REVISTA CIENTÍFICA MULTIDISCIPLINAR NÚCLEO DO

CONHECIMENTO ISSN: 2448-0959

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SEXUAL AND REPRODUCTIVE SEQUELAE OF COVID-19 IN MALE

PATIENTS: AN INTEGRATIVE REVIEW

REVIEW ARTICLE

FILHO, Antônio Hamilton Campos de Ávila1, MOURA, Daniel Augusto Mendes2,

NETO, Paulo Batista da Costa3, DIAS, Claudio Alberto Gellis de Mattos4, ARAÚJO,
Maria Helena Mendonça de5, SILVA, Anderson Walter Costa6, OLIVEIRA, Euzébio
de7, DENDASCK, Carla Viana8, FECURY, Amanda Alves9

FILHO, Antônio Hamilton Campos de Ávila. et al. Sexual and reproductive

sequelae of Covid-19 in male patients: an integrative review. Revista Científica
Multidisciplinar Núcleo do Conhecimento. Year. 07, Ed. 11, Vol. 12, pp. 119-136.
November 2022. ISSN: 2448-0959, Access link:
https://www.nucleodoconhecimento.com.br/health/reproductive-sequelae, DOI:
10.32749/nucleodoconhecimento.com.br/health/reproductive-sequelae

ABSTRACT

The emergence and proliferation of the new Coronavirus (SARS-CoV-2) has had an
incisive impact on the world, more specifically among health professionals who are
on the front lines in the fight against this pathology. This study specifically highlights
the reproductive and sexual health of men when affected by this pathology, which is
yet another concern for men's health, especially due to the real possibilities of having
a worrying impact on male fertility, which is already constantly impacted by factors
resulting from the environment and lifestyle habits of this population. The main
objective of the study is to know the sexual and reproductive consequences of
COVID-19 in male patients according to what the scientific literature indicates. For
this, searches were carried out in databases such as: Scielo (Scientific Electronic
Library Online), Lilacs (Latin American and Caribbean Literature in Health Sciences),
BVS (Virtual Health Library), MEDLINE (Pubmed) and PEDro and on the Google
Scholar search site, using the following keywords associations: COVID-19,
sequelae, reproductive health, male patients, testicles, infertility, erectile
dysfunction, penis. After the review study, it was inferred that it became evident that
the sexual and reproductive sequelae in men contaminated by SARS-CoV-2 are
severe to the point of harming the health and well-being of these patients. This
assumption makes it clear that studies with male patients after COVID-19 should
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continue in order to establish better strategies for diagnosis and treatment of this
population.

Keywords: COVID-19, Sequelae, Infertility, Testicles, Erectile Dysfunction.

INTRODUCTION

The emergence and proliferation of the coronavirus that causes acute respiratory
syndrome type 2 (SARS-CoV-2) had an incisive impact on the world, more
specifically among health professionals, as they are in direct contact in the fight
against this pandemic. Its lethality has been discussed, as well as more adequate
ways to protect the population from the infection; in addition to the search for a
variety of vaccines (CASTRO; POCHMANN, 2020; SILVA et al., 2020).

Viral transmission can occur even without the appearance of signs and symptoms
and the clinical picture is quite broad, ranging from a simple cold to severe
pneumonia, the most frequent being: fever, cough, difficulty breathing, muscle pain,
confusion, headache, sore throat, rhinorrhea, chest pain, diarrhea, nausea and
vomiting (OBI; ODOH, 2021; SILVA et al., 2020a).

On May 10, 2022, 515,748,861 confirmed cases and 6,255,835 deaths of people
infected with the new coronavirus were identified worldwide, with the majority of
deaths caused by the acute respiratory syndrome triggered by the virus (WHO,
2020).

It is interesting to note that the disease caused by the coronavirus in 2019 (COVID-
19) was initially identified as a respiratory disease, but it has now been realized that
it is a pathology with the involvement of several systems (BARRANTES, 2021;
CHAVES et al., 2021).

