feasi-
gen systems is not heavily affected by time, as hydrogen can be bility.
© 2025 Terra Science and Education 16 DOI: 10.36838/v7i3.4
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Overview of LIB and RHFC: gy per unit mass.⁵,⁷,¹¹,¹⁵ However, due to their extremely low
This section provides an overview and analytical compar- density, it has a low volumetric energy density (5.6 MJ/L when
ison between the characteristics of LIB and RHFC systems. compressed to 691 atm, compared to 32 MJ/L for gasoline
Hydrogen system: at ambient conditions),¹⁶ high diffusion rate, and destructive
Hydrogen energy is increasingly valued, as it does not capability such as hydrogen embrittlement, giving hydrogen
produce any emissions as a result of combustion reactions.¹¹ the ability to escape through material, which proposes some
Hydrogen systems often rely on a fuel cell, electrolyzer, and safety concerns due to their high flammability.²,¹⁷ Therefore,
hydrogen tank. When PVs generate excess energy, the surplus additional engineering measures are required to ensure safe
amount runs through an electrolyzer, producing hydrogen gas, utilization.⁵,¹⁵ These safety measures also result in a very low
which can be stored for later use for the reproduction of elec- self-discharge rate in undamaged pressurized hydrogen stor-
tricity in a fuel cell providing consistent and reliable power, age. One of the major highlights of “hydrogen energy storage
especially during low-generation periods.²,⁴,⁶ This process en- systems is their long life span, low maintenance cost”,¹¹ and
sures reliable baseload power, which is the minimum level of long-term energy storage, making them an ideal candidate for
electricity generation required to meet continuous demand on seasonal balancing.
the power grid. Since the efficiency of these systems remains Li-ion Battery:
high over long periods, incorporating them in energy balanc- Another method for solar energy balancing is LIBs. These
ing for renewable energy (RE) gives flexibility with adjustable continuously-improving secondary electrochemical batteries
storage capacities for longer periods.⁵,⁷ can be reused by discharging and recharging,⁵,¹⁵ and much
RHFC: like RHFC convert between electrical and chemical energy.⁹
Regenerative hydrogen fuel cells (RHFC) offer a clean and Compared to other available batteries, LIBs have a high ener-
efficient alternative to on-grid electricity sources by gener- gy density, “low self-discharge, high roundtrip efficiency, and
ating power through an electrochemical reaction (a reaction short reaction time”, making them well-suited for short-term
that occurs due to a passage or absorption of electric current)¹² storage.²,¹⁸ However, they are highly sensitive to temperature.
between hydrogen and oxygen through a proton exchange Temperatures above 45°C can rapidly deteriorate its battery
membrane (PEM).¹³ The RHFC performs the functions of lifetime,²,¹⁷ as well as the risk of facing safety problems that
an electrolyzer and a fuel cell but does not typically include include fire and explosion, 10 making it inherently difficult to
built-in hydrogen storage, so a separate component for storing implement this system in hot summer regions. Batteries are
hydrogen is needed. However, considerable losses have to be well established for equalizing electricity supply and demand
taken into account due to the kinetics of the evolution of oxy- in the seconds to hours timescale, however, they are less ideally
gen (energy lost during water electrolysis and the reduction of suited on a day to months timescale due to the high self-dis-
oxygen in a fuel cell).⁹ The integration of PEM electrolyzers charge rate of 0.1-0.3%, making them far more suitable for
in green energy production is ideal as they can sustain high short-term balancing.²,⁹,¹⁷,¹⁹ LIB can contribute to baseload
current densities, providing a certain ‘overdrive capability’ and power, especially covering for high peaks when coupled with
therefore, can be easily integrated with RE systems.⁹,¹⁴ RHFC a separate system that releases energy steadily over longer pe-
also has a relatively quick start-up time (compared to other riods.
fuel cells), high lifespans, and low maintenance costs.²,¹³ Comparison of systems with PV applications:
Equation 1: Reaction in electrolyzer Characteristics:
Table 1: shows the general comparison of LIB and RHFC:

Equation 2: Reaction in fuel cell

Hydrogen storage:
RHFC requires a separate component to store the hydro-
gen gas produced. There are many methods proposed for
the storage of hydrogen, such as cryogenic liquefaction, sol-
id storage, the binding of hydrogen to a storage material, or
through underground salt caverns.⁷,⁸ The preferred approach
in the literature is pressurized gas for domestic use due to its
low self-discharge rate and scalable storage capacity, making Seasonal storage requires high energy density and low
it a fitting candidate for seasonal storage.⁷ Hydrogen pres- discharge rate, hence RHFC and hydrogen tanks are more
ents a strong potential as a storage medium due to its highest suitable than LIB storage, as hydrogen can be stored for long-
gravimetric energy density of all fuels, (higher heating value term use.² However, the total round-trip efficiency of hydrogen
(HHV) of hydrogen= 39.4 kWh/kg, compared to HHV of systems is only 30-70%, which is less suitable for short-term
gasoline =12.9kWh/kg ) meaning it stores the highest ener- energy balancing compared to the higher efficiency of LIBs

17 DOI: 10.36838/v7i3.4
ijhighschoolresearch.org

(75-97%). This is due to the series of energy conversion pro- energy-balancing approach to local climate conditions may
cesses (electricity to hydrogen and vice-versa as seen in Figure lead to both cost savings and efficiency gains.
1).²,²⁰ Additionally, significant energy is required to compress A hybrid system combining LIB energy storage with a
or liquefy hydrogen for storage, which leads to further effi- hydrogen system would be optimal because it mitigates the
ciency losses. The main disadvantage for LIBs is the daily drawbacks of both LIB and RHFC technologies, LIB’s limit-
self-discharge issues that make them unfit for seasonal stor- ed long-term storage capacity, and hydrogen’s lower efficiency
age, while RHFC subsystems have negligible energy losses.²,⁹ for short-term needs.²,²¹ The utilization of different storage
Hence, LIB storage is better suited for “short-term storage” methods is determined by the desired behavior of the system.
(lasting seconds to hours), whereas RHFC is applicable to A simulation run in Finland concluded that standalone battery
“medium and long-term storage”, spanning hours to months.² or hydrogen systems are insufficient for annual off-grid oper-
A common control parameter for LIBs is the state of charge ations in “northern climate with typical isolation conditions”.
(SOC), which measures the ongoing charge level in the bat- However, combining these energy storage systems together
tery relative to its total capacity. The SOC greatly affects its enables an off-grid PV-based energy system. In Australia, a
lifetime as LIBs degrade faster (leading to a swift decline in simulation of different scenarios of energy balancing systems
capacity) when operated at unrestricted SOC ranges.² Hence, was analyzed. Results show that the PV hybrid LIB-Hydrogen
battery management systems must be incorporated into the system diminished “only 33% of RE generated”, in contrast to
PV-LIB system to monitor the operation of the battery to the 74.9% diminished energy in the PV-LIB system, which re-
keep SOC within a strict operational window. If the SOC of quires a continuous input or external energy source to achieve a
a LIB drops to 0%, the lifetime reduces to 47% of its origi- constant energy flow. The study concluded that the hybrid sys-
nal lifetime,²,¹⁸ whereas the percentage of capacity used in an tem is a “promising innovative approach for 100% renewable
RHFC does not show any effects on its lifetime. Therefore, energy-based stand-alone microgrid systems” as the combined
PV LIB systems have very limited design flexibility and must output of these components consistently meets the peak load
be paired with large PV and LIB capaciti es to maintain a rea- with a reliability of over 99.9%.⁵
sonably high battery lifetime. On the other hand, PV RHFC
systems have no such limitations.²,⁹
Another drawback for LIBs in extreme climates is their tem-
perature sensitivity. While the acceptable temperature region
is generally -10°C – 45°C,²,²⁰ its optimal temperature range
is 15 °C–35 °C.²,¹⁰,²⁰ It is also necessary to monitor the cell
operating temperature to avoid the operation of the battery
outside its limits, which would result in reduced efficiency.²,¹⁹
Temperatures out of this range may alter the performance and
cause irreversible changes to the LIBs.¹⁰ In contrast, RHFCs
are typically more temperature-tolerant, withstanding tem-
peratures up to 80°C. However, for optimal conductivity in
PEM fuel cells, there must be a sufficient amount of water in
Figure 1: Energy pathways of LIB and RHFC systems
the electrolyte membrane, imposing limitations on the operat-
ing temperature.²,⁹ Sustainability:
The sizing of each system is heavily dependent on its de- Previous methods for PV energy balancing, such as conven-
mand and environment. For example, a household in a tional diesel generators, are unsustainable because they rely
northern climate might require a larger electrolyzer and hy- on fossil fuels and produce greenhouse gas emissions.⁵ Fur-
drogen storage units as the seasonal fluctuations may be more thermore, diesel fuel for energy balancing is expensive and
drastic than a household at equatorial latitudes. While sizing continues to rise due to transportation and storage fees. Hence,
LIB systems may be easier due to their simple configuration, decarbonizing energy supplies through locally produced RE
they require more complicated management and operating is vital for future energy sustainability and further econom-
schemes to maintain operation within strict SOC ranges and ic growth.⁴,⁵ The clean energy conversion of RHFC and LIB
avoid premature battery aging.²,⁹ Sizing a hydrogen system is makes them essential in decarbonizing RE storage systems.
more challenging as it requires more integrated and calibrat- However, sustainability concerns may arise, such as recyclability
ed components that must be properly coupled to achieve the or material availability.²,⁹ For RHFC subsystems, the disposal
desired energy capacity. This process varies case by case and of fuel cell and electrolyzer stacks must be carefully managed,
can be complicated. Hydrogen systems are generally resistant as toxic materials are used as electrodes or catalysts.¹⁰ A large
to corrosion which reduces maintenance needs.²,⁹,²² Howev- number of LIBs will need to be recycled after reaching the end
er, they require more space due to hydrogen’s low volumetric of their lifetime; as improper disposal poses a significant envi-
density, whereas LIBs are compact and easily scalable. Due to ronmental threat due to toxicity, which is expected to become a
the significant influence of temperature and solar irradiation very challenging task. For LIBs, raw materials like lithium and
fluctuations on each technology's performance, tailoring the graphite are currently abundant (common materials for anode
and cathode are platinum, iridium, ruthenium,

DOI: 10.36838/v7i3.4 18
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and platinum on carbon).²² However, these materials could more electrical input energy to produce hydrogen and to warm
be depleted soon if demand continues to grow rapidly, which the system to its optimal temperatures.13
would also drive up costs.² For RHFC components, materials How temperature affects the efficiencies of the systems
are currently available, although their availability cannot be LIB/RHFC in cold climate:
safely predicted, especially if future demand increases.²,¹⁷ For Around and over 60° of latitude North or South, the climate
the widespread and long-term deployment of these technolo- can generally be considered cold, with temperatures reaching
gies, we must address the environmental impacts of improving below 0°C.26 During winter, the available electrical energy that
the recyclability of the material used or replacing the materials needs to be stored is low because PV-generated electricity is
with a sustainable alternative, as well as improving current re- low. If LIB storage is used, some battery units would have to re-
cycling methods. main inactive during this season. Inactive storage of LIBs may
Costs: lead to capacity reduction.² While LIBs are ideally operated in
Currently, PV systems are the most cost-effective option for lower temperature ranges, they are less suited for regions with
distributed electricity generation. Prices for solar panels have prolonged summer-like conditions.² However, at temperatures
decreased by 90% over the past decade, and further declines below 0°C, the performance of LIBs will degrade. A case study
are expected, supporting future growth.⁴,⁷,²³ In RHFC tech- showed that an operating temperature drop from 25 °C to −15
nology, both lifetime and cost are more difficult to estimate, °C gives a ~23% decrease in the maximum battery capacity due
because an RHFC subsystem consists of three main compo- to an increase in internal resistance.¹⁰,²⁷ This challenge can be
nents (in comparison to just a single main component in the countered by proper management of the operating tempera-
case of LIB storage). This is because these three main compo- ture of LIBs. Accurate temperature monitoring of LIBs is
nents do not necessarily have the same lifetime, so the exact one of the important processes in proper temperature man-
value can only be determined for a specific application. Addi- agement. It is, however, difficult to monitor the temperature
tionally, the total cost is the sum of these components, which distribution inside the tightly sealed batteries.10
may vary significantly in terms of a specific application. For A case study in Finland, where temperature can reach -20
example, Hydrogen storage units, which are typically simple C, repurposed the waste heat generated in the PEMFC (as 80
devices, have a much lower initial cost and much higher life- ◦C waste heat would be well-fitting for domestic hot water
time (~15 years) than LIBs.² Similarly, degradation rates may heating),²,⁷,⁹ effectively improving the overall energy efficiency
be affected, where for example the fuel cell may degrade faster of the hydrogen system.¹³ On the other hand, Operating at
than the Hydrogen storage units and electrolyzer.² Efficiencies lower temperatures can pose challenges in starting PEMFCs,
also play a major role in the overall costs of the system. A case as water freezing can lead to ice blockage.¹³ Proper water man-
scenario in Australia 5 concluded the hydrogen-PV system is agement systems in the fuel cells may minimize the effect of
less cost-effective than the PV-LIB system, however, it sig- icing and successfully start in temperatures below 0 C.
nificantly reduces wasted RE production by 56% more than Integrating waste heat recovery technology promises sub-
the battery system (due to the advantage of seasonal cycling ), stantial improvements in energy utilization efficiency, yet
enabled by its electrolyzer capacity. This efficiency allows for cost constraints and potential utilization inefficiencies pres-
fewer solar panels to be used while maintaining the same en- ent setbacks to commercialization and widespread adoption.
ergy balance. However, a proposed system of both hydrogen Developing an optimized waste heat recovery framework
and LIB is deemed the most cost-effective system for a 100% emerges as a crucial facet in propelling PEMFC technology
RE-based stand-alone microgrid, breaking even at 6.01 years and enhancing overall energy conversion efficiency.13
(compared to 7.91 years for LIB alone).⁵ A recent analysis re- LIB/RHFC in hot climate:
vealed a significant drop in LIB pack prices in the last decade, Climates with summers commonly reaching over 45 oC
from $1400/kWh in 2010 to $151-126/kWh in 2023,24 rep- may pose a threat to LIBs capacity and lifespans, risking future
resenting one of the "fastest cost declines of any energy storage safety problems that include fire and explosion.2,10,17 Increasing
technology".25 Whereas the estimated cost of RHFC is harder the operating temperature above the optimal scope will accel-
to decipher as each RHFC system is specific to its location, erate the aging process and lead to the degradation of LIBs.2
demand, and individual components. Therefore, the operating temperature outside their typical ac-
Effects of climate/ latitude on solar balancing: ceptable range (-10 – 45 oC) significantly affects the lifetime
The abundance and consistency of solar irradiation and of LIB storage units.20
temperature variation play a crucial role in the method of en- RHFC systems are designed to operate at higher tempera-
ergy balancing needed. A city in western Turkey,11 located at tures without a significant impact on their lifetime (70 oC or
37.76 ° N with a hot-summer Mediterranean climate, experi- higher).2 However, the PEM and catalyst layer degrades faster
ences varying hydrogen production rates throughout the year, if temperatures exceed the optimal range, reducing efficiency
with the highest rates recorded during the summer months and lifespan.13 Additionally, a specific amount of water reten-
when solar radiation levels peak. As solar flux increases, higher tion is required in the electrolyte membrane to provide peak
production of useful energy occurs, however, the efficiency of conductivity as low water content diminishes the conductivity
the system decreases as there is an increase in losses.11 Cold of the PEM, excessively high temperature can lead to water
climates may also cause a loss of efficiencies in the balancing loss from the electrolyte membrane.9,13 So implemented water
system due to loss of efficiencies at cold starts, as it requires

19 DOI: 10.36838/v7i3.4
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management systems are required to keep water content con- a surplus of electricity during central hours in the summer.⁶
sistent in the RHFC at all times. The energy deficit at night is supplied by the batteries while
PV efficiency by climate: the fuel cell is not required. The hydrogen storage system is
PV panels are sensitive to heat, so the efficiency decreas- used less frequently during autumn and spring.⁶ In contrast,
es linearly with increasing temperature; this property can be during winter, fuel cells are preferred over batteries to meet the
exploited in cold climates.11,26 Despite a reduction in solar irra- significant energy deficit in the middle of the day. Fuel cells
diation, it is worth implementing PV systems for certain uses. are heavily relied upon in winter, as PV and wind generation
It is reasonable that PV systems advanced under hot and sunny only partially meet energy demands.⁶
climates.26 However, in hotter climates like Iraq, where tem- � Conclusions
peratures in June and July can exceed 45 C, PV cells experience Immediate action must be taken to accelerate the growth
a reduced efficiency in energy production by 7.0% leading to a of renewable energy (RE) for global decarbonization. Lithi-
yearly energy degradation of approximately 96.6 kWh.1 Nev- um-ion batteries (LIB) and regenerative hydrogen fuel cells
ertheless, the total production of energy through PV cells in (RHFC) have been identified to be promising methods of im-
hot climates far surpasses the production in colder climates plementing sustainable solar energy balancing techniques. In
despite the decrease in efficiencies. this Review, we go over and compare RHFC, LIB systems,
Solar irradiation abundance effects on the viability of en- and the effects of climate and solar irradiation abundance. Im-
ergy balancing systems: plementing adaptive control systems that switch between LIB
Countries located near the equator often have hot Medi- and RHFC usage based on real-time and seasonal conditions
terranean climates coupled with high yearly solar radiation, could optimize energy balance while extending component
experiencing a milder change in day lengths regardless of lifetimes and lowering overall system maintenance require-
the season, hence they may be less reliant on seasonal energy ments.2,9
balancing systems. In arctic and antarctic latitudes, solar ir- There are 2 main factors regarding the effect of climate
radiation is abundant in the summer months yet insufficient on these systems which are solar irradiation abundance, and
during winter, requiring an energy storage capacity of a few temperature. As temperature increases from a certain point,
months. Consequently, energy consumption surges during the the efficiencies of the PV energy generation decrease.¹ Tem-
“dark, cold winter months due to increased heating demand”.⁷ peratures exceeding 45 oC may raise concerns for LIB as the
Such locations are heavily dependent on seasonal energy bal- degradation of their lifespan and capacity takes place and in-
ancing for sufficient yearly use of PV energy. In equilateral creases the risk of facing safety problems that include fire and
countries, a storage capacity of a few days will be sufficient explosion.2,9,10,20 Monitoring the cell operating temperature to
for the autonomous operation of the electricity supply. In re- avoid the operation of the battery outside its limits may be
gions such as Central Europe, the capacity must be increased necessary.2,19 RHFC are typically temperature tolerant, how-
to several weeks.⁹ Based on the average electrical energy con- ever, PEM and catalyst layer degrade faster if temperatures
sumption per day in Europe (16.2 kWh), a LIB being able exceed the optimal range (exceeding 80 oC), reducing efficien-
to store 15 days equivalent would weigh approximately 974kg cy and lifespan.13 The main concern for RHFC is their water
and cost in the range of 27.8k € - 33.4k € per person, which is content as higher temperatures may lead to water loss, reduc-
impractically large and costly for an energy storing unit. ing the efficiency. This issue can be resolved by implementing
A case study done in Finland (61.5° N)⁷ found that PV a water management system.13
electricity generation drops to almost zero during the winter In northern climates, where solar irradiation fluctuations are
months (November to February). To maintain energy balance, “drastic and highly abundant during the summer months, yet
the system relies heavily on a fuel cell that runs almost contin- mostly non-existent during winter”,⁷ long-term energy balanc-
uously to keep the battery charged. This approach significantly ing of a hydrogen system may be prioritized over short-term
reduces the surplus energy produced by the PV system during balancing. In solar-abundant climates such as Mediterranean
the summer. In contrast, during the summer months, the en- climates, a storage capacity of a few days will be sufficient for
ergy systems mainly relied on the LIBs. Algeria has good solar the autonomous operation of the electricity supply,⁹ so depen-
potential that can generate electricity.14 A simulation conclud- dency on RHFC for seasonal balancing will be minimal.
ed that the estimated amount of hydrogen produced was more Although RHFC and LIB systems are promising green en-
favorable in southern cities, with a higher yearly abundance of ergy balancing methods, the system’s performance depends on
solar irradiation as the hourly hydrogen production depends multiple aspects, such as climate conditions and monitoring
on the available solar radiation.14 Algiers (36.5° N) had more and control systems.²¹ The utilization of these energy-bal-
drastic seasonal changes and produced less hydrogen than Ta- ancing techniques is unique to every application and is
manrasset (22.5° N), with a more constant solar irradiation climate-dependant. Future research must focus on enhancing
throughout the year. However, in these conditions, LIBs may LIBs temperature tolerance so that it may be more applicable
be more suitable for providing a constant energy supply, as sea- in arid conditions, where the dependence of LIBs is typically
sonal balancing is less of a concern in Mediterranean climates greater. Additionally, research must be done for applications
with fewer fluctuations in solar irradiation. on hybrid RHFC and LIB for energy balancing in diverse cli-
A case study in Italy (41.2° N), using PV and wind turbine mates.
technology, showed that high PV energy production generates
DOI: 10.36838/v7i3.4 20
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� Acknowledgments olyser in Algeria. Int. J. Hydrog. Energy 2013, 38 (20), 8480–8490.

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RESEARCH ARTICLE

Forecasting Stock Market Movements with LSTM: A Case

Study of Amazon and NASDAQ Performance Across Different
Economic Cycles
Raj Vansh Bollineni
Oakridge International, Gachibowli, Hyderabad, Telangana, 500008, India; [email protected]

ABSTRACT: The paper investigates the predictive performance of artificial intelligence (AI)-based models. Amazon and
NASDAQ are used as proxies for individual stocks and the market index, respectively. We employ long short-term memory
(LSTM) models across pre-crisis, crisis, and post-crisis periods. The study aims to demonstrate how LSTM models perform
under various economic conditions, and how their prediction accuracy varies between individual stocks and aggregate stock
market indices. LSTM models were varied in aspects like train-test splits, denser layer, and layer type output shape while keeping
other parameters constant to find the best optimized LSTM model for each level of economic turbulence. It was observed that the
train-test splits have a major impact on the LSTM models’ ability to predict during different economic cycles. A higher training
dataset resulted in more accuracy in prediction during stable periods like pre-crisis and post-crisis and vice versa. The findings of
this study can aid investors, decision-makers, and regulators optimize their own LSTM models specifically tailored to the level of
market turbulence, thus allowing them to make comparatively more accurate predictions of the stock market behavior.
KEYWORDS: Robotics and Intelligent Machines, Machine Learning, LSTM, Stock Prediction, Economics Cycles.

� Introduction dependencies and model sequential data. LSTM models can

Artificial intelligence (AI) algorithms are increasingly used additionally identify complex patterns and trends in historical
for predicting financial market data because of their capaci- market data, making them suitable for predicting future stock
ty to efficiently examine complex data patterns. These models behavior. Furthermore, this paper investigates how economic
provide a strategic advantage for effectively managing volatile cycles—pre-crisis, crisis, and post-crisis—affect the reliability
market conditions. Their capacity to generate more precise of LSTM predictions. Previous research has typically focused
forecasts enables decision-makers to make well-informed de- either on predicting individual stocks or the aggregate stock
cisions in rapidly changing financial markets. market index. This paper aims to test the applicability of a sin-
Accurately predicting the future performance of the US gle prediction model to both individual stock and aggregate
stock market is crucial for various reasons. Investors rely on stock market indices.
these predictions to optimize their portfolios, while policy- The literature indicates that artificial intelligence-based
makers use them to assess the effectiveness of monetary and models generally perform better in forecasting than traditional
fiscal policies. Business managers also use stock market fore- methods.¹,² Thus, it contributes to the literature by assessing
casts to plan for future growth and adapt to changing market forecasting performance not only for stable economic peri-
conditions. Given the US stock market's substantial influence ods but also for turbulent periods. Moreover, by studying data
on the international economy, accurate forecasting is vital not spanning pre-crisis, crisis, and post-crisis phases, it aims to ex-
only for the US economy but also for the global economy. An- pand our understanding of how economic cycles influence the
alyzing stock market predictions during different time periods reliability and robustness of LSTM-based predictions.
(pre-crisis, crisis, and post-crisis) is essential for understanding For Amazon, it is clear that the best predictive model var-
the influence of economic conditions on forecasting perfor- ies across different periods. Model 5 performs best in both
mance. pre-crisis and post-crisis periods, whereas Model 3 performs
The purpose of this paper is to determine an effective best during the crisis period. For NASDAQ, Model 1 per-
forecasting model for predicting the performance of both formed the best in both the pre-crisis and crisis periods, while
individual stocks and stock market indexes. This study uses Model 5 stands out for its accuracy in the post-crisis period.
Amazon as an individual stock and NASDAQ as a stock mar- You cannot use the same model for different periods, and
ket index. This study explores machine learning-based models, the same forecasting model does not apply to both individ-
with a particular focus on the Long Short-Term Memory ual stocks and aggregate market indices. By examining data
(LSTM) model, to achieve accurate and reliable prediction. across the economic cycles, this study also shows evidence of
LSTM models are a strong choice for stock market forecast- how these economic cycles impact the accuracy and reliabili-
ing especially because they can effectively capture long-term ty of LSTM-based prediction. This paper proceeds as follows:
© 2025 Terra Science and Education 22 DOI: 10.36838/v7i3.5
 ijhighschoolresearch.org

Section 2 provides background information on the existing lit- for getting better forecasting performance.⁵,⁶ In addition to
erature; Section 3 highlights the methods; Section 4 showcases these loss functions, other metrics such as predicted R-squared
the results and discussion; and Section 5 concludes the paper. and hit rate were also used to get accurate forecasting perfor-
mance.⁹,¹²
� Literature Review
This study distinguishes itself from the existing literature Stock market forecasting involves analyzing different types
by integrating an artificial intelligence-based forecasting of data to make predictions about future market trends and
model across different economic cycles (pre-crisis, crisis, and behaviors. This includes examining closing price data,¹,¹¹
post-crisis), specifically focusing on both individual stocks and volatility data,⁸,¹³ exchange rates,⁵ interest rates,¹⁴ long-term
market indices. By using the LSTM model to forecast the historical data,¹³ and intraday data.⁷ Every study utilizes dif-
performance of both the market index and individual stocks, ferent forms of data to tackle various forecasting difficulties,
this study fills the gap left by prior research, which frequently which can range from predicting closing prices to analyzing
focused on either individual stock predictions or broader mar- intraday data.
ket index predictions. In 2009, Mahla Nikou et al. highlighted Several studies emphasize the geographical diversity in re-
the superior predictive performance of LSTM approaches cent stock market forecasting, demonstrating how the market
compared to traditional models.³ In addition, Körs and Karan dynamics of various countries or regions have a substantial im-
employ the MIDAS model to estimate volatility in several pact on the accuracy of forecasts. For example, in 1998 Brooks
markets and highlight its excellent ability to predict future focused on the US,¹³ while Bjørnland and Hungnes focused
volatility.⁴ In 2022, Ding et al.¹ and Akhtar et al.⁵ conduct- on Norway.¹⁴ In 2020, Körs and Karan examined multiple re-
ed a thorough evaluation of artificial intelligence models and gions, including the US, Japan, Hong Kong, and the UK.⁴ In
their dependability in predicting stock market performance in 2011, Harrison and Moore focused on Central and Eastern
China and Pakistan. They assessed these models across various European countries;⁸ Xu and Zhang focused on China,⁶ and
economic scenarios, providing a comprehensive review. Akhtar et al.⁵ and Alenezy et al.⁹ focused on Pakistan and Sau-
Recent financial forecasting research has utilized a variety of di Arabia, respectively.
approaches to improve the accuracy of predictions in various The influence of various market conditions on predicting
stock markets around the world. In 2019, Mahla Nikou et al. performance has been empirically demonstrated by several
specifically examined the LSTM model.³ In 2020, Körs and studies.¹⁵-¹⁷ For example, Lim et al. investigate the financial
Karan proposed that the MIDAS model offers a benefit in crisis's impact on the efficiency of eight Asian stock markets.¹⁵
predicting performance.⁴ In 2021, Xu and Zhang proposed the They emphasize that the crisis significantly reduced market
Shrinkage Composite Model as the optimal choice for pre- efficiency. Most markets improved in efficiency post-crisis.
dicting the Chinese stock index because of its high reliability.⁶ The increased inefficiency during the crisis is attributed to
In 2022, Akhtar et al. determined that the ARCH class model investor overreactions to both local and foreign adverse news.
exhibits greater prediction performance.⁵ In 2024, Tan et al. � Methodology
presented the Functional Time Series Approach as a meth- This study investigates the predictive performance of
od for accurately predicting intraday volatility in the Chinese LSTM models for stock market behavior, using Amazon and
stock market.⁷ In 2011, Harrison and Moore emphasized the NASDAQ as proxies for individual stocks and market indices,
efficacy of the asymmetric volatility model in predicting the respectively, across pre-crisis, crisis, and post-crisis economic
level of fluctuation in the stock market in Central and Eastern conditions. The Long Short-Term Memory (LSTM) model
European nations.⁸ By combining the Maximum Overlapping is known as a recurrent neural network (RNN) proposed by
Discrete Wavelet Transform (MODWT) with the Adaptive Hochreiter and Schmidhuber in 1997.¹⁹ Issues encountered
Network-based Fuzzy Inference System (ANFIS), Alenezy et in training traditional RNN neural networks have been com-
al. make daily stock price index predictions for Saudi Arabia's pletely addressed in LSTM. The methodology includes data
stock market more accurate.⁹ In 2019, Mallikarjuna and Rao preparation, model architecture design, training, and perfor-
found that conventional linear or non-linear models are more mance evaluation, as outlined below.
effective than artificial intelligence models in forecasting daily Data Collection and Preparation:
stock market returns in several worldwide marketplaces.¹⁰ In Data Source: The data is gathered from Yahoo Finance
2024, Song et al. demonstrated that the CNN-GRU model and includes individual stock data for Amazon (ticker sym-
enhances the accuracy of predicting stock market volatility bol: AMZN) and US stock market index data (ticker symbol:
in both China and the US.¹¹ It is clear that many different NASDAQ). The data covers the daily percentage equity return
methodologies and variables were employed in stock market for three selected periods: pre-crisis (1st January 2003 to 14th
forecasting to better understand market dynamics. September 2008), crisis (15th September 2008 to 31st March
Various performance metrics are used to evaluate forecasting 2010), and post-crisis (1st April 2010 to 30th December
models in stock markets, to determine their accuracy and ef- 2016). We can differentiate between the crisis and non-crisis
fectiveness. For example, some studies highlight RMSE (root periods by following the existing literature.¹⁸
mean square error) as the optimal loss function for evaluating Data Preprocessing: Data was preprocessed through normal-
forecasting accuracy,¹,³,⁴ while some other studies apply MSE ization to ensure values lie within a range suitable for LSTM
(mean square error), MAPE (mean absolute percentage error), models, accelerating training and improving model converge-
and MAE (mean absolute error) as the ideal loss functions
23 DOI: 10.36838/v7i3.5
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nce. Time series data were structured into sequences, using � Results and Discussion
lagged values of stock/index prices to predict future prices. Forecasting Outcome:
Train-Test Splits: Each model was trained separately for Table 1: Descriptive statistics of daily percentage equity returns for selected
each period (pre-crisis, crisis, post-crisis, and the total period) periods: Pre-crisis period (1st January 2003–14th September 2008), crisis
to evaluate performance under varying economic conditions. period (15th September 2008–31st March 2010), post-crisis period (1st April
A standard train-test split of 70%-30% was used for Models 2010–30th December 2016)
1–4, while Model 5 used an 80%-20% split to test whether a
larger training set impacts accuracy in a more stable post-crisis
period.
Model Architecture Design:
LSTM Layers: LSTM was chosen for its ability to retain
information over extended sequences, which is ideal for stock
data with temporal dependencies.
Layer Output Shape: The number of LSTM units was mod-
ified to optimize model complexity. For instance, some models
had an output shape of 50 units, while others used 30 units.
Dense Layer Conf iguration: Each model used different
LSTM layer configurations (output shapes: 50 or 30) and The empirical findings from Table 1 highlight distinct pat-
dense layer configurations to explore the effects of complexity terns in daily percentage equity returns for the Amazon and
on predictive accuracy. NASDAQ indexes across various economic cycles. Amazon’s
Training Parameters and Optimization: mean return during the crisis period unexpectedly rose to
All models used a fixed learning rate of 0.001, with different 0.1415, but with higher volatility (SDev = 3.7298) compared
combinations of epochs and batch sizes. Models were trained to both the pre-crisis (mean = 0.0991, SDev = 2.7487) and
using the Adam Optimizer. post-crisis periods (mean = 0.1005, SDev = 2.0387). This peri-
Learning Rate: Set at 0.001 across models to balance learn- od also exhibited increased skewness (Skewness = 0.7190) and
ing speed and stability. kurtosis (Kurtosis = 6.0757), indicating a shift toward a more
Batch Size: A batch size of 1 was selected to handle time-se- volatile and extreme return. Conversely, as expected, NASDAQ
ries data effectively, enabling the model to update weights after had a minimum mean return (mean = 0.0002) with higher vol-
each prediction. atility (SDev = 0.0235) than both pre-crisis (mean = 0.0004,
Epochs: Each model was trained for 15 epochs, enough to SDev = 0.0113) and post-crisis periods (mean = 0.0005, SDev
achieve convergence without overfitting. = 0.0111). Its kurtosis (Kurtosis = 3.3963) reflects higher mar-
Optimizer: The Adam optimizer was used for its adaptive ket risk compared to other periods, while negative skewness
learning rate and computational efficiency, enhancing the (Skewness = -0.1365) indicates an extremely negative return
models’ ability to converge quickly and handle non-stationary during the crisis period.
data. Tables 2 and 3 below reflect data gathered with different
Evaluation Metrics: LSTM models which vary based on parameters such as Layer
To compare LSTM model performance across economic Type Output Shape, Dense, and Train-Test Split. Parameters
conditions, several metrics were used: such as Loss Function (MSE), Layer Type (LSTM), Train-
Mean Squared Error (MSE): Measures the average squared ing Parameter, Epochs (15), Batch Size (1), and Optimizer
difference between actual and predicted values, with emphasis (Adam) have been kept the same for all models. The effec-
on larger errors. tiveness and accuracy of the models have been measured with
Root Mean Squared Error (RMSE): The square root of values of Mean Square Error (MSE), Root Mean Square
MSE, providing error measurements in the original units of Error (RMSE), Mean Absolute Percentage Error (MAPE),
stock prices. and Mean Percentage Error (MPE). To find out which model
Mean Absolute Percentage Error (MAPE): Reflects the aver- performs the best, a closer look is taken at MSE and RMSE
age error as a percentage, offering an easily interpretable error values. If the values of MSE and RMSE are comparatively
rate. the lowest, that model is considered to have the most predic-
Mean Percentage Error (MPE): Assesses model bias by tive accuracy. Vice versa, the model with the highest MSE and
showing whether predictions generally overestimate or under- RMSE values is considered to have the worst predictive ac-
estimate actual values. curacy.
Model Comparison and Analysis: Table 2a: Model Results for AMZN for the Pre-Crisis Period
Models were compared based on their performance across
pre-crisis, crisis, and post-crisis periods to understand how
different configurations respond to market stability and vola-
tility. By evaluating the train-test split’s impact on prediction
accuracy, the study identifies patterns in LSTM model effec-
tiveness relative to economic conditions.

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This showcases that Model 5, which contains a higher lay-

er type output shape and a higher training dataset (80%-20%
train-test split), is most suitable during stable economic cy-
cles. Model 5 could be comparatively a better option due to
its reliability in long-term forecasting and strategic planning
Table 2b: Model Results for AMZN for the Crisis Period where economic conditions are more stable. On the other
hand, Model 3, which has a higher dense layer and lower train-
ing data (70%-30% train-test split), has superior performance
during the crisis period. This highlights the model’s ability to
react relatively efficiently to the market’s volatility and abrupt
changes. This model would be more effective in the short-term
and it can provide insights for risk-management and deci-
sion-making for investors and traders during turbulent times.
Table 3a: Model Results for NASDAQ for the Pre-Crisis Period

Table 2c: Model Results for AMZN for the Crisis Period

Table 3b: Model Results for NASDAQ for the Pre-Crisis Period

Table 2d: Model Results for AMZN for the Crisis Period

Table 3c: Model Results for NASDAQ for the Pre-Crisis Period

Table 2 shows the performance of different LSTM models

applied to Amazon’s stock data across sub-periods: pre-crisis,
crisis, post-crisis, and total period. In the pre-crisis period,
Model 5 exhibits the lowest MSE and RMSE, indicating su-
perior predictive accuracy. During the crisis period, Model 3
showed the lowest MSE and RMSE, suggesting its effective-
ness in turbulent market conditions. In the post-crisis period,
Model 5 again displays the lowest MSE and RMSE. Overall,
across the total period, Model 1 demonstrates the lowest MSE Table 3d: Model Results for NASDAQ for the Total Period
and RMSE, highlighting its robust performance in predict-
ing Amazon stock prices consistently throughout the analyzed
period. It is clear that the best predictive model varies across
different periods. Model 5 performs best in both the pre-crisis
and post-crisis periods, whereas Model 3 performs best during
the crisis period.
25 DOI: 10.36838/v7i3.5
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ent economic phases. Model performance for Amazon and

NASDAQ differed significantly between pre-crisis, crisis,
and post-crisis periods, demonstrating the need for adaptive
forecasting approaches responsive to different economic con-
ditions.
Secondly, the study emphasizes the importance of consider-
Table 3 shows the performance of different LSTM models ing both individual stock predictions and market indices
applied to NASDAQ’s stock data across different periods. In in forecasting frameworks. While certain LSTM models
the pre-crisis period, Model 1 exhibits the lowest MSE and showed strong performance for Amazon during the crisis
RMSE, indicating strong predictive accuracy. For the crisis period, others achieved notable accuracy in predicting the
period, Model 1 again exhibits the lowest MSE and RMSE, NASDAQ index in stable economic environments. It has been
suggesting its effectiveness in volatile market conditions. In observed that a higher train-test split (80%-20%) has higher
the post-crisis period, Model 5 displays the lowest MSE and predictive accuracy in long-term and stable market dynamics.
RMSE. Overall, across the total period, Model 2 demonstrates This has been observed in the pre-crisis and post-crisis periods
the lowest MSE and RMSE, highlighting its robust perfor- of Amazon along with the post-crisis period in NASDAQ.
mance in predicting NASDAQ index values throughout the Vice versa, it has been observed that a lower train-test split
studied period. The best predictive model for the NASDAQ (70%-30%) has higher predictive accuracy in short-term and
index also varies across different periods: model 1 performs unstable market dynamics. This has been observed in the crisis
best in both pre-crisis and crisis periods, while model 5 per- period of Amazon along with pre-crisis and crisis periods in
forms best during the post-crisis period. NASDAQ.
This showcases that Model 1, which contains a high lay- Furthermore, our empirical evidence contributes to our
er type output shape and a lower training dataset (70%-20% understanding of the impact of economic cycles on the re-
train-test split), is most suitable during pre-crisis and crisis liability of AI-driven predictions. This study evaluates data
periods. This can suggest that Model 1 would be proficient from several sub-periods to demonstrate the influence of eco-
in capturing market dynamics with heightened volatility nomic conditions on forecast accuracy and model selection.
and rapid shifts. This can be due to its lower train-test split The findings have practical implications for decision-makers,
which was also observed in Amazon stock prediction, mak- investors, and policymakers. These stakeholders can use the
ing it effective during periods of uncertainty and instability. findings on train-test splits’ effects on prediction accuracy to
Alternatively, Model 5, which has the same layer type output modify LSTM models based on their needs, stock type (indi-
shape and a higher training dataset (80%-20% train-test split), vidual stock or aggregate market index), and market dynamics
is most suitable for post-crisis periods with stable economic of those stocks. Additionally, they can adjust other parameters
activity. This highlights the model’s ability to capture slower, like layer type output shapes and densities for more optimiza-
more stable trends and gradual recoveries. Investors can use tion. This allows investors, decision-makers, and policymakers
this information and accordingly adjust parameters like the to plan risk management during turbulent crisis periods and
train-test splits to tailor their models for specific market con- significant financial growth during stable pre-crisis and
ditions. post-crisis periods.
You cannot use the same model for different periods, and In conclusion, this study extends the boundaries of financial
the same forecasting model does not apply to both individual forecasting by showing the effectiveness of LSTM models in
stocks and the aggregate market index. This is critical to con- capturing complex market dynamics across distinct economic
sider when making predictions. Combining the analysis of an cycles. The findings not only enrich academic literature but
individual stock and an aggregate market index allows for a also provide practical implications for stakeholders seeking to
more comprehensive understanding of stock dynamics where optimize their strategies.
both micro-level trends and broader market movements at the This study showcases the capabilities of LSTM models in
macro-level are analyzed. This combined perspective is better forecasting stock market trends by capturing and modeling
as it allows insights into market correlations and diversifica- complex, time-dependent patterns. The findings indicate the
tion benefits that separated analyses may overlook. need for adaptive models that can respond to shifting market
conditions and economic cycles. A takeaway from this study
� Conclusion could be that the employment of such models that offer a
The study investigated the use of the Long Short-Term competitive edge in stock market prediction can be inaccurate
Memory (LSTM) model for predicting the performance of and the perfect model with maximum accuracy that can adapt
individual stock and stock market indices across various eco- to volatile market conditions does not exist yet.
nomic phases—pre-crisis, crisis, and post-crisis periods. This In the field of further studies, the number of individual
paper aimed to bridge the gap in the existing literature by eval- companies has expanded across many sectors, specifically in
uating the effectiveness of AI-based forecasting models under relation to the development of AI-based models for diverse in-
various market conditions, focusing on Amazon as an individ- dustries. Furthermore, we can compare LSTM's performance
ual stock and NASDAQ as a stock market index. with other AI-based methodologies to determine which AI-
Our findings highlight several key insights. Firstly, LSTM based models performed better across different sub-periods
models exhibit varying predictive accuracies across differ-
DOI: 10.36838/v7i3.5 26
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Future research can also explore LSTM performance in sions: The importance of the financial cycle. Journal of Macroecon
emerging markets, where volatility and low availability of data omics, 66, 103258.
give rise to unique challenges, or investigate their application 18. Chowdhury, B., Dungey, M., Kangogo, M., Sayeed, M. A., & Vol
in more diversified stocks such as stocks and indices from kov, V. (2019). The changing network of financial market linkages:
the Asian experience. International Review of Financial Analysis,
other countries like China and India to assess broader marker
64, 71–92.
adaptability and robustness. 19. Hochreiter, S. (1997). Long Short-term Memory. Neural Compu
� Acknowledgments tation MIT-Press.
I would like to thank my mentor, Dr. Abdullah Yalaman, for � Authors
guiding me through the process of conducting this research. Raj Vansh Bollineni, a 12th-grade student at Oakridge Internation-
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REVIEW ARTICLE

Emerging Novel Stem Cell Therapies for Cardiovascular

Diseases
Dominyka Virbickaitė
Šiaulių Didždvaris Gymnasium, Vilniaus g. 188, Šiauliai, 76299 Šiaulių m. sav; [email protected]

ABSTRACT: Cardiovascular diseases (CVDs), including atherosclerosis, ischemia/reperfusion (I/R), and heart failure (HF),
present a difficult problem with a high mortality rate. One method of treating various cardiovascular diseases (CVDs) could
involve using Mesenchymal stem cells (MSCs), which are multipotent non-hematopoietic cells and their exosomes that are being
researched as a promising tool for tissue regeneration. This review explores how MSCs work and their role in cardiac repair, with a
focus on key challenges that include the survival rate of cells after transplantation, incomplete differentiation, biosafety concerns,
and the complexity of the effective application of these therapies in vivo. Additionally, we go over cardiovascular diseases such as
heart failure (HF) and peripheral arterial disease (PAD) and discuss the potential of MSCs, MSCs-derived exosomes, or hPSCs
to treat these conditions, highlighting the latest breakthroughs in heart tissue reparative therapies. Finally, the paper will address
the most relevant issues involving this technology and current efforts to form solutions.
KEYWORDS: Biomaterials and Regenerative medicine, Cell and tissue engineering, Cardiovascular diseases (CVDs),
Mesenchymal stem cells (MSCs), exosomes.

