How Evidence-Based

Dentistry Has Shaped the

P r a c tic e o f Or al M ed i ci ne
Katherine France, DMD, MBE, Thomas P. Sollecito, DMD, FDS RCSEd*

KEYWORDS
 Oral medicine  Evidence-based dentistry  Evidence-based practice
 Oral potentially malignant disorders  Temporomandibular disorder
 Salivary dysfunction  Antibiotic prophylaxis

KEY POINTS
 The clinical practice of oral medicine requires guidelines formulated from evidence.
 Clinical Practice Guidelines in oral medicine define recommendations based in evidence.
 For areas with less clarity, emerging evidence base will provide the ability to shape future
management recommendations.
 Some areas of oral medicine currently contain only limited evidence, based in expert
consensus, and require further research.

INTRODUCTION
Evidence-Based Medicine
Evidence-based medicine has existed as a concept for many years, gaining recogni-
tion and respect especially in the past few decades. From its first appearance in the
literature, the term “evidence-based medicine”1 quickly gained prominence,2 inspiring
reviews and Clinical Practice Guidelines focused on using available, carefully gathered
proof to define recommendations.3 These works have defined recommendations for and
against medications, surgical interventions, management practices, and diagnostic
testing modalities, and they have equally focused scientific awareness on areas in which
convincing evidence does not yet exist. Of course, evidence-based medicine is fraught
with challenges, including the burden of proof required to formulate Clinical Practice
Guidelines, the necessarily narrow definitions of success and end points, and the

Disclosure Statement: K. France has nothing to disclose. T.P. Sollecito serves as a consultant for
the American Dental Association Council on Scientific Affairs.
Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, 240 South
40th Street, Philadelphia, PA 19104 USA
* Corresponding author.
E-mail address: [email protected]

Dent Clin N Am 63 (2019) 83–95

https://doi.org/10.1016/j.cden.2018.08.006 dental.theclinics.com
0011-8532/19/ª 2018 Elsevier Inc. All rights reserved.
84 France & Sollecito

inability for such combined statements to appropriately reflect individual patient presen-
tations or outcomes.4,5
Evidence-based guidelines, the studies that support them, and reviews of these
studies are formulated by a variety of stakeholders, including patients, practicing cli-
nicians, researchers, policy makers, and health care administrators. One major source
of this knowledge, and of support for the synthesis of available data, is the Cochrane
Collaboration.6 The Cochrane Collaboration employs dedicated staff to support
subject-specific systematic reviews and meta-analyses, and distributes standards
to guide the completion of such studies. Their efforts have helped to spread evidence-
based medicine and highlighted its importance for all health care practitioners.
In dental medicine, the importance of evidence-based medicine has experienced a
parallel evolution. Soon after evidence-based medicine became a recognized term,
the concept of “evidence-based dentistry” likewise started to appear in literature.7
In the past 15 years, this term has also become widely used to refer to dental practice
informed by scientific evidence.8 As they evolve,9,10 evidence-based dentistry recom-
mendations have recently become increasingly specialty-specific and procedure-spe-
cific.11–13 As in medicine, evidence must be synthesized and disseminated in dental
medicine to inform a Clinical Practice Guideline. The increase in available evidence-
based guidelines has and will continue to refine and improve the worldwide practice
of dentistry.

Oral Medicine
Oral medicine is a subset of dental medicine that has been defined by various sources.
These include the American Academy of Oral Medicine,14 European Association of
Oral Medicine,15 and multiple groups of practicing oral medicine physicians. In the
United States, the definition of oral medicine has been proposed as “the discipline
of dentistry concerned with the oral health care of medically complex patients,
including the diagnosis and primarily nonsurgical treatment and/or management of
medically related conditions affecting the oral and maxillofacial region.”16 The world-
wide training of practitioners in this emerging field also has been recently defined, sug-
gesting that residency programs focus on competency in the following:
 Diagnosis and primarily nonsurgical management of oral mucosal and salivary
gland disorders
 Diagnosis and primarily nonsurgical management of temporomandibular, orofa-
cial pain, and neurosensory disorders
 Management of the medically complex patient.17,18
Oral medicine competency in the United States is in line with the training of oral
medicine practitioners worldwide,18 although some variation exists between countries
in scope of practice.
Clinical care in oral medicine is available across the United States in many practice
settings, including hospitals, medical/dental schools, and private practice clinics. As
defined by a recent study, patients are referred for oral medicine evaluation by a
wide variety of practitioners, most commonly general dentists.19 Referrals also
come from specialty physicians, including otorhinolaryngologists, hematologists, on-
cologists, radiation oncologists, rheumatologists, and dermatologists. As a dedicated
link between dental and medical care, oral medicine physicians provide thorough
medical and dental evaluations to reach an accurate diagnosis and recommend
appropriate treatment. Broadly speaking, oral medicine providers are frequently con-
sulted for evaluation, diagnosis, and treatment of oral lesions, salivary gland diseases,
 Evidence-Based Oral Medicine 85

facial pain conditions, and care of medically complex patients. Some examples of
these conditions are highlighted in Box 1.
Treatment recommendations in oral medicine depend on the individual patient pre-
sentation, but in many cases consists of medications, behavioral modifications, and/
or oral appliance fabrication. Patients may also be referred for medical evaluation