The consequences of infection with SARS-CoV-2 can be the most varied,

significantly affecting the health and quality of life of men and women. However, it is
worth highlighting, in this study, the reproductive and sexual health of men, tracing

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the correlations between the impact of the infection in each system and its
implications in the general sexual function of the individual. There is also an
additional concern about the possibilities of repercussions on male fertility, since this
is constantly impacted by environmental factors and the lifestyle of this population
(TIAN; ZHOU, 2021).

From the tests on the first male patients with COVID-19, identifiable changes were
observed in hormonal and sperm tests, in addition to other changes that affect sexual
function in general, which constitutes a new challenge to better understand and,
consequently, help in the recovery of these patients (GRONER et al., 2020).

OBJECTIVE

To know the sexual and reproductive consequences of COVID-19 in male patients

according to the scientific literature.

METHODS

This is a literature review research, with an integrative nature. Gil (2017) expresses
the importance of this type of research, showing that it refers to the collection of data
from the scientific literature on the topic addressed. We used as a guiding question:
"What are the possible reproductive sequelae caused by COVID-19 in male
patients?" according to the steps characterized by Mendes, Silveira and Galvão
(2008).

Scientific articles related to the subject were included in this research, addressing
the sexual and reproductive consequences of COVID-19 in male patients, according
to the scientific literature, works published in the years 2020 to 2022, only free
articles being included. Scientific articles that are not related to the research topic,
articles published in the years before 2020 and any other events that are not
associated with the theme were excluded from this research.

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The study took place from the following stages:

1) Searches in databases such as: Scielo (Scientific Electronic Library Online), Lilacs
(Latin American and Caribbean Literature in Health Sciences), BVS (Virtual Health
Library), MEDLINE (Pubmed) and PEDro, and on the website Google Scholar
search engine, using the following keywords and associations: “COVID-19”,
“sequelae, reproductive health”, “male patients”, “penis”, “testicles”, “infertility”, and
“erectile dysfunction ”.

2) Selection of articles for inclusion in this review;

3) Analysis of study results;

4) Discussion of the results.

In scientific research in the databases, 243 articles were obtained in the

methodological stage corresponding to identification. When filtering the articles, 212
were excluded, since only 31 of the articles surveyed were adequate and eligible.
Articles unrelated to the topic, duplicate articles, paid articles or articles unavailable
to access that were identified after reading the title, reading abstracts and, when
necessary, reading the entire article were excluded.

The eligible articles were then read and the main findings of each work were
extracted in a summarized manner in order to establish an overview that would
answer the guiding question.

RESULTS AND DISCUSSION

CLINICAL CONDITION AND TRANSMISSIBILITY

The clinical picture presents several signs that resemble a simple cold, and may
progress to severe pneumonia and death. The most common symptoms are cough,
sore throat, runny nose, fever, headache and dyspnoea. The virus is characterized
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by high transmissibility, occurring from a contaminated individual to a healthy

individual through close contact. In this context, the healthy person comes into
contact with infected biological material via droplets of saliva, sneezing, coughing,
phlegm (FARIAS et al., 2020).

Another important issue involves the fact that the virus can survive on certain
surfaces, and the time for which it remains with infection power varies depending on
the type of material. In view of the above, the risk of contamination is clear if the
person touches the contaminated material and subsequently takes the member with
the virus to the mucosa of the mouth or nostrils. That's why it's so important to adopt
proper hygiene habits after touching public use structures, such as handrails,
buttons, public transport supports and others (BARRETO et al., 2020).

One of the measures to contain the pandemic is social isolation, which corresponds
to a measure in which the sick patient is isolated from non-ill individuals, in order to
avoid the spread of the disease (ABREU, 2020).

Horizontal social isolation is a measure in which the largest number of people are
isolated in their homes and, for this reason, it was the most indicated in the pandemic
scenario, since it had the greatest potential to contain the epidemic (SANTOS,
2020).

MALE SEXUAL AND REPRODUCTIVE HEALTH

Health care for the male population includes the use of methods and various
techniques and services that favor health and quality of life, as well as men's own
reproductive capacity. Male sexual and reproductive health, in recent times, has
become a priority concern in existing health policies in Brazil and in the world
(BRASIL, 2021).