� Introduction therapeutic promise in numerous studies about neurodegener-

Cardiovascular diseases (CVDs), which include heart dis- ative disorders, autoimmune as well as cardiovascular diseases
ease and heart stroke, are one of the leading causes of death (CVDs).⁵ Induced pluripotent stem cells (iPSCs) are derived
worldwide, contributing to approximately 17.9 million from adult somatic cells that had been genetically repro-
deaths annually and affecting over 500 million lives yearly.¹,² grammed to resemble ESC cells.² iPSCs have revolutionized
Traditional treatments such as heart transplantation, revascu- regenerative medicine because they resemble ESCs, with-
larization interventions, and pharmacotherapy deliver positive out the need to use human embryos, making their utilization
results, including better quality of life and progression man- ethical and providing opportunities for disease modeling. Fur-
agement. However, these therapeutic interventions often focus thermore, these cells have shown potential in treating blood,
on alleviating symptoms, rather than the root cause of the is- cardiovascular, and degenerative disorders.⁶
sue. One challenge in addressing the root cause of CVDs is First, this paper will go over CVDs, and discuss in detail
the heart’s limited ability to regenerate. This has led fields like heart failure (HF), and peripheral arterial disease (PAD),
regenerative medicine, tissue engineering, and cell-based ther- because these diseases result in cardiomyocyte death and
apies to shed some hope in improving the recovery of damaged damaged tissue. Additionally, the review aims to uncover the
tissues. current evidence on the workings of MSCs and iPSCs as well
Stem cells are undifferentiated cells that appear in hu- as explain the role of these cells in cardiac tissue engineering
man tissues and organs. These cells give rise to differentiated and regenerative medicine. Finally, we will uncover the main
cells that are the foundation of biological structures and are issues revolving around stem cells, because, despite the poten-
characterized by capabilities such as extensive proliferation tial of these cells, there are still a plethora of problems in using
(self-renew), clonality (arising from a single cell), and differ- them in vivo.
entiation into other cell subtypes.³ They can be derived from � Discussion
different sources and have contrasting differentiation potential. Cardiovascular diseases, risk factors, and characteristics:
For instance, embryonic stem cells (ESCs) are pluripotent stem Cardiovascular diseases (CVDs), despite their decline, re-
cells that naturally are found in the inner cell mass of the hu- main the leading cause of mortality and morbidity worldwide,
man blastocyst and can generate cell types from all three germ affecting over 500 million people’s lives yearly.⁷ CVDs occur
layers: mesoderm, ectoderm, and endoderm. Somatic stem cells for a plethora of reasons including modifiable risk factors
are found in most human tissues and are multipotent, mean- such as an unhealthy diet, inactivity, tobacco use, and alcohol
ing they can differentiate into cell types from a single germ consumption, as well as non-modifiable including age, sex,
layer.⁴ Mesenchymal stem cells (MSCs) are somatic cells that family history, and ethnicity. These behaviors are associated
have been recognized in stem-cell therapy for their ability to with conditions namely diabetes, obesity, hypercholesterol-
differentiate into bone, cartilage, muscle, neural, skin, and cor- emia, hypertriglyceridemia, and hypertension, that are linked
neal cells. This versatility has allowed MSCs to demonstrate to various CVDs. Approximately all cardiovascular disease
© 2025 Terra Science and Education 28 DOI: 10.36838/v7i3.6
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progression and pathology are of atherosclerotic origin, which however, we have to acknowledge the donor organ scarcity and
leads to coronary artery disease (CAD), venous thrombo- the high costs that come with it. This is why researching new
embolism, cerebrovascular disease, and peripheral vascular methods, like cellular-based therapies to treat HF that focus
disease.⁸ Eventually, these diseases are linked to stroke, myo- on reducing the level of inflammation, promoting the differ-
cardial infarction, and heart failure. In this paper, we will focus entiation of myocardial cells and inhibiting fibrosis is crucial.
on the potential to treat issues that result from CVDs such as Table 1: This table describes the current treatments for heart failure.
cardiomyocyte apoptosis and cardiac fibrosis with stem cells.
These conditions have been studied extensively in relation to
cell-based therapy and have demonstrated positive results in
cardiac regeneration.⁹,¹⁰
Heart Failure (HF):
Heart Failure is a heterogeneous clinical syndrome that
usually results from underlying diseases such as hyperten-
sion, cardiomyopathy, coronary artery disease, and valvular
heart disease that cause abnormal heart structure or function.
Common symptoms include breathlessness, swelling of body
parts, wheezing, and coughing. Medical specialists can identify
further symptoms like elevated jugular venous pressure, pul-
monary crackles, and peripheral edema.¹¹ If the diagnosis is
unclear elevated levels of natriuretic peptides in the blood and
evidence of pulmonary or systematic congestion are a sure sign
of HF.¹² HF is classified into acute and chronic syndromes.
Chronic heart failure (CHF) is a long-standing condition
when the heart gradually weakens and pumps blood less ef-
ficiently. It is assessed by a system, that emphasizes the left
ventricular ejection fraction (LVEF) which is classified into
three groups: a reduced ejection fraction LVEF ≤ 40%); a
mildly reduced ejection fraction (LVEF 41–49%); and a pre-
served ejection fraction (LVEF ≥ 50%).¹² Acute heart failure
(AHF) is typically described as a sudden worsening of heart
failure symptoms from events such as myocardial infarction,
severe valve dysfunction, or hypertensive crises that often lead
to hospitalization. In this review paper, we will focus on CHF,
because cell-based treatments aim to slowly regenerate the
damaged heart tissue and potentially reverse the progression of
HF. In contrast, AHF typically demands urgent interventions
like revascularization or mechanical support.
Current treatments for HF:
Currently, HF has four classified pharmacological treatments
depending on the LVEF (Table 1). First, there are renin-an-
giotensin-aldosterone system inhibitors (RAASi). These
include angiotensin receptor/neprilysin inhibitors (ARNI),
ACE inhibitors (ACE-I), and angiotensin receptor blockers
(ARB). The rest are beta blockers, including mineralocorticoid
receptor antagonists (MRAs), and sodium-glucose cotrans-
porter-2 inhibitors (SGLT2i).¹³ Other treatments may include
diuretics, device therapy, oxygen therapy, lifestyle changes, and
for patients with end-stage heart failure, heart transplantation,
and revascularization interventions. Even though the morbid-
ity and mortality of patients with HF have reduced, during Peripheral Arterial Disease (PAD):
the last decade the success rate of drug-development programs PAD is a common condition defined by abnormal narrow-
and clinical studies has been low, with a few exceptions. While ing of the peripheral arteries that supply blood into the limbs
pharmacotherapy alleviates symptoms and manages to stop and the periphery. The major cause of PAD is the build-up
progression, it often fails to achieve long-term recovery be- of plaques in arteries, known as atherosclerosis. Less common
cause the origin of problems like muscle fibrosis and the death causes include embolism, blood vessel inflammation, and inju-
of cardiomyocytes is not addressed. The only treatment for pa- ry. Typically, PAD affects the legs, but other arteries may also
tients with heart failure remains heart transplantation, be involved, such as those of the arms, neck, or kidneys.²⁴

29 DOI: 10.36838/v7i3.6
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Major risk factors for this disease include tobacco use, dia-
betes mellitus, hypertension, HIV, hypercholesterolemia, age,
obesity, family history, and elevated levels of homocysteine.
The general symptom of PDA is intermittent claudication,
an intense muscle pain that occurs during exercise and is lo-
calized to the thigh, hip, buttock, and calf muscles.²⁵ Other
symptoms can range from asymptomatic, in which patients do
not exhibit any noticeable symptoms, to chronic limb-threat-
ening ischemia (CLTI), a severe stage of PAD that is defined
by an inadequate supply of blood to a limb to allow it to func-
tion normally and includes manifestations such as lower-limb
rest pain, gangrene, ulceration, stroke, or myocardial infarction
(MI).²⁶,²⁷ Acute limb ischemia is another manifestation of
PAD, that can result in a loss of a limb. It typically occurs of
a sudden block of blood flow due to an embolism or throm-
bosis.²⁸
Current treatments of PAD:
Current treatments are based on age, risk factors, illness
severity, and functional status (Table 2). The therapies are
divided into two broad categories focused on improving symp-
toms and progress management. For early-stage PAD patients,
the primary approach is to reduce the risk factors of all CVDs
and make lifestyle changes, including diet, exercise, and elim-
ination of tobacco and alcohol. Pharmacotherapy for PAD
involves antiplatelet agents such as aspirin, clopidogrel, tica-
grelor, and vorapaxar. Furthermore, direct OAC medication
like rivaroxaban, antihypertensive therapies that use angio-
tensin-converting enzyme inhibitors (ACEI), angiotensin
receptor blockers (ARB), and statin therapy can help manage
the progress of PAD, usually alongside lifestyle changes and,
when necessary, surgery.²⁶ Stem cells:
Advanced-stage patients, specifically with Chronic Limb Stem cells have been researched since 1950, and had their
ischemia (CLI) or Chronic Limb-Threatening ischemia first breakthrough in 1956 when the first successful bone
(CLTI) are candidates for revascularization therapy, including marrow transplant was performed by Dr. E Donnal Thomas
endovascular, surgical, or combined endovascular and surgical in Cooperstown, New York.³⁷ They are undifferentiated cells
intervention, that aims to reduce the damage of tissue, relieve that can specialize into any cell type of an organism and make
symptoms, and prevent further complications such as limb up all biological materials of our body. Stem cells are char-
loss or myocardial infarction.²⁴ While pharmacotherapy and acterized by remarkable traits such as extensive proliferation
revascularization interventions offer some benefits, they do (self-renew), clonality (arising from a single cell), and differ-
not provide long-term solutions. Additionally, they have been entiation into other cell subtypes³ and can be found both in
related to side effects like abdominal pain, bleeding, flatulence, embryos and adult cells.⁴ They all could be characterized into
headaches, and limitations such as restenosis, complications five groups based on their differentiation potential: totipotent
from surgery, and limited effectiveness. Lately, researchers have or omnipotent, pluripotent, multipotent, oligopotent, and un-
been focused on finding more permanent solutions involving ipotent as well as based on their origin: ESCs, iPSCs, adult or
novel strategies such as cell-based treatments, regenerative somatic, and fetal stem cells.³ Totipotent stem cells are found
medicine, and gene therapy that provide fast recovery, the in the early stages of embryonic development and have the
growth of new healthy tissues, and fewer adverse reactions.²⁶ highest differentiation potential because they can divide into
Table 2: This table describes the current treatments of PAD. any adult cell including both embryo and extra-embryonic
structures. Pluripotent stem cells originally arise from the in-
ner cell mass of a human blastocyst and can differentiate into
cells of all three germ layers: mesoderm, ectoderm, and en-
doderm. Multipotent stem cells are more specialized and can
differentiate into cells of the same lineage. Oligopotent stem
cells have little differentiation potential and can only differ-
entiate into cell subtypes of a specific tissue. Unipotent stem
cells have the lowest development potential and are only able
to form and divide into one specific cell type.⁷,³⁸ This unique
DOI: 10.36838/v7i3.6 30
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ability to differentiate makes these types of cells crucial in the

research and progress of regenerative medicine. In the next
paragraph, we will evaluate the stem cells that are the most
appropriate for cardiac repair.
Stem cells for cardiac repair:
Stem cell therapy holds significant potential for cardiac re-
parative therapy, with various stem cell types demonstrating
certain advantages and drawbacks. ESCs and iPSCs are plu-
ripotent, which allows them to develop into cardiomyocytes,
endothelial cells, and smooth muscle cells. This makes them
suitable for generating personalized therapies because of their
ability to differentiate into a wide array of cell types (Figure 1).
However, the transplantation of ESCs or ESC-derived cells
is plagued by several formidable problems that involve graft
rejection, arrhythmias, and the potential risk of teratomas.
Figure 1: The figure demonstrates the differentiation potential of
ESCs can develop into mature, contracting myocytes in vitro, embryonic stem cells, induced pluripotent stem cells, mesenchymal stem
which provides potential for the regeneration of dead myo- cells, cardiac stem cells, and hematopoietic stem cells for cardiac repair.
cardium.³⁹,⁴⁰ However, there is a great possibility that ESCs Created in https://BioRender.com.
might form teratomas in the host cell, which paves the way
for a wide array of issues that include potential tumorigenicity, Mesenchymal stem cells:
ethical concerns, the need for long-term immunosuppres- MSCs represent a vast number of multipotent somatic stem
sion, and pro-arrhythmic actions.⁴¹ In contrast, iPSCs offer cells that are found in almost all existing tissues and have been
pluripotency similar to ESCs, not requiring lifelong immuno- a target of research for their versatility to differentiate into a
suppression. However, preclinical studies indicate an increased wide array of cell types. MSCs can differentiate into adipocytes,
risk for arrhythmogenesis and possibly tumor formation.⁴² chondrocytes, osteoblasts, myocytes, and neurons. Additional-
MSCs are favored due to their secretion of bioactive mole- ly, they are greatly involved in physiological and pathological
cules and microvesicles that activate tissue repair processes, processes such as cellular homeostasis maintenance, tissue
immunomodulatory properties, ability to differentiate into damage, tissue replacement, aging, and inflammatory diseas-
cardiac-relevant lineages, and ease of isolation. They are eas- es. Morphologically MSCs have a similar shape to fibroblasts
ily accessible from abundant sources such as bone marrow and are usually located near blood vessels.⁴⁵ They can be de-
and adipose tissue and show no evidence of tumorigenic or rived from various tissues and have specific qualities based on
arrhythmogenic risk, making them favorable candidates for their origin. For instance, bone marrow-derived mesenchymal
cardiac repair.⁴³, ⁴⁴ CSCs require access to adult cardiac tissue, stem cells (BM-MSCs) have shown high regenerative and
and it is still unknown whether there is a need for immu- immunomodulatory properties and have been used in many
nosuppression. Nonetheless, they are capable of stimulating clinical trials that highlighted their safety and effectiveness.
endogenous repair by paracrine signaling (growth factors and The dental pulp is also a source of MSCs with neurotropic
microvesicles) and are not tumorigenic or arrhythmogenic. properties since they originate from the neural crest. Adipose
Furthermore, they have a more focused role in cardiac repair, tissue-derived MSCs (AD-MSCs) can be obtained from
without concerning ethical issues. HSCs offer potential ben- abundant adipose tissue, with a minimally invasive procedure,
efits, contributing indirectly by generating immune cells that compared to (BM-MSCs), and result in a great number of
modulate inflammatory responses and tissue repair. HSCs are cells.⁴⁶ The unbiblical cord (UC-MSCs), placenta, amniotic
often derived from bone marrow and do not raise concerns fluid, and amniotic membrane are also sources of mesenchy-
about immune rejection. Furthermore, they can promote an- mal fetal cells.⁷ Synovial fluid-derived MSCs (SF-MSCs) can
giogenesis, which can improve heart function. However, there be useful for joint repair and cartilage repair and also exhibit
are certain disadvantages, such as limited differentiation range anti-inflammatory properties.⁴⁷ Similarly, periosteum-derived
into cardiomyocytes or vascular cells. Overall, while iPSCs and MSCs (P-MSCs) have potential in cartilage and joint repair,
ESCs offer extensive differentiation, MSCs, CSCs and HSCs however, they are more oriented towards bone formation.⁴⁸
provide more practical advantages for cardiac repair therapies. These stem cells can also be obtained from the skin (S-MSCs)
and aid in wound-healing properties.⁴⁹ Overall, MSCs can be
characterized by two important functions that make them the
main objectives in regenerative medicine. Immunosuppression,
tissue repair, and the paracrine action of MSCs give rise to
cytokines, chemokines, and growth factors to promote tissue
repair.

31 DOI: 10.36838/v7i3.6
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Induced pluripotent stem cells (iPSCs): presses those genes, it prevents cell death and creates a more
iPSCs are adult somatic cells that were reprogrammed to re- favorable environment for the survival of cardiomyocytes. For
semble ESC.³ This was first discovered in 2006 by Takahashi instance, when rat models with ischemia/reperfusion were
and Yamanaka and since then scientists managed to reprogram treated with miR-183-5p, it inhibited FOXO1, a protein that
various somatic cells including skin fibroblasts, hair kera- promotes oxidative stress and apoptosis.⁵³ MiR-183-5p was
tinocytes, mononuclear cells, and urine cells. However, even another miRNA that helped decrease cardiomyocyte death
though there are successful cases of reprogramming somatic and targeted a protein called Bax, which is proapoptotic.⁵³
cells to iPSCs, the differentiation is still often inefficient, with MiR-21a-5p can successfully downregulate the expression
only a few cells differentiating into specific cell lineages. Fur- of pro-apoptotic genes PTEN, Peli1, and FasL in the heart
thermore, the process is still not well understood and highly muscle tissue. Additionally, MiR-25-3p reduces the expres-
depends on the age and type of somatic cells used.⁵⁰ Over- sion of FasL and Pten, both genes that promote cardiomyocyte
all, iPSCs offer a great number of valuable factors that make death.⁵⁴ Other genes that encourage cell death are P53 and
them attractive for in vitro disease modeling, individualized Bak1. They were targeted by miRNA miR-125b found in
medicine, and regenerative medicine. Additionally, they helped BM-MSCs, which inhibited apoptosis and helped regulate
overcome the ethical limitations that are associated with hu- heart function.⁵⁵
man embryonic stem cells, because iPSCs are derived from However, despite the potential of these therapies, there are
adult somatic cells that come from plentiful sources such as still a plethora of challenges that occur while translating this
blood, skin, and urine. approach into clinical practice. One significant issue is ensur-
Stem cells and CVDs: ing the long-term survival and integration of the transplanted
There are many problems including cardiomyocyte apop- cells within the heart tissue. MSCs have been shown to im-
tosis, and cardiac fibrosis, that are still unaddressed by current prove cardiac function after MI in pigs⁵⁶, improve lower limb
treatments of CVDs. This is why we aim to address issues that ischemia in mice,⁵⁷ and lower limb movement after spinal
might develop from CVDs and provide solutions using stem cord ischemia in rats.⁵⁸ However, after transplantation, most
cell-based therapies in the next part of this paper. MSCs experience low retention rates and are characterized
Heart Failure, MSC-derived exosomes, cardiomyocyte by cell death due to the stressful environment, which results
apoptosis, and cell survival: from ischemia, oxidative stress, and inflammation.⁵⁹ Research
Acute and chronic heart failure patients, including those has shown that only 1-10% of transplanted cells survive a
with PAD, can suffer significantly from damaged muscle few weeks after injection into the heart.⁶⁰ One method that
tissue, especially after a myocardial infarction (MI). This is es- may prolong the survival of MSCs is the encapsulation of
pecially critical for PAD patients because the impaired blood MSCs in alginate microcapsules. The goal of this technique
flow further worsens the condition and makes it harder for is to enhance the therapeutic efficacy of MSCs by prolong-
the heart to regenerate. The problem occurs after MI when ing the local presence of MSCs and their secreted factors at
adult heart cells fail to restore due to ischemia which leads to a desired location. A study done by researchers showed that
the irreparable loss of cardiomyocytes. The current treatment the encapsulation of MSCs in alginate, a material used for the
is reperfusion, however, it is often linked to the worsening of protection of MSCs, can prolong the survival rate of these cells
cardiomyocyte function and tissue damage, a process called in a challenging environment. This approach was tested in rats
ischemia/reperfusion injury. This is why there is a crucial need with osteoarthritis which showed that the encapsulated MSCs
for novel treatments that help lower oxidative stress and apop- stayed alive and active for at least 8 weeks.⁵⁹ Another prom-
tosis after intense therapies.⁵¹ ising approach is the use of bioactive scaffolds, like hydrogels,
MSCs are appealing for the treatment of heart disease that have been shown to promote tissue repair and reverse
because they promote angiogenesis and aid in the recovery heart damage. For instance, hydrogels can improve retention
of ischemic tissue. They can be derived from many sources, rates of MSCs at the injection site because they provide a sup-
however, BM-MSCs are particularly attractive because they porting matrix that prevents the cell from being flushed out or
are characterized by multidirectional differentiation, weak im- migrating away from the target area.⁶¹ Furthermore, hydrogels
munogenicity, high transplantability, and successful clinical can deliver growth factors and oxygen to the cells, resulting in
trials. Furthermore, the exosomes from BM-MSCs can reduce longer survival rates and improved integration.⁵⁹ A study on
cardiac injury and achieve positive therapeutic effects on joint live animals showed that the hydrogel is an excellent retention
action with regulatory RNAs that may help heal tissue injury platform for MSCs and might improve the paracrine effect of
following MI.⁵² The inhibition of cardiomyocyte death with the transplanted MSCs, contributing to better heart function.
BM-MSCs and their secreted exosomes is a complex task in- Additionally, interstitial fibrosis was decreased significantly in
volving microRNAs (miRNAs) found in the exosomes that the left ventricle, which may inhibit the remodeling process
can influence the process through various pathways.⁹ of the left ventricle. This shows the important role hydro-
Current studies of miRNAs in exosomes have provided gel-based MSC transplantations could have in cardiac repair.
some positive results by targeting specific pro-apoptotic genes. Nevertheless, while they provide benefits, the gels fail to allevi-
These studies are focused mainly on finding miRNAs that ate the harsh microenvironment in the damaged myocardium,
could potentially suppress genes, such as PTEN or P53, that which could affect the long-term survival of MSCs. Hence,
regulate the cell cycle and apoptosis. When the miRNA sup- the hydrogel method still requires further research.⁶¹

DOI: 10.36838/v7i3.6 32
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Overall, the ongoing studies of MSC-derived exosomes hydrogel as the shell. This provided a three-dimensional struc-
for treating cardiomyocyte apoptosis are making significant ture that mimics the ECM that formed a suitable environment
improvements. Recent research done on mice shows that the for cellular nutrient exchange and mechanical protection.
mi-RNA found in the BM-MSCs can decrease the apoptosis Additionally, it induced cell alignment and elongation. Un-
of cardiomyocytes and aid in the process of heart regenera- fortunately, this technique of making traditional scaffolds
tion by targeting proteins and genes that increase the death increases the complexity of cell culture, and the precise organi-
of these cells. Additionally, using exosomes provides a great zation of 3D cell printing is limited. However, 3D printing by
delivery approach because they can be engineered to carry computers has shown great promise in fabricating 3D complex
specific miRNAs. Nonetheless, translating these approaches structure scaffolds that overcome these limitations. Progres-
into clinical practice presents challenges. Guaranteeing the sion of HF leads to the formation of non-elastic scar tissue
survival and retention rates of the transplanted cells remains a that affects heart contraction. 3DBP can potentially develop
significant issue due to the harsh environment in the ischemic heart patches that may be able to promote functional CMs
myocardium, which leads to cell apoptosis and low retention migration for repairing the cardium, instead of scar formation.
rates. However, techniques like alginate microcapsules and For instance, Bejleri et al.⁶⁷ developed heart patches using a
bioactive scaffolds such as hydrogels provide hope of improv- combination of gelatin methacryloyl (GelMA), and cardi-
ing the therapeutic efficacy of stem cell therapies. Moreover, it ac ECM hydrogel scaffolds with human cardiac progenitor
is worth mentioning that while these methods work, they still cells (hCPCs). As a result, during cell culture hCPCs showed
require further research to optimize their effects, particularly high viability and exhibited transcriptor factors that regulate
inhibiting inflammation and ensuring the long-term survival the formation of heart cells and a protein troponin T, which
of transplanted cells. is crucial for muscle contraction. Ajdary et al.⁶⁸ developed a
Cardiac fibrosis, transplanted cell integration: 3D-printed curcumin-releasing heart patch using nanofibri-
Cardiac fibrosis usually occurs from MI, when a great num- lated cellulose, polyglycerol sebacate (PGS), and polypyrrole
ber of cardiomyocytes die, or hypertension. This triggers the (PPy) that helped form structural support, elasticity, and elec-
activation of myofibroblasts that produce collagen and other trical conductivity for cardiac repair. In addition, the slow
extracellular matrix (ECM) proteins that create a scar in the degradation of cardiac patches made the heart patch suitable
damaged area. The myofibroblast on the muscle becomes stiff for long-term drug release. Nevertheless, this novel technolo-
from excess deposition of ECM, resulting in disrupted cardiac gy still has some unresolved challenges that include printing
function that causes reduced ejection fraction or the impair- resolution, controlled vascularization, and the limited ability
ment of electric conductance of the heart which can lead to to print soft materials, therefore, further research is needed.
HF or even death.⁶²,⁶³ For more details on the advancements of 3DBP, please refer to
Stem cell therapies have been researched widely to find new the research by Wang et al. which reviews 3D bioprinting in
treatments that could reduce cardiac fibrosis and its conse- cardiac tissue engineering.⁶⁹
quences. Both hPSCs and MSCs have been widely researched, It is important to mention that while stem cell therapy for
however, judging from the clinical trials in this case hPSCs heart tissue repair has a promising future, it does have certain
provided more success. hPSCs are highly expandable and limitations. While stem cells, including MSCs, hPSCs can
can differentiate into cardiomyocytes (hPSC-CM), therefore aid in cardiac repair by reducing inflammation and support-
serve as a promising treatment for cardiac fibrosis by reducing ing angiogenesis, evidence of whether the cells fully integrate
the scar and increasing vascular density. Furthermore, hPSCs and contract in sync with native heart tissue is mixed. One
secrete growth factors, cytokines, and other molecules that en- promising method is using bioactive scaffolds, which improve
hance cardiac tissue regeneration. Nevertheless, when directly cell retention rates and alignment with native cardiomyo-
injected into the myocardium, the cell transplantation rate is cytes, however, ensuring consistent contraction strength and
less than 10%.⁶⁴ Therefore, there has been extensive research synchronization remains difficult. There are ongoing studies
done on how to improve cell retention rates during cell trans- that explore genetic modification, and bioengineering tech-
plantation. For instance, a successful study by Ye Laboratories niques that may amplify MSC differentiation and make these
has reported that using thymosin β4 (Tβ4) in combination cells more responsive to the cardiac electrical signaling that
with hPSCs-CM promotes angiogenesis, implantation suc- is required for synchronized contraction.⁷⁰ For instance, a
cess, and proliferation of endogenous cells in a pig model of promising genetic approach is to engineer MSCs to express
myocardial infarction.⁶⁵ A study by Zhao et. al described that cardiac pacemaker ion channels, such as HCN2, which may
the overexpression of Cyclin D2 in hPSC-CMs decreases the help MCSs create electrical impulses compatible with car-
apoptosis of cardiomyocytes, increases heart function, and diomyocyte function. Recent research suggests that MSCs
reduces fibrotic scar tissue damage.⁶⁶ In addition, other new engineered to express the pacemaker “funny” current (If ) can
ways have emerged that focus on cell transplantation efficiency generate electrical impulses similar to the cardiac rhythm.
in the field of cardio TE. 3D bioprinting is a technique that HCN2-MSCs transferred into the cardiac tissue can electri-
has a lot of potential for fabricating biomimetic scaffolds be- cally couple with surrounding cardiomyocytes, resulting in the
cause it gives a supportive framework for cell proliferation and creation of biological pacemakers.⁷¹ This method provides an
differentiation. In a recent study core-shell scaffolds were cre- alternative approach for patients with heart rhythmic disorders
ated with electrospun nanofiber yarns (NFYs) as the core and as well as could help integrate the engineered MSCs with the

33 DOI: 10.36838/v7i3.6
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surrounding cardiomyocytes, leading toward more stable heart

contractions.
In summary, cell-based therapy is an advancing technology
that holds a lot of promise for developing novel treatments for
cardiac fibrosis. Continuous research and technology develop-
ment are making new treatment strategies that shed hope for
better recovery after events like cardiac fibrosis. Nevertheless,
many issues related to this field still need to be conquered, such
as biosafety concerns, the selection of the right stem cell sourc-
es, and ensuring the successful survival of transplanted cells.
Furthermore, limitations such as the integration of the trans-
planted cells and correct synchronization with the native heart
tissue are yet to be solved. However, bioengineering techniques
such as bioactive scaffolds and genetic modification that engi-
neer MSCs to express cardiac pacemaker ion channels provide
hope that the transplanted cells will be able to integrate with
Figure 2: Novel stem cell therapies for cardiac repair using BM-MSCs,
the native heart tissue. MSCs, and iPSCs. Adapted from.76 Stem cell-based approaches in cardiac
The future of stem-cell therapy research: tissue engineering: Controlling the microenvironment for autologous cells.
The field of cardiac tissue repair is mainly focused on im- Licensed under CC BY 4.0. Created in https://BioRender.com.
proving techniques for improved cell retention, enhanced cell � Conclusion
specialization, and the optimization of cell integration with In conclusion, the potential of cell-based therapies partic-
native heart tissue. The first approach that holds great promise ularly involving MSCs, hPSCs, and iPSCs provides promise
is the use of hydrogels. Hydrogels are characterized by bio- in treating cardiovascular diseases, such as heart failure. These
compatibility, biodegradability, and bioactivity, which can help therapies aim to address the root cause of CVDs by focus-
restore heart function after MI. They are great agent delivery ing on cardiomyocyte apoptosis, ischemia, cardiac fibrosis, and
systems for cardiac implants due to their qualities, such as bind- muscle regeneration. While current treatments focus primarily
ing, swelling, and absorption. Furthermore, hydrogels have also on decreasing disease progression and alleviating symptoms,
been shown to be great at enhancing electrical conductivity, stem cells provide more targeted strategies for treating CVDs
resulting in better contraction. They can be injected or applied with the potential to repair the myocardium. Nevertheless, de-
in hydrogel-based cardiac patches, which can work as mechan- spite the progress of research related to cell-based therapies,
ically supportive biomaterials. However, to be used clinically, there are still issues that need to be addressed. Those chal-
certain challenges must be overcome.⁷² Furthermore, research- lenges include the survival rate of cells after transplantation,
ers have been exploring different stem cell types- particularly incomplete differentiation, cell integration and the complex
MSCs and hiPSCs, that may aid in cardiac regeneration. hiP- problems of the effective application of these therapies in vivo.
SCs are great candidates for cardiovascular regeneration. Nonetheless, recent research on MSC-derived exosomes for
Efforts have been made towards optimizing methods of hiP- threatening cardiomyocyte apoptosis, and the genetic manip-
SC differentiation into vascular cells like endothelial (EC) and ulation of hPSCs for better transplantation potential show
smooth muscle cells (SMC). Studies on animal models show significant progress in the field of cardiac TE. Furthermore,
that hiPSCs-derived ECs have great potential for promoting new methods of cell application with 3D patches offer exciting
neovascularization, which is the formation of new blood ves- potential in healing the injured cardiac muscle and regenerat-
sels.⁷³ This is crucial in treating various CVDs including PAD ing the damaged tissue. These innovations still require a lot
and HF, because it restores blood to the ischemic, oxygen-de- of research and clinical trials to overcome existing challenges,
rived tissues, resulting in an improved heart’s ability to pump however, they hold significant promise for better and novel
blood effectively and reduce damage from ischemia.⁷⁴ Addi- treatments that ultimately improve outcomes for patients with
tionally, genetic engineering is another key strategy that helps cardiovascular diseases.
modify cells for improved responses to cardiac signaling and � Acknowledgments
functional integration. For instance, iPSCs engineered with I sincerely thank my mentor, Professor Hamidreza Shaye, for
specific gene modifications are showing promising results in his invaluable guidance and support throughout this research.
enhancing electrical and mechanical coupling with host car- I am also grateful to Joani Estkovitz and Taylor Hailstock for
diomyocytes.⁷⁵ In summary, future directions for cardiac repair their helpful insights and encouragement. Your contributions
involve advances in hydrogels, hiPSCs-derived vascular cells, have been essential, and I deeply appreciate your support.
and genetic engineering. While these approaches show great
promise additional research is essential to address clinical � References
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� Authors
Dominyka Virbickaitė is an aspiring orthodontist from Lithuania,
currently studying in the International Baccalaureate (IB) program
with a strong focus on biology and chemistry. Her goal is to study
dentistry at UCLA, where she hopes to build a solid foundation for
her future career in orthodontics.

37 DOI: 10.36838/v7i3.6
 ijhighschoolresearch.org

REVIEW ARTICLE

Promoting Female Entrepreneurship: Investigating Strategies

for Japan
Elias R. Nakajo
The American School in Japan, Nomizu 1-1-1, Chofu, Tokyo, 182-0031, Japan; [email protected]

ABSTRACT: Entrepreneurial activity drives higher-income economies, which is why countries emphasize and put effort into
growing the entrepreneurial sector. However, with only one in three entrepreneurs being female, markets don’t maximize the
diversity of potential perspectives and ideas. In this paper, the spotlight is on Japan, a country that ranks 118th out of 146 countries
in the 2024 Global Gender Gap Report (GGGR), with the widest gender gap among developed countries. This study explores
the successful approaches in economies that face a similar challenge to Japan–Egypt with its gender gap, Poland with its low start-
up motivations, and South Korea with its ingrained cultural values that lead to low self-confidence. Ultimately, a combination
of the approaches is proposed. This research aims to shed light on the gender inequality issue, specifically the deficit of female
entrepreneurs in Japan, and propose effective approaches to tackle it. Approaches that surfaced include Egypt’s government
initiatives, Poland’s mentorship and role models, and South Korea’s entrepreneurial education. Japan’s situation is rarely brought
to light, making for a slow process of change. With the continuation of this system, future projections for the Japanese economy
can be stagnant and slow, a future the country wants to avoid.
KEYWORDS: Entrepreneurship, Japan, Women, Gender Inequality, Government Initiatives, Education, Mentorship.

� Introduction higher risks of depression, anxiety, and post-traumatic stress

Entrepreneurship–the activity of setting up a business or disorder (PTSD), according to Medical News Today.⁶ Gen-
businesses, taking on financial risks in the hope of profit–has der inequality also negatively impacts the economy of nations
been an increasingly growing field globally in recent years. In due to its connection to unequal pay, lower female participa-
addition to the expansion of the field, with a positive correla- tion in the economy, and lower entrepreneurial activity. Gender
tion between entrepreneurial activity and economic growth, inequality causes many adverse psychological and economic as-
entrepreneurship also further excels the economy of nations.¹ pects; therefore, research on possible successful approaches to
While many benefits follow entrepreneurial activity, there are increasing female entrepreneurship is relevant.
issues within the entrepreneurial industry worth focusing on. This paper argues that Japan’s outlook on female entrepre-
With only one in three entrepreneurs worldwide being female, neurship can change. A domino effect can occur with carefully
there is a significant gender gap in the entrepreneurship sec- assessed proposals and implementation; encouraging more fe-
tor, and this shows us that there is still room for improvement male entrepreneurs will close the gender gap, increasing female
in this field.² The World Bank estimates that by closing this entrepreneurship, spurring more entrepreneurial activity, and
gender gap in entrepreneurship and employment, the global ultimately positively affecting the economy.
GDP could grow by more than 20 percent.³ Further, research This paper examines successful approaches in Egypt, Poland,
suggests that entrepreneurial attitudes “positively affect GDP and South Korea in three overseas countries. A successful ap-
in high-income countries,” demonstrating that the internal proach to promoting female entrepreneurship increases female
mindset is as important as the actions taken.⁴ However, al- entrepreneurs' performance, attitude, and motivation. Key indi-
though sufficient evidence of increased entrepreneurial activity cators include a rise in the percentage of female entrepreneurs
leading to economic growth is presented, some still struggle to and enhanced entrepreneurial skills and confidence in women.
trigger more entrepreneurial activity in their economies, Japan Additionally, such an approach supports women by facilitat-
being one of them. ing access to learning, funding, mentorship, or networking
The relevance of this research can be explained by the cur- opportunities. Success is also sometimes reflected in women's
rent state of gender inequality and the economy in Japan. broader social and economic empowerment, seen through job
Japan’s global position among other developed countries in the creation and leadership roles in the business sector.
most recent 2024 Global Gender Gap Index presented by the The rationale for picking these specific nations is due to their
World Economic Forum might be shocking, with Japan rank- similarity to Japan. Further details of the rationale are includ-
ing 118th out of 146 countries in the report.⁵ ed in the approaches section. After investigating the strategies
Gender inequality critically affects psychological and eco- of the countries, this paper assesses what approaches have the
nomic aspects, which makes gender inequality all the more highest chances of succeeding while also becoming a reality in
crucial to tackle. Significant psychological effects include the context of Japan. By processing secondary data and analyz-

© 2025 Terra Science and Education 38 DOI: 10.36838/v7i3.7

 ijhighschoolresearch.org

ing successful approaches in overseas nations similar to Japan, Mainichi.¹¹,¹² The UN has further forecasted that the propor-
the paper aims to better grasp the possible strategies Japan can tion of women in managerial positions in Japan will only reach
implement. 15.15% 25 years from now in 2050, which is nowhere close to
� Methods the goal of 30%.¹³
A careful literature review was held using Google Scholar Gender Gap:
and the standard Google search, reviewing papers published Since 2006, the World Economic Forum has released an
from the years 2018 to the present and using keywords for annual report on gender parity observed in different coun-
the search such as “female entrepreneurship,” “gender gap,” tries. It has since been a significant source of measurement of
and “entrepreneurial education.” Sources, including the Eco- each country’s performance in gender inequality. The report
nomic Forum, Global Entrepreneurship Monitor (GEM), measures gender parity in countries by four main subindex-
and the World Bank, were used to collect data for topics such es: Performances in economic participation and opportunity,
as gender inequality and entrepreneurship on a global scale. educational attainment, health and survival, and political em-
Furthermore, the abstract, methodology, conclusion, and other powerment, which are all considered for translation to the
potentially relevant sections were reviewed most heavily for ultimate score of the country. There were no outstanding
information when studying the sources. Finally, each country shocks in the 2024 Global Gender Gap Report (GGGR), in-
researched–Egypt, Poland, and South Korea– was selected cluding Japan’s ranking, 118th out of the 146 countries in the
based on whether the country faced a similar challenge to Ja- report.
pan. Japan’s ranking has risen seven places since 2023, largely due
The Current State of Japan to improvements in the Political Empowerment dimension
Economy: and positive changes in Economic Participation and Opportu-
Although Japan’s post-war economic miracle is widely con- nity. Nonetheless, Japan still ranks as the second-lowest Asian
sidered one of the most successful economic growth stories nation and by far the lowest among the G7 nations. Its con-
by a country, increasing the nation’s GDP and quality of life tinued low-ranked position can be explained by the low scores
massively, the Japanese economy has been stagnant for the past across many of the measured categories, including a 17.1%
30 years or so in a period often referred to as the ‘lost decades.’ gender parity score in senior roles and a 58.3% earned income
Some scholars say Japan is still in its ‘lost decades’ period, score. While the rise in ranking from the previous year was
with Japan’s 2020 to 2025 average annual growth rate expected due to improvements in Political Empowerment, the subindex
at only 0.3%.⁷ However, some also say Japan has escaped the remains Japan’s weakness, with women holding 25% of minis-
lost decades and regained its power as the Nikkei 225 stock terial roles and 11.5% of parliamentary seats.
average finally hit record-breaking marks after 34 years.⁸ When looking at Japan’s profile in Figure 1, a radar chart
When looking at an economy, in addition to the GDP and (on the left-hand side) that reflects the score, on a 0 to 1 scale,
stock numbers, the first statistic many people would look at is of each subindex relative to complete gender parity can be
the labor force participation rate. In Japan, the labor force par- observed. Having a skewed score overall, the chart shows Ja-
ticipation rate has been on an upward trend, and on top of that, pan’s highs and lows, making it clear what aspects Japan has
gender equality seems to be achieved if one only considers the to work on to close the gender gap further and climb higher
employment rate, which among females is 54.9% and among in the rankings. The two most critically ranked subindexes are
males is 71.5% in 2023.⁹ However, when referring to the em- Economic participation and opportunity and political empow-
ployment rate, it is necessary to consider the pay gap between erment. For the sake of this research, the economic subindex
regular and non-regular employees. In Japan, regular workers will be the focus, but the gender gap present in Japan’s political
are paid 64% higher wages than non-regular workers.¹⁰ How- world also has to be improved.
ever, what is more outrageous is that in 2023, more than half
of the female working population worked in non-regular em-
ployment compared to only 23% of men.⁹ This means that
female employees are paid less than male employees, showing
the gender gap in the economy.
The gender ratio in managerial positions is where Japan
falls back significantly among the other developed nations.
However healthy the labor force gender ratio seems, if the
position that is ultimately in control of the firm’s decisions is
dominated by one gender, it will impact the representation of
companies and raise questions about the process of leadership
role selection. Although the Japanese government announced
they will aim to have women hold at least 30% of executive Figure 1: Japan’s Economic Profile.5
positions in top companies by 2030, “Japan ranked worst in the
ratio of women in managerial positions at 14.6%, significantly Delving deeper, the economic participation and opportunity
lower than the Organisation for Economic Cooperation and subindex encompasses several individual indicators, including
Development (OECD) average of 34.2%”, according to The the labor-force participation rate and wage equality seen in

39 DOI: 10.36838/v7i3.7
ijhighschoolresearch.org

Figure 2. However, the indicators that rank the lowest out of

all indicators are the legislators, senior officials, and managers
indicators. Ranked 130th out of 146 countries, this indicator
alone pulled down the score of the economic subindex and,
therefore, the overall ranking of Japan in this report.

Figure 3: Expert ratings on different aspects of entrepreneurship in Japan

compared to other Level B economies.14
Countries and Their Successful Approaches:
Deciding how Japan should approach gender inequality in
its current entrepreneurial field can be difficult. Brainstorm-
ing ideas can only do so much; therefore, taking inspiration
Figure 2: Japan’s Indicators on Economic Profile.5
from other economies is proposed. Investigating successful
examples from other countries is crucial, acting as a helpful
Entrepreneurship: template for Japan. Three countries—Egypt, Poland, and
The 2024 Global Entrepreneurship Monitor (GEM) gath- South Korea—were carefully selected by narrowing down op-
ered experts who scored countries across 13 aspects of the tions from a batch of countries to be subjects of this research.
entrepreneurial framework conditions, which can be seen in A past successful strategy from each country was selected and
Figure 3. These aspects include entrepreneurial finance, gov- then further researched.
ernmental policy, and cultural norms, to name a few. The report A simple criteria based on two main factors was used to nar-
separated the world’s economies into three levels (A, B, and C) row down the options used for research since having a criteria
according to their GDP per capita for these expert ratings. further supports and strengthens the overall research. For ex-
Japan was put at level B and was ranked among the 18 oth- ample, the first factor considered was the country's similarity
er economies at the same level. Overall, Japan’s performance to Japan's current state. It is crucial to have a similarity be-
is not the strongest, but the two entrepreneurial education tween the country researched and Japan because that similarity
ratings stand out as lacking out of the aspects scored. Japan’s will increase the reliability and probability that a strategy in
ranking in entrepreneurial education at school is 16th out of one economy can work in another. If countries were chosen
19 in the level B economies, and entrepreneurial education randomly, there would likely be less common ground between
post-school is also at a low 11th out of 19 economies. the researched country and Japan, increasing the variables to
Here, there is an important distinction to note. Figure 1 consider. The similarities were also not chosen randomly but
shows Japan’s strength in the educational attainment subindex, rather in relevance to the research topic, such as the gender
however, Figure 3 shows Japan’s weakness in education. gap situation in the country. The second factor was to have
To clear up the contradicting claims, education in Figure an economy that was as different as possible for each nation.
1 is about gender inequality in the realm of education in Ja- This does not mean the countries researched should be very
pan; For example, if there is a high number of male students different compared to the Japanese economy, but rather that
and a significantly lower number of female students attending all three countries selected should be relatively different from
secondary school. On the other hand, education in Figure 3 each other so that the three countries are globally spread out
is specifically the amount of or the quality of entrepreneur- and cover more ground. Having all three countries in the
ial education taking place in Japan. The experts assessed that exact geographical location, for example, would undoubted-
entrepreneurial education is lacking not only at school but ly increase the similarity of each country but will ultimately
post-school as well. Progress in entrepreneurial education is affect the research negatively. Countries will likely have sim-
insufficient in Japan, which is likely one major cause of the ilar approaches when the research appreciates many of these
low female entrepreneurship rate, proving that improvements approaches. This approach will also raise questions about if
must be made. other regions were considered. The above criteria allow for the
selection of countries similar to Japan in important aspects but
are all very different economies, diversifying and strengthening
the research results. For this research, the author chose three
countries that are not often seen in the same sentence and are
located on different continents.

DOI: 10.36838/v7i3.7 40
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Egypt’s Rationale: influenced by gendered norms regarding the role and behav-
The first country chosen to be researched was Egypt, an ior of women in society”, and the gendered norms in Japan
African nation with a population of 111 million and a rapid- point to Confucian values.¹⁶ Confucian values have multiple
ly growing economy. Egypt was selected due to the similarity examples of virtues and practices that “relegated women to a
of the gender inequality situation, specifically, the gender gap position inferior to men”, and the country still holds onto some
in both the Japanese and Egyptian economies. When inves- of these ideas which have planted their roots in Japanese soci-
tigating the total early-stage entrepreneurial activity (TEA) ety.¹⁷ Once again, one motivation for selecting a country based
on a country basis, looking at both the female and male TEA on cultural similarity is the gender gap rankings. China, South
percentages, Japan and Egypt had the widest gender gaps.² Korea, and Japan have Confucian values firmly rooted in soci-
The two countries also had similar female-to-male ratios, with ety and have similar rankings in the gender gap index. South
Egypt’s ratio at 0.38 and Japan’s at 0.39. Additionally, both Korea ranked 94th, China ranked 106th, and Japan ranked
had similar TEAs of men’s and women’s percentages, meaning 118th. With these results, an additional question arises: Are
Japan and Egypt were almost identical if only looking at this cultural values a significant factor in the gender gap preva-
data set. Although the success of the strategies in Egypt does lent in Japan? Although China and Vietnam are also countries
not guarantee success in Japan, success in one country could be where Confucianism is deeply rooted in society, South Korea
helpful for another struggling against the same problem. was selected due to its similar scale, geographical location, and
Poland’s Rationale: industries to Japan's. Researching the approaches that brought
The second country selected for research was Poland, a Eu- successful outcomes in South Korea, a country that also histor-
ropean country with a population of 37 million and a growing ically has cultural values potentially negatively affecting female
economy. Poland was selected as a country to research primar- participation in the economy, could present an approach Japan
ily due to the low start-up motivation for Japan’s and Poland’s could implement to break through those limiting values.
female populations. Start-up motivation is a must-have for � Results
entrepreneurship to thrive in a country because there will be Egypt’s Approach:
no activity if people do not have the drive to proceed. There- Some strategies Egypt uses to increase female entrepreneurs
fore, it is essential to include Poland, a country where women in their economy include microfinance institutions, business
do not have much motivation to start a company, in the re- development centers, and government-supported initiatives.
search. Including Poland as a country for research will allow Although Egypt faces the same challenge as Japan in lacking
for finding what a successful approach would look like in an female entrepreneurs—leading to a wide gap in the male-to-
economy where female entrepreneurial motivation is shallow. female entrepreneurial activity numbers—success has been
Japan's and Poland’s women’s startup interest in 2022 was the seen in a specific approach that the nation has implemented.
two lowest among countries in the GEM report, with Poland Government initiatives have played a crucial role in creating a
having 2.3% and Japan having 3.9% of the female population supportive environment for female entrepreneurs in Egypt.¹⁸
surveyed interested.² Looking at successful approaches from By establishing business incubators that promote gender
another country that struggles with the female population’s equality, the government has taken significant steps to em-
start-up motivation is helpful for Japan because it is evidence power women to pursue their entrepreneurial goals.
that the approach was practical even with low start-up moti- An example of a business incubator is the Heya Raeda
vations. program, which is government-funded and implemented by
South Korea’s Rationale: the Egyptian Technology Innovation and Entrepreneurship
The third and final country chosen for the research is South Center (TIEC). The program was established in 2017 and
Korea, an East Asian country with a population of 52 mil- is active to this day. The initiative aims to empower female
lion and a favorable economy. Compared to Egypt and Poland, entrepreneurs by providing them with the training, resourc-
South Korea has more common ground with Japan, which is es, and networks necessary to succeed as entrepreneurs and
vital for the possible success rate of South Korean approaches leaders. Some unique ways the program offers training in
in Japan as it reduces the variables that must be considered business management, financial literacy, and leadership skills
when using overseas strategies. Geographically, Japan and are through group discussions and case studies, among others.
South Korea are neighbors and have proximity, historically This not only increases the entrepreneurs’ skillset but sparks
making each other’s existence and relationship very important. self-confidence, too.
Both Japan and South Korea also share similar major industries Being a relatively new project, however, in 2020, the pro-
that power the nation's economy, including but not limited to gram saw only 300 female entrepreneurs graduate, proving
car manufacturing, steel, and electronics. The final and pos- their challenge to reach its target audience.¹⁹ To address this
sibly most influential reason is that Japan and South Korea challenge, TIEC is forming partnerships with various organi-
have similar cultural values or beliefs, significantly impacting zations dedicated to promoting female empowerment. With
society's functions. Studies have explained that one reason for the initiative being funded by the Egyptian government, the
the shortage of female entrepreneurs in Japan is the “lack of program not only gains financial stability and credibility but
self-confidence in women’s perceptions of their capabilities”, also gains access to more connections that will fuel future part-
and this can be directly tied to cultural values that persist in nerships.
the nation.¹⁵ The absence of self-confidence is “significantly

41 DOI: 10.36838/v7i3.7
ijhighschoolresearch.org

Poland’s Approach: A contract-like style idea should be proposed to ensure the

Poland has found several effective strategies to increase government continues to support the program and prevent the
female entrepreneurship in the nation. These strategies in- possibility of the program becoming lazy and not getting the
clude offering financial support, providing mentorship and expected work done.
role models, and creating networking opportunities, to name This can be done by implementing Key Performance Indi-
a few. As previously stated, Polish women have relatively low cators (KPIs), ensuring the program stays effective, driven, and
start-up interests, hindering the opportunity for a larger fe- growing. Examples of KPIs may be reaching a certain number
male entrepreneur population in the country. Reflecting on of participants, the number of successful start-ups made, or the
Poland's significant challenge, it will be adequate to empha- number of graduates who thought the program was helpful.
size a strategy that pinpoints this issue and aims to increase A proposal may look like the following: If the program
confidence and start-up motivation in females. Therefore, the successfully achieves the KPIs set for the half-year or whole-
focus is on the mentorship and role models approach. This year checkpoint, the government will guarantee the program's
approach provides female entrepreneurs with guidance, sup- sustainability and continue to support it through funding and
port, and inspiration from successful role models and is highly resource allocation. Implementing this process creates check-
effective in boosting their confidence and intentions.²⁰ Nota- points for both the program and the government to take a step
ble mentorship programs such as Youth Business International back and see if they align with their goal and mission.
have significantly impacted female entrepreneurs, and female Potential benefits of the implementation include increased
leaders have spoken to the younger generation, which has all skill sets and self-confidence among female graduates. While
helped increase the interest and motivation to start a company. there should be hope for good news of the results, a slow and
South Korea’s Approach: gradual process should be expected, just like the Heya Raeda
South Korea tackles the shortage of female entrepreneurs program in Egypt.
through three main strategies: Entrepreneurship education, The Potential implementation pitfalls, however, may be the
business development centers, and financial support. Out of societal and cultural norms in Japan. With traditional gender
these three strategies, the strategy that stands out is entre- roles that often expect women to prioritize family responsi-
preneurial education. Globally, “entrepreneurial education at bilities over professional pursuits, women may feel pressure to
school in most economies continues to be assessed as poor”, in- conform to these roles.²⁵ This may result in fewer than expect-
dicating that significant room for improvement still remains.¹⁴ ed participants due to how hard it is for women to take the
Secondary schools in countries such as Lithuania, Poland, first step–to feel that their career is worth investing in–.
Slovenia, and Sweden incorporate entrepreneurial education In contrast, Poland's focus on mentorship and role models
in their curriculum and recognize the course as compulsory.²¹ addresses the challenge of the low start-up interest among
However, many South Korean secondary schools do not have women in Poland. Mentorship and role models help by pro-
entrepreneurial education as part of their curriculum; in 2012, viding inspiration and guidance, which is critical in building
the South Korean Ministry of Education, to achieve a more confidence and motivation in individuals. Poland's strategy
‘creative economy,’ installed entrepreneurship centers in 61 demonstrates that they value personalized, individual support
universities.²² The benefit of entrepreneurial education is not rather than focusing on large groups of people.
only how it “provides adequate know-how and skills and mo- In Japan, the mentorship and role models approach can
tivates them to develop their entrepreneurial careers” but also also be implemented. Examples are highlighting successful
how it increases the self-confidence of the individual (Hwan, female entrepreneurs–the role models–through various media
2020).²³,²⁴ Further, research on South Korean university stu- platforms and business forums or incorporating mentorship
dents suggests that entrepreneurial education plays a crucial programs in education and training, such as in universities or
role in “enhancing entrepreneurial self-efficacy and entrepre- the workplace.
neurial orientation of young people”, proving the effectiveness The mentorship and role model approach can help shift
of entrepreneurial education in South Korea.²⁴ society’s perception of the female gender by providing visi-
� Discussion and Recommendation ble examples of women’s success. This challenges traditional
The results from Egypt, Poland, and South Korea highlight gender roles and can encourage further entrepreneurial par-
these countries' diverse strategies to increase female entre- ticipation.
preneurship, reflecting each nation's cultural and economic The mentorship and role model approach can benefit Jap-
contexts. anese society by raising the motivation to start up. This is
Egypt’s approach emphasizes the role of government ini- possible by increasing self-confidence with mentorship and
tiatives in promoting gender equality. This strategy stresses breaking through traditional gender roles with role models.
the importance of systemic support in overcoming traditional This can ultimately lead to an increased number of female en-
barriers. Implementing this approach in Japan would mean trepreneurs.
building a similar relationship between the Japanese govern- However, this approach has several potential pitfalls when
ment and a program just like the Egyptian government and applied to Japan’s society. In addition to the cultural resistance
the Heya Raeda program had. The government does not have to gender equality, limited access to high-quality mentorship
to limit the number of programs to one since the more, the and an overreliance on independent mentorship can surface.
better. First, there could be a deficit due to the significantly lower

DOI: 10.36838/v7i3.7 42
 ijhighschoolresearch.org

number of experienced female entrepreneur mentors. Sec- emerging economies; therefore, a weaker emphasis on en-
ond, relying too heavily on one-on-one mentorships may be trepreneurship exists for emerging economies.⁴ With Egypt
limiting when many women don’t have the time or energy to being the only emerging economy out of the three researched
participate in the mentorship programs. economies, its government might not prioritize entrepreneur-
On the other side of the world, South Korea implements ship like Poland, South Korea, and Japan do.
entrepreneurial education in universities by equipping stu- Due to the positive results associated with the three ap-
dents with a skillset to prepare for entrepreneurial journeys. By proaches from the three nations, implementing a combination
taking an education approach, South Korea acknowledges the of the three countries’ strategies is proposed for Japan when
long-term impact of knowledge and self-efficacy in creating a attempting to increase female entrepreneurs. It is recommend-
better entrepreneurial country. Together, these approaches il- ed that Japan further integrates entrepreneurial education into
lustrate how different strategies—from policy intervention to its university programs, with consideration of integration into
educational reform—can significantly enhance female partici- secondary school curriculums and post-university experiences.
pation in entrepreneurship. In addition, further exposure to female leaders who will act as
Entrepreneurial education can be addressed in different role models for the students will boost their confidence and
ways in Japan. Change can range from a curriculum change intentions.²⁰ Furthermore, the government can do its part by
to a one-day discussion on entrepreneurship. Boasting an implementing and more heavily supporting initiatives to cul-
impressive and developed education system, incorporating tivate a supportive environment for female entrepreneurs. By
entrepreneurial topics in curriculums can generally expect pos- incorporating aspects of all three approaches, Japan can tack-
itive outcomes.²⁶ le three significant challenges: The existing gender gap, low
The educational approach is very powerful, as it most ef- start-up motivations, and low self-confidence.
fectively changes mindsets and ways of thinking and the roots � Limitations
of the societal and cultural gender norms in place. By going This study has some limitations. One limitation arose when
the extra step to incorporate discussions, activities, or proj- selecting the countries to research in comparison to Japan.
ect-based learning, students can better internalize the learning There was only one control variable: the country's challenge
and develop critical thinking skills that will be useful in the to increase female entrepreneurs. The countries are not in the
future, especially as entrepreneurs.²⁷ same situation as Japan, so you cannot guarantee that the same
There aren’t many potential pitfalls when implementing success will be achieved in both countries. Ideally, it would be
the strategy in Japan, mostly due to Japan’s status as a lead- best if a country had the same conditions and challenges as
ing economy and strength in education. If, for example, the Japan, mimicking Japan. Assessing its successful approaches
country did not have the same quality or amount of resources will lead to a confident guess of how an approach will im-
as Japan, pitfalls could include limited access to resources or pact the Japanese economy. However, two nations can't be the
infrastructural challenges. same in all aspects, and technological advancements have yet
However, one challenge is the overemphasis on individual to reach a simulation as realistic as this. Therefore, the decision
success rather than collective success. Since entrepreneurship to research countries that share one challenge with Japan in
often focuses on individual success, and Japanese society tends achieving gender equality in entrepreneurial participation was
to lean toward a collectivist culture, there may be some push- made.
back in terms of this. Another limitation is that the proposed approaches are not
It is also important to consider the economic difference be- steps that every person could initiate but steps for the gov-
tween the countries and Japan as this largely affects how these ernment or organizations. When attempting to initiate these
approaches are carried out and the results. For reference, Japan, approaches individually or with a group of people, it is chal-
the fourth largest economy in the world, had a GDP in 2023 lenging mainly because it is so far out of reach for ordinary
of 4,212,945 Million USD. people.
With a GDP in 2023 of 395,926 Million USD, Egypt is the
lowest ranked out of all of the countries discussed in this paper � Conclusion
This paper claims that Japan's efforts for female entrepre-
in terms of GDP.²⁸ Egypt is often referred to as an emerg-
neurship can improve. By introducing thoroughly considered
ing economy. With a GDP in 2023 of 811,229 Million USD,
proposals and implementing them effectively, a domino effect
Poland is the second lowest ranked out of all of the countries
can occur: encouraging more female entrepreneurs will help
discussed in this paper in terms of GDP.²⁸ Poland is consid-
close the gender gap, boost female entrepreneurship, stimu-
ered a high-income economy. Finally, with the GDP in 2023
late greater entrepreneurial activity, and ultimately benefit the
at 1,712,793 Million USD, South Korea is the highest ranked
economy.
out of the three countries researched and the closest to Japan
Japan's economy has experienced stagnation for the past 30
in terms of GDP.²⁸ South Korea is also considered a high-in-
years, with a continued gender gap in employment, especially
come economy.
in managerial roles, despite the increasing female labor force
Studies show that there is a possibility entrepreneurship
participation. The country also ranks poorly in gender parity,
has a greater positive impact in high-income economies while
especially in economic participation and political empower-
having minimal impact in emerging economies.¹ Some stud-
ment, and its entrepreneurial education system is notably
ies state entrepreneurial activity could even negatively affect
weak, contributing to low female entrepreneurship.
43 DOI: 10.36838/v7i3.7
ijhighschoolresearch.org

When choosing the countries to research as examples for women in business, it can help create a more inclusive entre-
Japan, three countries were selected based on how they were preneurial ecosystem where everyone has the same chance to
also facing similar challenges to those faced by Japan. Egypt be successful and active. Currently, men hold many positions
was selected for this research because of its similarity to Japan of power. Men are more likely to be in leadership roles in pol-
in terms of its gender inequality situation. Egypt and Japan itics, businesses, and other influential areas, which means they
have extremely wide gender gaps in their respective econ- have the power to make decisions that either reinforce or chal-
omies, meaning a successful solution in one of the countries lenge gender stereotypes and biases. In short, the fight against
could hint at success in the other.² Poland was selected for gender inequality in the entrepreneurial world cannot only be
this research because the female population had abnormally fought by females. Men should also do their part to narrow the
low start-up interest rates, a characteristic of Japan’s female gender gap between the genders in the entrepreneurial world.
population. South Korea was selected because both Japan and � Acknowledgments
South Korea have strong Confucian values rooted in society. The author thanks Professor Michellana Jester and Neil Bui
Patriarchal ideas that position females at a lower rank than for their mentorship and guidance in global entrepreneurship
males are some of the core beliefs, and a correlation between and research.
cultural values and the small number of female entrepreneurs
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45 DOI: 10.36838/v7i3.7
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RESEARCH ARTICLE

The Underrepresentation of Women in the Finance Industry:

Causes and Solutions
Emilie Kassis
Madison High School, 170 Ridgedale Ave, Madison, NJ, 07940, USA; [email protected]

ABSTRACT: Gender inequality is prevalent in many professions but is more pronounced in the finance industry, which has
among the largest gender pay gaps. The average woman earns $0.61 for every dollar earned by a man. The picture did not improve
when researchers examined the ratio of men to women in the finance industry occupying C-suite positions. The numbers were
uneven, favoring men over women. This article investigates the leading causes of women's underrepresentation in the finance
field and suggests solutions to strive for equality. This literature review selected relevant studies, extracted and evaluated the data,
and discusses the results to inform potential solutions. The research findings indicate that the most influential causes of women's
underrepresentation in the finance industry are gender biases, a lack of female mentors, family responsibilities, internal battles,
and unequal opportunities. This article explores the effects of gender inequality in the finance industry and suggests strategies and
techniques that can be employed in the workforce to mitigate its pernicious consequences. It also offers some examples to combat
the damage caused by gender inequality, such as implementing HR policies, paid daycare services, pay transparency, and female
mentoring.
KEYWORDS: Workforce, Business, Finance, Gender Equality.

� Introduction ternal research papers on the topic of women in business and

The average woman earns $0.61 for every dollar earned by a specifically finance.
man.¹ The picture did not improve when researchers examined � Discussion
the ratio of men to women in the finance industry occupying The Causes of the Underrepresentation of Women in the
C-suite positions. The numbers were uneven, favoring men Finance Industry:
over women. The gender equality movement in the workforce The ratio of men to women in the finance industry has been
has advanced significantly within the past few decades with found to be skewed against women. A 2023 study found that
more women participating in the workforce than ever.¹,² How- women accounted for 18% of C-suite positions globally in the
ever, despite considerable progress, the underrepresentation of financial industry.⁴ This section will discuss some of the im-
women in the financial services sector persists today. Accord- pediments that hinder women's ability to emerge and succeed
ing to McKinsey & Company, while women comprise 52% of in an industry studies have found is dominated by men. It syn-
the financial industry workforce at the entry level, their repre- thesizes several sources discussing some of the root causes of
sentation falls by 80% at the C-suite level. The McKinsey & the underrepresentation of women in finance to aid in under-
Company study further unveiled that in North America 64% standing the issues that plague the industry.
of financial services C-suite executives are still white men and Gender Biases:
23% are white women³ highlighting other inequities in the in- The authors of one publication found that women in en-
dustry. try-level positions are less likely than men to have managers
There are an abundance of challenges in the workforce that advocating on their behalf or to help them identify oppor-
hinder one’s ability to attain professional success. Why are tunities to pursue.⁵ In addition, “male mentors can even be
there challenges in the finance industry due to gender? What resistant to mentor women because of the low expectations.
barriers are placed on women that hold back their occupational These include perceptions and assumptions of women being
advancement? How can companies and businesses solve gen- more emotional, less skilled than men at the problem-solving
der inequality in the financial services sector and mitigate its tasks and the fear and risk of the sexual harassment issues.”¹¹ In
subversive effects on the industry in general and women in an experimental study, the anti-female bias was substantiated;
particular? For businesses and corporations to work to create “based on 136 experimental studies, it was found that women
solutions, it is crucial to identify why specific opportunities are were evaluated more negatively than men in male-dominated
not going to women. This paper investigates the causes and fields and that these biases were driven by male evaluators.”⁷
potential solutions to the underrepresentation of women in fi- Biased opinions can alter the course of a woman's career by
nance. preventing her from embarking into the finance industry and
To investigate why women are underrepresented in the getting promotions and jobs once in the industry due to sys-
finance field this article undertook a qualitative analysis of ex- temic prejudices.
© 2025 Terra Science and Education 46 DOI: 10.36838/v7i3.8
 ijhighschoolresearch.org

Workplace stereotypes also play a role in the challenges therhood is rewarded with an increase in men’s earnings.”¹⁴
women face in the industry. It is commonly believed that men The net effect is significant as the average mother’s earnings
exhibit “assertiveness, independence, rationality, and decisive- decreased 20 percent throughout her career compared to her
ness” in the workplace while women are seen as “acting in a male counterpart.¹⁵ Mothers are also rated as less competent,
manner consistent with showing concern for others, warmth, committed, and suitable for hire, promotion, and management
helpfulness, and nurturance.”⁸ Beliefs associated with men are training¹⁶ driving them to exit the field or avoid it altogether.
measurably different than those associated with women. Qual- To explain the unequal treatment of women in finance, it has
ities of successful leaders are often associated with those of been theorized that mothers are both discriminated against
men and not women which often makes it difficult to imagine and held to a higher standard than men.¹⁶
a woman as a successful leader.⁹ The impact of disparate treatment of mothers versus those
Women experience poor evaluations and stereotypical who do not shoulder the burdens associated with parenting can
perceptions which hinder their career progression. Based on be defeating. A participant in a study on female professionals
conducted studies, male colleagues’ biases can prevent women working in the finance industry expressed frustration about
from receiving mentorship and lead to negative evaluations.⁶,⁷ the idea of managing her workload and family responsibilities.
The stereotypical gender perceptions that are reflected on She states, “I have to go out and find new clients and pitch,
women discourage others from feeling confident in their lead- and it's super demanding. So, I think it would be challenging
ership abilities. to combine children with my customer base today and at the
Lack of female mentors in the industry: same time have an ok income.”¹⁷ As illustrated, the real-world
Mentorships are credited for being essential to the success effects of family responsibilities have an overwhelming ability
of an individual's career regardless of sex. The inadequate or to hinder mothers' career advancement. Oftentimes, balancing
complete lack of guidance for women “limits the visibility of work with family life seems unfeasible and in this case, even
female role models and perpetuates the notion that women deterred the participant from currently having children.
are less capable in leadership roles.”¹⁰ Having a mentor of the Internal Battles:
same gender provides many benefits like “understanding and Being in the finance industry as a woman can negatively
overcoming the gender bias and challenges the men do not affect one’s confidence. The toll stereotyping has on women
face and experience at the workplaces.”¹¹ The support women serving in traditionally male positions can be profound and
require from a female preceptor is different from the men- impact not only performance but also earning capacity.¹⁸ A
toring required from a male mentor, and according to data study that analyzed female and male participation when ne-
conducted by the Center for Creative Leadership, it was found gotiating salary suggests that “women are between 12 and 23
that both male and female mentors are equally supportive for percent less likely than men to have negotiated their pay at
men, but for women, male bosses were rated less supportive of various points in their careers and 13 percent less likely to an-
career development compared to female bosses.¹² Compared ticipate negotiating in the future.”¹⁹ The preconceived ideas
to men, female mentors fulfill and support their women sub- about women in finance engenders an internal battle leading
ordinates better.⁶ to self-doubt which undermines their confidence and work-
The career mentoring experiences of men and women are place performance.¹⁸ When working at something that has
different and female mentors play a crucial role in the devel- been stereotyped as a male role, women can become anxious
opment of other women in the workplace. With fewer women which can cause them to be more reluctant to share their ideas
achieving C-suite or management-level roles in the finance in group discussions.²⁰,²¹
industry, the empirical data lends support to the notion that In a research report conducted by the Center for Creative
a lack of female mentors in the financial industry contributes Leadership, one participant was asked what the greatest dis-
to the imbalance. advantage women face in the modern workplace is and she
Family Responsibilities: responded, “Being heard. Sometimes I feel like I’m invisible.”¹²
Gender equality continues to lag in the home and con- This personal narrative highlights women's struggle to gain
tributes to women’s inability to compete in male-dominated recognition. The feeling of invisibility experienced by women
industries. According to The Center of Creative Leadership, perpetuates self-doubt and traditional biases.
gender role expectations are particularly strong around family The mental toll that is taken on women in this industry
responsibilities with 70% of women and 48% of men agree- impacts their earning capacity both in the short and long
ing that society expects women to behave in certain ways that term. Unequal treatment takes a mental toll on women, re-
hinder them from becoming senior leaders.¹³ This is equally ducing their confidence, inciting a sense of incompetence, and
true in the finance arena. Of those senior-level women in fi- preventing women from feeling accepted, which is directly
nancial services who live with a spouse, one study found they reflected in their hesitancy to ask for promotions and salary
are “seven and a half times more likely than their male peers increases.
to say they are responsible for all or most of the household Unequal Opportunities:
responsibilities.”³ A study conducted of MBAs in the financial and corpo-
The uneven distribution of household responsibilities has rate sectors who graduated from the University of Chicago
given rise to a phenomenon called the “motherhood penalties” between 1990 to 2006, shows that women earned $115,000
where “women’s earnings are penalized with children while fa-

47 DOI: 10.36838/v7i3.8
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on average at graduation and $250K nine years out, while men means intended to be exclusive steps to tackle the issues that
earned $130,000 and $400,000, respectively." but it reads like face women in finance, nor are they perfect. Further studies
this in the proof "A study conducted of MBAs in the finan- might reveal the efficacy of implementing these actions and
cial and corporate sectors who graduated from the University other methods to combat the problem.
of Chicago between 1990 to 2006, shows that women earned Implementing HR Policies:
$115,000, $130,000 and $400,000, respectively. In addition, The implementation of gender diversity policies has been
a man in the ninetieth percentile earned over $1 million at a tactic many companies have employed, including compa-
10 to 16 years out, compared to $438K for the ninetieth per- nies such as Chase Bank, Bank of America, CitiGroup, Wells
centile woman.²² This study not only demonstrates the wage Fargo, and Goldman Sachs.²⁷ Creating new policies within
disparities but highlights unequal opportunities for career ad- businesses and enforcing them for their employees is an ef-
vancement due to limited access to high-paying positions. In fective solution by spreading awareness and promoting a new
addition to this, "men have a more aggressive and ambitious way of business and corporate culture. Some initiatives in-
approach to their careers, and they are more culturally biased clude “unconscious bias training, mentoring, and sponsorship
toward their own gender."¹¹,²³,²⁴ The gravitation toward one’s programs, and promoting a culture of inclusivity and equal op-
own gender explains the predominance of males in leadership portunities.”²⁸ Specifically, at JP Morgan Chase, the Women
positions and supports the claim that “gender stereotypes and on the Move Initiative has made tremendous improvements
homophily are the main explanation for the persistence of the toward gender equality and women’s representation. Formal-
glass ceiling and gender discrimination in career advance- ized in 2018, the program has since been able to offer over
ments.”²⁵ The high prevalence of men in the industry attracts 500 programs to eligible employees to support and accelerate
more men - and vice versa - the low prevalence of women their careers, and of these participants, 48% saw career mobil-
makes it difficult for women to emerge. In a case study, one ity in 2022.²⁹ By implementing female-centered policies and
interviewee stated that she was prevented from having a top programs as well as gender diversity workshops and seminars,
managerial position because the company did not hire women women can learn new skills to navigate the industry, develop
at that high level.¹¹ Women are not considered to be promoted an authentic leadership style, and create newfound confidence
to high leadership positions like their male counterparts. to excel.
Although women achieve a certain level of success in the Paid Child Daycare Services:
finance industry at very junior levels, they experience a “broken Childcare responsibilities negatively impact women’s careers
rung” on the promotion ladder and are “significantly less likely by forcing them to take time away from their jobs and dedicate
than men to be promoted” at the first step from entry-level less effort and time to work. Many financial companies have
to manager.³ Despite women getting higher performance rat- successfully implemented childcare services, including Gold-
ings on average and a 7.4% higher chance of getting the top man Sachs, which “offers numerous benefits geared toward
performance rating, women are still 13% less likely to get pro- helping employees balance work demands with family needs.
moted.⁹ Beyond entry-level positions, women are promoted to In addition to backup child care facilities, examples include
management positions at a significantly slower pace than men expectant parent seminars, transitional programs for employ-
and are looked at as less capable than men despite comparable ees returning from parental leave, and adoption stipends.”³⁰
statistics.⁵ “Within financial services, only 86 women are pro- One way to instill childcare services within corporations, is for
moted to manager for every 100 men.”³ Women face hiring businesses to partner with childcare providers such as Bright
biases, fewer promotions, fewer networking opportunities, and Horizons, “a top provider of company-sponsored child care
lower pay, with women earning less than men at every educa- services for thousands of organizations across the globe.”³¹ By
tion level.²⁶ connecting employees with childcare resources, Bright Hori-
Solutions for the Underrepresentation of Women in the zons helps “design, implement, and manage child care services
Finance Industry: to enhance workforce productivity.”³¹ According to Bright
This section discusses potential solutions to the barriers that Horizons, more than “90% of employees attribute child care to
impede women from succeeding in an industry dominated by their success at work” and similarly 79% of employees said that
men. they were “more likely to spend time at the office if utilizing
The underrepresentation of women is particularly nota- [an] on-site child care center.”³¹
ble in the finance industry compared to other sectors due to By implementing better-paid childcare services, women
deep-rooted negative systemic beliefs of women. The historic can focus on their jobs more, engender more respect in the
underrepresentation of women in this field has been an on- industry, earn more money, and reduce or eliminate the under-
going trend and only contributes to gender inequality. In all, representation of women in the finance industry. The employer
gender biases, lack of female mentors in the industry, heavy also benefits by potentially reducing turnover rates, increasing
and unequal childcare responsibilities, burdensome internal productivity, and having overall happier employees.
battles, and unequal opportunities can all be traced back to Pay Transparency:
how women are perceived. There are several measures that When completing the same tasks, working the same hours
companies can implement and have implemented to mitigate (in some instances more hours), performing at the same lev-
the biases against women to increase female headcount in the el, and being accredited with the same job title, individuals
finance space. The proposed solutions that follow are by no should be paid the same, regardless of gender. In an evaluation

DOI: 10.36838/v7i3.8 48
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of the gender wage gap using survey and administrative data, skills, qualities, and relationships to help them succeed in the
it was discovered that finance was among the top industries male-dominated field. A strong relationship between a mentor
with the highest wage gap where “women earned 70 percent of and mentee is crucial and must have the following elements:
men’s earnings, a 30 percent wage gap.”³² Some governments “reciprocity, learning, relationship, partnership, collaboration,
and global institutions have proposed reforms to reduce gen- mutually defined goals, and development."³⁷ Seeking assur-
der-based pay inequality, with pay transparency being central ance from women who have been successful in the finance
to such initiatives under the belief that pay transparency in industry is inspiring and provides hope for other aspiring busi-
itself can reduce an existing gender wage gap.³³ nesswomen. In a study analyzing components of an effective
Specifically, in the United Kingdom, “Exploiting the vari- "mentor-protégé" relationship, it was revealed that "specific
ation across firm size and over time in the application of the mentor-protégé behaviors and interactions, identified needs of
UK’s transparency policy, we show that increased transparency both protégé and mentor in the relationship, and desirable per-
leads to an 18 percent significant reduction in the gender pay sonal qualities of mentor and protég锳⁸ are key components of
gap.”³⁴ This significant reduction in the UK’s gender pay gap forming a fruitful mentoring relationship.
after introducing transparency policies shows the effectiveness Women in the financial industry have indicated that it is
of pay transparency measures and is an inspiring statistic for helpful to have female mentors, who can better understand
other countries to follow. One way to implement these pay and relate to the personal challenges of being a woman in the
transparency policies is through equal pay audits which “re- industry and who can discuss topics about which a woman
quire an analysis of the proportion of women and men in may not feel comfortable speaking to male mentors.³⁹ How-
different positions, an analysis of the job evaluation and classi- ever, due to limited female leaders in the financial industry,
fication system used, and detailed information on pay and pay it is challenging for women to find these mentors.³⁹ Despite
differentials on the basis of gender.”³⁵ Equal pay audits serve as this, various businesses have successfully increased their female
“the most comprehensive government strategy for using wage mentoring, such as Bank of America which “has been a pivotal
transparency to address gender wage gaps.”³⁵ partner in the development of the Cherie Blair Foundation for
Yet, despite measures designed to combat the gender pay Women’s Mentoring Program, which has now enabled over
gap in the finance sector, the problem persists today. One liter- 2,500 women entrepreneurs to access personalized support
ature study suggested that the predominant explanation of the through 1:1 mentoring and an online support and learning
persistently high gender pay gap in finance despite the imple- platform.”⁴⁰
mentation policies that target them is that talented women are Mentorship programs that might be most effective would be
less likely to be employed in the financial sector compared to a formalized program that pairs someone with a mentor after
“skilled male employees sorting relatively more into finance.”³⁶ considering their mutual background, personalities, and shared
The authors “hypothesize that this sorting effect is due to the interests. In addition, some women at the junior/entry level
fact that working in the finance sector might be costlier for prefer to be paired up with a mentor, as opposed to fending for
talented women” in terms of the sacrifices borne on women themselves to find one, and more structured programs “make
when compared to their equally qualified counterparts.³⁶ The it easier for one’s transition to the firm at the entry-level and
demanding, long hours typically associated with employment help newer employees develop relationships in an unfamiliar
in the finance industry act like a natural barrier for talented setting.”³⁹
women entering this field. Women most often assume primary Additional Discussion:
responsibility for child-rearing to the detriment of their ca- No findings in this study were particularly shocking or
reers. This usually results in a higher number of talented males unexpected, but when examining our discussed data, it is im-
entering finance receiving stronger performance reviews than portant to acknowledge the impact of surrounding factors
less skilled females entering the field holding similar positions. such as geographic location. Depending on the country and
The finding of the study suggests higher social costs associated economic stability, the leading causes can differ, as well as the
with working in the financial sector for women than for men extent to which possible solutions will be successful. For exam-
act like barriers to equally talented women entering finance. ple, less developed countries may not have the financial means
The authors found that women are more likely to be attract- to implement possible solutions such as paid childcare services.
ed to occupations offering more flexibility and a better overall Despite these factors, our study and main takeaways remain
work-life balance than the finance sector demands. Neverthe- valid as they apply to many different locations and are relative-
less, while parity between women and men remains elusive, ly universal across countries.
skilled women have been increasingly entering the financial Expanding the study to include racial or LGBTQ under-
sector over time relative to men, and the pay gap is narrowing, representation in the financial industry could be valuable for
helped by the implementation of pay policies designed to level future studies. Doing so would reveal unique barriers and raise
the playing field.³⁶ By requiring companies to be clear about more awareness of inequality in the finance industry. Based on
their compensation practices, they will be forced to self-adjust database searches, there has not been a significant amount of
their policies to be more fair and equitable toward women. studies conducted on these particular groups. Another recom-
Increased Female Mentoring: mendation for further studies is to analyze different countries
By having more women serve as role models in the indus- worldwide and their experiences with the underrepresentation
try, such as mentors and sponsors, females can acquire specific

49 DOI: 10.36838/v7i3.8
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of women in finance. It would be interesting to compare other A Global Assessment. Deloitte Insights. https://www2.deloitte.c
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� Author
Emilie Kassis is a 12th grader at Madison High School. This
literature review was inspired by her experience working in a local fi-
nancial advisory firm where she witnessed unequal participation rates
of women. Emilie is interested in studying business in college.