The diagnosis of sexual dysfunctions is as important as the identification of any other

health problem and is of paramount importance, since it interferes with people's
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quality of life. It is also observed in primary care what type of dysfunction and where
to refer the patient for proper treatment (BRASIL, 2013).

Therefore, the main purpose of reproductive health care is to improve the quality of
life and established personal relationships, and not just advice or adequate
assistance related to reproduction and Sexually Transmitted Infections (STIs)
(HADDAD, 2018).

THE SEXUAL AND REPRODUCTIVE COMPROMISE OF COVID-19

IN MEN'S HEALTH

For men, the damage resulting from SARS-CoV-2 contamination covers the most
varied systems, also affecting reproductive and sexual health (KAYNAR et al., 2022).
This is because the virus has a wide range when located in the body. For example,
when reaching the testicles, the virus attacks both sperm-producing cells and
testosterone-secreting cells. In addition to direct cell damage, there is also vascular
impairment in the small vessels that are responsible for irrigation in the genital
region, consequently reducing the supply of oxygen and nutrients to the tissues. This
fact was observed in many men with different degrees of severity of the disease,
affecting both those who had the mildest form of the disease and those with the most
severe forms (FRAIETTA et al., 2020).

It should be specified that in order to gain access to cells, SARS-CoV-2 needs to

establish a connection with a receptor as its main task. One of the receptors currently
identified as a gateway for the virus is the Angiotensin-Converting Enzyme 2 (ACE2)
receptor, which normally exists in abundance in various tissues, but especially in the
lungs and, in the case of men, in the testes (FRAIETTA et al., 2020).

Once SARS-CoV-2 manages to settle and multiply, the pathogen eventually results
in the appearance of lesions that result in the impairment of the regular production
of the hormone called testosterone and, consequently, of spermatozoa. These

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discoveries are essential for creating procedures and programs that will reverse
commitments that directly affect sexual and reproductive health resulting from the
action of this virus (HALLAK et al., 2021).

In this sense, it is normally advised by health professionals that male patients who
are affected by the SARS-CoV-2 infection take the time to undergo periodic
evaluations, for at least two years after being infected with this virus. In the case of
men who are in adolescence and youth, as they generally have a more competent
immune system and develop mild or asymptomatic forms, special attention should
be given to this issue (PACHECO et al., 2020).

Because it is a disease that causes systemic involvement, COVID-19 brings damage

that extends from the structure of the lungs, through the cardiovascular system, even
reaching the health of the patient's neurological system. Based on this information,
it is inferred that sexual dysfunction may have a mixed cause, being related to
testicular, vascular, pulmonary involvement and also at the neuropsychological level,
since this has a primordial function in male sexual and reproductive health, proving
to be one more target for diagnostic investigation and also for establishing an
appropriate therapeutic approach. Erectile dysfunction itself can have both structural
and psychogenic causes and, considering that both can be affected by SARS-CoV-
2, it is important to be aware of this correlation when approaching patients who have
had the disease and refer to complaints of this nature (KAYNAR et al., 2022).

Another point to be noted is the reduced oxygenation capacity of the blood that
results from what is called pulmonary fibrosis, often associated with moderate to
severe versions of this disease. (TEIXEIRA et al., 2021) This reduction in the
patient's ability to perform aerobic work also negatively affects sexual health, since
maintaining an erection and the sexual act itself are activities that involve energy
consumption, therefore, they require a capacity adequate blood oxygenation and
tissue perfusion. This is another fact that contributes to putting together the puzzle

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of sexual and reproductive sequelae in individuals who have had COVID-19

(HALLAK et al., 2021).

ANOSMIA AND AGEUSIA

It is already known that one of the main sequelae commonly found in post-COVID
patients is the loss or reduction of smell and taste. It is interesting to note that the
loss of smell in these patients is not usually associated with nasal obstruction,
suggesting that the mechanism involved in this event is damage to the olfactory and
gustatory receptors (VAIRA, 2020). The relevance of these findings with regard to
sexual health is related to the importance of smell for the sexual stimulation of human
beings. Sex pheromones, chemicals produced by specialized glands that affect
sexual and dominance behavior in animals, are detected by olfactory receptors.
Although human sex pheromones have not yet been isolated, it is already known
that smell is an important factor in sociosexual behavior in contact between people
and this is significantly impaired in patients who have loss of smell due to COVID-19
(BERTOLO et al., 2021).

PULMONARY IMPAIRMENT

COVID-19 primarily manifests itself in the respiratory system (ZHOU et al., 2020).
The epithelium of the respiratory system has a large number of ACE2 receptors,
which partially explains why the symptoms are mostly expressed in this location
(TEIXEIRA et al., 2021). Typical factors present in the pulmonary manifestations of
COVID 19 are clots, endothelial damage, and inflammation. The presence of
microthrombi in capillary alveoli and neoangiogenesis are associated with severe
endothelial damage (CAMPOROTA et al., 2021).

Later in the course of the disease, these factors are triggered by the “cytokine storm”,
an inflammatory response to SARS-CoV-2, in which a positive feedback process is
likely responsible for the accumulation of inflammatory cytokines in the lung. Patients

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then experience increased dead space ventilation, bilateral pulmonary infiltrates and
oxygenation difficulties (CAMPOROTA et al., 2021).

It is important to highlight that the deterioration in the individual's aerobic capacity

has a direct impact on sexual performance, since the act itself has an important
energy demand, reaching 6 METS for men and 5.6 METS for women (FRAPPIER
et al., 2013).

BLOOD VESSEL COMPROMISE

What research carried out and consolidated to date indicates is that the
pathophysiology of inflammation that affects the lung has important similarities with
the pathophysiology of vascular involvement, since the inflammatory cytokines
released by the immune response to the infection affect both sites. However,
vascular involvement has other ramifications, as the infection by SARS-CoV-2
affects the ability of the blood to clot, increasing the predisposition to the formation
of thrombi and clots, which may, in some cases, progress to disseminated
intravascular coagulation, which it is a serious complication and difficult to manage
(CAMPOROTA et al., 2021).

In objective terms, it is noted that the occurrence of a reduction in the body's

oxygenation capacity causes inflammation in the vascular endothelium, since
hypoxia triggers the body to release vasodilator factors, a physiological response
that aims to increase the supply of oxygen to the tissues. However, in the patient
with COVID-19, these mechanisms are deregulated and impair the balance, since
once damaged by the virus, the endothelium has its ability to synthesize nitric oxide,
one of the main substances responsible for vasodilation, compromised (GAVRIILAKI
et al., 2020).

Speaking specifically of the penis, in research carried out by (KRESCH et al., 2021)
with patients who recovered from COVID-19 and developed severe erectile

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dysfunction, it was possible to report the presence of viral RNA in the endothelium
of penile vessels, as well as a reduction in expression of nitric oxide receptors, which
may explain the reduction in blood flow and consequent inability to have erections in
this population.

TESTICLES, EPIDIDYMIS, FERTILITY

The testes express, inside, a large amount of ACE2 receptors (TIAN; ZHOU, 2021).
However, the mere presence of the receptor is not enough to allow the virus to enter,
requiring the expression of the TMPRSS2 protein to activate them. Therefore, the
absence or lower expression of this protein ends up acting as a protective agent
(TIAN; ZHOU, 2021). This fact explains why, although it has a density of ACE-2
receptors similar to the testes, the lungs are organs more frequently affected by
COVID-19, since they express a greater amount of TMPRSS2 protein (TEIXEIRA et
al., 2021).

When discussing the reproductive and sexual sequelae of COVID-19 on male

patients, (TIAN; ZHOU, 2021) reinforces the fact that inflammatory cytokines can be
produced locally, in the testes, but can also be produced systemically, reaching the
testicular tissue by hematogenous spread and affecting organ function by this route.