51 DOI: 10.36838/v7i3.8
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REVIEW ARTICLE

Parenting Styles, ACEs, & Neurobiological Effects on

Attachment Styles for High-Functioning ASD Children
Fengqi Wang
Annie Wright Schools, 827 N Tacoma Ave, Tacoma, Washington, 98403, United States; [email protected]

ABSTRACT: Autism Spectrum Disorder (ASD) affects 1 in 36 children in the U.S. This disorder causes symptoms such
as having trouble making social connections with others, and this ability is important in making secure attachment styles with
caregivers. This study examines parenting styles, adverse childhood experiences (ACE), and neurobiological processing to find
their impacts on children aged 7-11’s ability to form secure attachment styles. How do parenting styles, adverse childhood
experiences, and neurobiological differences for middle-childhood children with High-Functioning ASD affect the creation of
a secure attachment style? It is found in this paper that authoritarian, permissive, uninvolved, and inconsistent parenting styles,
a high number of ACEs, and neurobiological abnormalities can cause children with ASD to have difficulty forming secure
attachment styles with their caregivers.
KEYWORDS: Clinical and Developmental Psychology, Neuroscience, Autism, Attachment, Parenting, Adverse Childhood
Experiences.

� Introduction disorganized children. Secure attachment is when the child

People with Autism Spectrum Disorder (ASD) frequent- shows distress when the caregiver leaves and happiness when
ly exhibit symptoms listed in the Diagnostic and Statistical returned. Insecure-avoidant children showed little reaction to
Manual of Mental Disorders (DSM-5) published in 2013, a whether the caregivers left or returned. The insecure-ambiva-
manual developed by the American Psychiatric Association lent children showed high distress when the caregivers left and
and used by medical professionals to diagnose mental disor- were not easily soothed after their return. The disorganized
ders. Autism Spectrum Disorder shows they are as follows: 1) children showed odd behaviors such as approaching the care-
Having trouble interacting and communicating with others, 2) giver but then stopping or wanting comfort but also showing
limited passions and habitual actions, and 3) symptoms that fear towards the caregiver (Table 1) found by Salter Ainsworth,
impair their capacity to perform in their job, education, and 1984.⁴
other spheres of life.¹ ASD is a spectrum disorder because it Table 1: Convergence and divergence between reactions of different
appears in different severity and symptoms. DSM-4, which attachment styles in children for the Strange Situation experiment.
was published in 1994, did not categorize all autism disor-
ders into one called ASD. Otherwise, there were five forms of
autism, and one of them was Asperger’s Syndrome. Asperger
Syndrome | Autism Speaks, n.d. proves It was a milder ver-
sion of Autism Disorder, and now it would be categorized as
Level 1 ASD or High-Functioning ASD using the DSM-5.²
Attachment Theory sparked from attachment behavior, which
is the tendency for infants to want to be in close proximity to
their primary caregivers. According to the Attachment Theory
developed by Bowlby et al., this bond will influence the child’s
emotional and social development, and whether this is formed These attachment styles are directly related to attachment
will impact the child’s future in their ability to form healthy representations, which is the way that individuals develop and
interpersonal relationships.³ Mary Ainsworth conducted the form emotional relationships and how it affects their sense of
“Strange Situation” experiment in the 1970s, an observational self and others found by Winnie Lau & Candida C. Peterson,
study to assess attachment styles. The infants were left alone n.d.⁵ Gallitto & Leth-Steensen shows that many adults with
in a room, left with a stranger in a room, and then reunited Asperger Syndrome have an insecure avoidant attachment
with the caregiver. This experiment found children with four style, and ones with autistic traits have less emotional closeness
types of attachment styles: securely attached children, inse- with their romantic partners in a non-clinical setting with a
cure-avoidant children, insecure-ambivalent children, and positive relationship between autistic traits and attachment
© 2025 Terra Science and Education 52 DOI: 10.36838/v7i3.9
 ijhighschoolresearch.org

avoidance.⁶ Although there are several pieces of research on influence of culture on attachment styles. Culture influenc-
preschool children with ASD and the effects of different at- es parenting styles, which then influences attachment styles.
tachment styles on their future interpersonal relationships, There are four types of parenting styles: Authoritative, author-
there are a few research gaps that this paper aims to fill, as itarian, permissive, and uninvolved. Authoritarian parenting
stated in papers by McCarthy, R.M. Pasco Fearon & Roisman, is often telling the child to listen just because the parent “said
and Aber & Allen.⁷-⁹ There is little research on the effect of so,” and the child needs to obey the parents’ strict rules. Per-
late childhood attachment representation, the impact of ad- missive parenting is giving space for the child to explore on
verse childhood experiences, the impact of parental influences, his/her own, giving limited rules. Uninvolved parenting is ful-
and the neurobiological and sensory processing effects on at- filling the child’s basic needs but not being involved in any
tachment styles of children with ASD through research by way otherwise. Authoritative parenting is the parenting style
Giannotti & de Falco, 2021.¹⁰ Therefore, the research question that is considered the most effective for establishing a secure
is produced: How do parenting styles, adverse childhood expe- attachment with the child. Appropriate amounts of rules are
riences, and neurobiological differences for middle-childhood established, and disciplinary methods are taken instead of
children with High-Functioning ASD affect the creation of a merely punishment without reason, as stated in Sanvictores
secure attachment style? & Mendez.²⁰ Lastly, not included above, there is also incon-
� Research Group sistent parenting, which includes a combination of the above,
As children enter elementary school, they are exposed more with different parenting styles performed by the caregiver or
to the outside world as they make friends and speak to others multiple caregivers. Through reviewing studies on parenting
who do not have the same background. A typical child during styles for children with ASD in different cultures, it is found
the concrete development stage should be able to develop by O’Nions et al., that in the United Kingdom, the most used
self-reliance, responsibility, cognition, and emotional regula- parenting styles include Accommodation, Reinforcement Ap-
tion found by Brumariu & Kerns, Bosmans, G. & Kerns, K. proaches, and Reducing Uncertainty.²¹ Accommodation is
A., and Brumariu & Kerns.¹¹-¹³ This creates a fundamental the action of the parents changing their behavior or the en-
difference in their attachment styles. Ainsworth reports they vironment that the child is in to reduce the child’s distress.
go from proximity as an infant to availability during middle For example, the parent can hold the child in place when the
childhood.¹⁴ It is vital for children this age that their parents child is externalizing behaviors. This is influenced by child be-
are available to act as a haven for them, and they do not need havior, often because the child is rigid in socialization. Using
to be near their primary caregivers to be securely attached. rewards to encourage positive behavior is called Reinforce-
According to Piaget’s developmental theory, they are in the ment Approaches, and this is not influenced by child behavior.
Concrete Operational stage (age 7-11 years old). The children For example, the parent can give the child a piece of candy
at this stage should be able to develop cognitive skills related to after the child uses his/her words to communicate with the
“understating, comprehending, analyzing, synthesizing, evalu- parent. The parenting style/strategy of Reducing Uncertainty
ating, and differentiating between two objects.” As stated in is producing consistency in the parents’ actions and allowing
Rachana Maurya & Khan.¹⁵ Kids with ASD have trouble with the child to feel secure. This is influenced by the child’s behav-
these skills, such as conservation of liquid and number, classifi- ior. These three parenting strategies can be categorized into
cation, and spatial reasoning. Moreover, they also have trouble authoritative parenting styles. On the other hand, in Ameri-
forming secure attachments with their parents/caregivers due can and Asian cultures, poor child executive functioning leads
to their lack of social abilities. Williams shows that 47-53% to authoritarian and permissive parenting, so authoritarian
of children with autism are securely attached, compared to parenting is often used. In a study conducted in the United
65% of ones without ASD.¹⁶ They possess difficulties with States, a questionnaire study showed more parenting stress
social performance, such as eye contact, repetitive behaviors, and a greater use of permissive parenting compared to typical-
and the impaired ability to relate to others, as proved by the ly developing children. Hutchison et al. state, “Authoritarian
HEALIS AUTISM CENTRE.¹⁷ Children should become and permissive parenting styles were associated with poorer
more socio-centric and focused on others at this stage. Autism child executive functioning”.²² Through reviewing three stud-
Diagnostic Criteria.¹⁸ says this tends to be more difficult for ies conducted in Asia (Indonesia, Hong Kong, and Taiwan), it
children with ASD because there is an impairment in forming is found that the authoritarian parenting style is the most used
social bonds. in these countries. In Indonesia, 101 families with children
Parental Impacts on Attachment Styles: with ASD were surveyed in the study by Yulina Eva Riany et
Lanjekar et al. prove it is commonly known that parenting al., and they reported greater use of authoritarian parenting
styles have a large impact on the development of a child.¹⁹ compared to families without children with developmental
These parenting styles are often associated with cultural influ- delays. ²³ In Hong Kong, forty-five parents were surveyed and
ences, but it is not always. The cultural influences, for example interviewed by Kathleen Tait et al. about their experience with
in Asian culture, Confucianism is a common religion. In Con- their children with ASD, and it was found that they often feel
fucianism, children are obligated to perform “Xiao,” which is embarrassed about their children having developmental delays
reciprocating the care that the parents give to the child. This and ASD. Hutchison et al. prove that parental stress leads to
heavily influences the parenting style, which changes the at- more authoritarian parenting, therefore. Hong Kong parents
tachment style the child forms. However, there is no direct are also more likely to perform authoritarian parenting

53 DOI: 10.36838/v7i3.9
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styles.²⁴,²⁵ In Taiwan, 151 children were recruited, and results 40 studies of 5,619,584 participants by Hartley et al. found an
show the ones with more behavioral problems received less overall average Odds Ratio (“an OR > 1 means greater odds of
affection and more overprotection and authoritarian control association with the exposure and outcome” as stated by Smith
from their parents than the children without ASD, as found 2018) of 2.11 of the relationship between a diagnosis of autism
by Susan Shur‐Fen Gau et al.²⁶ These parenting styles have and ACEs.³³,³⁴ Hoover & Kaufman show that children with
different impacts on children with ASD. For one, Chao states ASD get bullied by peers at a rate 3-4 times compared to chil-
authoritarian parenting styles cause children to externalize be- dren without autism.³⁵ This hurts the academic and mental
haviors.²⁷ That means that the children are displaying more health of ASD children. Moreover, ACEs like parental divorce
bad behavior, for example, aggression, rule-breaking, etc. They and income insufficiency occur often for children with ASD
also display lower emotional regulation and the ability to adapt because of the large amount of money that needs to go towards
to stress. This impacts their future interpersonal relationships therapy. Hoover & Kaufman say this often causes comorbid
because they tend to be more shy, socially inept, and unable to psychiatric and mental health problems for these children.³⁵
make their own decisions, as proved by Sanvictores and Men- Through reviewing three articles on the effects of ACE, it is
dez.²⁸ Permissive parenting also has the same impact, with found that they cause large amounts of externalized behavioral
children exhibiting externalized behaviors. They have some problems. The age of the children studied ranged from 3-18,
self-esteem and decent social skills, but they can be impul- with the majority in elementary school. One study done in 4
sive, demanding, selfish, and lack self-regulation. Inconsistent southwestern United States elementary schools showed that
parenting creates a disorganized-insecure attachment style for the “number of ACEs was able to predict 100% of the variance
children, especially children with ASD. Feuerman argues they in social-emotional competencies and 98% of [the] variance
tend to become more untrusting and show more inconsistent in behavioral problems.” Moreover, the amount of ACEs also
behaviors.²⁹ negatively correlates with social-emotional competencies and
positively correlates with the number of behavioral problems
that are reported by parents as found by Ray in 2020.³⁶ An-
other study done by Choi et al. for children aged 3-16 who are
seeking primary care and mental healthcare services in Chi-
cago, Illinois did a 28-item version of the Traumatic Events
Screen Inventory and the results showed an OR of 2.93 for
emotional abuse or neglect, 3.89 for natural disaster, 2.95 for
forced separation from a parent or caregiver, 2.43 for incar-
ceration of a family member, 2.84 for physical attack, and
2.35 for community violence.³⁷ However, after adjusting for
Figure 1: Brain regions with reduced surface area are associated with
inconsistent parenting. the overall ACE level, only 1 item remained statistically sig-
nificant: forced separation from a parent or caregiver (OR of
Inconsistent parenting style also alters brain development, as 2.44). A study done on 845 children from primary to high
longitudinal magnetic resonance imaging by Whittle showed school found a higher emotional intelligence correlated with
a decrease in surface area in medial parietal and temporal pole higher well-being and resilience, and “a negative correlation
regions and reduced cortical thinning in medial parietal re- between experiencing difficult situations, students’ well-be-
gions (see Figure 1).³⁰ This affects the development of neural ing, and the level of resilience they reported.” Then a T-test
circuits that subserve sensorimotor and social functioning in was done to find which factors influenced well-being and
children. resilience the most. The results showed violence from family
Therefore, it makes creating secure attachment difficult for and colleagues and parental divorce had the largest impact on
children with ASD because it harms the ability to function well-being, while family violence, famine, and violence from
socially, including with parents. colleagues had the largest impact on resilience. These effects of
Adverse Childhood Experiences (ACE) Impacts on ASD are important because it was originally difficult for chil-
Forming Secure Attachment Styles: dren with ASD to form secure attachments, as shown earlier
Adverse Childhood Experiences include “experiencing vi- in this paper. More research shows that although they show
olence, abuse, or neglect, witnessing violence in the home or a range of attachment behaviors that are similar to children
community, witnessing violence in the home or community, without ASD, “they displayed impairments in the use of the
having a family member attempt or die by suicide, or growing caregiver as a secure base and co-regulating agent”, supported
up in a household with substance use problems, mental health by Keenan et al.³⁸ This is because they have impairments in
problems, instability due to parental separation, or instability”, forming social bonds, specifically having trouble making eye
stated in About Adverse Childhood Experiences | Adverse contact, turn-taking, conversation, joint attention, and other
Childhood Experiences (ACEs) | CDC.³¹ ACEs are more aspects of interpersonal relatedness. This heavily impacts the
prone for children with ASD, as outlined by CDC.³² This is attachment style because these social bonds are essential for
because they are more likely to be bullied at school because secure attachment. On top of this difficulty for children with
of their difference, which adds stress for parents and causes autism to form secure attachment styles, ACEs further com-
parents to react impulsively under pressure. A meta-analysis of plicate the process because ACEs decrease social-emotional

DOI: 10.36838/v7i3.9 54
 ijhighschoolresearch.org

competencies, increase levels of cortisol (the body’s primary be able to explain how the children tend to grow up to be more
stress hormone), and decrease the child’s overall well-being, socially inept or unable to self-regulate, either because of their
found by Coan.³⁹ challenges to form secure attachment with their caregivers or
Neurobiology Processing Effects on Secure Attachment: because of their biological differences. For future studies, it
Children with ASD have structural abnormalities in the is important to consider that the results of empirical studies
brain compared to children without ASD, and this can severe- may not be accurate because of the confounding variables that
ly impact the formation of secure attachment. A child with might influence the results. For this study, the same applies be-
ASD’s brainstem, cerebellum, and limbic system, including the cause the three factors compared in this study cannot control
amygdala and the cortex, have abnormalities. Specifically, the variables that were done in the studies that were analyzed. For
amygdala shows abnormal developmental patterns, including example, when researching the neurobiological differences, the
the frontal and prefrontal lobes responsible for executive func- parental influences cannot be controlled in the studies that
tions and social cognition. These abnormalities are linked to were analyzed. Moreover, there is a need for more longitudinal
social isolation. The structural MRI shows consistent findings studies to find the actual impacts of parenting styles, adverse
of early brain overgrowth, specifically in white matter and the childhood experiences, and neurobiological differences on the
amygdala during a child with ASD’s first few years as proved attachment styles/representations of children with ASD. The
by Parici et al.⁴⁰ When comparing the structural abnormalities existing cross-sectional studies may not successfully show the
of the brain of a child with ASD to the parts of the brain that precise impact the three factors that the children with ASD
need to be activated for secure attachment, it is found that experience during their childhood have on their future. There
there are many overlaps. For example, secure attachment needs can only be a prediction of what impacts the experiences and
the anterior cingulate cortex, the prefrontal cortex, and the neurobiological factors have. A large number of longitudinal
hippocampus. These three parts of the brain are all included studies with the same results can reveal the true relationship
in the limbic system, which a child with ASD has abnor- between the factors and the attachment representations, which
malities in, as shown. Moreover, the striatum and amygdala can impact their quality of life due to the number of healthy
are activated in secure attachment, as found by Vrticka et al., relationships that can be built.
and “Securely attached children showed greater activation in � References
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uman Amygdala and Striatum Activation during Social Appraisa
l. PLoS ONE, 3(8), e2868–e2868. https://doi.org/10.1371/journ
al.pone.0002868
42. Choi, E. J., Taylor, M. J., Hong, S.-B., Kim, C., & Yi, S.-H. (2018
). The neural correlates of attachment security in typically develop
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1016/j.bandc.2018.04.003
� Authors
Fengqi Wang is a 12th grader at Annie Wright Schools. She is
interested in psychology, studying children with ASD. Volunteering
at the Huiai Integrated Childrens’ Development Center, she became
acquainted with the VB-MAPP assessment guidelines for ASD. She
realized it needed factoring in variables like home conditions and de-
velopmental differences.

57 DOI: 10.36838/v7i3.9
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RESEARCH ARTICLE

Effects of Obesity on Human Health and the Emerging Role of

GLP-1 Based Therapies
Gauri Bansal
Winchester High School, Winchester, Massachusetts, 01890, USA; [email protected]

ABSTRACT: Obesity is a chronic disease whose effects are growing daily. The effects of the disease spread through the entire
body, making it one of the leading causes of death internationally. Recent drug discoveries have found new pathways in the
gastrointestinal tract that can be targeted to promote weight loss and reduce the effects of obesity on the population. This is a novel
addition to the current weight loss treatments. This paper will review the biological mechanisms behind Glucagon-like peptide-1
(GLP-1) based therapies and their effects on obesity treatment. We will begin by discussing the emergent need to research the
field of obesity through a global health lens. We will discuss the economic impacts as well as the causes and effects of this disease.
Then, we will discuss the current treatment landscape, addressing any disparities and drawbacks with current treatment options.
Following this the paper will go in-depth about different gastrointestinal hormones, such as GLP-1, GIP, and Glucagon, being
used to treat this chronic disease. This article is intended to give an overview of GLP-1-based therapies and the effect it has on
various biological activities relating to obesity.
KEYWORDS: Transitional Medical Sciences, Disease Treatment and Therapies, Obesity, Endocrine system, GLP-1,
Weightloss.

� Introduction news outlets like the New York Times and NPR have written
Obesity is one of the most prevalent diseases worldwide. This articles about the obesity epidemic that the world is confronted
chronic illness is characterized by an excess accumulation of with. Obesity is now a major global public health issue. This has
adiposity, which can arise from a long-term excess of positive led to research and investment from scientists and the govern-
energy intake over expenditure, driven by a complex interac- ment to develop strategies to prevent and treat this burgeoning
tion between the Endocrine System and the Central Nervous epidemic. One newly emerging treatment for obesity comes in
System. The World Health Organization categorizes a person as the form of peptide drugs, working to mimic the role of es-
overweight if their body weight is above the ideal range where sential hormones such as Glucagon-like peptide-1 found in the
their Body Mass Index (BMI) is between 25 and 30, while a digestive system. Part of its revolutionary essence is due to the
BMI greater than 30 is considered obese. Moreover, a study strong results it yields and the vast room for further develop-
done by WHO showed that 2.5 billion adults are overweight, ment.⁵ It is currently one of the most prescribed drugs on the
and 890 million people suffer from obesity. Since the 1990s, the market and is steadily growing in popularity.
number of adults with obesity has doubled, and the number of
adolescents with the disease has more than quadrupled.¹ The
effects have found that close to 2.8 million people die each year
due to obesity-linked diseases.² Many countries with rising
Gross Domestic Product (GDP) and socioeconomic situations
are seeing a rise in obesity rates as the increasing income of
the population allows them to purchase greater amounts of
energy-dense food. Economic growth leads to an increase in
overweight and obesity in developing countries, where a 1%
increase in income leads to around a 0.2 and 0.3% increase in
overweight and obesity prevalence.³ The World Health Or-
ganization's research further indicates that in countries with
income in the upper to high-income ranges, 20-30% of the
population have obesity, as seen in Figure 1. In contrast, low-
er-income countries see a much lower percentage, around 10%.
It has become clear that as the world becomes more affluent,
so does the number of people with obesity.⁴ World-renowned

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Figure 1: Counties Average Income Versus the Percentage of Obesity in the of adiposity are vastly influenced by controllable and uncon-
Nation. This figure depicts the prevalence of obesity across countries with
varied income levels, showing higher obesity rates in upper and high-income
trollable factors, but the effects of inflammation in the gut are
countries compared to significantly lower rates of obesity in low-income pernicious.
countries. The figure visually highlights the relationship between a nation's Diseases Linked to Obesity:
economic status, measured by the average income made by families in the Obesity leads to various complications, such as diabetes, car-
nation, and the proportion of the country affected by obesity. Adapted
from Bhurosy, T., & Jeewon, R. (n.d.). Overweight and obesity epidemic in
diovascular diseases, and even some types of cancers, which
developing countries: a problem with diet, physical activity, or socioeconomic lead to high mortality rates. The correlation between high
status? Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/ adiposity and inflammatory cytokines is high since when ex-
PMC4212551/. Created by Canva. cess nutrients are in the system, adipocyte cells release more
Genetic Links to Obesity: cytokines such as IL-6, TNFα, C-reactive protein (CRP), IL-
Over the past two decades, there have been studies that 18, resistin, and visfatin. ¹⁴ These cytokines affect many of the
have found that there are polymorphisms and genetic muta- body's organ systems and cause cellular function deterioration
tions that cause a predisposition for being overweight. Genetic due to their signaling power. Cytokines are proteins that move
conditioning of obesity has created three different types of chemicals and send signals to the immune system. An excess
obesity: monogenic, polygenic, and syndromic. ⁶ of cytokines can lead to autoimmune disorders, causing the
Monogenic obesity is caused by a gene mutation that alters body to attack its healthy cells.¹⁵
the leptin-melanocortin pathway.⁷ The leptin-melanocortin Heart disease, in any form, whether that be heart attacks,
system (LMS) exerts major control on appetite and insulin heart failure, or angina (chest pain due to a lack of oxygen-rich
production. Leptin is an appetite-controlling hormone that blood), can be exacerbated by obesity. This is due to raised
is secreted by adipocytes and β-cells. It is signaled to the me- levels of leptin, which causes high blood pressure, or overcon-
lanocortin 4 receptor (MC4R). This is how the signal crosses sumption of food, which causes lipid abnormalities.¹⁶
the blood-brain barrier and promotes a sense of satisfaction Some forms of cancer have been linked to obesity, as the
in the body. People with high levels of fat cells can eventually disease is caused by the abnormal and uncontrolled growth of
develop leptin resistance, which signals to the hypothalamus cells in the body. Adipose tissue is a known producer of es-
that the body still needs food.⁸ Monogenic mutations cause trogen, high levels of which have been seen to cause breast
severe obesity starting at a young age and feature hyperpha- cancer.¹⁷ Additionally, obese women are at an increased risk
gia (extreme hunger). A medication called Setmelanotide is for developing cancers of the endometrium (uterine lining)
an MC4R agonist that has been found effective in managing and gallbladder, while obese men have higher susceptibility
the symptoms of monogenic obesity as it helps promote sat- to cancers of the colon, rectum, and prostate.¹⁸ These risks
isfaction signaling in the body.⁹ Polygenic obesity is caused are partly due to the inflammatory processes associated with
by simultaneous genetic mutations that have a conglomerative visceral fat, which can disrupt hormone regulation and al-
effect on the body. Some of the common mutations include ter cellular life cycles, increasing the likelihood of malignant
that in the minor alleles of the polymorphisms coding for transformations.¹⁹
isoleucine instead of valine at amino acid position 103 (103I) Many studies have shown that people affected by obesity
and for leucine instead of isoleucine at position 251 (251L) of are at greater risk of developing Type 2 Diabetes (T2DM).
the receptor protein are negatively associated with obesity.¹⁰ T2DM is caused by multiorgan insulin resistance in parallel
Many of these genes affect the insulin cycle in the body and with β-cells secreting less insulin. β-cells in the pancreas typi-
play a part in the nervous and digestive systems. Each muta- cally secrete insulin directly to the portal vein, which travels to
tion causes a small effect, but their build-up can harm the body the liver effectively to control the liver’s glucose metabolism.
in the wrong environment. Syndromic obesity is characterized People with obesity typically have an impairment in the abil-
by developmental disorders, often caused by disruptions in ity of insulin to suppress liver glucose production. Increased
neurodevelopment, and involves a variety of genes and biolog- liver glucose production occurs when the increased secretion
ical pathways that can cause dysmorphic features¹¹ and organ of insulin is inadequate to compensate for insulin resistance.²⁰
abnormalities.¹² Since there are so many different combina- Obesity and T2DM also have adverse effects on liver fat
tions of genetic factors that can make a person predisposed to metabolism and are a major cause of fatty liver disease. In fact,
obesity, there is a lack of drugs targeted at genetics to solve this around two-thirds of adults with either obesity or T2DM are
issue. Instead, Researchers are working to tackle obesity using diagnosed with nonalcoholic fatty liver disease (NAFLD),
drugs that mimic hormones found naturally in the body.⁸ largely due to an increase in triglyceride production.²¹
Other factors also contribute to obesity, including physical Circulating insulin also plays a crucial role in the movement
inactivity, excessive caloric intake, and intrauterine develop- of glucose into the cells, enabling the formation of ATP mol-
ment.⁷ Previous research about obesity showed that the disease ecules that can be used as energy in the body. Obesity leads to
was a simple imbalance of energies, meaning more calories insulin resistance, so the circulating insulin cannot act upon
were going in than out. However, the energy-based model of the cells effectively. This inhibits the entry of glucose into cells,
obesity was quickly disproven as scientists developed the car- which are depleted of energy, and a rise in blood glucose levels,
bohydrate-insulin model. This model shows how the digestion resulting in diabetes. While initially, insulin resistance results
of carbohydrates, through the production of insulin and hor- in a compensatory increase in insulin secretion, the pancreatic
mones, can cause an increase in fat deposits.¹³ Excess levels β-cells ultimately become exhausted. This leads to a combina-

59 DOI: 10.36838/v7i3.10
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tion of insulin resistance and deficiency, resulting in progres- One of the most effective treatments that is available for obe-
sively worsening diabetes.²² sity, and consequently diabetes, is bariatric surgery. There are
People with higher numbers of adipocytes have the metabol- several types of bariatric surgery. In one popular method, the
ic flexibility to adjust to changes in energy balance. They can surgeon divides your small intestine and connects the shorter
adjust to more long-term changes in energy balance, and adi- part to the stomach. In turn, the body will absorb less calories
pose tissue can expand or shrink accordingly. Studies suggest from the food. This surgery also changes the hormonal levels
that excess abdominal fat causes fat cells to release ‘pro-inflam- and bacteria in the digestive system, which affects metabolism
matory’ chemicals, which can produce insulin resistance. Thus, and appetite. Patients who have received this surgery can see
having excess abdominal fat (i.e. a large waistline) is known as results that show immediate stabilization of insulin levels, re-
central or abdominal obesity, a particularly high-risk form of sulting in diabetic markers such as blood sugars returning to
obesity.²³ normal range. This surgery is also reversible if needed.²⁶
Obesity is a disease with widespread impacts across multi- Drugs with high lipophilicity (highly soluble compounds
ple physiological systems, including the nervous and muscular that have permeate properties allowing them to transfer
systems, as illustrated in Figure 2 below. This comprehensive through the body effectively)²⁷ can be used as a treatment for
influence on the body's systems underscores the importance of obesity because they function as lipase inhibitors. Lipase is an
targeted medical interventions, which hold significant poten- enzyme responsible for breaking down fats in the digestive sys-
tial to improve quality of life and long-term health outcomes. tem. By inhibiting lipase, these drugs reduce the fat absorbed
from the diet. So, when a drug with high lipophilicity acts as
a lipase inhibitor, it can effectively reduce fat absorption in the
intestines. This means that less dietary fat is absorbed into the
body, which can help reduce overall calorie intake and promote
weight loss. The inhibitors use a compound called tetrahydro-
lipstatin, which disrupts the body's process of breaking down
triglycerides. Many gastric lipases found locally in the stomach
and the small intestines covalently bond with the compound,
restricting triglyceride from breaking down into fatty acids. ²⁸
Role of Gastrointestinal Hormones :
Hormones in the Gastrointestinal Tract (GI) play a pivot-
al role in controlling insulin and glucose actions. In response
to food intake, Glucagon-like peptide-1 (GLP-1) is released,
Figure 2: Effects of Obesity on Different Body Systems. This figure
stimulating insulin secretion and regulating blood glucose
highlights the extensive health risks associated with obesity, showcasing levels by delaying gastric emptying, which maintains a steady
its impact on multiple organ systems. The figure underscores the supply of nutrients and glucose to the bloodstream, creating
systemic nature of obesity as a chronic illness and its role as a major glucose homeostasis. This helps control postprandial (post-
contributing factor to a wide range of comorbidities. Created by Canva and
Biorender, information gathered by https://pmc.ncbi.nlm.nih.gov/articles/
meal) glucose levels and promotes satiety, thus limiting further
PMC3096264/ food intake.²⁹ GIP and GLP‐1 promote β-cell proliferation
and inhibit apoptosis (cell death), thereby increasing pancreat-
Current Treatment Landscape: ic β-cell mass. GIP enhances postprandial glucagon response,
Due to the detrimental effects of excess fat on the body, re- while GLP‐1 suppresses it. In adipose tissues, GIP but not
searchers have worked to create and test drugs and strategies GLP‐1 facilitates fat deposition.³⁰ The final essential protein
since the 1990s that assist individuals in reducing weight and in the GI tract is glucagon, which signals the liver and muscle
subsequently decreasing their risk of certain illnesses. Many of cells to convert the stored glycogen back into glucose.³¹ Drugs
these drugs have different mechanisms of action, so patients that use these pathways are very effective in weight loss and
can take the drug most appropriate to their situation. T2DM treatments.
A major function of weight loss treatments is appetite sup- GLP-1 Therapeutics:
pression. Drugs such as Benzphetamine stimulate the nervous GLP-1, an incretin hormone, stimulates insulin secretion
system, specifically the hypothalamic and limbic areas of the after food is consumed, delaying gastric emptying.³² Gastric
brain, which together control satisfaction while also increasing emptying is the process of food moving from the stomach into
the amount of energy used by the brain. These medications are the duodenum, ensuring that the nutrients and glucose con-
typically prescribed alongside a reduced-calorie diet and daily sumed are delivered through the digestive system in a limited
exercise. These are prescribed more for short-term use due to and consistent way. By slowing gastric emptying rates, GLP-1
their addictive nature.²⁴ Historically, obesity was seen as only produces a lingering sense of fullness in the stomach and re-
a cause of overeating with little to no pathological ties, which strains further food intake. Gastric motor functions are also
is why drugs that have previously been approved to fight the impacted by acute changes in blood glucose levels. There is an
disease are used short-term. These drugs have dosing that will inverse relationship between blood glucose levels and the rate
last around 12 weeks, which is about the time it takes to build of gastric emptying. During hyperglycemia (high blood sugar),
a new habit.²⁵

DOI: 10.36838/v7i3.10 60
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GLP-1 is secreted, and gastric emptying slows down, thus pre- ously, allowing rapid absorption into the bloodstream, with
venting further movement of glucose into the bloodstream.³³ peak concentrations reaching within hours. Once absorbed,
In addition, GLP-1 can inhibit glucagon production from GLP-1 RAs exhibit a low volume of distribution, meaning
the α-cells in the pancreas. If blood glucose levels are out of they primarily remain within the bloodstream, which is critical
normal range, the presence of glucagon helps ensure they drop for their targeted effects. These medications selectively bind to
back to normal levels. Glucagon triggers the liver to convert GLP-1 receptors located in tissues involved in glucose regula-
stored glucose into a usable form and release it into the blood- tion. Their ability to remain concentrated in the bloodstream
stream by a process called glycogenolysis.³⁴ A summary of and selective binding allows the drug to yield effective results.
these processes can be seen in Figure 3. The various mecha- Native GLP1 is naturally broken down in the body through
nisms of GLP-1 can be used to decrease caloric intake and various pathways. Enzymes such as Dipeptidyl Peptidase-4
stabilize energy creation in the body, helping reduce weight. (DPP-4) and Neutral Endopeptidase (NEP) have proven to
As seen previously, there is a clear link between T2DM and play roles in this metabolic process, leading to the formation of
Obesity. Many T2DM treatments currently on the market are smaller, biologically inactive fragments that are subsequently
revolutionary since GLP-1 targets both the stabilization of eliminated. The drug semaglutide is resistant to the action of
blood sugar and a decrease in appetite. the DPP4 enzyme. Being a polypeptide, it is metabolized into
Drugs like semaglutide, available by the brand names Ozem- individual amino acids by serum and tissue proteases, ensur-
pic® and Wegovy®, are GLP-1 receptor agonists (RA) that ing complete breakdown without residual active metabolites.
mimic GLP-1 and can activate GLP-1 receptors.³⁵ For obe- The kidneys play a pivotal role in clearing GLP-1 medications
sity, these drugs have been shown to cause substantial weight from the body, and the rate of renal excretion significantly in-
loss, often about 15% of one's body weight. This amount is fluences their duration of action and dosing frequency. Unlike
drastically more than other weight loss techniques and medi- other GLP-1 medications, Semaglutide stands out due to its
cation used in the past to battle obesity.³⁶ More importantly, extended-release (ER) profile, which provides a significantly
this class of drugs has been seen to lower both systolic and dia- prolonged half-life compared to shorter-acting formulations
stolic blood pressure while also decreasing total cholesterol, all like Exenatide.³⁷
of which assist in shielding the body from heart disease caused Blood-Brain Barrier:
by excess adipose tissue. Native GLP-1 has been found in the Central Nervous
Some additional functions of GLP-1 drugs include increased System (CNS), showing that the hormone and the drug rep-
glucose intake in muscle cells, decreased glucose production in licating it also have the power to pass the Blood Brain Barrier
the liver, and increased neural satiety due to stimulation of the (BBB). BBB is a selective semipermeable membrane between
hypothalamus.³⁷ the blood and the interstitium. It is comprised of capillary cells
Mechanism of action covered by various connective tissues such as tight junctions,
basal lamina, pericytes, and tightly packed astrocytes. Tight
Junctions (TJs) restrict the movement of substances through
the paracellular aqueous diffusion pathways between adjacent
endothelial cells. Their adhesive properties function to seal
microvessels, thereby limiting the passive diffusion of proteins
and polar solutes. Pericytes, located in the capillary basement
membrane, play a crucial role in angiogenesis, supporting the
formation and stability of blood vessels. They contribute to
microvessel integrity by regulating endothelial cell function,
promoting the formation of TJs, and controlling vascular per-
meability. Astrocytes are types of Glial cells found on the axon
of neurons and allow for the passage of informational signals.
This assists in regulating material passing between nerves and
blood vessels that ultimately connect the brain and spinal cord
to the body and help the brain maintain homeostasis. The
Figure 3: The Functions of the Glucagon Cycle. This figure illustrates
semipermeable nature of BBB restricts the movement of large
the glucagon cycle, depicting the dynamic interplay between insulin molecules from passing through to protect the brain from un-
and glucagon in regulating blood sugar levels, providing a visual aid for wanted molecules and bacteria from entering. However, many
understanding the systems and pathways through which Obesity drugs GLP-1 drugs have been designed to meet the sizing standards
impact the human body. Adapted from https://old-ib.bioninja.com.au/
standard-level/topic-6-human-physiology/66-hormones-homeostasis-and/
by increasing levels of circulating free fatty acids, inflamma-
insulin-and-glucagon.html. Created by Canva and Biorender. tory cytokines (TNF-α, IL-1β, IL-6), and chemokines, which
increase BBB permeability. GLP-1 is also expressed in the
Metabolism: arcuate nucleus and paraventricular thalamic nucleus of the
Semaglutide, a generic name for the drugs Ozempic and hypothalamus, both of which control food intake. The cross-
Wegovy, uses GLP-1 RA channels to target various aspects ing of GLP-1 RA through the BBB promotes weight loss by
of glucose metabolism. The drug is mainly given subcutane-

61 DOI: 10.36838/v7i3.10
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acting on those nuclei, signaling satiety earlier, thus causing mutations.⁴³ This drug has the potential to save lives when
appetite reduction.³⁸ research on it is completed. Additionally, other novel pathways
Side Effects: that may yield similar results are ones that work on Amylin.
Medications that yield such high success rates of weight loss This hormone is secreted alongside insulin and acts on amylin
also have many side effects. It is often up to the doctor to pre- receptors in the brainstem in response to nutrient stimuli. It
scribe the medication and the patient to decide what is best for is elevated in T2DM patients and regulates gastric emptying.
them. Gastrointestinal side effects include nausea, vomiting, It may be possible to activate the release of this hormone and
diarrhea, and constipation. These are the most common and its receptor, which may cause a decreased rate of gastric emp-
mild effects, and they can be controlled with increased water tiness, a similar effect that GLP-1 RA drugs create. Thus, it
intake or little changes in diet. There are, however, more seri- may make the pipeline more efficient and promote more sig-
ous side effects, some of which are pancreatitis, inflammation nificant weight loss in patients with obesity.⁴⁴ Other emerging
of the pancreas causing abdominal discomfort; gastroparesis, therapies that may become more prevalent in this field include
the slowing or stopping of the food movement in your stom- nanotherapy: the application of biological molecules smaller
ach; bowel obstruction; gallstones; and bile duct blockages. than 100 nm in size. They would have the power to target the
These would need to be treated by a medical professional and same GI pathways in a more selective manner, exceeding the
may entail the patient stopping the mediation for a period of abilities of current pharmaceutical drugs. However, at present,
time.⁵ no Nanotherapy drugs have been approved for clinical test-
Dual Pathway Medication: ing.⁴⁵ As researchers gain a deeper of the ever-growing field
Tirzepatide is a dual antigen medication that works to of the Endocrine System, it will serve as a preemptive step in
promote weight loss and insulin stabilization through two solving one of the world's most prominent diseases— Obesity.
pathways: GLP-1 and glucose-dependent insulinotropic � Acknowledgments
polypeptide (GIP) receptors. It has been found to maximize I would like to thank my advisor for the insightful guidance
benefits similar to GLP-1 medications and is typically used on this topic and for helping me collect my research. I also
second in line with GLP-1 drugs. The FDA approved this attest that the ideas, graphics, and writing in this paper are
medication in May 2022 for the treatment of T2DM.³⁹ entirely my own.
GLP-1 and GIP are very similar incretin hormones. GIP is
a 42‐amino‐acid hormone secreted from K-cells in the small � References
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� Author
Gauri Bansal is a Senior at Winchester High School. She intends
to pursue a career in Public health and Biology. Her passion lies
in genetics and disease advocacy, and she aspires to strengthen the
communities while advocating for advancements in drug discovery.
During her free time, she can be found rowing on the Mystic River
or volunteering for various causes like health and nutrition for under-
served communities.