SARS-CoV-2 enters the cell and, together with inflammatory cytokines, acts directly
on Leydig cells, responsible for secreting the hormone testosterone, whose local
action is also important in the process of spermatogenesis. Add to this the fact that
the blood-testis barrier, which often prevents any type of virus invasion, is vulnerable
to inflammation caused by cytokines, which ends up increasing its permeability to
invading agents (TIAN; ZHOU, 2021).

Peirouvi et al. (2021) when analyzing testicular tissue samples from patients who
died due to COVID-19, found that there is an inflammation process and disruption of
the blood-testis barrier, resulting in a reduced number of Leydig cells, presence of

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inflammatory cells and destruction in the seminiferous tubules. The same author
explains in his research that there are some conditions that increase the chance of
the virus entering and breaking the testicular tissue, including high viral load in the
blood, local inflammation, hyperpyrexia and an imperfect blood-testicular barrier.

Reinforcing this finding, Hallak et al. (2020) managed to show that COVID-19 and
its variants also affect Sertoli cells, which help in the sperm maturation process, and
in spermatogonia, which are responsible for the production of gametes.
Simultaneously, SARS-CoV2 infection contributes to the inflammatory process of the
tissues, which can cause both fibrosis and hemorrhages, similar to those that occur
in the lung structure (HALLAK et al., 2020).

This author, one of the main exponents investigating the repercussions of SARS-
CoV-2 on the sexual and reproductive health of men and the different consequences,
informs that the alterations can result in molecular changes that can be perceptible
in the sexual glands (TEIXEIRA et al., 2021). Among these, it is possible to mention
the quantitative loss of cells that produce spermatozoa, a decrease in cells that
stimulate the production of testosterone, the male hormone, in addition to the death
of cells that act in the maturation of gametes and support testicular functioning as a
whole (FRAIETTA et al., 2021).

Another important structure for male fertility that is also affected by COVID-19 is the
epididymis. A study using color Doppler ultrasonography showed the presence of
epididymitis in a relevant number of patients, noting the presence of an increase in
the head of the epididymis, increased flow on Doppler and thickening of the scrotal
skin, findings that may be correlated with fertility problems (CARNEIRO et al., 2021).

THE TESTOSTERONE DROP

According to Kaynar et al. (2022), studies carried out from the first quarter of 2021
established a clear relationship between COVID-19 and the sexual and reproductive

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health of men who were affected by this pathology, significantly affecting the sexual
performance of adult men.

This occurred for several reasons, including the reduction of testosterone levels
significantly. As already mentioned, the abundant presence of ACE-2 receptors in
the testes, more specifically in Leydig cells, allows the virus to enter, damaging the
cell whose function is to produce testosterone (GRONER et al., 2021).

Hallak et al. (2021) explains this finding by conceiving that, upon gaining access to
the male reproductive system, SARS-CoV-2 causes direct and indirect damage to
various organs, including the reproductive system, both by entering the cell and by
the storm of inflammatory cytokines. Confirming this information, (GOONER, 2021)
also reinforced this finding, confirming the marked number of ACE2 receptors in the
testicles and their relationship with the tissue damage caused by the virus.

PSYCHOLOGICAL EFFECTS

Bowling et al. (2021) states that during the beginning of the pandemic there was a
change in society regarding the interpretation of what is considered “risky sex”.
Having come to consider as risky sex any sexual activity involving an individual
infected with SARS-CoV-2, an individual who has been exposed or even who does
not comply with social isolation.

Thus, although COVID-19 is not a sexually transmitted infection, it manifests itself

as a primary concern in relationships due to its pandemic character and its high
transmissibility via the oral route, making it difficult to create new intimate
relationships (PENNANEN-LIRE et al. , 2021).

NEUROLOGICAL REPERCUSSIONS

According to Taquet et al. (2021), SARS-CoV-2 infection can result in several

neurological consequences, including intracranial hemorrhage, stroke, dementia,
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encephalitis, neuropathies, among others, especially in patients undergoing

hospitalization or who manifested encephalopathy during admission hospital.