DOI: 10.36838/v7i3.10 64
 ijhighschoolresearch.org

RESEARCH ARTICLE

Combatting Misinformation: Divergences and Similarities

Between American and Brazilian Electoral Institutions
Hugo de Cunto Bueno
Colégio Santo Agostinho, Rua José Linhares, 88, Rio de Janeiro, Rio de Janeiro, 22430220, Brazil; [email protected]

ABSTRACT: This paper analyses Brazil’s and the United States’ approach to combat electoral misinformation. It seeks to
explain the differences in fake news containment measures in recent years, as both countries have recently experienced similar
political environments. The research employs a comparative political science lens - paired comparison method - to analyze the
institutional differences between the two nations’ federal electoral regulating entities: Brazil’s Tribunal Superior Eleitoral and
America’s Federal Election Commission. The study found that broader, more centralized, independent, and innovative institutions
provide better opportunities for combating misinformation. This research’s findings can have potential policy implications in
electoral regulation, addressing online misinformation, and democracy protection.
KEYWORDS: Behavioral and Social Sciences, Other with Politics, Political Science, Comparative Politics, Misinformation
Combat, and Electoral Institutions.

� Introduction the questions at the heart of this investigation: Why has Bra-
Since the mid-2010s, global politics have been reshaped by zil been more successful at combating misinformation than
the Internet and social media. While it certainly has democ- America? How can government institutions combat misinfor-
ratized access to essential information surrounding current mation? This paper argues that Brazil’s solidified, centralized
political events, the digital environment has increasingly proved electoral institution, as opposed to America’s decentralized
to be a medium for the spread of misinformation. While misin- approach, accounts for the different actuation scopes on con-
formation is not yet a consensual definition among academics, taining digital fake news.
the most common definition is “false and misleading informa- Brazil and America have been selected as analysis targets for
tion.”¹ Some argue that misinformation is false and misleading their similar political climates. The two countries have wit-
information unintentionally spread, while disinformation is nessed the rise of populist politicians to the heights of power:
false and misleading information with spread the intention Trump in 2016 and Bolsonaro in 2018. Their governments
to cause harm. Regardless, this paper will use misinformation were also marred by misinformation on a wide variety of po-
and disinformation interchangeably, defining both as “false litical debates. Both have also experienced the electoral defeat
and misleading information”, regardless of intentionality.¹ of their movements in misinformation-tainted elections on
Populist politicians have particularly benefited from the eas- electoral fraud that culminated with attacks on political institu-
ing of content sharing. Digital misinformation (“fake news”) tions; in America, the January 6th, 2021 attacks on the Capitol,
has dangerously affected public health during the COVID-19 and in Brazil, the January 8th, 2024 attack on Congress, the
pandemic and the integrity of democratic systems in certain Presidential Palace, and the Supreme Court. Additionally, both
countries. Two such nations are Brazil and the United States have complex, developed digital social networks.
of America. These countries have used different approaches to This research article claims that stronger, centralized in-
address the threat, ranging from non-interference to regula- stitutional checks and balances and innovative social media
tory attempts. Both are still experiencing the consequences of moderation technology account for the different results ob-
misinformation within their political systems. However, Brazil tained by these nations. After a brief literature review, the first
changed an already-existing centralized institutional mech- section provides a general introduction to both countries’ re-
anism to curb the threat. Meanwhile, the U.S. demonstrated cent political pasts and their struggles with misinformation.
a more relaxed, decentralized, and non-coordinated approach. The second and third sections delve deeper into the respec-
The results are visibly different. In Brazil, extremist politicians tive cases of Brazil’s and America’s electoral institutions and
publicly espousing anti-democratic beliefs have been latent, their designs. The fourth section compares the two through an
and the political environment has cooled from the January institutional interest lens, demonstrating that different levels
8th climax. Misinformation posts have been consistently re- of centralization, autonomy, and acting scope play a defining
moved in the country, showcasing relative success. In America, role in how political misinformation is addressed, impacting its
the same political group maintained its strength and expanded success. Finally, the conclusion summarizes the findings of this
in the context of the 2024 election. These differences inspire research and outlines some of its potential policy implications.
© 2025 Terra Science and Education 65 DOI: 10.36838/v7i3.11
ijhighschoolresearch.org

� Methodology ability was such that it provoked official FBI investigations

This paper utilizes a paired comparison methodology into a series of supposed Russian-backed accounts accused
originating in comparative politics to explore how different of colluding with surrogates of Republican candidate Don-
variables - namely, institutional centralization, institutional ald Trump’s campaign against Democratic candidate Hillary
strength, and innovativeness - generated greatly distinct re- Clinton. The investigation itself became a contentious topic
sults. For this, the analytical lens of this article, inspired by that shaped a chapter of the Trump administration. The same
Acemoglu and Robinson, and Mahoney’s work, will focus on techniques were employed during the 2020 election, marred
electoral regulating institutions, the Federal Electoral Com- not only by misinformation which was political in nature
mission (FEC), and its Brazilian counterpart, TSE, Tribunal but also health policy lies as COVID-19 spread through the
Superior Eleitoral.²,³ country.⁸ After Donald Trump’s defeat, the then-president
Data was compiled using research articles on the two elec- embarked on an official fake news journey which put into
toral bodies and information from the two organization’s question the electoral process’ legitimacy. His claims spurred
websites. A direct comparison between the three different the “Stop the Steal” movement, which claimed that the 2020
variables was made. This paper emulates the comparison elections were rigged to remove Trump from office. Another
process by separately introducing the two mechanisms and fake news-inspired movement, QAnnon, claimed Trump was
drawing parallels between aspects such as membership and a victim of a coup from “pedophile globalist elites."⁸ The two
power structure. movements’ supporters stormed the Capitol on January 6th,
The existing academic literature on misinformation is 2021, to try and stop the certification of the election results.
mainly focused on two main points of interest. The first one is In Brazil, the same phenomenon occurred in 2018, stirred by
misinformation itself. Hunter focuses on a quantitative evalu- a wave of anti-establishment sentiment within the populace.
ation of misinformation and its effects on the political arena.³ During that year’s presidential election, the left-wing Worker’s
Resende et al. quantitatively analyze a pool of misinformation Party, which governed the country between 2002 and 2016,
shared through WhatsApp, to identify their source and how candidate Fernando Haddad faced then-federal deputy Jair
they spread.⁴ The second evaluates the systematic usage of Bolsonaro, a former Army captain and populist right-winger.⁵
misinformation within specific electoral contexts through case The Workers Party’s reputation had fallen after an extenuat-
studies. Batista Pereira et al. and Machado et al. employ this ing economic crisis beginning in 2014, a systematically-wide
technique to examine the 2018 Brazilian Presidential election; corruption scandal known as Operation Car Wash, and the
Guo et Vargo do the same for the 2016 US Presidential Elec- impeachment of former president Dilma Rousseff for high
tion; and Kennedy et al. explore it in the context of the 2020 crimes and misdemeanors.⁸ False information targeting the
US Presidential election.⁵-⁸ Worker’s Party spread quickly within WhatsApp, Brazil’s
Articles on the electoral institutions described in this article main messaging app, and fact-checking efforts proved inef-
have distinct features. Research on the FEC is heavily skewed fective.⁶ During 2020, the same networks were used to spread
toward an analysis of its lackluster role within the generally COVID-19 misinformation, in an attempt to downplay the
decentralized American electoral system (see Franz 2009).⁹ virus severity. Later, in 2022, the agents targeted the TSE,
On the other hand, research on the TSE is either focused on Brazil’s electoral body.¹¹ Emulating America’s “Stop the Steal”
its specific duties within Brazilian elections’ organization and movement, they put the election’s credibility into question to
oversight or on the measures themselves, adopted under the prepare the ground for a possible defeat of Bolsonaro, which
institution’s unique position.¹⁰,¹¹ Research to date has yet to ultimately happened. Supporters assembled next to army bar-
offer a paired comparison of the US and Brazil in the con- racks to urge a military intervention and blocked highways
text of their electoral institutions or an examination of how throughout the country. As in America, official investigations
the electoral system of these two countries has been protect- were opened by the Supreme Court and TSE to investigate the
ed from misinformation. Thus, this article seeks to utilize the networks, dubbed “digital militias”.¹¹
similarity of these countries’ political environments to enrich The similarities between the two, however, have produced
the existing literature, providing a comparative perspective on very distinct observable results today. While both Americans
combatting fake news in populist democratic contexts. and Brazilians prepare for their next electoral cycle, and so-
cial media apps have adopted misinformation combating
� Results and Discussion
General Overview: measures, misinformation agents have encountered a still
The COVID-19 pandemic brought havoc upon the world permissive ambiance within American social media.⁸ On the
and plagued each country with another virus: misinformation. contrary, Brazilian agents have had their actions restricted and
The resurgence of populism many nations had already been ex- their influence diminished.¹¹ The difference begs the question:
periencing became a global point of concern in the mid-2010s. What factors are responsible for these distinct results? Why
Fake news has been employed in many different political and, has Brazil been more effective at combating fake news? To do
especially, electoral contexts. In the United States, the usage so, a deeper delve into both countries' systems is required.
of fake news became more widespread after the 2016 election, Brazil’s Electoral Institution - TSE:
in which misinformation campaigns were systematically em- Brazil employs a unique system of electoral organization. In
ployed as political weapons. The main vectors spreading such the country, all elections, whether municipal, state, or federal
content were Twitter and Instagram.⁷ Misinformation’s scal- level, are organized under the supervision of Justiça Eleitoral,

DOI: 10.36838/v7i3.11 66
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or Electoral Justice.¹⁰ This is a judicial sub-branch preclud- content has to be removed, withdrawn, or apologized for, de-
ed (included/present in) by all Brazilian Constitutions since pending on how it was shared and according to TSE’s ruling.
its establishment in 1932. The Judiciary in Brazil divides it- Punitive measures fall upon the offenders. To illustrate,
self into branches of action, defined by hearing specific case former President Bolsonaro has been condemned by the
themes. Justiça Eleitoral is the sub-branch that deals with court for spreading misinformation about digital ballot ma-
election-related cases.¹⁰ chines in an official meeting with many ambassadors. He is
Created as a response to a period of rampant electoral fraud, currently barred from running for office until 2030. These
known in Brazilian historiography as the “Old Republic”, its two idiosyncratic mechanisms, together with the institution’s
main enforcer agent is the Tribunal Superior Eleitoral (TSE), constitutionally-defined responsibilities, have been key in po-
Superior Electoral Court. Its role is that of an ultimate, cen- sitioning the court as Brazil’s main defender against political
tralized arbiter of potential electoral disputes, working to misinformation.¹¹
uphold electoral laws. It functions as a judicial body composed With the rise of social media and digital misinforma-
of seven magistrates. Two come from the Superior Tribunal tion accounts, the Court expanded its acting scope to engulf
de Justiça (STJ), Superior Justice Court in English. Anoth- the virtual world. Social media accounts that shared misin-
er two are appointed by the President from a three-candidate formation came under the same scrutiny faced by TV or
list crafted by the Supremo Tribunal Federal (STF), Brazil’s advertisement-spread electoral falsehood. The misinforma-
Supreme Court, under the constitutional requirement of pos- tion-spreading network was, thus, slowly dismantled through
sessing an honest record and ample judicial expertise. The last court-imposed content removal in platforms like Twitter and
three are themselves STF members.¹⁰ The non-partisan com- Instagram. Repeating offenders’ accounts were restricted with-
position of TSE is built to avoid any abuse of the electoral in Brazilian territory, despite resistance from certain Big Tech
system for political gains. companies.¹¹ The court also formalized an initiative signed
TSE’s seven-member structure is replicated by its state-lev- with other 34 politically-relevant actors on combating disin-
el equivalent, the Tribunal Regional Eleitoral (TRE). There formation. Since 2020, every election has had a meeting with
is one TRE for each state. This hierarchical web is further political parties and their representatives outlining cooperative
subdivided into municipal levels. Nevertheless, the bulk of measures against disinformation and reaching an agreement
electoral regulation is concentrated within TSE’s helm. TRE’s with anti-misinformation measures to be adopted, showcasing
and municipal counterparts work as enforcers of the Court’s constant institutional innovation.⁵
determination, and as assisting bodies in election organization However, WhatsApp’s omnipresence in Brazil meant politi-
and coordination within Brazil’s 26 states and its Federal Dis- cal misinformation sharing had a facilitated environment.⁶ To
trict.¹⁰ fight it, TSE and WhatsApp have signed a cooperation mem-
This centralized chain of command entails a wide range of orandum. There is an active chatbot created by and directly
duties for TSE. The organism is responsible for many essential linked to TSE, fact-checking political messages and providing
electoral measures. Among these are ensuring universal voter accurate information, while WhatsApp flags constantly shared
registration, according to Brazil’s mandatory voting require- messages, restricting its sharing to at most 3 contacts at a time,
ments; issuing voter identification documents; organizing which slows down false content spread.
electronic voting machines distribution; registering all candi- Innovation is not only restricted to judicial rulings. New
dates; compiling candidate’s net worth reports; and distributing departments within TSE are being created to combat more
public campaign funds proportionally to their Legislative pres- complex misinformation forms. One such example is the Cen-
ence, according to Brazilian electoral law.¹⁰ These are typical tro Integrado de Enfrentamento à Desinformação e Defesa
of election-organizing institutions. What differentiates TSE da Democracia (CIEDDE), or the Integrated Center for the
from its counterparts in other nations is its official affiliation Combat of Disinformation and the Defense of Democracy in
with Brazil’s Judiciary.¹⁰ English, a body of experts hired by TSE to centralize digital
Possessing judicial powers conferred by the Justiça Eleito- content removal measures, focused heavily on high-complexity
ral’s structure, TSE also hears cases on electoral law.¹¹ For this falsehood, such as “deep fake” videos of politicians.¹¹ It also
reason, this institution has a more extensive range of powers researches potential new response mechanisms.
than other electoral regulating parts, including police pow- This is not to say that TSE doesn’t face challenges regarding
er within electoral periods. The court has the unique ability misinformation combatting. The two primary limitations to
to punish candidates for breaching electoral law within and TSE’s action are a monolith block of populist politicians with-
outside of the electoral period, for acts committed during in Congress and Big Tech Companies. They form what Jon
it.¹⁰ This means the court can apply a broader range of mea- Elster would classify as a coalition: a union of distinct politi-
sures against offenders. These can range from simple fines to cal agents over a shared, rational or irrational, interest.¹² The
outright removal from office and temporary suspension of populist block has fought against TSE’s measures and tried to
political rights. It also hears cases of slander and defamation block attempts to regulate Brazilian social media. They do so
within the election period. Campaigns can file complaints on with tacit support from Big Tech companies and their plat-
the subject, and the court has to decide whether the content is forms, who deem those projects as too burdensome on their
shared by political organizations or personalities. TSE can also business model. This coalition most noticeably came into ac-
open investigations on these offenders. If deemed untruthful, tion in 2023, when it was able to filibuster Bill 2630/2020,

67 DOI: 10.36838/v7i3.11
ijhighschoolresearch.org

locally known as the Fake News Act, which would entail a se- edge of the law like their TSE counterparts, they do not come
ries of measures to legally specify fake news spreaders and their from judicial careers. Rather, they emerge from the political
used vehicles and social media companies for misinformation. party’s legal teams under the guidance of bipartisanship. The
Excessively radical measures taken by TSE have also fur- even number of commissioners means there is a possibility for
thered opponents' claims of judicial activism and political gridlock in case of divided decision-making, which does not
persecution undertaken by the court. Some of the most con- happen in odd-numbered TSE.⁹
troversial ones include the forced removal of social media The range of power available to FEC is also much more
accounts and passport confiscation of suspected misinfor- restricted than that available to TSEs. As it is a Commission
mation agents to prevent them from fleeing the country and under the control of Congress, it operates under a legislative
escaping justice. Many are also concerned about its potential power framework according to Montesquieu’s tripartite power
lack of oversight from other institutional checks and balances, division.¹³ The FEC has the ability to pursue investigations
especially from the Supreme Court, since some of its mem- into breaches of campaign finance law, including auditing of
bers accumulate function within the two courts.⁵ Critics are campaign funds and pursuing criminal charges against offend-
also worried about potential hindrances to freedom of speech ers.⁹ Unlike Brazil’s public financing, the US does not divert
in the name of democracy’s security, denouncing the Court’s any government funds to political campaigns. The FEC, thus,
efforts as illegal censorship. Brazilian law, however, distin- solely supervises campaign finance, while TSE is directly re-
guishes itself from its American counterpart in the extent to sponsible for resource distribution.
which speech is protected. While America’s First Amendment The Federal Electoral Commission falls short of operating
protects almost all speech, Brazil’s legislation on freedom of within the election organization. The commission cannot cre-
speech considers hate speech, racist speech, injury, defama- ate norms and regulations or outright act on essential aspects
tion, slander, and incitement of crime or violence, including of the democratic process, such as voter registration, ballot dis-
violent abolition of the democratic state and the rule of law, tribution, or vote counting.⁹ It also cannot indirectly regulate
as unlawful abuses of this constitutional right. Most political the electoral process through proposed modifications. It is not
misinformation spread on the Internet falls under these crim- within the body’s scope to suggest better ballot design, ballot
inal offenses, which, according to the Supreme Court Justices, distribution, or voter registration measures. All these policies
justifies the court’s actions against offenders. are under full control of local and state Boards of Elections,
Nevertheless, the presence of a proactive, centralized in- under each Secretary of State or equivalent department. The
stitution with specific goals and an ample arsenal of powers organization is completely restricted to campaign financing
meant Brazil had a solid protective mechanism against mis- regulation, which prevents its official actuation as an agency to
information. While TSE’s actuation is not unanimous nor prevent misinformation. Another barrier to the commission’s
perfect, it allowed Brazil to effectively coordinate a system- ability to properly conduct its job is the lack of coordination
atic state-sponsored campaign against misinformation agents, between it and the American Judiciary. Brazil’s TSE, being
both within and outside of populist governments because of officially affiliated with the judiciary, possesses the autonomy
its independence from political parties.¹¹ The same cannot be to propose and enforce norms according to the body’s deter-
said for the American case. minations.¹⁰ Having Brazilian Supreme Court Justices serving
America’s Electoral Institution – FEC: within the organization at all times also aids the coordination
American electoral organization is very decentralized, being of measures between the electoral court and its immediate
regulated by counties, the country’s smallest political division.⁹ superior, meaning electoral and anti-political misinforma-
The country’s federalist ideology, dating back to the American tion regulations are solidified and are not easily revoked by
War of Independence, grants autonomy for states to define the STF. By comparison, the FEC has had a troubled rela-
their own electoral laws. Not even federal elections are truly tionship with the American Supreme Court. Many political
federal: The electoral college system ensures states have a say organizations and individuals have sued the Commission for
in organizing presidential elections. For this reason, there is controversial campaign finance regulations. The most signif-
no appropriate universal regulatory electoral body. Each state’s icant is the landmark 2010 case Citizens United v FEC. It
Secretary of State has the responsibility to conduct and orga- reallowed unlimited corporate and union donations, prompt-
nize elections according to the state’s electoral law. However, ing the creation of “Super” political action committees, a type
this is an official cabinet role of a state executive power; it does of campaign fundraising organization, fed on by their funds.⁹
not function as an apolitical regulatory institution. The closest SCOTUS has also evaluated other litigations over limitations
organ to an electoral regulatory body is the Federal Electoral on campaign financing that have also reduced the FEC’s over-
Commission (FEC). The FEC was established in 1974, under sight and power.
the Federal Election Campaign Act.⁶ It is responsible for the The FEC’s limited acting scope, its partisan composition,
oversight of federal elections and enforcing campaign finance and constant judicial revision of its measures empty any poten-
laws. Its structure is also very different from TSE’s. Its six com- tial official institutional response to political misinformation.
missioners are appointed by the President and confirmed by One can say the FEC is the antithesis of the TSE as an insti-
the Senate, and its members are affiliated with America’s two tution: decentralized rather than centralized, dependent rather
main political parties: The Republican and the Democratic than autonomous, and fragile rather than solidified. It is too
Party.⁹ While the commissioners also possess ample knowl-

DOI: 10.36838/v7i3.11 68
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incipient to properly enforce any regulatory or punishing acts broader set of resources promote innovation and research in
against those spreading fake news. the misinformation-combat field, through larger investments
With the FEC’s bureaucratic apparatus not being prepared in misinformation identification software, for example.
to contain electoral misinformation, content moderation is left Decentralized, more specific, and politically affiliated insti-
in the hands of social media companies’ internal departments. tutions like the FEC do not possess the same incentives or
The businesses themselves do not have any vested interest or resources, compromising any efforts to combat misleading
institutional duty to protect democracy from threats. Their content and its spreaing agents. They are also more prone
actions are based on unique terms and conditions, subject to to delegitimizing efforts than centralized institutions, for their
their digital realm, and are not done systematically. Individual restrictive action scope combined with potential partisan grid-
accounts can be temporarily suspended or banned, but there lock makes them vulnerable to misuse. This can legitimize
is no official investigation into who’s behind misinformation false narratives of electoral fraud, manipulation, and vote rig-
campaigns; after all, that is not their role. The reliance on “Big ging among the general public, having a negative effect on
Tech’s” own mechanisms to contain misinformation further misinformation combat efforts. Additionally, they lack enough
weakens any response efforts from the US, who might not co- political and legal strength to either edict national-wide
operate with authorities when not legally obliged. measures or broader-fielded measures necessary to fight mis-
The American decentralized electoral system, with its weak information within the Internet.
federal institutions, has offered disjointed responses to the rise This research’s findings on the effects of centralization and
of misinformation. The FEC’s limited power to oversee feder- the power range of electoral institutions can have further
al elections translates into an inefficient institution not only at policy implications for countries threatened by political mis-
containing false narratives with democracy destabilization po- information networks, offering insights into how choices of
tential; it also fails at creating sufficiently fair rules that could institutional design influence its effectiveness. Future exam-
help legitimize the ever-more controversial American electoral ination of this topic would benefit from the incorporation of
system. It should not come as a surprise that much more mis- quantitative research on digital misinformation and its regu-
leading content and claims circulate more frequently and with lation. Such research would help to investigate to what extent
less restriction on American social media as compared to its centralized electoral institutions help in the fight against
Brazilian counterpart. misinformation and to what extent centralized electoral in-
stitutions and their measures effectively reduce the number of
� Conclusion
American and Brazilian electoral regulating institutions play false political content circulating within the web. This research
a key role in shaping each country's misinformation-combat would also benefit from a qualitative evaluation of the differ-
strategies and their subsequent success or failure. Brazil’s cen- ent approaches adopted by TSE and FEC under the tradeoff
tralized, innovative, and coordinated actions, particularly those between freedom and security, to better understand the dis-
led by the TSE, have weakened digital misinformation net- tinct rationales adopted and their consequences for the general
works that currently do not enjoy the same operational ease as populace.
before the institutions’ intervention. America’s decentralized, � Acknowledgments
rigid, and non-universal approach did not allow for any offi- I’d like to thank all the guidance from my mentor Dr. Aviezer
cial, state-sponsored attempts at combatting disinformation. Tucker and Dr. Audrey Wozniak for helping me throughout
The FEC’s limited range of action prevents any coordinated my research journey. Your assistance has been invaluable in the
federal response; the Secretaries of State and local Board of crafting of this article.
Elections do not have enough power or specialized bureau- � References
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digital nature, reaches far beyond their jurisdiction. The out- f Expert Views on Misinformation: Definitions, Determinants, S
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� Author
Hugo de Cunto Bueno is a senior at Colégio Santo Agostinho –
Leblon, in Brazil. Passionate about politics, economics, and inclusive
education, Hugo seeks to further his studies in this area, pursuing a
double major at university. He also plans on pursuing post-secondary
education.

DOI: 10.36838/v7i3.11 70
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REVIEW ARTICLE

Comprehensive Solutions to Variations of the Knight’s Tour

Problem
Caleb I. Yates, Jordan Y. He, Noah J. Schmidt
Emmanuel College, 17 Birmingham Rd, Gold Coast, Queensland, 4211, Australia; [email protected]

ABSTRACT: This paper explores solutions for various alterations of the classic Knight’s Tour problem, focusing on finding
general solutions for certain board classes. The Knight’s tour problem involves the movement of a knight from the game of chess,
requiring a path to be found for the knight to travel through a grid, landing in every square only once. This paper involves rigorous
proofs for standard rectangular boards and through the expansion of these solutions towards non-rectangular 2D boards and to
solvable 3D shapes. These solutions are supported by both mathematical proofs and the innovative Knight’s Tour Chess Analysis
Program (CAP), which allows observation and analysis of knight piece movements on specially designed boards. Through a
multidisciplinary approach encompassing graph theory, geometry, algebra, and CAP, this research enhances our understanding of
the Knight’s Tour problem and its broader implications in computer science and graph theory.
KEYWORDS: Mathematics, Combinatorics, Graph Theory, Game Theory, Knight’s Tour, Special Boards Computational
solutions to the Knight’s Tour Problem.

� Introduction Building upon this foundation, mathematicians further

The study of graphs began with the famous Swiss mathe- explored paths that visit each vertex exactly once, known as
matician Leonhard Euler, who needed an efficient method to Hamiltonian paths.⁴ Furthermore, Hamiltonian Cycles were
solve the Königsberg Bridges problem. This problem poses the explored where the starting vertex and the final vertex of a
question of whether it was conceivable to walk around Königs- Hamiltonian path are a single edge apart. This line of investi-
berg once while passing over each of its seven bridges once and gation was applied to the study of the Knight’s Tour problem
then returning to the beginning point. on the chessboard. A Knight’s Tour refers to a sequence of
This was soon solved by Euler through abstracting the land- moves executed by a knight where it covers every square on
masses and bridges as vertices and edges. Euler introduced a n × m chessboard precisely once. This can be done by cre-
the notion of a graph as a mathematical structure. His graph ating a graph (V,E) where the set of vertices V is denoted by
consisted of a set of vertices and a set of edges, associating the squares on a chess board and where E is the set of edges
each edge with two vertices, which marked the birth of a new between the vertices that are defined by a knight’s move. The
branch of mathematics named graph theory. It was observed by square in the bottom left of a standard 8×8 chess board will be
Euler that whenever one enters a landmass (vertex) via a bridge (1,1) while the bottom right square will be (8,1) and the top
(edge), one must leave that landmass (vertex) using another right (8,8). A knight’s move will be defined as either a horizon-
previously untraveled bridge (edge). Euler deduced that for a tal knight’s move (u,v)→(u ± 2,v ± 1), or as (u,v)→(u ± 1,v ± 2),
solution to exist, each vertex must have an even number of edg- a vertical knight’s move.
es connecting to it, a condition known as an even degree.¹ This This study endeavors to move beyond standard solutions and
profound insight paved the way for the study of Eulerian paths: common board layouts, engaging in new and innovative paths
a trail that traverses every edge in a graph exactly once while to solve new chessboard configurations through both advanced
starting and ending at different vertices, establishing a funda- mathematical discoveries and computational software. This is a
mental connection between the existence of Eulerian paths and valuable area to further research in, as developing these general
the condition of even degree for each vertex in a graph.² tools and ideas will allow further research in graph theory and
cryptography to advance quicker with a basis to build upon in
similar future problems. In the first section of the paper, the
methodology and terminology will be extensively discussed,
which will be used frequently in the subsequent part of the
paper describing the solutions and proofs of extensions to the
Knight’s Tour problem.

Figure 1: Konigsberg bridge problem.3

© 2025 Terra Science and Education 71 DOI: 10.36838/v7i3.12

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� Methods extremely optimized release binaries (A snippet of high-level

To properly investigate the Knight’s Tours and Hamiltonian logic was presented below).
Cycles, we developed a software tool to graphically analyze Some preliminary examples of how the program is used are
chess boards quickly and easily, and to present findings in a given below. We utilized this program first in an attempt to
user-friendly manner. This program is called the Chess Anal- locate a Knight’s Tour without the usage of disabled cells (col-
ysis Program (CAP), whose primary function is to find open ored in red) and target selection (or any square if no targets
knight tours. This algorithm incorporates two methods to are specified). For example, to show that a 3 × 3 board has
search for a complete open Knight’s Tour and one method for no knight’s tours, CAP creates an accurate output as seen in
a closed Knight’s Tour. The Warnsdorff 's heuristic, mentioned Figure 2, or to show that a 3 × 3 board with the center re-
below, says to always pick the next knight move that ends on a moved has a Knight’s Tour solution starting in the top left,
square with the lowest degree (where ‘degree’ means the num- showcasing an output like Figure 4. Some of the time, howev-
ber of possible squares a knight can reach when on a cell). The er, specific solutions are not necessary, and only their existence
three algorithms utilized to find Knight’s Tours include: (or non-existence) is useful. After checking all the other cells
(a) Brute force: This algorithm starts on the specified cell, in Figure 3, we ended up with Figure 4, demonstrating that a
and then makes a list of possible next cells. It then sorts this Knight’s Tour exists starting on all cells.
list using Warnsdorff 's heuristic, and recursively tries every
possible knight path until it reaches a solution (hits the safety
cap) or has exhausted every possible path, in which case it is
guaranteed that no knight's path exists. It contains no heuris-
tics for targets. In practice, the Warnsdorff biassing reduces
computational time significantly, although not changing the
fundamental Big O time complexity scaling with board size in
the general case. Figure 2: 3 × 3 chess Figure 3: 3 × 3 board Figure 4: 3 × 3 board
(b) Warnsdorff only (incomplete): This method strictly board in CAP showing with centre removed, with centre removed, not
follows Warnsdorff 's rule, restricting the set of possible next that no knights tours showing specific showing specific solution
exist from any starting solution starting from but simply that solutions
knight moves to only those with the lowest degree. As such, squares. top left. exist on all outer cells.
this algorithm might miss possible solutions that a complete
algorithm would find (see above Brute Force) but will ter- Furthermore, for clarity, we define the terms that are com-
minate significantly quicker. This algorithm does implement monly used or abbreviated in the following sections of this
backtracking for equivalently ranked next moves in the case of paper;
a tie for Warnsdorff Rank/cell degree. (a) Boards: A board is a specific collection of vertices that
(c) Hamiltonian cycle: The algorithm implemented was the knight will be moving on, defined by the dimensions m × n
copy-pasted from a reliable source and extensively tested. where m is the number of files and n is the number of rows the
The completeness of the implemented Hamiltonian cycle board has. The order in which these variables are written does
algorithm is not required to vindicate the correctness of the not matter. As graphs are not dependent on any other shapes
theorems presented in this article. or positions, rotating a board 90° is trivial and unimportant.
All the algorithms included allow for the manipulation of This means that 3 × 4 and 4 × 3 boards are equivalent when
the standard chessboard’s width (2 ≤ m ≤ 20) and height (2 evaluating general cases, which is important as boards are ori-
≤ n ≤ 20), as well as the ability to disable any cells (which ap- ented horizontally for visualization purposes when some may
pear red when disabled). For the brute force and Warnsdorff think they should be oriented vertically according to the order
algorithms, there is also the ability to place targets on which of the boards. Note that u × v will be considered equivalent to
a successful (open) tour must finish. For each cell computed, m × n, and occasionally the variables m and n will be used as
the status of the computation is placed above the cell: A green parametric constants.
tick for success, or a red cross for failure (and a yellow warning (b) Degrees: The degree represents the total number of
in case the computation safety limit was surpassed). For suc- edges connected to a vertex as an endpoint.⁵ For example, in
cessful tours, green lines representing the exact path a knight Figure 4, the knight piece placed anywhere on the board will
can take are also rendered, with red numbers appearing on the have a degree of two.
top right of the cell the knight lands on in order of movement. (c) Connected graph: A graph is connected when every
Together, this program can create a variety of oddly shaped vertex is connected to every other vertex through some path.
boards that can be easily visualized, as shown throughout this Therefore, there will always be a path leading through the
paper, particularly in the section Special Board Observations graph, meaning that any path can be found from any starting
Using CAP. The output can also be visually modified, for ex- point to any ending point.⁶
ample, the removal of the sequence numbers for clarity. (d) Hamiltonian cycle/closed knight’s tour: A Hamiltonian
The language used was Rust. For brevity, complete refer- cycle is a special case of a Hamiltonian path where the final
ence implementations are not provided in this document since vertex for the Hamiltonian path is within a single move from
the real implementations involved caching, recursion, compile the first vertex; for example, if a knight were to start on the
time inflection, and rather a lot of code in general to enable square (1,1) and finish its tour on the square (3,2) it would be

DOI: 10.36838/v7i3.12 72
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a Hamiltonian cycle, which also known as a ‘closed knight’s even n values having all squares ticked, being able to complete
tour’.⁷ an open knight tour in all squares. A continuation of the pat-
(e) Hamiltonian path/open Knight’s Tour: A Hamiltoni- tern will be shown in Figures 8 to 11 (Figure 11 shows that
an path is a path that reaches every vertex (or square) once the board does not have to be n×n to produce a checkerboard
without repetition. Within the context of a Knight’s Tour, it is pattern).
known as an ‘open knight’s tour’.⁸
(f ) Paths: A path refers to a type of graph structure where
the vertices are arranged in a specific sequence, and each vertex
is directly connected to the next one in the sequence.⁹
(g) Vertical knight’s move: A vertical knight’s move is where
a knight completes the move (u,v)→(u ± 1,v ± 2), moving two
squares vertically and one square horizontally.
(h) Horizontal knights move: A horizontal knight’s move is Figure 8: 6 × 6 board Figure 9: 7 × 7 Figure 10: 8 × 8 board
where a knight completes the move (u,v)→(u ± 2,v ± 1), mov- open tour. board forming a allowing open tours on
ing two squares horizontally and one square vertically. ‘checkerboard’ pattern. all squares.
(i) Vertices/cells/squares: Throughout the report, verti-
ces will be interchangeably denoted with the terms ‘cells’ or
‘squares’, and when talking about specific vertices/cells/squares
the notation (u,v) will be used where u is the file the vertex
is on, moving horizontally, while v is the rank of the vertex,
moving vertically.
� Results and Discussion
Using the methods discussed above, the following section
will explore solutions and general observations on an array Figure 11: 9 × 5 board forming a ‘checkerboard’ pattern.
of problems derived from an extension of the Knight’s Tour
problem. This paper will explore general observation on n × n
rectangular boards, solutions to u × v boards with a rectangle The ‘checkerboard’ pattern occurs due to the condition that
removed from the center, innovative general solutions for all 3 a Hamiltonian path with an odd number of squares has an
× m, 4 × m, 5 × m boards and a brief overview of three-dimen- even number of moves, meaning the path must end on the
sional board layouts. same color square it started on. Odd-sized boards require a
Open Tours Observations for n × n Boards using CAP: Hamiltonian path to use k squares of one color and k+1 squares
Paths for n × n can be easily found when n ≥ 4, starting from of the other remaining color. Therefore, the color that has
any square. However, the more interesting and valuable ques- fewer squares on the board (in these cases above, the white
tion to be proposed is to see to the extent to which an open squares) will not have a Hamiltonian path because it cannot
Knight’s Tour can be applied for varying values of n on an n × end on the color it started on. This applies to all boards with
n board. It can be observed, using CAP, that when n=2,3,4, all an odd number of squares where one color has k squares and
squares are crossed, indicating that no open tours can be found. the other has k+1 squares. If there is a difference of more than
n=1 is not supported as it is not considered to be a graph due one square between the two colors, then there would not be
to it not having any edges. any Hamiltonian path. This restriction applies to any ‘special
boards’ (boards that do not follow conventional board shapes).
This is shown in Figures 12 and 13, rebalancing a board by
removing one square from the k+1 color and unbalancing a
board by removing one square from the k color.

Figure 5: 3 × 3 board Figure 6: 4 × 4 board Figure 7: 5 × 5 board in

in CAP program in CAP program CAP program showing
showing no open tours showing no open tours the ‘checkboard’ pattern
can be found. can be found.

When n=5, the following pattern can be observed where ev-

ery white cell is unable to complete an open knight tour, while Figure 12: A 5 × 5 odd board Figure 13: A 7 × 7 odd board
with a black square removed. with a white square removed.
every black cell can. When n=6, the above pattern can be ob-
served where all squares can complete an open Knight’s Tour. General Hamiltonian Path Solutions of 3 × m Boards:
Repeating ad infinitum, a pattern of boards pertaining to an Theorem 3. Every board where m ∈ {x∈Z and x=4 or x ≥ 7},
odd n value forms a ‘checkerboard’ pattern with white squares has a Hamiltonian path that starts on a corner square and ends
crossed and black squares ticked. Where boards pertaining an
73 DOI: 10.36838/v7i3.12
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on the middle square of a rank that is one rank away from an ond move (3,2) → (5,3) of the path and the end of the second
edge of the board: set will be able to finish on the vertex (3,4). This proves 4×m
To start this proof, smaller 3 × m boards will be examined boards can be used as composite boards.
using the CAP solver. It can be proved that 3 × 1, 3 × 2, and 3 Theorem 3. For every 4 × m board a Hamiltonian path does
× 3 boards do not have a Hamiltonian path, while 3×5 and 3×6 not exist starting from any cell on ranks two & three.
can be seen to not have a solution from the CAP outputs be-
low. 3 × 4 boards have three main solutions, ignoring rotations
of the board or directions of the paths. The path that will be
utilized in this report is the path of the opposite corner, shown
below.

Figure 15: An example 3 × 7 board featuring a Hamiltonian path that

Figure 14: The opposite corner solution is shown for the 3 × 4 board started on a corner square and finished on the connector square.
using the CAP solver, while other boards (3 × 5 and 3 × 6) are shown,
demonstrating no knights’ tours exist from any starting position.
The beginning of this proof was found by C. Flye Sainte-Ma-
rie at the 18 April 1877 meeting of the French Mathematical
The corner-to-corner solution for the 3×4 board is import- Society, and below shows the explanation and further applica-
ant as it can be applied to the board compositing method. For tions of this proof. To begin with, for every 4×m board, divided
example, if two 3×4 boards were placed together to form a 8×3 into two sets: the top two blocks of the even-numbered files
board then the Hamiltonian path could be used for the first and the bottom two blocks of the odd-numbered files.
board and then linked to the bottom left corner of the second This shows that a knight’s move from an outer cell of one
board i.e., the move (4,3)→(5,1). This technique can be repeat- set can only go to an inner cell of the same set. Therefore, a
ed to infinity, proving the solution for every 4k × 3 board where crossing between two sets can only be done with the inner
k ∈ N. This technique of adding 3 × 4k boards can be utilized cells. An open tour has 4m-1 moves on a 4 × m board, and
for a variety of boards to prove every 3 × n board has a solution: as it is required to have a knight’s move on the inner squares
specifically, the boards 3 × 8, 3 × 9, 3 × 10 and 3 × 7 which can between sets, there can be no more than 4m-2 moves linking
be respectively written as 3 × 4(2),3 × 4(2) +1,3 × 4(2) + 2,3 × to an outer square (linking means traveling to or from an outer
4(1) + 3. Each of these boards has a Hamiltonian path from square). However, there can be no less than 4m-2 moves link-
a corner square to a middle square on the second file to an ing outer squares as there are 2m outer squares, and at least
edge on the opposite side of the board (see Figure 15), which 2m-2 of these squares require two knight moves to be linked
will be referred to as the connector square for 3×n boards. As to them. The two squares that don’t require two moves being
the path finishes on the middle square and starts on a corner the start and the end of the tour, which only require one move
square, it can be used within compositing boards, creating the each. This means that there must be at least 2(2m-2)+2=4m-2
general solution 3 × 4(1+k) + 3. Using this for all baseboards moves linked to the outer squares.
proves four general equations, 3 × 4(1+k)+3,3 × 4(2+k),3 ×
4(2+k)+1,and 3 × 4(2+k)+2, that can be independently linearly
scaled to prove solutions to any 3 × n board. Therefore, for
every 3 × n board, there exists a Hamiltonian path.
Extending 4×m for Further General Solutions; 4 × m
Boards and Hamiltonian Paths:
Figure 17: 4 × 6 (M = 6) board Figure 18: A 4 × 7 (M = 7) board,
split into 'domino' sets. The top visually demonstrating that any
two rows and the bottom two possible way to cross from the
rows are considered separate sets bottom set to the top set requires you
in this argument do not work as to pass through the centre two rows
a starting position to a Knight’s
Tour.
Figure 16: A 4 × 8 and 4 × 11 board showcased in the CAP solver to show
the middle ranks do not work as a starting position to a Knight’s Tour. This result proves that there can be only one crossing between
To use the 4×m board for compositing boards, it must start the two sets present in any 4×m board, therefore meaning that
in a lower corner and finish in a square that can reach the bot- each set must have a Hamiltonian path completed with at least
tom corner of the board above it. On a 4 × m board, a vertex one of the ends of the tour being on an inner cell. However, it
that is a finishing point that allows this is the vertex (3,4). can be proven that for each set, if an ending of a Hamiltonian
This square is three knight moves away from the square (1,1). path is on an inner cell, the other ending must be on an outer
This is relevant as when connecting two domino sets, the first cell. This proof is below. Within one of these sets, what will be
domino set will finish on the first move (1,1) → (3,2) of the referred to as a domino set, every move must alternate between
path from (1,1) to (3,4), the second set will start with the sec- inner and outer cells, which can be seen as all outer cells being

DOI: 10.36838/v7i3.12 74
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one color and inner cells being the other color, and every after completing the vertices the knight missed the first time,
knight move must change colors (Figure 20). it will end one move away from the initial vertex, a Hamilto-
nian cycle.
2. Even Boards
The pattern for boards of even length is similar to the solu-
tion for odd boards but is slightly more complex. It involves
switching between the top and bottom half of the board every
move before getting to four files before the end of the board;
before doing either of the following patterns dependent on
Figure 19: 4 × 7 board, Figure 20: 4 × 6 board split into being on an outer or inner cell when reaching the fourth file
demonstrating using the CAP a domino set, showing that various from the end, and then returning the other way to repeat the
program that starting on the edges moves must change colours (e.g. from process before going back towards the middle.
(where the tick marks are) always has black -> white and white -> black)
a solution (an open Knight’s Tour)
ending in the centre two rows (where
the targets are)
If a knight is on a white square, after 2m-1 moves, the knight
will be on a black square, and vice versa. If a domino set has
2m squares, it will have 2m-1 to move, therefore, the square
Figure 22: Even domino set completed using pattern starting from (7,2)
it starts on must be the opposite color to the square that it and ending at (5,1) where the green lines are the first time around the board,
finishes on, which means that for a Hamiltonian path within a the orange lines the second time around the board and the blue lines the
domino set, one end must be on an outer square, and one end moves done in the last 3 files of each side to reach every square on these
must be on an inner square. This proof shows that the second edges before going back through the middle.
set the knight enters will have an ending on an outer cell since This ends up reaching every square throughout the board,
when entering the new set, the knight will be on an inner cell. and as the middle of the pattern is repetitive, it can be extend-
Therefore, proving that for every 4×m board there cannot be ed to any length board. Because the solution must go through
an ending on the inner ranks. the entire board twice (think of it as a circle that loops), this
Domino Sets and Hamiltonian Cycles: means that for every starting square, you can loop back around
Theorem 5: Every vertex on a domino set can be used as the to it, making a Hamiltonian cycle.
start or end of a Hamiltonian cycle if the domino set is of size Therefore, by showing Hamiltonian cycles exist for every
2m where m ∈ N and m=3 or m ≥ 5. domino set of size 2m where m ∈ N and m=3 or m ≥ 5, this
Two patterns can be used to establish that every vertex has shows that 4×m boards have many solutions, including solu-
a Hamiltonian cycle, one for odd-length boards and one for tions allowing connector boards.
even-length boards. The one for odd boards is rigorously prov- General Hamiltonian Path Solutions of 5 × m Boards
en, while the solution for even boards is a conjecture with a Knight’s tours for five by five, six, seven, eight, and nine
large basis of evidence and reasoning. boards are presented below:
1. Odd Boards
This pattern works with every vertex. To be able to follow
the path in Figure 21, start on the lower half of the board, then
move in horizontal knight’s moves to whichever edge of the
board you are closest to while staying on that half of the board.
Once at the edge of that half of the board, move vertically
to the top half of the board and repeat the process until the
other end. Return to the bottom half and complete the whole
process again, overall continuing around the board twice. This
occurs because after going around the board the first time, the
knight will land on the square below the starting vertex, and

Figure 28: A 5 × 11 board solved using an m = 6 solution (green), a

connector move (orange), and an m = 5 solution (flipped along the horizontal
so as to align the connector move to the start of the solution). The targets
presented are purely visual indicators.

Figure 21: 4 × 11 domino set completed using pattern starting from (7,2)
and ending at (5,1) where the green lines are the first time around the board,
the orange lines the second time around the board and the blue lines the
connecting moves between the two halves of the board.

75 DOI: 10.36838/v7i3.12
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pathway because it cannot end on the color it started on. This

applies to all boards with an odd number of squares.

Figure 23: 5 × 5 (M = 5) Figure 24: 5 × 6 (M = 6)

solution solution
Figure 29: 5 × 5 board in CAP Figure 30: 5 × 6 board in CAP
program. The cells with solutions program. Any cells with a tick (all
form a checkerboard pattern. of them) demonstrate a Knight’s
Tour starting on that square exist.

General Hamiltonian Path Solutions for Every Board:

Theorem 6: A Hamiltonian path exists for every m × n
board besides the boards: 1 × m, 2 × m, 3 × (3,5,6) and 4 × 4:
Figure 25: 5 × 7 (M = 7) Figure 26: 5 × 8 (M = 8) solution 1 × m and 2 × m boards can trivially be seen to have no solu-
solution tions, while the CAP solver can be used to prove the invalid
cases of 3 × m and 4 × m boards.

Figure 31: CAP proofs of non-existence of open Knight’s Tours on various

boards: 1 x m is left as an exercise to the reader, since currently CAP doesn’t
support m = 1 board sizes.

All viable boards can be written as a composite of smaller

boards. Compositing 3 × n boards and 4 × n boards, simply
stacking and connecting them on top of each other, allows for
Figure 27: 5 × 9 (M = 9) solution the creation of any board. The numbers six, seven, and eight
can be written as the sums of threes and fours 3+3,3+4,4+3
respectively. These numbers can be written as 3(2),3(2)+1,and
For Figure 27, the colors are arbitrary but show an interest- 3(2)+2. Simply adding any a multiple of three, in this case, 3
ing separation between the 'left half ’ solution and the right × n boards generates the equations 3(2+a),3(2+a)+1,3(2+a)+2,
half solution. where a ∈ N that represents every possible number greater
Given these solutions, it can be shown that it is possible to than five. Adding multiples of three is important as any 3 × n
connect solutions to extend a board’s width, increasing m by board can be stacked in directions perpendicular to any board
intervals of five, six, seven, eight, and nine (corresponding with that can composite. This means all boards that can be com-
known solutions, as presented above). Since the span (over posited can be extended both horizontally and vertically by
addition) of the set of m values already solved includes all in- multiples of three. Combining this with the proof for 3 × m, 4
tegers greater than five (e.g. 16 = 9 + 7), you can construct a × m and 5 × m boards prove the theorem ‘A Hamiltonian path
solution for a 5 × m board for all m greater than or equal to five. exists for every m × n board besides the boards: 1 × m,2 × m,3
Hence, a 5 × m board contains a Knight’s Tour for m greater × (1,2,3,5,6) and 4 × (1,2,4)’.
than or equal to 5. Analyzing u × v boards with a (u-2a) × (v-2a) sized rectan-
Additionally, using CAP it was observed that all even boards gles removed from the center:
where m>5 have a solution on all start locations, and all odd m This section focuses on an analysis of chess boards with a
≥ 5 solutions formed a checkerboard pattern (with a solution rectangular shape removed in the center (marked in red). This
on the bottom left & symmetrically the corners as expected). section of the paper focuses on analyzing u×v chess boards with
The reason that this checkerboard shape happens is because a centrally removed (u-4) × (v-4) square. Exploring how the
every Hamiltonian path with an odd number of squares has removal of this square divides the board into four rectangles
an even number of moves, meaning the path must end on the and considers boards with specific dimensions, particularly
same color square it started on. Odd-sized boards require the those with a (u-2a) × (v-2a) removed rectangle
path to use k squares of one color and k+1 squares of the other.
Therefore, the color that has fewer squares on the board (in the
Figures above the white squares) will not have a Hamiltonian

DOI: 10.36838/v7i3.12 76
 ijhighschoolresearch.org

Analyzing u × v boards with a (u-4) × (v-4) sized rectangle as a connected graph. In other words, we will restrict our re-
removed from the center: search to removed rectangles of the form containing removed
width =u-2a and removed height =v-2a from the center of the
board.
For rectangular boards, we have proven that for any m × n
board where m,n ≥ 3, there exists a solution besides the 3 × (3,5
or 6) board. The reason for this can be seen in the fact that it is
not considered a connected graph, with the square at the cen-
ter of the board being allocated with a degree of 0, meaning it
has no connecting squares. Using this, it can be stated that any
u × v*a where a ≥ 3 has a path as they comprise m × n rectan-
gles that can connect with each other.
Figure 32: u × v board with a (u - 2a) × (v - 2a) rectangle removed, creating The reason 2 × m boards do not have paths is that they can
4 separate rectangles, 2 blue rectangles of size u × a and 2 green rectangles be defined as four different connected graphs, as each square is
of size a × v - 2a, representing the basis for the proofs used throughout this of degree two and cannot connect to other sets.
section.

Firstly, a solution for a u×v board where a centered rectan-

gle size (u-4) × (v-4) has been removed is investigated, or in
other words analyzing boards of size u × v where u,v ∈ { x ∈
N where x ≥ 5}, and v ≥ u with a rectangle of size (u-2a)×(v-
2a), where a is the number of rows between the edges of the
board and the removed rectangle, for a ∈ N where a<u/2≤v/2 .
A visual evaluation shows that the removal of a rectangle from
the center of a board will result in the board being divided into
four rectangles: two rectangles of size 2 × u and two rectangles
of size 2 × (v-4). The inner removed rectangle will have the Figure 33: A specific example of a 8 × 8 * 3 board with an open tour.
vertices (1+a,1+a),(1+a,v-a),(u-a,1+a),(u-a,v-a).
Removing a (u-2a) × (v-2a) sized rectangle from the center
of a board will divide it into four rectangles, two rectangles of
size u×a (the blue rectangles in Figure 32) and two rectangles
of size (v-2a) × a (the green rectangles in Figure 32). The proof
for any subdivided rectangles that are of a size greater than
u × 3 can be solved using the general solution for rectangu- Figure 34: a 2 × 8 board, coloured in such a way as to demonstrate the four
lar boards found earlier, meaning this section will be divided distinct connected graphs (4 different colours)
into three parts: finding non-Hamiltonian paths for any board However, for every board-sized u × v*2 there is a solution,
with a rectangle removed, finding Hamiltonian paths when but the method is different from the one given before; where if
a=2, and finding paths when a ≥ 3. It is important to note that four cells in a square shape can be proven to be able to all reach
for both sections below, the notation u×v *a indicates the size each other. On a u × v*2 board there will be a path around the
of the board and the size of the rectangle removed from the board. This is because the individual rectangles that the u × v*2
center of it. boards are divided into all contain four individual connected
Paths for any Board with a Rectangle Removed: graphs that can be passed through one at a time.
For a path to exist on any board, the board must be a con- If every vertex at one of the rectangles can be reached, then
nected board. In graph theory, a graph is connected when there all four graphs can be connected, and therefore, that 2 × u sec-
exists a path (one or more continuous edges) from every vertex tion of the board can be passed through. Therefore, starting
to every other vertex, meaning that there always exists some in a 4-celled square and reaching every cell within that square
set of edges that can connect any two vertices. From this, it can proves that a path exists around every u × v*2 board. It can also
be observed that starting at any vertex, we can reach any other be proven that a 4-celled square in the corner of a u × v*2 can
vertex on a graph. As an application of these concepts to the have every cell reach every other cell within that square. From
Knight’s Tour problem, it can be understood that any board this, it can clearly be seen that a path exists around every u ×
where all vertices can be represented as a connected graph will v*2 board.
have a path.
The inherent complexities of the Knight’s Tour are exem-
plified by the fact that a king being able to move around a
chessboard freely does not make it connected. There exist
infinitely many variations of possible boards with removed
squares. There can be no definite proof regarding the eligibility
Figure 36: 2 × 7 board with different colours to show different paths
of boards, besides the element of attempting to represent them around the board.

77 DOI: 10.36838/v7i3.12
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Combining this with the statement that there exists a path meaning that they are simplistic in their possible paths, only
around every u × v*a board, where a ≥ 3, shows there is a path having one direction/square to move to after they have been
for every board of size u × v*a where a ≥ 2. This is only one moved into (See Figure 38).
specific case of a special board, and further explorations into a
variety of special board patterns could be conducted, but this
paper will not examine any more arbitrarily chosen special pat-
terns, instead now focusing on Hamiltonian paths for u × v*a
boards.

Figure 37: 8 × 8 * 2 board showing two specific cells with a degree greater
than two (allowing for set switching).

Because these squares are essentially ‘passing squares’, the

Figure 35: 8× 8 * 2 board where it is shown every cell in a 4-celled corner only importance of these squares is how many there are, as
square can be reached from any other cell in the corner square, with the path they just act as intermediary squares between the corners of
from each cell in the corner square to the other represented in a different the board. Therefore, proving they can be extended will allow
colour. existing solutions for u × v*2 to be extended, proving the ex-
Analyzing General Hamiltonian Path Solutions For u × istence of general solutions. These pathways can be extended
v*2 Boards: by four squares. The reason for this can be seen in how hori-
Theorem 1. A Hamiltonian path exists on every board of zontal knight moves work (Figure 38). Two horizontal knight’s
size u × v*2 , where u=4k+1 and v=2l+1 or u=2k and v=2j+1 moves on a 2×m board will create a simple pattern, where if
where k,l,j∈N,where j≠1,2 and l≠1: a knight starts on the square (a,b) it will have the following
This theorem uses induction to prove the general case stated move pattern:
above. Removing a rectangle of the size (u-4) × ( v-4) from a u (a,b)→(a ± 2,b ± 1) → (a ± 4,b)
× v board will result in various 2 × u rectangles, as can be seen
in Figure 32. While a singular 2 × n rectangle does not have a
solution, these four connected rectangles can have a Hamilto-
nian solution.
Examining the properties of 2 × u boards shows the basis for
this proof. Each color shows a self-contained path, a set that Figure 38: a 2 × 9 board with a move starting from square (1,2) and
cannot connect to any other set. When each path is combined, finishing on square (9,2). The red lines indicate how the original two moves
were extended by four columns by adding in an intermediate two moves that
every vertex is visited exactly once. Because the u × v*2 board
extended the path by two squares.
has four 2 × m rectangles arranged in a quasi-circular motion,
there will be some boards where the four sets can be complet- This indicates that a knight can move from square (a,b) to
ed through four ‘circuits’ around a board. A circuit must reach square (a ± 4,b). This notion is a vital component of this proof
every square in a set and then switch over to another set for as lengthening a board by four squares will not affect the final
another circuit. Looking at Figure 36, shows that at any point location of a set. From what was explained before about the
on the board, there will be a square of four cells where each cell four different sets as four cells in a square, the entirety of the
is part of a different set. As this happens at any point of a 2×m four sets will not be impacted if an extra four rows are added.
board, what this means is that the four sets together form every Below, Figure 39 shows both a 5 × 7 board and a 9 × 7 board
square of the board in these rectangles. divided into four circuits with each different color representing
The solution for this section relies on two main sections of its own circuit. The corner squares have the same arrangement
these boards: Firstly, the corner squares, groupings of four cells of colors, indicating no change has occurred due to this exten-
in each corner of the board that will be in the same form on ev- sion method. Because the arrangement of sets in the corner
ery single board and can therefore be used as part of a general squares is the basis of any u × v*2 board, therefore extending
pattern. These corner squares’ bordering cells that have degrees the board in any direction by rows will provide a Hamiltonian
greater than two, giving them the ability to switch between path.
sets. If a Hamiltonian path starts in the bottom left corner Therefore, if a solution exists on a certain board u × v*2, then
square, all circuits will conclude and end in that bottom left a solution exists on the board (u+4a) × (v+4b)*2. Using this
corner square. basis, a variety of boards can be proved. A gallery listed be-
Secondly, the inner pathways, the cells in between each cor- low will show examples of boards where u=4k+1 and v=2l+1,or
ner square, have a simple structure and can be extended by u=2k and v=2j+1 where k,l,j∈N,where j ≠ 1,2 and l ≠ 1. Using
a certain length. These squares will all have a degree of two, this and the notion that every board can be extended

DOI: 10.36838/v7i3.12 78
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by four squares in any direction proves the theorem stated in Any board where the subdivided rectangles all have a Ham-
“Extending 4×m for Further General Solutions; 4×m Boards iltonian path will contain a Hamiltonian path. Essentially, the
and Hamiltonian Paths”. larger the board grows, the more likely a Hamiltonian board
exists. As stated before, a u × v*a board will contain four rectan-
gles of two sizes: two rectangles of size u × a and two rectangles
of size (v-2a) × a. As larger rectangles are much more likely to
have a solution, v ≥ u ≥ 7, v must be greater than u so that the
rectangle v-2a × a is as large as possible. The reason why both
u and v must be ≥7 is because for (u-2a) × (v-2a) boards where
a ≥ 3, both (u-2a) and (v-2a) must be greater than 0, ∴ u,v ≥
7. To prove a solution exists, it must be proven that (v-2a) × a
and u × a boards have a solution. It is important to note that
the following proof does not state every possible Hamiltoni-
an path but states cases for which there will be Hamiltonian
paths. There may be some boards that this proof fails to evalu-
ate that other methods succeed in finding a Hamiltonian path
for. As there are only solutions for m×n boards where m ≥ n ≥
Figure 39: A 9 × 7 * 2 and 9 × 5 * 2 board placed next to each other with
3, it can be generally stated that a solution exists when:
each circuit around the board coloured in a different colour to showcase how
adding rows doesn’t affect the patterns of the circuits. v-2a ≥ 3
v ≥ 3+2a
Gallery of Boards: (v-3)/2 ≥ a
Since the boards below show solutions for (4k+1) × (4l+1) Limitations of this solution:
and (4k+1)×(4l+3) boards, it can be simplified to say that a The problem with this solution is that it is incomplete: some
solution exists for every (4k+1)×(2l+1) board. Hamiltonian Paths are not found or discovered that other
Figure 41 (shown below) shows solutions for both 4k × (4l methods of inference find. According to this formula, as a ≥
+ 1) * 2 boards and for 4k × (4l + 3) * 2 boards; this can be 3 and a solution does not exist for a 3 × 3 board, v ≠ 9 when
simplified to state that a solution exists for every 4k × (2l + 1) a=3, it can be seen that v>9. For this method to be used when
a ≥ 4,v ≥ 11, meaning the only time v=10, is for when a=3.
* 2 board
Additionally, no solutions can be found when a=3 and v=11,12
as the solutions for the boards 3 × 5 and 3 × 6 do not exist. Fi-
nally, a solution doesn’t exist for a=4 and v=12 as there are no
solutions for 4 × 4 boards. Since a solution exists for every u×a
board where u ≥ 7 (and a ≥ 3) there are no special cases to be
concerned about. Thus, a Hamiltonian path exists on every u ×
v*a board where: u ≥ 7,a ≥ 3 and v ≥ 3+2a, besides the boards
u × (9,11,12) * 3 and u × 12*4.

Figure 40: 9 × 9 board showing a solution for (4k + 1) × (4l + 1) * 2 boards

and 9 × 7 board showing solutions for (4k + 1) × (4l + 3) * 2 boards

Figure 42: Solutions / Hamiltonian Paths for 8 × 8 * 2 board shown using

CAP solver
There is an issue with the above solution, which is the fact
Figure 41: 8 × 7 * 2 showing a solution for 4k × (4l + 3) * 2 boards and 8 × 9 that it’s not categorically true for every single board. The above
* 2 board showing a solution for 4k × (4l + 1) * 2 boards solution states that the boards 7 × 7*3,7 × 8*3 ,8 × 8*3,9 × 8*3,9
General Hamiltonian Path Solutions for u × v*a Board × 9*3 do not have a solution, contradicting the results pro-
Where a ≥ 3: duced by CAP for boards. To see this, the example board 8 ×
Theorem 2. A solution exists for u × v*a boards where (v- 8*3 was used. For this board, both u,v=3 and a=3, contradicting
3)/2 ≥ 3 ≥ a and v ≥ u, however, other boards will have solutions: the statement that v-2a ≥ 3 as 8-2(3)=2.

79 DOI: 10.36838/v7i3.12
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Solutions for 3D Boards: Miscellaneous Board Observations Using CAP:

Theorem 7. A Hamiltonian path exists for every board of
size a × b × c where the boards a × b,a × c and b × c exist:
This section will focus on 3D boards that can be represented
as unfolded 2D boards. This will specifically generalize solu-
tions for rectangular prisms but will give some standard ideas
for other board shapes. Prism can be created by folding togeth-
er a simple 2D shape template on a piece of paper (see Figures
44 and 45).

Figure 43: Unfolded 3D shapes10

Through this, a path around a 3D prism can be represent-

ed as multiple rectangles that can be linked by Hamiltonian
paths. Special prisms such as triangular prisms can be proved
to exist if a Hamiltonian path exists for whatever special face
is being used. Note that this section will only consider the sur-
faces of the 3D objects. Specifically for this section, we will
find the general cases in which a rectangular prism of size a
× b × c exists. A rectangular prism will always consist of three
types of rectangles, each appearing twice. These rectangles will � Conclusion
be of size a × b,a × c and b × c. Therefore, a solution will exist In this comprehensive study on Knight’s Tours across a
for a Hamiltonian path if a solution exists for the smaller rect- spectrum of chessboard configurations, we determined that for
angular boards. all n×n boards where n ≥ 4, and m × n boards with m, n ≥ 5, a
To be clear for this section, this method will work when path exists. Extending beyond conventional board layouts, the
using a specific 2D shape that becomes a rectangular board investigation delves into configurations with central rectan-
due to the way connecting boards work. The problem with the gles removed, yielding solutions to these board arrangements
Figure above is that some of the smaller rectangles would have and expanding the conventional understanding of Knight’s
to be traveled through twice for a solution to exist. Using the Tour layouts. This study also covers several general theorems
specific board shape shown below, smaller rectangles can have used to solve different board types. These theorems—rang-
their Hamiltonian paths connected, proving a Hamiltonian ing from specific solutions tailored for 3 × m, 4 × m, 5 × m,
path exists around every a × b × c board where the boards of a and 6 × m boards and their application to m×n boards later
× b,a × c and b × c exist. to complex 3D board theorems generated using 2D theorem
foundations—provide a robust framework for understanding
Hamiltonian paths in varied contexts. Collectively, these find-
ings not only cement foundational principles in graph theory
and combinatorics but also pave the way for novel methodol-
ogies and applications in these fields. This exploration stands
as a testament to the intricate interplay between mathematical
theory and practical application.
� References
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m Situs Pertinentis; 2018. https://scholarlycommons.pacific.edu/
cgi/viewcontent.cgi?article=1052&context=euler-works.
2. Levin, O. Euler Paths and Circuits. discrete.openmathbooks.org.
https://discrete.openmathbooks.org/dmoi2/sec_paths.html.
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m Situs Pertinentis; 2018. https://scholarlycommons.pacific.edu/
cgi/viewcontent.cgi?article=1052&context=euler-works.
Figure 44: Unfolded rectangular prism that will create a cube of size 3 × 4
4. Brown, A. J. Knight’s Tours and Zeta Functions. https://doi.org/1
× 7.
0.31979/etd.e7ra-46ny
5. Wilson, R. J. Introduction to Graph Theory Fourth Edition. https:
//www.maths.ed.ac.uk/~v1ranick/papers/wilsongraph.pdf.
6. Réveillac, J.-M. Elements of Graph Theory. Optimization Tools f
or Logistics 2015, 11–29. https://doi.org/10.1016/b978-1-78548
-049-2.50002-5.
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7. Parberry, I. An Efficient Algorithm for the Knight’s Tour Problem

. Discrete Applied Mathematics 1997, 73 (3), 251–260. https://do
i.org/10.1016/s0166-218x(96)00010-8.
8. Parberry, I. An Efficient Algorithm for the Knight’s Tour Problem
. Discrete Applied Mathematics 1997, 73 (3), 251–260. https://do
i.org/10.1016/s0166-218x(96)00010-8.
9. Douglas Brent West. Introduction to Graph Theory; Pearson: Uni
ted States, 2018.
10. Unfolded nets (128 x 128 px) (256 x 64 px). Canva. https://www.
canva.com/design/DAGem_rkHNo/dNIrzyLALzPwZK9FP3R
uYg/edit (accessed 2025-02-09).
� Authors
Noah Schmidt is a year 12 student at Emmanuel College who
greatly enjoys mathematics, taking many opportunities outside of
required school to further learn about math either through early uni-
versity courses in coding, calculus, and physics or self-learning aspects
of graph theory and abstract algebra, as well as encouraging math
participation in school through cofounding math tutorials and a math
club.
Caleb Yates is a Year 12 student at Emmanuel College, interested
in Computer Science and passionate about programming in Rust. He
has demonstrated proficiency in coding through various projects such
as CAP and SmilePal, which won the Mayor’s Technology and Inno-
vation Award in 2022.
Jordan He is a year 12 student at Emmanuel College who cur-
rently takes Specialist Mathematics and is interested in researching
economic networks involving graph theory and statistics. He is a
member of the mathematics club at his school and a researcher cur-
rently studying housing policy models.

81 DOI: 10.36838/v7i3.12
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RESEARCH ARTICLE

Examining the Fast Fashion Industry and the Multifaceted

Oppression of Downtown Los Angeles Garment Workers
Ileana Nguyen-Garay
Chadwick School, 26800 S Academy Dr, Palos Verdes Peninsula, CA 90274, USA; [email protected]

ABSTRACT: The fast fashion business model used by well-known fashion brands demands high production rates at low prices
to maximize profits. This, however, has detrimental effects on the environment and comes at the expense of the rights of garment
workers. Wage theft and abuses of power, among other serious labor law violations, are commonplace. While global issues are
well publicized, little attention has been paid to garment work issues in the United States. Downtown Los Angeles’s Fashion
District comprises 83% of the cut-and-sew manufacturing in the U.S. This current field study was conducted using a semi-
structured interview with the Garment Workers Center, a garment workers’ rights organization, to highlight current issues with
the Los Angeles garment manufacturing industry. Not surprisingly, L.A. garment workers, primarily women, people of color, and
immigrants, are paid below minimum wage, face wage theft and intimidation, and work in unsafe conditions. Although legislation
ensuring proper wages and safe working conditions has been passed, enforcement has been difficult. Continued efforts are needed
to address these persistent injustices.
KEYWORDS: Behavioral and Social Sciences, Sociology and Social Psychology, Workers’ Rights, Women’s Work,
Gentrification, Fast Fashion.

� Introduction � Methods
Most people are aware of fast fashion, a business mod- Study Design:
el infamous for its adverse impact on the environment that This study consisted of a semi-structured interview over
maximizes profits by maximizing and cheapening production. Zoom with Communications Manager, Jonathan Coleman, for
Globally, the fashion industry produces 92 million tons of tex- the Garment Workers Center, an organization that advocates
tile waste and accounts for 20% of global wastewater each year.¹ for Downtown Los Angeles (L.A.) garment workers.⁹ Jona-
The exploitation of garment workers in terms of low wages than Coleman has worked as the Communications Manager
and dangerous working conditions is also well documented.² for the GWC since 2022. Questions (Table 1) were admin-
However, an often overlooked reality of fast fashion is the dis- istered by the author directly to Mr. Coleman, and responses
proportionate impact of climate change and exposure to toxic recorded during the interview were subsequently paraphrased
chemicals on low-income communities.³-⁵ Factories that create in this paper. Data from journal publications and news articles
pollutants are often strategically placed in these communities. were used to provide additional insight into Mr. Coleman’s re-
Socioeconomic vulnerability exposes inhabitants of these com- sponses.
munities to health hazards while also not providing adequate The objective of this study was to describe the current work-
resources to combat them. ing conditions of garment workers in Downtown L.A. and
One does not have to search far to find these issues. Count- describe the role of the Garment Workers Center in protecting
less immigrant women work in garment manufacturing jobs in workers’ rights. We also explored the compounding and inter-
the Downtown Los Angeles Fashion District. Paid cents per connected impact of immigration, race, and gentrification of
piece, workers toil for long hours in small, cramped spaces with L.A. garment workers.
little ventilation, access to water, and filled with health haz- � Results
ards, which have earned these factories the appropriate label of The Garment Workers Center in Los Angeles:
“sweatshops.”⁶ In addition, widespread gentrification efforts in Founded in 2001, the Garment Worker Center is a 501(c)(3)
low-income black and brown neighborhoods have made hous- non-profit organization whose mission is to organize low-wage
ing unaffordable for its current inhabitants whose wages are garment workers in the fight for social and economic justice for
unable to cover rent and other basic essentials for survival.⁷,⁸ tens of thousands of Los Angeles garment workers. The orga-
This current field study examined the effect of exploitive prac- nization is headed by a board of directors and staff of various
tices of the Downtown Los Angeles (L.A.) fashion industry professions with backgrounds in law, labor organization, com-
on garment workers. It also explored the compounding and munications, small business, fashion design, and public affairs.
interconnected impact of immigration, race, and labor on L.A. The GWC provides legal assistance and general counseling for
garment workers. immigrant workers, women of color, and their families who

© 2025 Terra Science and Education 82 DOI: 10.36838/v7i3.13

 ijhighschoolresearch.org

are impacted by unfair employment practices in the fash- Effects of Gentrification of Downtown Los Angeles on
ion industry. The GWC also develops leaders who demand Garment Workers:
enforcement of strong labor laws and accountability from Currently, the majority of Downtown L.A. garment work-
manufacturers and fashion brands. Lastly, the GWC has col- ers reside in the Downtown neighborhood itself as well as
laborated with politicians to sponsor bills protecting garment surrounding areas including the Westlake, MacArthur Park,
workers’ rights. Most recently, the GWC collaborated with and East L.A. neighborhoods, as stated by Jonathan Coleman.
Senator Kirsten Gillibrand (NY) and House of Representative Some of the poorest areas in L.A., these densely populated
Carolyn Maloney (NY) to introduce the FABRIC Act/S.4312 neighborhoods are inhabited primarily by Latinos. The vast
to protect American garment workers and revitalize the U.S. majority of rent and the neighborhoods are made up of pri-
garment industry.⁹,¹⁰ marily multifamily properties and condos. Jonathan Coleman
Job Conditions of Garment Workers in Los Angeles: added that some workers, especially those residing in Down-
According to Jonathan Coleman, L.A. garment workers face town L.A., have been forced to relocate due to increased rents.
unfair employment practices on an almost daily basis. They The lack of affordable housing for L.A. garment workers is
work long hours and are either prohibited from taking breaks a continuing focus of the GWC. In 2021, the GWC learned
or pressured into not taking breaks at all; it is not uncommon about the DTLA40 Community Plan Update,¹³ launched in
to hear of a workday where a worker did not drink water, go 2014 and adopted by the Los Angeles City Council. The plan
to the bathroom, or suffer job-related injuries that were not intends to revitalize the Downtown area and accommodate fu-
unattended to. Although entitled to minimum wage, L.A. ture growth of business and housing. The Plan creates zoning
factories often dodge giving proper wages by paying garment for 100,000 additional residential units downtown and would
workers a piece rate for garments sewn; this results in work- have allowed residential development in areas traditionally oc-
ers being paid 2 to 3 cents per piece. The GWC discovered cupied by the garment industry. This sparked concerns about
high frequencies of wage theft in factories producing clothing displacement and job loss. The GWC lobbied for amendments
for well-known companies, including Forever 21, Ross Stores, to the Plan that included protections for an estimated 20,000
TJ Maxx, Windsor, Nordstrom, Macy’s, Burlington, Dillard’s, downtown garment workers, an increase in the amount of
and Urban Outfitters. Many factory floor managers also use manufacturing space required for new housing developments
several ways to steal wages from garment workers, including in the Fashion District, and a requirement to include freight
charging a fee for workers to collect their paycheck, using a elevators and loading docks for manufacturing. The updated
cashier’s check or cash as payment, or just not recording a plan was approved by the Council’s Planning and Land Use
payroll at all. To complicate matters, retailers would provide Management committee in May 2023.
only a fraction of the money contractors needed to pay their � Discussion
employees; garments were made at a lower cost, and workers History of Garment Work and Women’s Role in the Field:
earned subminimum wages. In many of these cases, the big To fully understand how the role of women in garment work
retailers passed the blame down the supply chain and often has developed to the state today, it is important to first look
evaded accountability. into the origins of mass-manufactured clothing production.¹⁴
Currently, the Los Angeles garment manufacturing work- Ready-to-wear garments began as clothing for the poor and
force is approximately 60% women, as estimated by Jonathan oppressed. Dating back to the 1840s, mass-manufactured
Coleman. Given that many L.A. garment workers are un- clothing was most often produced for sailors and enslaved
documented middle-aged to older Guatemalan and Mexican people. Businesses offered a service to plantations where they
women, Mr. Coleman states that factory floor managers will would ship large quantities of cheaply made one-size clothing.
threaten job loss, violence, and deportation to prevent report- Seamstresses, often women, were forced to produce extremely
ing of abusive workplace practices. Language barriers and high quantities of clothing for low wages, introducing the ex-
overall lack of knowledge of civil rights also make immigrant ploitative aspects of the new industry.
garment workers easy targets for exploitation. A major leap forward for ready-to-wear clothing came with
Jonathan Coleman stated that these exploitative practices the advent of standard sizing. Mass body measurement sizing
prompted the passage of California Senate Bill 62 (SB-62) in data for men were obtained during the Civil War and refined
2021.¹¹,¹² The GWC co-authored Senate Bill 62 with State during the Spanish-American War and World War I. Mass
Senator Maria Elena Durazo. This bill eliminated piece-rate industrialization made ready-to-wear clothing more accessi-
wages in the garment manufacturing industry, required a legal ble to the public. By the 1880s, women’s clothing was being
minimum hourly wage for workers, and ensured that brands mass-produced in distribution networks organized initially
were held liable for labor law violations. He also added that by German-Jewish immigrants. By 1920, women’s fashion
the enforcement of these regulations has just barely started, comprised 76 percent of the ready-to-wear industry and rep-
three years later, and that workers in California continue to be resented a convenient luxury afforded only by wealthy elites.
paid per piece under the table and face wage theft in countless Women’s Garment Work and Devaluation:
other forms. It is undeniable that gender has played a significant role in
devaluing garment work. Women have long predominated in
trades such as teaching, service, domestic work, nursing, and
garment making.¹⁵ Western gender norms suggest that women
83 DOI: 10.36838/v7i3.13
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are naturally and biologically talented in these fields because Macy’s, Burlington, Fashion Nova, Urban Outfitters, Neiman
of the apparent dainty, feminine, or motherly nature of these Marcus, and Forever 21.²²-²⁴ Workers in this industry are in-
professions. Women’s work has traditionally been viewed as separably tied to undocumented immigrants making it fertile
supplemental to that of her husband’s “breadwinning” work.¹⁶ ground for wage theft, worker intimidation, and unsafe work-
Both the idea of women’s work being supplemental and the ing conditions. In what has been described as modern-day
belief that traditionally women-dominated fields are innately slavery, workers in these garment factories toil in unsafe con-
feminal abilities have contributed to the overall devaluation ditions and are paid extremely low wages.²³-²⁵ CBS News
of women’s work. In the case of garment work, since women reported that a 2016 U.S. Department of Labor investigation
sewed clothing for their families before the age of mass pro- found pay violations in 85% of the L.A. garment shops inves-
duction, it is believed by the patriarchal society that the ability tigated.⁶ Garment workers described working conditions that
to cut and sew clothing is a natural behavior in women rather included a lack of air conditioning, cockroach infestations, and
than a learned skill and not deserving of high wages.¹⁶ unattended job-related injuries. Workers were paid on a piece
The Fast Fashion Business Model: rate system and earned approximately 5 to 6 cents for each
The American advertising industry, born in the 1920s, also garment sewn. To earn the minimum wage rate of $15 per
played a critical role in the fantasy ready-to-wear industry.¹⁴ hour, a worker would have to sew 300 pieces in an hour.
Displayed in urban department stores and mailed to people in Many hailed the passage of the Garment Workers Pro-
the countryside, the advertising industry promoted fantasized tection Act, SB-62, which made California the first state to
visions of ready-to-wear clothing to a wider and younger audi- prohibit a piece-rate wage system, made all parties involved
ence. Some of the first consumers of mass-produced fashions in garment facturing liable for ensuring proper wages, and
were poor shop girls and garment workers. provided a system for workers to recover stolen wages. De-
The mass manufacturing model has morphed over time into spite the passage of SB-62 in 2021, unlawful wage practices
what is now known as the fast fashion business model fueled persist in California. In a survey of more than 50 Southern
by social media. TikTok, a widely popular short-form video California garment-sewing contractors and manufacturers
app, is a major culprit of the casual bombardment of adver- conducted by the U.S. Department of Labor, 80% had violated
tising that has contributed to a hyper-consumerist culture. the Fair Labor Standards Act.²⁶ More than 50 percent of the
TikTok uses an adaptive and responsive algorithm to bring the time, employers were also found to have illegally paid work-
viewer extremely tailored content. Companies take advantage ers part or all their wages off the books, with payroll records
of the highly addictive nature of TikTok to advertise brand either deliberately forged or not provided. The survey also
deals with influencers and sell directly to users through the found 32% of contractors paying garment workers piece-rate
e-commerce marketplace.¹⁷,¹⁸ This form of advertisement has wages, a practice prohibited by the State of California on Jan
given rise to microtrends – a short-lived trend that focuses on 1, 2022. Contractors and manufacturers included in the sur-
achieving a certain aesthetic and usually does not last longer vey produce garments for sale by national retailers, including
than a few months.¹⁹ Trends and styles are given appealing Dillard’s, Neiman Marcus, Nordstrom, and Stitch Fix, among
names and prey on users’ insecurities regarding their appear- others. California’s first arrest for garment industry wage theft
ance. The constant exposure and psychological pressure to occurred on October 12, 2022.²⁷ The California Labor Com-
follow the latest trend, in turn, drives excessive consumerism. missioner and the Los Angeles District Attorney’s Office
As trend cycles shorten, clothing is worn very few times before announced felony criminal charges against Lawrence Lee, a
being discarded. This pattern goes hand in hand with the de- co-owner of a garment manufacturing business, and Soon Ae
terioration of clothing quality. The number of times clothing Park, a garment contractor with a history of stealing wages.
is worn before being discarded has decreased by around 35% Their alleged misdeeds included compensating workers with
since 2008.¹ To produce large quantities of low-priced cloth- as little as $6 per hour, many earning an average of $350 for
ing to satisfy ever-increasing demand, manufacturers produce a 50-hour workweek. Mr. Lee also failed to provide worker’s
lower quality products, utilize more synthetic materials, and compensation insurance coverage and information about paid
underpay and overwork employees.²⁰ sick leave.
Today’s Garment Work Industry in Los Angeles: � Conclusion
For years, the “Made in USA” movement rested on the be- At its most basic level, fast fashion involves producing mass
lief in better quality compared to foreign competitors. There quantities of trendy, low-quality, inexpensive clothing. The
was also an assumption that garments were produced more surge in clothing production and consumption, fueled by so-
ethically than their lower-priced foreign competitors. These cial media, has had deleterious effects on the environment and
assumptions about the U.S. garment industry are unfortunate- garment workers. While unfair wage practices and dangerous
ly false. working conditions in the garment industry in countries such
Tucked away in Downtown Los Angeles’s Fashion District is as China and Bangladesh have been highlighted in mainstream
83% of the cut-and-sew manufacturing and 58% of registered media, the “hidden” cut-and-sew industry located in Down-
garment industry contractors in the United States.²¹ These town Los Angeles has been ignored until recently. Workers in
factories, located in the cramped warehouses, basements, and the L.A. garment manufacturing industry face wage violations,
upper floors of buildings, are owned and used by the biggest intimidation, and unsafe working conditions similar to work-
names in fast fashion: Ross, TJ Maxx, Windsor, Nordstrom, ers in other countries. These ongoing issues are shouldered by
DOI: 10.36838/v7i3.13 84
 ijhighschoolresearch.org

women, people of color, and immigrant workers. Organiza- 9. Garment Workers Center Home Page. https://garmentworkercenter.
tions such as the Garment Workers Center directly support org/ (accessed 2024-11-04).
L.A. garment workers by building a culture of solidarity within 10. The FABRIC Act Home Page. The FABRIC Act (accessed 202
the industry, recovering unpaid wages, enforcement of labor 4-11-04).
11. California Legislative Information, Bill Information, Senate Bill
standards, and partnering with politicians to put forth workers
No. 62 published September 28.2021. https://leginfo.legislature.c
protection legislation. Despite successful passage of legislation a.gov/faces/billNavClient.xhtml?bill_id=202120220SB62 (access
such as California Senate Bill 62, enforcement has been de- ed 2023-11-04).
layed and difficult. Continued efforts are needed to address 12. State of California Department of Industrial Relations, Labor C
these persistent injustices both in the U.S. and globally. ommissioner's Office, Garment Manufacturers. Garment Worker P
rotection Act Frequently Asked Questions, updated February 2022 ht
� Acknowledgments
tps://www.dir.ca.gov/dlse/Garment/ (accessed 2023-11-04).
First and foremost, I would like to acknowledge and express
13. Los Angeles City Planning, Plans and Policies. Downtown Los A
my gratitude to my mentor, Dr. Laura Kenner, Ph.D., whose ngeles Community Plan Update Home Page, updated 2024 https://p
support and guidance throughout the entire process made the lanning.lacity.gov/plans-policies/community-plan-update/down
completion of this paper possible. Her patience and feedback town-los-angeles-community-plan-update#about (accessed 2023
inspired me to push myself and continue improving. -10-30).
I also want to thank Jonathan Coleman of the Garment 14. Thanhauser, S. (2022, January 17).A Brief History of Mass-Manuf
Workers Center for his insight. His willingness to discuss the actured Clothing. Literary Hub. https://lithub.com/a-brief-history
work of the Garment Workers Center and his experiences with -of-mass-manufactured-clothing (accessed 2023-11-03).
the organization helped me immensely in writing this paper. 15. Limani, D.; Sodergren, M.C. (2023, November 7). Where Women
Work: Female-Dominated Occupations and Sectors. ILOSTAT. https:
Furthermore, I wish to acknowledge Dr. Carla Macal for
//ilostat.ilo.org/blog/where-women-work-female-dominated-oc
taking the time to discuss her work with me. Her insight and cupations-and-sectors/ (accessed 2023-12-12).
suggestions helped me throughout the research and writing 16. English, B. Global Women’s Work: Historical Perspectives on th
process. e Textile and Garment Industries. Journal of International Affairs
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� Authors
Ileana Nguyen-Garay is a senior attending Chadwick School in
California, U.S.A. She is passionate about social justice as well as eq-
uity and inclusion. She plans to study political science and hopes to
pursue a career in public policy.
Laura Kenner is a feminist scholar who received her PhD in Art
History and Architecture from Harvard University in 2022.