During COVID-19 infection, the state of hypoxia faced by the patient is responsible
for indirect neuronal injury, given that neurons are highly sensitive to lack of oxygen.
There is also direct injury by the virus infection itself in neuronal cells, which also
express the ACE2 receptor (MERINO et al., 2021).

Critical illness polyneuropathy is particularly more common in men in the context of

COVID-19 (94%) (FRITHIOF et al., 2021). It has a variable manifestation that
includes muscle atrophy, hyporeflexia, tetraparesis, which may make it difficult or
even impossible to perform the sexual act.

CONCLUSIONS

Despite being a recently discovered disease, several studies have already been
carried out and attested that the sexual and reproductive sequelae in men
contaminated by SARS-CoV-2 are severe to the point of causing damage to the
health and well-being of these patients. This assumption makes clear the need to
continue with studies on this topic.

Especially worrying is the situation of patients who have been diagnosed with the
most severe forms of COVID-19, with manifestations that include the presence of
the virus even in semen, orchitis, epididymitis, in addition to a reduction in both the
quantity and quality of semen during the duration of the pathology. These alterations
still need to be studied to verify if there is an improvement in the long term or not,
also highlighting the need to maintain vigilance in patients who have recovered from
the disease.

Another point worth mentioning is the complexity of the male sexual function, since
it depends on the full functioning of several body systems. This became clear when
analyzing how SARS-CoV-2 can negatively affect the individual psychologically,
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neurologically, on the cardiovascular system, on the ability to perform aerobic work

and even on the ability to perceive odors and flavors.

It became clear, during the production of this work, that much progress had already
been made towards elucidating the pathophysiological mechanisms of the disease,
as well as to identify possible sequelae that, at first, we had no idea of the
occurrence. However, the literature shows a lack of efficient therapeutic alternatives
for this population, which highlights the need to continue studies in this direction.

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Submitted: November, 2022.

Approved: November, 2022.

1 Medical Student. Group 7. 12th semester. Universidade Federal do Amapá - UNIFAP (UNIFAP).
2 Medical Student. Group 8. 11th semester. Universidade Federal do Amapá – UNIFAP (UNIFAP).

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3 Medical Student. Class 12. 7th semester. Universidade Federal do Amapá – UNIFAP (UNIFAP).
4 Biologist, PhD in Theory and Research of Behavior, Professor and researcher at the Degree
Course in Chemistry at the Instituto de Ensino Básico, Técnico e Tecnológico do Amapá (IFAP), at
the Programa de Pós Graduação em Educação Profissional e Tecnológica (PROFEPT IFAP) and
at the Programa de Pós Graduação em Biodiversidade e Biotecnologia da Rede BIONORTE (PPG-
BIONORTE), Amapá pole.
5 Physician, Professor and researcher at the Medical Course at the Universidade Federal do Amapá

(UNIFAP).
6 Physician, Specialist in Systems Management and Health Services. Professor, preceptor and

researcher at the Campus Macapá Medicine Course, Federal University of Amapá (UNIFAP).
7 Biologist, PhD in Tropical Diseases, Professor and researcher of the Physical Education Course

at, Universidade Federal do Pará (UFPA).

8 PhD in Psychology and Clinical Psychoanalysis. Doctorate in progress in Communication and

Semiotics from the Pontifícia Universidade Católica de São Paulo (PUC/SP), Master's Degree in
Religious Sciences from Universidade Presbiteriana Mackenzie. Master in Clinical Psychoanalysis.
Degree in Biological Sciences. Degree in Theology. He has been working with Scientific
Methodology (Research Method) for more than 15 years in Scientific Production Guidance for
Master's and Doctoral Students. Specialist in Market Research and Health Research.
9 Biomedical, PhD in Tropical Diseases, Professor and researcher at the Campus Macapá Medicine

Course, Universidade Federal do Amapá (UNIFAP), and at the Programa de Pós-graduação em

Ciências da Saúde (PPGCS UNIFAP), Pro-Rector of Research and Postgraduate Graduation
(PROPESPG) from the Universidade Federal do Amapá (UNIFAP).

24
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