DOI: 10.36838/v7i3.13 86
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RESEARCH ARTICLE

Comparison of Classical and Hybrid Quantum Models in

Secondary Structure Protein Prediction
Quaid Shubin
Windward School, 11350 Palms Blvd, Los Angeles, CA 90066, U.S.A; [email protected]

ABSTRACT: Protein structure prediction (PSP) is one of the most challenging and vital problems in modern biochemistry,
with far-reaching implications for biological research and medical applications, particularly in drug design and disease treatment.
This paper introduces how PSP has been tackled in recent decades, from wet lab experiments to new models like AlphaFold, as well
as their computational limitations. We then present our perspective on how quantum computing can address the computational
challenges in PSP, and investigate classical and quantum approaches for solving a subset of the PSP problem: a binary secondary
structure classifier for protein primary sequences. We evaluate traditional feedforward neural networks against quantum neural
network hybrid models using the CATH dataset. We found that the quantum-classical hybrid model outperformed the classical
model on a 5-trial average, achieving 84.5% accuracy versus 79.75% with 13 input features. These results highlight the significant
challenges in transitioning to tertiary structure predictions, but also the potential and need for further research in the integration
of quantum methods to obtain more accurate predictions in larger, more diverse protein datasets.
KEYWORDS: Biochemistry, Structural Biochemistry, Quantum Computing, Quantum Neural Networks, Machine Learning,
Protein Structure Prediction.

� Introduction the most likely to be observed in nature).⁴ The specific prob-

The self-assembly of cells and structures within biological lem of finding the structure of a protein, given its amino acid
organisms is one of the most studied aspects of biology and bases, regardless of finding the optimal path to that structure,
is done through proteins. A protein's function and ability to is called protein structure prediction (PSP).⁵ The difficulty of
bind to other molecules is determined by its folded three-di- PSP results from the exponentially expanding number of pos-
mensional structure, which results from its primary amino acid sible conformations a protein can adopt as its length increases.
sequence, the polypeptide. The process by which the poly- Along with the exponential search space, prediction algorithms
peptide determines the protein structure is one of the biggest also face problems due to the multitude of overlapping bio-
questions in biochemistry and is known as the “protein struc- chemical interactions that form a protein’s energy landscape.
ture prediction problem.”¹ Understanding how proteins fold is Traditionally, the discovery of new drugs has been ac-
fundamental to the understanding of many biological process- complished through time-consuming and expensive wet lab
es, including understanding the causes of certain diseases and experiments like nuclear magnetic resonance (NMR),⁶ X‐ray
how to design therapeutics. Abnormal protein structures, or crystallography,⁷ and cryo‐electron microscopy.⁸ Realizing their
misfolded proteins, are linked to numerous disorders, includ- shortcomings, researchers turned to deep learning to solve PSP.
ing Alzheimer’s, Parkinson’s disease, Huntington’s disease, and One of the leading deep learning methods is template-based
cystic fibrosis. Many of the drugs used to treat various diseases models. Algorithms like Deepmind’s AlphaFold2, for instance,
target such misfolded proteins, so understanding how the fold- are making progress by using the large database knowledge of
ed protein is shaped, along with back-engineering amino acid the Protein Data Bank.⁹ However, due to their architecture,
sequences from desired structures, holds the key to the design database models are limited to the types of proteins in their
and implementation of drugs that can alter protein function.² training data and struggle to maintain high accuracy when
Generally, knowing how proteins fold can allow for the devel- tested on novel proteins.
opment of any specific protein that can perform any desired Alternatives to these database frameworks are models that
function. attempt to simulate the physics of protein folding. But simula-
The field of protein prediction was based on the idea that all tions also have their own set of problems, including sufficiently
the information needed for protein folding is contained in the accurate computational models (forcefields) and the needed
energy landscape of a protein polypeptide (Anfinsen’s thermo- computational power when scaling protein size.¹⁰ To address
dynamic hypothesis).³ This also forms the reasoning behind the computational size of this problem, we propose turning to a
methods of protein structure prediction, where possible shapes computational system that could potentially handle the size of
(or conformations) of a protein are scored based on their energy the problem: quantum computing. With breakthroughs and re-
level and then sorted from lowest to highest energy levels, with search in quantum computing, and the beginning of theoretical
the lowest energy structure being the most stable (and thus research illustrating the application of integrating quantum ap-
© 2025 Terra Science and Education 87 DOI: 10.36838/v7i3.14
ijhighschoolresearch.org

proaches in studying protein prediction,¹¹ we believe that the solvable in polynomial time. The class of NP-hard problems
integration of quantum computing could lead to more accurate includes those that are at least as hard as the hardest problems
predictions, especially for novel and large protein structures.¹² in NP and often take exponentially more time to solve as the
In this paper, we compare a feedforward neural network size of the input increases. The protein folding problem is NP-
(FFNN) to a hybrid quantum-classical system, which uses a hard because the number of possible shapes that a protein can
quantum neural network (QNN) coupled to a classical output take increases exponentially with its length because any one
layer, in solving a simplified version of the protein-structure amino acid can and will interact with the other amino acids in
prediction problem: a binary classifier. This classifier classifies the chain.¹⁶-¹⁷
amino acid sequences into an alpha-helix (α) or a beta sheet The Energy Landscape of Proteins:
(β). Compared with the problem of predicting full tertiary The theory of energy landscape started with Anfinsen’s
structures (the standard and most computationally challenging thermodynamics hypothesis, stating that all information need-
version of protein folding), secondary structure prediction is an ed for protein folding was encapsulated within the primary
intermediate step in the folding process, though still integral sequence of amino acids and that the protein found its native
to understanding full tertiary structure. Research has shown state by finding the state of lowest free energy.¹⁸ This allows
that the secondary structure is closely tied to the protein's a protein’s final structure to be predicted through its sequence
overall conformation and that incorporating secondary struc- alone if the energy landscape could be accurately modeled and
ture prediction alongside residue-residue contact information traversed.³ Levinthal’s Paradox states that it would be longer
can improve tertiary structure prediction accuracy.¹³ Addition- than the age of the universe for an average-length protein to
ally, coupling the two predictions can enhance the accuracy find its native state. Yet, proteins fold in microseconds.¹⁹-²⁰
of secondary structure predictions.¹⁴ Through these trials, we Energy landscape theory answers this.²¹ It describes protein
illustrate that quantum-classical hybrid models have the po- folding as a trip through an energy landscape funnel (Figure
tential for predicting protein structures and hope to inspire 1). The unfolded protein at the top of the funnel has high en-
future research into quantum integration in PSP. ergy, entropy, and possible conformations and is then driven
This work reviews the history and analysis of protein struc- by energetically favorable interactions as it folds. The protein
ture prediction to illustrate the limitations of database and follows these interactions until it reaches its native folded state
physics-based classical machine learning methods. It then at the bottom of the funnel.²²
introduces quantum computing fundamentals and quan-
tum neural networks to address how quantum computing
can combat the limitations of classical models and provide
its unique advantages in PSP. The paper showcases the clas-
sical and quantum models we used for our comparison and
the CATH dataset we used to train and test our models. Our
results demonstrate that the hybrid quantum-classical model
achieved slightly higher accuracy on a 5-trial average, with a Figure 1: This graphic was created and published in the public domain
by Ken A. Dill. Original caption: The illustrations of proposed energy
4.75% improvement over the classical model when using 13 landscapes that each demonstrate the degree of freedom a protein possesses
input features (qubits). The findings suggest potential advan- in terms of configurations and the multidimensional routes that a protein
tages of incorporating quantum approaches into predictions can take to achieve its final configuration. From left to right for the proposed
and protein folding while also highlighting the need for funnel-shaped energy landscapes: the idealized smooth funnel, the rugged
funnel, the Moat funnel, and the Champagne Glass funnel (Dill & Chan,
further research in scaling quantum methods for broader ap- 1997)
plications in PSP.
Protein Structure Prediction in Classical Machine Learn- In addition, it was later found that the energy landscape was
ing: rugged (Figure 1b). This ruggedness results from the interac-
NP-Hard Problem: tions between amino acids, including hydrogen bonding, van
Any folded protein can be described by its amino acid se- der Waals forces, electrostatic interactions, and hydrophobic
quence, and if we knew the sequence of a protein’s amino acids, effects. The balance of favorable (lowering the energy) and
we could, in theory, predict the protein's shape. Yet protein unfavorable (raising the energy) interactions creates local vari-
prediction is still barely understood. Simply, the longer the ations in the energy landscape, such that each point on the
protein, the harder it is to predict its native structure. This dif- funnel corresponds to a specific protein conformation, and
ficulty is quantified through PSP classification as NP-hard in small changes in the amino acid positions can lead to signif-
computational complexity theory.¹⁵ Computational complex- icant changes in the energy topology. From the perspective
ity theory classifies problems based on how much time and of the prediction models, the valleys represent local energy
input size they require to be solved. Polynomial-time algo- minima (conformations where the protein is in a metastable
rithms can be executed in a computational time that increases but not native state). Prediction algorithms can get trapped in
at a polynomial rate as the input size grows. Such problems these energy barriers, mistakenly taking them for global min-
are known as P (or P-time). The class NP (nondeterministic ima. Proteins solve this problem by using chaperones, which
polynomial time) refers to problems where the proposed ‘solu- help them to escape local minima and flatten the energy land-
tions’ can be verified in polynomial time, yet they may not be scape. Adding chaperone effects to the prediction algorithms

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adds yet another layer of complexity since it now becomes nec- Physics-Based Approaches to PSP:
essary to model not just the protein but also its interaction The other prevalent method for protein prediction comes
with outside molecules. from kinematically simulating how proteins go through the
Database Approaches to PSP:: energy landscape funnel to their native state. Physics-based
Database PSP approaches are based on the assumption ab initio modeling to PSP is based on molecular physics and
that a similar protein sequence is likely to fold into a similar involves simulating the protein’s thermodynamic or kinetic
structure. These models rely on the huge amount of experi- behavior at the atomic level. The most commonly used tech-
mentally determined protein structures available in databases, nique is all-atom molecular dynamics (MD) simulations. By
and then for an unknown protein sequence, the model deduc- modeling the kinetics of the atoms and molecules in a protein,
es the most likely structure through a comparison between MD provides us with a detailed, time-resolved picture of the
the unknown sequence and experimentally known structures. folding process.²⁵ A mathematical model called a force field
The biannual Critical Assessment of Techniques for Protein regulates the interactions of particles representing the protein
Structure Prediction (CASP) competition was established in and particles representing the molecules (eg, water) surround-
1994 to evaluate these methods. Currently, most PSP models ing it. Based on empirical data and molecular calculations, the
base their predictions on comparative or homology modeling. force field describes bonded and non-bonded interactions be-
Homology modeling is performed by comparing the predicted tween amino acids. The simulation tracks how the particles
sequence against the sequences in the PDB. If a homologous move in time by solving Newton’s equations of motion in min-
structure is found, the coordinates of a model’s backbone at- ute time steps (typically 1 to 2 femtoseconds). Since the total
oms in the temple are mapped to the atoms of the backbone time for protein folding can be in the range of microseconds
in the new sequence.²³ The accuracy of these models is related to milliseconds, this requires approximately 10¹² femtosecond
to how closely the target and the template sequence match. As time steps to simulate larger proteins.²⁶
a result, the accuracy drops drastically for dissimilar sequenc- As a consequence, early MD approaches were stunted by
es, and the GDT-TS falls below 50 for more difficult targets the computing power required to model even a single fold-
(Figure 2).²⁴ ing event; and the result’s accuracy depends on the forces of
The iterative database model AlphaFold2 (released at computational algorithms, with new sampling methods and
CASP14, 2020) is the highest-accuracy PSP model.⁹ It uses a improved biasing techniques speeding up computations. Cur-
deep learning transformer architecture with a refinement pro- rently, physics-based models using deep learning algorithms
cess where the computed residue distances and angles between like trRosetta with MD simulations provide increasingly ac-
residues are used to re-assess the amino acid sequences itera- curate simulations of proteins' energy landscapes and more
tively.⁹ Accuracy increases in the CASP models from 1994 to reliable predictions of structure and folding pathways. For
2020 are shown in Figure 2 below, with AlphaFold2 obtaining instance, Audagnotto et al. (2022) demonstrated that their
a prediction accuracy above 90 for even some difficult tar- computational pipeline could observe entire folding events
gets. Database models can still give errors, however. The most from denatured conformations to native states in proteins
sophisticated database models can still be challenged by pro- like adenylate kinase and T4 lysozyme, successfully capturing
teins with disordered regions, complex structures, membrane the conformational changes and intermediate states observed
proteins, and overall novel protein structures. Furthermore, experimentally.²⁷ Since then, these approaches have been re-
database models do not capture dynamic aspects of protein fined regarding the force fields used in MD simulations and
functions and lose substantial accuracy on proteins that are computational algorithms, with new sampling methods and
significantly different from known structures. improved biasing techniques speeding up computations. Phys-
ics-based models provide increasingly accurate simulations of
the protein’s energy landscape and more reliable predictions
of structure and folding pathways. In some cases, it's possible
to observe entire folding events, from denatured conforma-
tions to native states.²⁸ While force-field accuracy has also
been greatly improved, electrodynamic and hydrogen bonding
inaccuracies, for example, still lead to significant errors in pre-
dicting the native state of proteins.²⁹,³⁰ As simulations of larger
proteins progress, there is a growing need for either more effi-
cient models or more powerful computing techniques, with a
potential method being quantum computing.
� Quantum Computing
Quantum computing is a type of computing that uses the
Figure 2: Combined results of all the CASP competitions. The dotted
line is predictions made by automated servers. The dashed line includes principles of quantum mechanics to make calculations. The
all predictions assisted by humans besides the highest performing group; next two sections provide an overview of quantum computing
the black line represents the predictions by Group 427, or AlphaFold 2. and quantum neural networks (QNNs), respectively. Readers
This plot uses the GDT_TS score, in which 100 is a perfect result, and 0
are encouraged to read³¹ and³² for a more in-depth introduc
is a meaningless prediction. GDT-TS refers to the global distance test: a
quantitative measure of structural similarity between two structures.
89 DOI: 10.36838/v7i3.14
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tion to quantum computing. As well as³³ for more information gate takes in a |0⟩ or |1⟩ state and transforms the qubit into an
on QNNs. equal superposition of |0⟩ and |1⟩. Mathematically, the Had-
A Brief Introduction to Quantum Computing: amard gate Η is represented as the matrix:
A quantum bit (or qubit) in quantum computing is the When applied to the basis states, the Hadamard gate oper-
quantum analog of the classical bit. A qubit, unlike the fa-
miliar 0 or 1 of a classical bit, can be in a superposition of two
states where it has a probability of being in either a 0 or 1 state.
Dirac notation is used to describe quantum states, where |0⟩ ates as follows:
represents the qubit being in the 0 state and |1⟩ represents the This means that after applying the Hadamard gate to a qubit
qubit being in the 1 state. In quantum mechanics, the wave
function ψ(psi) is used to describe the overall quantum state
of a system, |ψ⟩ in ket notation. Any qubit can be represent-
ed as the superposition |ψ⟩= α|0⟩+ β|1⟩, where α and β are initially in the state |0⟩ or |1⟩, the qubit will be in a superposi-
probability amplitudes such that α|² + β²=1. This normal- tion of |0⟩ and |1⟩, with equal probability amplitudes for both
ization condition means that when the qubit is measured, it states. The power of quantum computing becomes apparent
has a probability |α|² of being measured in a |0⟩ state and a when we consider multiple qubits systems. Looking at a
probability |β|² of being measured in a |1⟩ state. system with two qubits. If both qubits are in the state |0⟩

Figure 3: Illustrations of quantum gates and the Bloch Sphere. (a) Bloch
Sphere Representation: This panel shows the Bloch sphere, representing
Figure 4: Illustrations of quantum gates and Bell States. (a) Matrixes and
qubit states with the poles as |0⟩ and |1⟩ and X and Y axes indicating
descriptions for the Pauli, Hadamard, and C-NOT gates. (b) The before and
possible rotations (created using QuTiP). (b) Hadamard Gate Rotation:
after snapshot of the CNOT gate entangling 2 qubits into the 4 Bell States.
This panel depicts the rotation of a qubit state from |0⟩to a superposition The target bit flips the control bit (via an X gate) if the control is in a |1⟩
state on the X-Z plane after applying a Hadamard gate (created using state and does nothing if the control is in a |0⟩ state. (c) Quantum circuit
QuTiP). (c) Quantum Circuit Outcomes: This panel shows the effects of diagram for the first Bell State. The control qubit first goesΗ through a Η
various quantum gates (CNOT, Y, Z, Hadamard) on a qubit, visualized with gate, resulting in an equal superposition. After going through the C-NOT
measurement probabilities and Bloch sphere states (created using Quirk). gate, the target qubit becomes entangled with the control qubit, such that if
the control qubit is in a |1⟩ state, the target qubit will flip to a one |1⟩ state,
A qubit can also be represented graphically as a point on and otherwise, they will both be in a |0⟩ state. This results in the entangled
the surface of a unit sphere known as the Bloch sphere (Fig- Bell state shown in the diagram. (Created with IBM Qiskit)
ure 4a). The Bloch sphere shows the information stored in a
single qubit, where every possible superposition of the qubit and we apply the Hadamard gate to each qubit, the system will
is represented by a point on the sphere’s surface. The sphere's turn into a superposition of four possible states:
poles correspond to the basis states |0⟩ and |1⟩, while any other Expanding this expression, we get:
point on the sphere represents a superposition of these states.
In Cartesian coordinates, a qubit state can be expressed as the
following superposition:
where θ and Φ are angles that determine the position of the |00⟩, |01⟩, |10⟩, and |11⟩ are the four possible states for the

qubit on the Bloch sphere, the angle θ represents the superpo- two-qubit system. Each of them is equally likely, and scaling
sition amount between |0⟩ and |1⟩ (the likelihood of each state to a system with n qubits, each will have a probability of 1/2n,
when measured), and Φ represents the relative phase between and they can exist in a superposition of 2n states. This scaling
the two states, represented in the Bloch sphere as a rotation in is exponential, which is one of the key reasons why quantum
the X-Y plane. Adjusting these two angles with quantum gates computers are considered to be powerful for certain compu-
changes the qubit's state, forming the basis for data encoding tations, such as searching large databases or simulating NP
on qubits. The most basic gates are the Pauli Gates: X, Y, and systems.
Z. They correspond to rotations around the three axes in the The other main difference between quantum and classical
Bloch Sphere. Figure 4a summarizes them, and Figure 3c il- computing is entanglement, where the states of two or more
lustrates their effects on a quantum circuit. Another important qubits become correlated such that the state of a single qubit
gate to quantum computing is the Hadamard gate, which is cannot be determined without also determining the state
one of the main ways superposition is created. The Hadamard

DOI: 10.36838/v7i3.14 90
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of other qubit(s). In many quantum algorithms, the CNOT in a vector of input data and applies these rotations across
gate is used to produce entangled states. The CNOT gate acts multiple qubits, resulting in a quantum state that encodes the
on one control qubit and one target qubit. When the control entire dataset. The result is a combined quantum superposition
qubit is in the state |1⟩, the CNOT gate inverts the state of , where all the information from the input data
the target qubit; otherwise, if the control qubit is in the state
|0⟩, the target qubit does not change (Figure 4b). The matrix is encoded.
representing the CNOT gate is seen in Figure 4a. To create
an entangled state, you can apply a Hadamard gate to the first Following the embedding, the quantum layers, represented
qubit (putting it into a superposition of |0⟩ and |1⟩) and then by the W(θ) operator in Figure 4a, perform the main com-
apply the CNOT gate, using the first qubit as the control qubit putations in a QNN. These layers consist of a sequence of
and the second qubit as the target. The result is an entangled quantum gates that tweak the quantum state to explore the
state (Figure 4c), specifically it is one of the four Bell states: solution space efficiently. Generic rotation gates R(θ) are used
within the quantum and can rotate the qubit around any axis
on

the Bloch sphere, providing the model greater control over

the quantum state. These rotations adjust the quantum state
Each Bell state is a superposition of two-qubit states in like weight adjustments in classical neural networks. The
which a measurement of any one qubit instantly determines quantum layers also include entanglement operations that
the precise state of the other, no matter how far away it might create connections between qubits that cannot be replicated
be. Although non-local correlation cannot be used to send in classical systems. In Figure 5b, the entanglement layer is
information faster than the speed of light, it is a valuable re- shown as a cyclical entanglement pattern, where each qubit is
source for quantum information processing. It has been used entangled with its neighbor in a circular fashion (e.g., qubit 1
to create the quantum communication protocols of quantum entangles with qubit 2, qubit 2 with qubit 3, and so on, with
teleportation, superdense coding, and quantum cryptography. the last qubit entangled back to the first). Mathematically, this
These quantum-mechanical phenomena–superposition is represented by a sequence of Controlled-NOT
and entanglement–can be used to design quantum algorithms
that efficiently search cost landscapes. Quantum speedup, the
ability of quantum computers to solve problems faster than
classical computers, means that specific problems like factor-
ization,³⁴ that are intractable using classical computers, are
significantly more efficient when using quantum computers. Figure 5: QNN Backbone. (a) Depicts the basic structure of a QNN circuit.
Quantum Neural Networks: The operator U(θ) is the embedding block. The main techniques for said
embedding are angle embedding and amplitude embedding. The W(θ)
QNNs are the quantum version of ANNs, and they work operator illustrates the hidden quantum layers that consist of rotation gates
based on superposition, entanglement, and quantum par- and entanglement layers. The M operator illustrates the end of the QNN
allelism. Figure 5 illustrates the three parts of a QNN: the when the qubits are measured, and their state is saved or sent to classical
embedding layer, the quantum layers, and measurement. The layers. (b) Quantum circuit of one hidden layer in the W(θ) operator. The
hidden layer consists of a series of rotation gates, R(θ), and an entanglement
embedding layer is the first part of a QNN, where classical data layer, in this case, cyclical entanglement. The entanglement layer is a series of
is embedded into quantum states through a quantum gate, the C-NOT gates placed on each qubit to entangle them. These two operations
U(x) operator in Figure 5a. One of the most common methods are repeated for every quantum layer in the QNN.
this is done through is angle encoding. In angle encoding, each
classical input data point n is mapped onto a qubit by rotating (CNOT) gates, which, when applied to a superposition
the qubit’s state on the Bloch sphere. The generic rotation op- state, result in an entangled quantum state:
eration R(θ) applied to a qubit can be defined as

This layer’s function is to increase the complexity of the

quantum state, enabling the QNN to represent more intricate
where θ= xi represents the angle determined by the data patterns and find more correlations in the data.
point, is the axis of rotation along the Bloch sphere, and σ In a QNN, each qubit stores the superposition of both states,
and operation on the qubits affects the |0⟩ and |1⟩ components
is the vector of a Pauli matrices (σx or σy or σz). This op- simultaneously. In a classical counterpart, the only way to pro-
erator allows the qubit to be rotated to a specific point on the cess the result is by evaluating each of the 2n possible states
Bloch sphere, encoding the classical information into some one by one. However, using quantum parallelism a QNN can
quantum state . The embedding layer takes process multiple states at once. This property allows QNNs to
explore certain solution spaces faster than classical networks.
For instance, when a quantum gate is applied to a qubit in
superposition, it simultaneously affects all possible states rep

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resented by the superposition, allowing the QNN to per- tion-based (transformer) architecture.⁹ Though research into
form multiple computations in parallel, significantly proving quantum approaches to PSP is still largely unstudied, as seen
the processing power of QNNs. in pilot studies 12 and 37, some specific quantum models have
The final stage in a QNN is measurement, represented by had success in localized prediction cases. Having an archetype
the M operator in Figure 4a. Measurement collapses the quan- of QNNs with entanglement layers in our models, we could
tum state back into classical information, where each qubit is capture and model the relationship between amino acid inter-
observed in the |0⟩ or |1⟩ state, with the probability of each actions when looking at secondary structure.
state being determined by its probability amplitude. For each � Methods
qubit, the probability p of measuring a specific state, for exam- Dataset:
ple, |1⟩, is given by , with |ψfinal⟩ being the state The protein sequences were taken from the CATH (Class,
Architecture, Topology, Homology) database, which classi-
of the qubit before measurement. In real quantum computers, fies protein domains into their evolutionary lineages based on
the measurement process is inherently probabilistic. Unlike specified structure details. Two different groups were selected:
numerical simulations, where exact expectation values can be ‘Mainly Alpha’ and ‘Mainly Beta’ for a balanced dataset that
calculated, real quantum hardware only allows for approxi- our secondary structure binary classifier would use. One thou-
mate values based on a finite number of measurements. The sand sequences were extracted from the FASTA files for each
outcome is a set of discrete measurement results, each with group, denoted by the prefixes cath-superfamily-seqs-1 and
a certain probability. The process is repeated many times to cath-superfamily-seqs-2 for the α and β sequences, respective-
obtain a reliable estimate of the probability p(1). Specifically, ly. Amino acids within these sequences were encoded using a
the error is quantified by the Chernoff bound, where O(1/ε2) standard 25-character alphabet formalized by the UPAC-IUB.
repeat measurements are needed to obtain an expectation val- General Approach:
ue with a combined error up to ε.³⁵ The general approach involved transforming the protein se-
Quantum Application in PSP: quences into a set of features that could be used as inputs to
The use of quantum computers in PSP could result in stron- both classical and quantum models. Specifically, we selected
ger, more accurate models. These advantages stem from the 30 features based on key physicochemical properties linked to
unique properties of quantum computing systems, namely protein folding, like hydrophobicity and charge. Each feature
superposition and entanglement, which allow quantum com- was calculated using specific groups of amino acids that have
puters to explore certain solution spaces more efficiently than been found to align with the property being measured.³⁹
classical computers.³⁶ The most urgent challenge for database For example, the “hydrophobic” feature was determined by
and physics-based methods alike is that PSP’s computational counting the occurrences of known hydrophobic residues (A,
complexity increases exponentially with the size of the protein. I, L, M, F, W, V) within the sequence. Given an example input
A quantum computer’s ability to control exponentially large sequence, MPENPAAEKMQVLQVLD, the hydrophobic
state spaces using a linear number of qubits might be able to residues (M, A, A, M, V, L, V, L) would be tallied, resulting in
solve the scaling problem, allowing prediction of the structure a “hydrophobic” value of 8 for the sequence. All other features
of larger proteins or protein complexes. In addition, as depicted were handled similarly to ensure uniform input preparation
in Figure 1b, the energy landscape funnel is characterized by across the dataset for classical and quantum models.
myriad local minima and, thus, a rugged shape. The ruggedness Since our quantum model was simulated, the classical sys-
of the landscape is an obstacle for classical algorithms as they tem needed to simulate the exponential scaling of a qubit
might be trapped in local minima, which prevents them from system, causing the training time to increase exponentially
finding the native state of the protein. In such cases, quantum with the number of input variables (qubits). In our initial tri-
algorithms that can exist in superposition may use parallelism als, we lowered the total inputs to 9 distinct features, then in
to explore more than one conformation at the same time, and our final trials back up to 13 features (where the number of
the superposition property may help quantum systems avoid qubits is equal to the number of features and input variables).
the barriers between local minima, which restrict classical al- To determine these 13 inputs, we calculated all 30 features'
gorithms in navigating through the rugged energy landscape. average values over the α and β sequences. Then to find which
The ruggedness of the energy landscape at the bottom of the features gave the most useful data, we calculated and plotted
folding funnel can be correlated with the conformational het- the difference in the averages (Figure 6).
erogeneity of the protein. Rugged, multi-minima landscapes
can lead to more flexible proteins that bind non-specifically
to ligands. They do this by selecting a conformation from a
possible distribution of low-energy states that is complemen-
tary to each ligand.³⁸ It is possible that the use of entangled
states would allow quantum computing models to better
encode these many-body interactions, as they would, in prin-
ciple, allow us to correlate different quantum interactions with
each other. The concept of correlation has already emerged in
PSP in models such as Alphafold2 through the use of atten-

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Classical Model:
For the classical model, we used a 4-layer fully connected
feedforward neural network (FFNN) implemented through
TensorFlow’s Keras API. The architecture included input
layers mapping the processed features of the amino acid se-
quences to four dense layers, ranging from 10 to 50 nodes with
ReLU (rectified linear unit) activations, which were found to
be the most accurate when using cross-validation with random
search. To account for overfitting, each dense layer incorpo-
rated a dropout rate of 0.2. The output layer used a binary
softmax function to classify each sequence as belonging to ei-
ther the α or β secondary structure.
Figure 6: A plot of all 30 chosen features, ranked in order of descending Quantum Model:
magnitude of the difference in average values of the feature in the α and β The quantum neural network (QNN) was implemented
datasets.
using PennyLane, which interfaces with TensorFlow to build
hybrid simulated quantum models. In the quantum model,
By plotting the differences, we could identify features that,
amino acid sequences were first encoded into quantum states
on average, provided distinct values for the two secondary
using angle embedding, where the features calculated from
structures. We selected the features with the largest differences,
the sequences were used to determine the rotation angles of
as these are likely to help the models differentiate between α
the qubits on the Bloch sphere. The QNN circuit consisted
and β sequences. The 13 most distinct features, after account-
of multiple quantum layers, including rotation gates (param-
ing for overlap, are shown in Figure 7, with their descriptions
eterized by trainable weights) and entanglement layers. The
listed in Table 1.
entanglement pattern used in this study was cyclical, ensuring
each qubit interacted with its neighbors, creating a highly in-
terconnected quantum state. Following these quantum layers, a
final measurement step converted the quantum state back into
classical data³⁴, then processed by a classical neural network.
The quantum circuit used in the QNN is depicted in Figure 8
and the final classical layer of the model is illustrated in Figure
9.

Figure 7: This graph shows the average values for the two secondary
Figure 8: Our final Pennylane QNN Circuit. The diagram above illustrates
structures on the 13 features we chose as inputs. For each feature, we plotted
the QNN portion of our hybrid model. Only 6 quantum layers are shown for
its average value for the α and β sequences and ordered them in descending
clarity; our final models had 15 total quantum layers.
order according to the differences in the two averages.

Table 1: This table displays the 13 selected features and their descriptions,
explaining how each feature helps to differentiate between structures α and
β structures.

Figure 9: Illustrates the final classical layer for our hybrid quantum-classical
model.

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� Results and Discussion as, in the 13-qubit trials, this gap increases with the average
We first ran our models with qubit counts of 9 input features, accuracy of QNN models outperforming classical models by
from which we plotted the averages of 5 trials of both the clas- 4.75%. As this average was calculated through a small number
sical and QNN hybrid models. Figure 10 gives the “Loss vs. of trials (5 for each model type), a greater number of trials,
Epoch” and “Accuracy vs. Epoch” graphs for our 9-qubit model with a larger data size, would need to be run to statistically
comparison. We also ran a larger experiment with a 13-input validate these results. Despite our increased dataset size (1,000
feature model to see how the QNN hybrid model compares to sequences per structure), we still observed signs of overfitting.
the classical model as we increase the qubit count. The results This was particularly evident in the classical model and, to a
of the 5-trial average can be seen in Figure 11. lesser extent, in the QNN hybrid model. This suggests that
1,000 sequences is not a large enough data set to provide suffi-
cient diversity in the problem space for optimal model training.
The apparent performance gap between QNN and classical
hybrid models suggests that quantum approaches might have
some advantages in capturing complex relationships in the
protein structure data, which is in line with our predictions
that quantum systems can navigate the rugged energy land-
scapes characteristic of protein folding more efficiently, and
that a quantum advantage might scale with the level of com-
plexity. However, this also highlights the need for large-scale
studies. Moving on from this fairly simplistic binary classifier
to more complex tertiary structure predictions is likely to re-
quire a significant leap forward on both fronts: in terms of the
size and robustness of the quantum hardware (measured by the
number of qubits) and in terms of the algorithm design. While
these results are promising, they should be seen as an early
indicator rather than proof of quantum advantage in protein
structure-prediction problems.
Higher accuracy in the QNN hybrid model could be due to
Figure 10: Graphs of the classical and QNN hybrid models with 9 feature quantum-specific advantages in data-relationship processing,
inputs. Our classical models used 20 epochs, and our QNN models used 30
epochs. In 5 trials, our classical models achieved an average highest accuracy
and it may be that the quantum model’s ability to represent
of 78.0%, and our QNN models achieved 78.5%. and process high-dimensional spaces enabled by superposition
is helping it to capture the subtlety of amino acid sequence
to secondary structure relationships. The non-linear transfor-
mations performed by the quantum circuit, through its series
of rotations and entanglements, may give it a more expressive
feature space, especially good at distinguishing alpha from beta
structures. Further, quantum parallelism in the circuit may al-
low it to explore conformational protein space more efficiently,
analogous to the way that proteins sample conformations in
parallel during folding. The larger accuracy gap between the
9 and 13 qubit trials signifies the possibility that our quan-
tum models excel when facing a more diverse dataset, where its
ability to correlate features via entanglement could be a factor
in explaining the higher relative accuracy scores.
As these findings are based on a simplified binary classi-
fication task (alpha vs. beta structures) and a limited set of
input features, more research needs to be done in scaling these
models to more expansive secondary structure datasets and
eventually tertiary folding. While the full quantum advantage
is yet to be realized, combining classical and quantum methods
offers a practical approach today. Classical models can process
Figure 10: Graphs of the classical and QNN hybrid models with 13 feature
inputs. Our classical models used 14 epochs, and our QNN models used simpler tasks effectively, while quantum circuits are integrat-
30 epochs. In five trials, our classical models achieved an average highest ed into parts of the pipeline that require handling complex,
accuracy of 79.750%, and our QNN models achieved 84.5%. high-dimensional patterns. In terms of quantum application
From our trials, we found that QNN hybrid models outper- in PSP, more studies in implementing quantum computing
formed their classical counterparts. In the 9-qubit trials, we see into specific tasks within classical models will bring greater
a modest 0.5% accuracy increase over classical models, where- insight into the ability of higher qubit systems to excel. To

DOI: 10.36838/v7i3.14 94
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test the hypothesized quantum speedup and potential com- he Next Cryo-EM Resolution Barrier – Atomic Resolution Deter
putational advantages of quantum computing in PSP, more mination of Proteins! bioRxiv 2020, https://doi.org/10.1101/2020.
extensive experimentation with higher qubit systems and 05.21.106740.
larger proteins is needed. Future work could involve train- 9. (1) Jumper, J.; Evans, R.; Pritzel, A.; Green, T.; Figurnov, M.; Ron
neberger, O.; Tunyasuvunakool, K.; Bates, R.; Žídek, A.; Potapen
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computers instead of computationally slow classical simulators T.; Petersen, S.; Reiman, D.; Clancy, E.; Zielinski, M.; Steinegger,
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RESEARCH ARTICLE

The Impacts of Artificial Intelligence on Reducing Surgical

Errors in Heart Surgeries
Yonas Getenet Bekele
Menelik II Secondary School, King George VI St, Arat Kilo, Addis Ababa, Ethiopia; [email protected]

ABSTRACT: Of all surgeries, heart surgeries are considered to pose a higher risk of surgical errors due to the intricacies of the
heart’s anatomical structures, surgical complexities, the critical nature of procedures, and stress on the surgical team. In this paper,
considering the significant impact of artificial intelligence (AI) on enhancing patient outcomes in healthcare, we explore AI’s
potential in reducing errors in heart surgeries. To that end, we reviewed recent papers on the intersection of artificial intelligence
and heart surgeries. We analyzed their efficiency in reducing surgical errors and their promise to mitigate the risks involved
in cardiac surgeries. Large language-based surgical assistants, such as CARES Copilot 1.0 and ChatGPT, are cost-effective
solutions for underprivileged areas with high demand for cardiac surgeries because they enhance surgical outcomes, shorten ICU
and hospital stays, and thus give opportunities to other patients awaiting surgery. At the same time, despite reducing surgical
errors and improving patient outcomes, AI has some limitations, including hallucinations, biases in training data, threats of job
displacement, and high deployment costs, especially for robotic surgeries and fine-tuning large language models, all of which
remain significant barriers to AI’s adoption, requiring further research.
KEYWORDS: Artificial Intelligence (AI), surgical errors, robotic surgery, machine learning, cardiac surgery, CARES Copilot
1.0, ChatGPT, AI hallucinations.

� Introduction measurements used to reduce surgical errors in cardiac sur-

Heart surgery, also known as cardiac surgery, is a medical geries was the Institutional Coronary Artery Bypass Surgery
procedure that doctors use to treat diseases affecting the heart Checklist (the InCor-Checklist), which significantly decreased
and its blood vessels. The surgeries include repairing defects the mortality rate after surgery from 8.2% in 2013 to 3.1% in
in the heart, repairing damaged blood vessels, replacing heart 2019.⁶ Integrating the InCor-Checklist with artificial intelli-
valves, and removing blood clots from veins.¹ Access to heart gence will help ensure necessary steps during cardiac surgeries
surgeries is costly and not easily accessible globally. Currently, 6 are followed properly. The integration can even decrease the
billion people worldwide do not have access to cardiac surgical mortality rate and improve the procedure’s overall safety and
care.² This is even worse for middle- and low-income coun- efficiency.
tries. In Ethiopia, there are only five cardiac surgeons serving AI and machine learning can be used in heart surgeries
120 million people, and more than 15,000 patients are on the during the entire treatment process, from preoperative, re-
waitlist for surgery.³ AI systems can play a potential role in al-time surgical monitoring to postoperative predictions. AI
improving the accessibility of cardiac surgical care through in- assistant copilots can help cardiovascular surgeons plan com-
tegration with the entire treatment process, allowing surgeons plex surgeries using 3D models of the heart and surrounding
to perform intricate surgeries in less time with high precision organs to analyze defects and damaged areas. During cardio-
and accuracy. vascular surgeries, AI can continuously monitor patient data,
Medical errors can occur in several forms, including surgical, such as blood pressure and heart rate. If any sudden changes
diagnosis, medication, equipment, patient identification, test- occur, AI can track them and alert the surgical team to ad-
ing, and transfusion errors.⁴ Among those errors, surgical errors just treatment, assisting the surgeons in making better and
are the most damaging and the costliest. They have harmful informed decisions. In the postoperative stage, AI helps detect
effects on patients, including temporary or permanent dam- complications through medical imaging before they become
age and even significant mortality rates.⁵ This affects not only severe, leading to shorter recovery time and better patient
the patients but also their families, burdening them financially. outcomes.¹ Other applications of AI focus on aiding robotic
Surgical errors can happen during preoperative, operative, and surgeries in performing complex procedures under surgeons’
postoperative processes. Like other complex surgeries, heart supervision. This reduces surgical errors and enhances surgical
surgeries are considered to pose a higher risk of surgical er- performance. Applications of AI are not limited to only en-
rors due to the intricacies of the heart’s anatomical structures hancing cardiac surgical accuracies but also avoiding untimely
and surgical complexities. Reducing surgical errors is neces- deaths by improving the medication system. According to the
sary to mitigate mortalities and unnecessary costs related to European Union study, 1.7 million people aged less than 75
prolonged hospital stays and reoperations. One of the early
© 2025 Terra Science and Education 97 DOI: 10.36838/v7i3.15
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This is due to the lack of proper medical knowledge and tech- ac patients. Overall, the synergy of AI-based surgical assistants
nology.⁷ From these deaths, heart-related diseases take the first and robotics holds immense potential in improving both the
place, with more than 180,500 preventable deaths, or 32% of safety and efficiency of surgical procedures, leading to better
total avoidable deaths. The study indicates that implementing long-term outcomes.
AI and technology in medication can significantly reduce such While numerous studies have explored the impact of robot-
preventable fatalities by improving early detection, diagnosis, ic-assisted cardiac surgeries on enhancing surgical outcomes,
and treatment. the integration of LLMs in cardiac surgeries is in its nascent
Chan and colleagues analyzed data from the Australian stage and remains unexplored. This work demonstrates that
and New Zealand Audit of Surgical Mortality (2009-2015) integrating robotic systems and LLMs with cardiac surgeries
to identify clinical management issues affecting cardiothorac- can help reduce surgical errors and improve surgical outcomes.
ic surgical care. Nine hundred-eight cases were identified of We first define artificial intelligence and its applications in
those 769 that were cardiac-related and determined to have surgical procedures. We then discuss robotic-assisted surgery,
at least one clinical management issue. The analysis included how it works, its historical background, and the benefits it
the three most common cardiac surgery procedures: coronary brings to surgeons and patients. Then, we compare mortality
artery bypass grafting, aortic valve replacement, and mitral rates, cost, duration of surgery, intensive care unit (ICU) stay,
valve surgery. Of the reported clinical management issues, length of hospital stay, and complications for robotic-assisted
47.4% were probably preventable, and 17% were definitely and nonrobotic cardiac surgeries. Subsequently, we introduce
avoidable. These numbers indicate that 64.4% of CMIs were two large language model-based systems (1) ChatGPT and
likely preventable if the necessary measurements were taken, (2) CARES Copilot 1.0, and discuss how they can be used
particularly for those involving technical issues.⁸ The most in surgical procedures during preoperative, intraoperative, and
common preventable CMI for cardiac surgeries was found postoperative phases of surgeries. Additionally, we examine
to be technical issues. These technical issues in intraoperative the challenges and limitations of the systems preventing their
phases may include but are not limited to, unintentional injury widespread adoption in surgical procedures. Lastly, we outline
to surrounding anatomical structures, inadequate myocardial our conclusion and discuss future research.
protection, and the wrong surgical approach, especially per- Artificial Intelligence in Cardiac Surgery:
formed by junior trainee surgeons with insufficient supervision. Artificial intelligence (AI) is a system that models human
Technical issues occurring during intraoperative phases and reasoning to solve a wide array of problems, from simple tasks
other issues that arise in postoperative phases can be addressed such as recognizing text and speech to complex tasks such as
with the augmentation of surgical procedures with AI. By large-scale data analysis and performing intricate surgeries.¹²
leveraging the capabilities of AI, such as predictive analytics AI systems extensively use large datasets in their training
for forecasting potential complications, real-time monitor- process to make predictions and draw conclusions based on
ing, decision support, and anomaly detection, it is possible to patterns in the sample training data. In today's world, AI is
prevent intraoperative and postoperative issues. According to integrated into our daily activities, helping users complete
Chan et al.⁸ and The Michigan Society of Thoracic and Car- tasks more efficiently. In the medical industry, AI systems
diovascular Surgeons⁹ analysis of mortality in cardiac surgical are improving the efficiency and efficacy of clinical out-
cases, postoperative phase clinical management issues were the comes. Within surgery, AI and machine learning algorithms
most contributor to mortalities, followed by preoperative and are employed throughout the surgical process, from planning
intraoperative issues. It is possible to prevent these issues with operations to predicting postoperative complications.¹³ Ad-
improved clinical management practices and appropriate in- ditionally, AI algorithms help develop personalized surgical
terventions. Postoperative issues such as communication issues plans by considering individual patient data, such as medical
and inadequate patient monitoring can be addressed through history and genetic information. This benefit enables surgeons
advanced training focusing on interdisciplinary collaboration, to tailor surgical plans for each patient, lowering the risk of
which can improve communication and teamwork skills in complications.
surgical settings.¹⁰,¹¹ 1. Robotic-assisted cardiac surgery:
The integration of large language models (LLMs) in sur- Robotic surgery is often considered as a robot performing
gical assistants alongside robotic surgery can significantly surgical procedures autonomously without human interac-
enhance the accuracy of cardiac procedures by providing re- tion; however, the robots are guided by surgeons to perform
al-time evidence-based guidance, personalized surgical plans, complex surgeries with high precision. Robotic surgery is a
intraoperative monitoring, and predictive analytics for com- minimally invasive surgery that uses robotic systems, which
plications during surgery. LLMs' capability to assist surgeons consist of a console where the surgeon sits and controls the
by offering them precise recommendations, flagging poten- robotic arms, equipping tiny surgical tools through the joy-
tial complications, and optimizing surgical procedures can sticks that translate the surgeon’s hand movements into highly
ultimately streamline workflows and improve patient safety accurate actions by the robotic arms.¹⁴ The robotic arms can
throughout the surgical process. With a combination of sur- make precise movements with tiny incisions, reducing pain,
gical robotic systems, LLMs enhance precision and support less tissue damage, less blood loss, less scarring, faster recovery
minimally invasive approaches, leading to less tissue trauma, times, and fewer risks. The system uses a high-definition cam-
faster recovery times, and a reduced risk of infections for cardi- era, providing a magnified and enhanced view of the surgical

DOI: 10.36838/v7i3.15 98
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site. The Da Vinci® Surgical System by Intuitive Surgical, Ion compared to non-robotic surgery. Chi et al.¹⁶ and Coyan et
by Intuitive Surgical, and Mako by Stryker are the most com- al.²² found that the mitral valve procedures with the use of
mon surgical robotic systems.¹⁵ Several procedures use robotic robotics resulted in a 0% mortality, while with conventional,
surgical systems, including cardiologic, colorectal, urologic, gy- non-robotic surgeries, the mortality rates were much higher.
necologic, thoracic, head and neck (transoral), metabolic, and Hawkins et al.²³ and Wang et al.²⁴ also reported that robotic
intra-abdominal surgery.¹⁴ Numerous studies have indicated surgery, as compared to conventional surgeries, reduces the du-
that robotic-assisted cardiac surgeries offer significant bene- ration of both ICU and hospital stays. This means that robotic
fits, including reduced hospital stays and fewer complications interventions are associated with better chances of recovery.
than non-robotic surgeries.¹⁶ Although these robotic procedures could consume more oper-
In 1995, Intuitive Surgical manufactured the da Vinci® sur- ative time (Hawkins et al.,),²³ total patient outcomes, especially
gical system (Figure 1) in California, which uses a minimally in recovery and complications associated with each procedure,
invasive approach for complex surgeries. Approved by the Food depict a considerable advancement.
and Drug Administration (FDA), the da Vinci® surgical sys- While robotic surgery is associated with significant benefits,
tem was initially developed for cardiac surgeries but has since it is not without its limitations. Importantly, numerous stud-
been deployed in various types of surgeries, including urologic, ies have revealed that the length of hospital stays and ICU
gynecologic, pediatric, colorectal, and general surgeries.¹⁷ On stays don't reduce significantly compared to conventional
May 7, 1998, using the da Vinci® surgical system, Carpentier methods (Chemtob et al.,; Yanagawa et al.,).²⁵,²⁶ While few-
and Loulmet performed the first open-heart robotic cardiac er complications are evident following robotic surgery than
surgery, an endoscopic aortocoronary bypass, in Paris to re- conventional procedures, according to studies conducted by
pair an atrial septal defect via mini-thoracotomy.¹⁸ Because of Yanagawa et al.²⁶ and Hawkins et al.,²³ complications can
the success of the surgery, it opened a new era of using robots arise. These mixed outcomes can be attributed to the precision
in open-heart cardiac surgeries. More than 750,000 surgeries of the robotic equipment and the learning curve associated
have been performed using the da Vinci® surgical system¹⁹ with implementing and handling robotic systems. With that,
since its approval from the FDA in 2000, enhancing surgical even though robotic-assisted cardiac operations have proved
procedures and producing better patient outcomes. It has been to be effective in many ways—such as reduction in mortality
more than 25 years since the first robots entered the surgi- and improvement in most aspects of recovery—there are still
cal world, but their adoption in cardiac surgery has been slow. elements in this technology that require improvement to elim-
This situation was due to skepticism and resistance to change inate variations in surgical efficiency and reduce problems.
within the surgical community since there were failed early Table 1: This table summarizes all-cause mortality rates, complication rates,
operations and the high costs of surgical robotic systems and intensive care unit (ICU) stays (mean hours), and length of hospital stays
(LOS, mean days) of robotic-assisted and conventional (non-robotic) cardiac
their maintenance costs.²⁰ Heart transplantation, transcathe-
surgeries, including coronary artery bypass grafting (CABG), mitral valve
ter aortic valve replacement (TAVR), aortic stenosis, coronary repair/replacement surgery (MVS), and general cardiac surgeries.
artery bypass graft (CABG), postoperative atrial fibrillation
(POAF), and robotic mitral or tricuspid valve surgery are the
most common cardiac surgeries where robotic procedures are
utilized.¹³,²¹

The costs of robotic-assisted and nonrobotic cardiac surgical

procedures were compared across different surgical procedures
Figure 1: The da Vinci® surgical system (Table 2), including coronary artery bypass grafting (CABG),
mitral valve surgery (MVS), aortic valve surgery, and cardiac
In comparisons of outcomes of robotic-assisted procedures vessel surgery. Yokoyama et al.)²⁷ and Dokollari et al.²⁸ com-
versus traditional cardiac approaches, the observed differ- pared the costs of robotic-assisted and non-robotic CABG
ences are significant, especially for mitral valve surgeries and surgeries. The costs of robotic cardiac surgical procedures were
coronary artery bypass grafting (Table 1). One of the few con- significantly lower than non-robotic surgeries with an approx-
sistent findings from the various extant studies has been the imate decrease in costs of $4,879 for Yokoyama and $16,854
fact that robotic-assisted procedures register much lower rates for Dokallari respectively (Yokoyama and Dokollari). Particu-
of all-cause mortality and fewer complications of any kind larly, Dokollari and colleagues' recent data indicated definite

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financial benefits from robotic-assisted CABG surgeries. In 2. Large language model-based systems in cardiac surger-
some studies, the decreased cost associated with robotic proce- ies:
dures is due to fewer complications, transfusion requirements, Beginning from the introduction of machine learning con-
readmission rates, hospital ICU stays, and hospital stays.¹⁶,²⁹ cepts by Alan Turing in 1950, AI has dramatically evolved
For example, Alemozaffar et al.²⁹ compared hospital costs over the past seven decades. The invention of transformers like
associated with laparoscopic and robot-assisted partial ne- Bidirectional Encoder Representations from Transformers
phrectomy. The robotic-assisted surgery resulted in shorter (BERT) and self-attention culminated in the development of
operating room time and length of hospital stays, decreas- natural language processing. Using these transformers, espe-
ing the mean costs with better patient outcomes.²⁹ However, cially BERT, was pivotal in the advancement of LLMs that
research by Coyan et al.,²² Paul et al.,³⁰ and Suri et al.³¹ demon- generate coherent and well-structured texts.³² Large language
strates that total costs between robotic and conventional MVS model evolution has now reached the era of GPT-4, Llama,
are less pronounced and comparable. In contrast, Yanagawa et and other models with multibillion parameters, making them
al.²⁶ reported higher costs for robotic surgeries across several capable of processing large amounts of reasoning tasks with
cardiac procedures including aortic valve, mitral valve, and car- higher computational capabilities.
diac vessel surgeries. The differences were as high as $4,280 Large language models are computational models that can
for the mitral valve, $4,943 for the cardiac vessel, and $3,788 understand and generate human-like language based on in-
for the aortic valve surgeries, which were significantly higher put by predicting the likelihood of word sequences.³³ They
as compared to nonrobotic procedures. This suggests that the are trained on in-context learning to generate text based on a
cost-effectiveness of robotic-assisted surgeries may vary based given context or prompt, making them generate coherent and
on the specific procedure either mitral, CABG, aortic, or over- contextually relevant responses with great accuracy.³⁴ LLMs
all procedures depending on their cost, with some of the cases can learn from mistakes using reinforcement learning from
favoring the non-robotic methods. Overall, data suggests that human feedback—a machine learning technique involving
while robotic-assisted surgeries can be more cost-effective in fine-tuning the model using human-generated responses as
specific cardiac surgery types like CABG, this is not necessar- rewards based on their responses.²⁸ This improves the mod-
ily true for all cardiac procedures. el's performance in generating accurate text. GPT-4, Claude,
Drawing meaningful conclusions from the cost comparison BERT, Llama 3.1, and Gemini are examples of language mod-
of robotic to non-robotic surgery is challenging for multiple els. LLMs have a wide range of applications, including but
reasons. It is difficult to quantitatively evaluate whether the not limited to natural language processing tasks like content
decrease in complications and shorter ICU and hospital stays summarization, translation, reasoning, sentiment analysis, and
offset the costs of robotic-assisted cardiac surgeries.²⁹ Most of question answering, as well as synthesizing large amounts of
the studies did not consider the initial capital investment of data, content creation, and automating services. Furthermore,
robotic equipment, maintenance, implementation period, and the impact of LLMs extends to diverse fields, such as law,
direct technical hospital costs. Additionally, factors such as medicine, robotics, social sciences, computational biology, and
the impact of improved ergonomics on surgeon longevity and so on.²⁸ In the following sections, we will explore the applica-
shorter intervals between surgery and the patient's return to tions of two LLM-based surgical assistants in cardiac surgeries
productive employment should be considered in cost compari- and how they help mitigate surgical errors.
sons. In the previous section of the paper, we reviewed the role A. Applications of ChatGPT in Cardiac Surgery:
of robotic-assisted surgery in reducing cardiac surgical errors. ChatGPT is a large language model launched by OpenAI
In the next section, we will discuss LLM-based surgical assis- in November 2022 that uses GPT (generative pretrained
tants and how they can be integrated into surgical procedures. transformer model) technology, which plays significant roles
Table 2: This table summarizes the costs of robotic-assisted and in several industries. GPT models are developed to generate
conventional (non-robotic) cardiac surgeries, including coronary artery bypass human-like responses for tasks such as summarizing texts and
grafting (CABG), mitral valve repair/replacement surgery (MVS), and
answering questions.³⁵ The medical industry uses ChatGPT
general cardiac surgeries. Costs are presented in US dollars.
to support medical education, summarize patient diagnosis
reports, keep healthcare providers updated with the latest re-
search, and assist with telemedicine.³⁶ ChatGPT evidently has
the potential to enhance the medication process and assist car-
diac surgeons.
ChatGPT has the following potential applications in heart
surgery:
1. Preoperative planning and surgical simulation: Heart
surgery is complex and requires meticulous planning, prepara-
tion, and risk assessment. ChatGPT can help with preoperative
planning by summarizing patients’ medical histories, genetic
Notes. CABG = coronary artery bypass grafting; MVS = mitral histories, and electronic health records to provide the surgical
valve surgery. team comprehensive understanding of their conditions and
potential risk factors. This helps decrease the time that surge-

DOI: 10.36838/v7i3.15 100

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ons commit to a single patient and allows them to see more techniques, best practices, and guidelines while minimizing er-
patients who are requesting their services than they otherwise rors and inaccurate responses, leading to improved patient care.
could. ChatGPT can also be used in surgical simulations to However, the cost of fine-tuning became a significant chal-
train surgeons, visualize surgical scenarios in advance, and pre- lenge to its adoption. Additionally, biases on ChatGPT related
dict potential complications.³⁷ to surgeries are a big concern, leading to misdiagnosis, dis-
2. Intraoperative monitoring: ChatGPT can monitor pa- parities in treatment recommendations, and potential harm to
tient data in real-time, including heartbeat, blood pressure, patient safety.³⁷ Another significant challenge of ChatGPT
anesthesia levels, and blood loss. This provides surgeons with and other LLMs is hallucinations—inaccurate, misleading,
opportunities to spot anomalies in the surgery and readjust op- fabricated, or contextually irrelevant information generated
eration procedures. Another surgical error that ChatGPT can by large language models. Hallucinations occur due to the
help with is administering the correct anesthesia dose by ana- model's reliance on the patterns learned during the training
lyzing empirical patient data, such as age, weight, allergies, and rather than access to real-time and verified information. This
anesthesia records. This helps anesthetists respond efficiently can lead to substantial complications and risks, especially in
to the risk of complications such as overdosing, underdosing, medicine, if not addressed effectively. Furthermore, the inabil-
or adverse reactions.³⁷,³⁸ ity to understand patients' sentiments' is another limitation of
3. Decision-making support: Instantaneous decision-mak- AI models. As they only consider patients' quantitative data,
ing is critical during surgery. Surgical teams can use ChatGPT their emotions, and psychological status are not considered,
to make informed decisions founded on recent research that is negatively impacting the overall treatment process.⁴⁴ In this
less resilient on personal experiences. This can reduce surgeons’ section, we discussed the potential applications of ChatGPT
cognitive biases that may be caused by a lack of necessary in- in heart surgeries. In the next section, we will discuss CARES
formation such as patient medical history, surgical risk factors, Copilot 1.0, a large language model specifically developed to
and best practices and guidelines, which can influence surgery assist surgeries.
outcomes.³⁹,⁴⁰ B. CARES Copilot 1.0: The Game-Changing AI Surgi-
4. Education and training: Large language models, such as cal Assistant:
ChatGPT, are crucial learning tools for students. ChatGPT is CARES Copilot, officially launched globally at the Huawei
trained on many textbooks, literature, and internet data, so it CONNECT conference 2023, aims to improve the safety and
can answer questions for surgeons with high accuracy, depend- efficiency of surgical operations. CARES Copilot 1.0 (Figure
ing on the most recent information available to it. Trainees 2) is an advanced large language model-based surgical assis-
can access extant surgical case studies and step-by-step proce- tant developed by the Centre for Artificial Intelligence and
dural guides using ChatGPT’s platform. In medical research, Robotics (CAIR). Based on Meta Platforms Inc.'s Llama 2.0
ChatGPT can be used to analyze medical records to predict large language model, CARES was trained and fine-tuned
patient outcomes and support personalized medicine research on over 3,000 pages of literature and optimized by surgical
via its ability to help researchers develop medications that are professionals.⁴⁵-⁴⁷ It outperformed medical exams, achieving
tailored to an individual’s specific circumstance, leading to bet- state-of-the-art performance. According to the CARES Co-
ter patient outcomes.⁴¹ pilot 1.0 research team, the copilot was rigorously tested using
5. Postoperative care: Postoperative care is crucial in help- a challenging zero-shot top token selection standard (output
ing patients recover completely.³⁸,⁴² Insufficient or poorly selection strategy) across five public datasets and two propri-
managed postoperative care can result in complications for etary neurological knowledge evaluation datasets.⁴⁸ With the
patients. ChatGPT can help doctors develop comprehensive, ability to handle more than 100,000 tokens, CARES Copilot
personalized rehabilitation plans for postoperative patients and can rapidly understand surgical textbooks and medical doc-
choose appropriate medications. ChatGPT’s postoperative uments within seconds and generate accurate answers.⁴⁹,⁵⁰
roles include scheduling doctors’ appointments, identifying Its integration with medical devices and capability to process
patient symptoms and recommending treatments or therapies, multimodal surgical data—including images, text, voice, video,
medication reminders with the appropriate doses and possi- MRI, ultrasound, and CT scans—makes it an ideal solution
ble side effects, providing instant advice to patients as needed, for complex surgeries like heart surgeries, boasting an impres-
scheduling virtual follow-up consultations, and helping doc- sive 95% accuracy rate as tested on brain surgeries in more
tors with the documentation and reporting processes.⁴² than seven hospitals across Hong Kong and the Greater Bay
To use ChatGPT in surgical practices, it is necessary to area.⁴⁵
fine-tune the model with domain-specific surgical data, expert
feedback from cardiologists, and up-to-date medical guide-
lines and protocols. Fine-tuning means training pre-existing
models on a specific dataset to enhance their performance
in a particular domain. Instead of training a new model for a
specific task, fine-tuning provides a cost-effective approach to
leverage pre-acquired knowledge of base models, like GPT and
Llama.⁴³ Fine-tuning ChatGPT for surgical procedures can
provide surgeons with more accurate information on surgical Figure 2: CARES Copilot 1.0 Chatbot. Extracted from "CARES
Copilot,"49 https://www.cares-copilot.com/ (accessed August 24, 2024).
101 DOI: 10.36838/v7i3.15
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CARES is considered the world's first real-time simulator Limitations of AI-Enabled Systems in Cardiac Surgeries:
for neurosurgery. With real-time brain-instrument interac- Artificial intelligence systems in healthcare usually use
tion, CARES can simulate brain surgeries to enhance surgical automated decision-making techniques, including machine
precision, reduce errors, provide a risk-free training process learning, natural language processing, and convolutional neu-
for surgeons, and increase the confidence of the surgical ral networks to perform tasks in the clinical setting, which
team while reducing stress.⁴⁹ Another significant advantage usually require human intelligence. These systems also use
of CARES is its lightweight private deployment capability, huge amounts of data to provide the best outcomes, making
which facilitates its use in hospitals and surgical rooms. Its easy them highly reliant on the model training data. Based on these
deployment makes CARES a potential solution for low- and techniques, AI chatbots and surgical robots are continuously
middle-income countries, where many patients are waiting for helping surgeons make well-informed decisions during surgi-
enhanced and safe cardiac surgical care. cal procedures while minimizing significant amounts of time
and clinical errors. AI assistants are also potential solutions
for places where there is a scarcity of resources and educated
experts in the surgical field. Their capability of saving the time
and energy to perform experiments requires huge amounts of
research literature that is probably beyond individual exper-
tise.⁵²
Although its utility is apparent, the application of AI in
medicine has been the point of contention among many scien-
tists.⁵³ Some justify using AI to support efficient and effective
diagnosis and guide appropriate treatment. The proponents
of the use of AI in medicine endorse the use of AI based on
Figure 3: CARES Copilot 1.0: A Trustworthy and Explainable AI its ability to store vast amounts of data that can subsequently
Framework for Enhancing Surgical Decision-Making and Outcomes. be analyzed to suggest proper diagnosis and treatment. Other
Extracted from "Multimodal AI Large Model,"51 https://www.cair-cas.org. researchers and medical doctors do not agree with the current
hk/articles/ai (accessed August 24, 2024).
application of AI in medicine. Some opponents are concerned
At the preoperative stage, CARES uses various cameras that, in the future, AI is going to take over from a medical prac-
to monitor medical staff and ensure all pre-operation prepa- titioner by reducing his or her potential to practice medicine
rations are complete. (Figure 3 shows the overall CARES using a humanistic touch.⁵³ Instead of adopting AI to create
Copilot framework, while Figure 4 illustrates its integration diagnosis and treatment, opponents argue that AI is intended
into surgical procedures.) During operations, CARES uses to supplement medical decision-making where the final deci-
endoscopy video to track surgical progress and simulate tool sions are made by the human practitioner. But for others, AI
and tissue segmentation.⁴⁷ The system leverages computer vi- is perceived to be a threat to medicine and the treatment of
sion and deep learning techniques to support decision-making patients. Some of the limitations of AI include hallucinations,
during surgeries. By integrating endoscopy and AI, CARES biases, job displacement, and ethical concerns, preventing their
tracks every step of the surgical procedure and provides sur- wider application in the surgical setting. In this section of the
geons with detailed real-time feedback and operational paper, we will discuss the two most significant limitations of
reminders, warning surgeons from taking risky procedures to AI-enabled systems: hallucinations and biases in cardiology
enhance precision and reduce the likelihood of errors. Despite and healthcare as a whole.
its capabilities, researchers want CARES Copilot to take more 1. Hallucinations
active roles during surgeries and develop more reliable ones What is an AI hallucination?:
that doctors can rely on. However, the lack of access to the AI hallucination, as defined by ChatGPT-4 (August 7,
cutting-edge Nvidia's advanced chips restricted its computing 2024),
power and expansion to more advanced surgeries, hindering its “An AI hallucination occurs when an artificial intelligence
development.⁴⁶ model generates information or statements that are plausi-
ble-sounding but factually incorrect, misleading, or entirely
fabricated. These errors can appear in various forms, such as
false facts, imaginary sources, or nonsensical responses that
seem coherent at first glance. AI hallucinations are more com-
mon in complex tasks, like language generation, where the
model "guesses" rather than retrieves or calculates the exact
answer. These hallucinations typically arise because AI mod-
els generate responses based on patterns in data rather than
true understanding. The AI's algorithms prioritize producing
contextually relevant and syntactically correct responses, which
Figure 4: Overview of CARES Copilot Foundation Model Integration can sometimes result in convincing but erroneous outputs.”
in Surgical Procedures. Extracted from "Multimodal AI Large Model,"51
https://www.cair-cas.org.hk/articles/ai (accessed August 24, 2024).
DOI: 10.36838/v7i3.15 102
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One of the biggest concerns with modern large language Hallucination Detection Model and a New Leaderboard,"57 https://www.
vectara.com/blog/hhem-2-1-a-better-hallucination-detection-model (accessed
models is their tendency to produce hallucinations. AI halluci- August 7, 2024).
nations are instances where erroneous, delusional, or fabricated Various methods can mitigate hallucinations. Prompt-
responses that are not based on any information or data on ing techniques like chain-of-thought, tree-of-thought, and
which the models are trained.⁵⁴ Recently, ChatGPT has hallu- self-consistency have enhanced LLM reasoning ability by
cinated by generating fake legal opinions, which led a law firm using logical steps to answer each prompt and cross-check
to get into trouble for submitting these fabricated claims.⁵⁵,⁵⁶ its answers.⁵⁸ Retrieval-augmented generation architecture,
In 2023, Aljamaan et al.³² challenged medical AI chatbots which uses relevant documents from external sources such as
with medical prompts (inputs) and reported a reference hal- search engines, databases, and news feeds, helps LLMs generate
lucination score (Table 3), aiming to evaluate the authenticity more accurate, up-to-date, and verifiable answers. Fine-tuning
of AI chatbots’ citations. Hallucinations were observed in all is another technique commonly employed in LLMs to mit-
parts of the references, including article title, journal name, igate hallucinations in domain-specific contexts.⁵⁹,⁶⁰ It uses
author name, DOI (Digital Object Identifier), and reference high-quality and reliable datasets to adapt general-purpose
web link. These results imply that chatbots are likely to gen- LLMs, like GPT-4 and Llama, toward specific domain mod-
erate irrelevant, inaccurate, or nonexistent references when els,⁶¹,⁶² including CARES Copilot 1.0—which is based on
asked about complex medical topics. Among the chatbots Llama. These techniques and other strategies will help develop
examined, ChatGPT (GPT-3.5) and Bing were reported to coherent and reliable models for surgical applications.
have the highest reference hallucination score of 11, which Xu et al.⁶³ and other researchers have concluded that it is
reflects worse performance compared to other chatbots, such impossible to completely avoid hallucinations from LLMs, as
as SciSpace and Elicit, which have a score of 1. ChatGPT’s they are inevitable and innate characteristics. No matter how
performance in reference generation raises concerns about its LLMs are trained, they always miss some possibilities, just as
application, particularly in education, the training of surgeons, we cannot list out all real numbers (infinite set) even if we
and medical research. try.⁶³ When LLMs face novel and complex prompts (inputs),
Table 3: Reference Hallucination Scores with Bivariate Analysis of the they can make errors by retrieving data that seems right but is
Artificial Intelligence Chatbots. Adapted from Aljamaan et al.32
not actually true. This is because they are highly reliant on the
data patterns on which they are trained. Additionally, Xu et al.
claimed that restricting LLMs to simpler models will still re-
sult in errors at certain complex inputs, as their computational
ability is limited to the information they can process and verify.
Even if it is impossible to eliminate hallucinations with LLMs,
it is crucial to use models with fewer hallucinations to widely
deploy artificial intelligence in the cardiac surgical field.
AI chatbots produce varying degrees of hallucinations 2. Biases:
in content generation, as shown in Figure 5. Chatbots with In the era of artificial intelligence, where most clinical prac-
higher degrees of hallucinations cannot be reliably deployed tices are aided by AI systems, AI biases widen and exaggerate
in the healthcare domain, where a higher degree of accuracy existing healthcare disparities, benefiting only certain groups
is paramount. As indicated in the LLM hallucination lead- with their highest performance.⁶⁴ Historically, women and
erboard below, LLMs like GPT-4 (ChatGPT) and Llama 2 minority groups in the US—Black and African Americans,
(CARES Copilot 1.0) have fewer hallucinations and higher Hispanics, Asian Americans, and Native Americans—are
accuracy rates, making them preferable for surgical and clinical underrepresented in cardiology in terms of research studies,
applications. Though ChatGPT performed worse in reference treatment, and clinical outcomes.⁶⁵ AI models are trained
generation, it has the lowest overall hallucination rate in vari- with real data from previous medical experiences and trends,
ous fields, according to HHEM 2.1, a hallucination detection so they tend to reflect biases that were once part of clinical
model (Figure 5). practices. Bias in AI usually manifests as the occurrence of
unequal or disproportionate outcomes of AI systems. These
disparities usually result from factors such as race, gender, and
socioeconomic status. For example, an AI model used for risk
prediction for heart surgeries may not perform well for Black
and underrepresented patients if the model is primarily trained
using data from predominantly White populations. AI biases
widen and exaggerate existing healthcare disparities, causing
only certain groups to benefit from AI’s highest performance.
Strategies to Mitigate Biases:
Biases may occur at each level of the model’s development
steps, including data collection and preparation, model train-
ing, validation, and deployment. Therefore, bias-mitigating
Figure 5: HHEM-2.1 Hallucination Evaluation Model LLMs
Hallucination Leaderboard. Extracted from "HHEM 2.1: A Better
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strategies must focus on these developmental stages and may to reduce complications and yield better patient outcomes. By
include, but are not limited to, the following approaches: augmenting LLM-based surgical assistants (such as CARES
Using Heterogeneous Datasets: It is important to ensure Copilot and ChatGPT) with robotic surgical systems, it is
that AI models are trained on diverse and representative data- possible to reduce the risks of surgical errors throughout the
sets, including a wide range of geographic and socioeconomic procedure and enhance overall patient outcomes.
groups.⁶⁶ Using data sampling techniques like oversampling Robotic technology is rapidly advancing in the surgical
underrepresented groups or undersampling overrepresent- field. Autonomous and semi-autonomous robotic systems are
ed groups helps to balance the dataset before training.⁶⁷,⁶⁸ increasingly investigated in surgical procedures, from low-level
Employing these data sampling methods helps reduce class automation early surgical robots to high-level autonomous ro-
imbalance (population) by changing the dataset distribution bots performing complex endoscopic operations. For example,
through repeating/dropping samples, respectively. In 2021, the in 2022, the Smart Tissue Autonomous Robot (STAR)—de-
FDA published the Artificial Intelligence/Machine Learn- veloped by Johns Hopkins University—performed the first
ing (AI/ML)-Based Software as a Medical Device (SaMD) fully autonomous laparoscopic surgery in four experiments in
Action Plan⁶⁹ and the Good Machine Learning Practice for pig tissues.⁷³ STAR performed intricate surgeries with higher
Medical Device Development: Guiding Principles (GMLP).⁶⁶ accuracy and consistency than humans performing the same
The FDA’s guidelines recognized the challenges and impor- procedures. It is expected that soon AI-driven autonomous
tance of addressing biases when developing AI or ML medical robots will enter the cardiac surgical field and improve the out-
devices and systems. comes of surgeries.¹² By reducing the costs of robotic surgical
Model Training: During model training, fairness-con- systems, it is possible to replace conventional cardiac surgeries
scious algorithms such as adversarial debiasing or fairness with robotic ones while reducing mortalities, surgical errors,
constraints⁷⁰ can adjust for disparities in model performance and unnecessary costs. Future research will require an interdis-
across different demographic groups. Certain clinical features ciplinary effort involving biomedical engineers, AI developers,
such as race, gender, or socioeconomic status affect the perfor- and medical professionals to develop highly reliable surgi-
mance of AI models if not used appropriately. Using machine cal systems. However, AI-based systems should not replace
learning methods such as adversarial learning, which works by healthcare professionals but augment them in providing better
training models to minimize the performance of a "discrim- patient care. Therefore, while leveraging the benefits of AI in
inator" tasked with identifying protected attributes (such as cardiac surgery, it is crucial to adopt the human-AI approach⁶⁶
race or gender), helps to ensure that the model does not rely in surgical procedures where the central decision-making re-
on these attributes to make predictions.⁷¹ Prioritizing other mains to surgical professionals. This approach will help us
clinically relevant features (e.g., comorbidities, laboratory test medical professionals' skills and expertise, safeguard their
results, and physiological measurements) overprotected fea- roles, and preserve jobs in the medical field.
tures helps mitigate bias, in the model training phase. Future work should focus on new ways of reducing bias-
Deployment and Monitoring: During the post-develop- es, particularly in surgery, that can lead the model to amplify
ment phase, developers continuously monitor and assess AI biases from training datasets, reflecting historical disparities
systems performance, which helps them identify any emerging and inequities in healthcare care. These biases may include
disparities in the real clinical setting.⁶⁶ After the deployment cultural, gender, or socio-economic biases, impacting surgical
of AI-enabled systems, tracking patients’ outcomes by demo- care by providing misdiagnosis and unequal treatment recom-
graphic groups in the system helps pinpoint changes in patient mendations.³⁷ Additionally, the medical AI field should aim
population dynamics. Evaluating model performance not only to develop AI systems with reduced hallucinations, reducing
across the overall population, but also across specific popula- costs related to fine-tuning LLMs, and producing more sur-
tions—women, racial minorities, and elderly patients—ensures gical systems to address accessibility of cardiac surgical care
equitable assessment on how well the model generalizes across worldwide. This way it is possible to create systems that are
each demographics.⁷² efficient and highly reliable. Moreover, government officials
� Discussion and policy-makers should set clear policies and regulations re-
This paper highlights critical applications of AI-based garding job displacement resulting from artificial intelligence.
systems for preventing surgical errors in cardiac surgical As AI advances, it is crucial to balance its significant benefits
care by introducing ChatGPT and the novel surgical assis- with workforce protection to ensure that AI systems augment
tant—CARES Copilot 1.0. The potential applications of AI with humans, rather than replace their expertise.
in cardiac surgery range from preoperative planning and risk � Conclusion
assessment to intraoperative real-time surgical support and Overall, robotic-assisted cardiac surgery has significantly
postoperative rehabilitation care. With ongoing research and reduced complications, mortality rates, and length of hospi-
advancement in AI, ChatGPT, and CARES Copilot 1.0 have tal stays compared with conventional surgeries. Furthermore,
immense potential to transform surgical care, enhance surgical the wider integration of robotic surgery and AI systems will
training, and support medical research. As CARES Copi- bring a transformation in surgical precision and patient out-
lot 1.0 has been successfully implemented in neurosurgeries, comes. AI’s real-time surgery simulation will help track every
demonstrating its ability to optimize surgical procedures with step involved and prevent surgical errors through operation
higher efficiency, it should also be used in cardiac surgeries remainders and real-time surgery feedback. AI-based surgical
DOI: 10.36838/v7i3.15 104
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