Box 1
Conditions evaluated and managed by oral medicine physicians

 Oral mucosal diseases/oral and perioral lesions20,21

 Oral lesions, including erythroplakia, leukoplakia, oral submucosal fibrosis, pigmented
lesions, ulcerations, or lesions associated with systemic conditions, including human
immunodeficiency virus (HIV) disease
 Mucosal and perioral growths, such as fibroma, papilloma, hemangioma, seborrheic
keratosis, actinic keratosis
 Ulcerative diseases, including recurrent aphthous stomatitis and Behçet disease
 Fungal infections, including angular cheilitis, candidiasis, or deep fungal infection
(aspergillosis, histoplasmosis, mucormycosis, blastomycosis)
 Viral infections, including herpetic infections, Coxsackie infections
 Immune-mediated disorders, including erythema multiforme, oral lichen planus, mucous
membrane pemphigoid, pemphigus vulgaris, or systemic lupus erythematosus
 Granulomatous disease, including orofacial granulomatosis and oral manifestations of
systemic granulomatous disease
 Malignant conditions of the oral cavity
 Complications following medical treatments, including oral mucositis, oral graft-versus-
host disease, osteonecrosis of the jaw
 Salivary gland disease and dysfunction22
 Objective hyposalivation, caused by medications or previous exposure to radiation therapy
 Reduced salivary flow secondary to systemic diseases, including Sjögren syndrome and
other autoimmune diseases
 Xerostomia, the subjective feeling of oral dryness
 Sialosis, enlargement of salivary glands
 Sialoadenitis, including infections of the salivary glands, such as parotitis
 Sialolithiasis, stones in the salivary glands
 Enlargement of salivary glands, as can occur in bulimia nervosa
 Diffuse infiltrative lymphocytosis syndrome in HIV disease
 Salivary gland malignancies
 Facial pain conditions23
 Pain and dysfunction originating from the temporomandibular joint (TMJ) complex
including myalgia, myofascial pain, TMJ capsulitis, TMJ arthralgia, and internal
derangement of the TMJ
 Intraoral pain, including pain of odontogenic, periodontal, mucosal, or bone origin
 Neuropathic pains involving the oral cavity, including glossodynia or burning mouth
syndrome
 Persistent idiopathic facial pain (atypical facial pain)
 Neuralgias of the orofacial region including trigeminal, auriculotemporal, and
glossopharyngeal neuralgias
 Headache disorders, including tension-type headache, migraine, cluster headache, and
rare autonomic cephalgias
 Pain of intracranial origin
 Referred pain from other sites or associated structures
 Pain arising as a complication of mental illness
 Medically complex patient dental care
 Assessment of patient fitness for dental treatment
 Provision or modification of appropriate dental treatment to patients with multiple or
complex systemic diseases
86 France & Sollecito

when an oral cavity finding suggests a systemic disease. For patients with significant
medical comorbidities, the role of the oral medicine practitioner also includes consul-
ting with other members of the health care team and advising on the appropriate mod-
ifications to dental treatment or timing of treatment.
The importance of evidence-based practice in oral medicine stems directly from the
theoretic and practical complexity of the field. The wide variety of conditions encoun-
tered in an oral medicine practice, as well as variations in the individual patient presen-
tation and response to treatment, defines the need for careful evaluation and synthesis
of practice recommendations to provide appropriate and effective treatment. The
remainder of this article presents examples of how evidence related to each practice
area of oral medicine has shaped clinical practice. Our examples show how the use of
Clinical Practice Guidelines varies by topic and has evolved over time. They include a
recently published Clinical Practice Guideline on the detection of potentially malignant
oral disorders to show how evidence guides diagnostic practice, a review on treat-
ment of salivary gland dysfunction that illustrates how existing data inform practice
and refine additional study, a review of treatment for temporomandibular disorders
that highlights the need for definitive diagnostic criteria, and a Clinical Practice Guide-
line on the use of prophylactic antibiotics in patients with prosthetic joint replacement
to show how evidence-based dentistry benefits society. By highlighting existing ex-
amples, we also call attention to the need for further evidence-based guidelines to
refine all areas of oral medicine practice.

ORAL LESIONS

Oral lesions present a broad and primary focus of oral medicine practices. As exem-
plified in Box 1, oral lesions can take on an almost infinite variety of clinical appear-
ances based on their size, location, color, texture, and number. They may
themselves be benign, premalignant, or malignant, and each lesion may provide infor-
mation about underlying systemic conditions. Distinguishing based on these and other
signs, as well as on symptoms and history can provide clues to the diagnosis of these
lesions.
Oral lesions are common in the general population. In an early study, it was esti-
mated that 10% of 23,616 patients studied had at least one oral lesion.24 These lesions
ranged from solitary to widespread, from benign to malignant, and included all sur-
faces of the oral mucosa. Recognition and evaluation of these lesions is an important
aspect of dental treatment. Accurate and thorough clinical evaluation and diagnostic
testing are required to determine whether a given lesion may represent a potentially
cancerous or a cancerous process.
The importance of early and accurate diagnosis of potentially malignant conditions
cannot be overstated. Cancers of the oral cavity, 90% of which are squamous cell car-
cinoma,25 are estimated by the American Cancer Society to have accounted for
32,670 new cases and 6650 deaths in 2017.26 These are separated from cancers of
the oropharynx, which accounted for approximately 17,000 new cases and 3050
deaths in 2017. The separation between the oral cavity and the oropharynx is defined
as the soft palate, tonsillar pillars, and the base of the tongue, with the oral cavity
comprising those areas anterior, including the mobile portion of the tongue, and the
oropharynx including these borders and structures posterior. Squamous cell carci-
noma of the oral cavity has an overall 5-year survival rate of 64.3% in the United
States, with the rate dropping to 38.5% in patients who present with distant metasta-
ses.27 A wide body of literature covers the importance of careful screening of patients
in general and specialty dental practice by trained providers to ensure early diagnosis
 Evidence-Based Oral Medicine 87

and appropriate referral to treatment for all patients with oral lesions to improve these
rates.28–32
Given the importance of a timely and accurate diagnosis of malignancies, the
assessment of potentially malignant oral lesions depends closely on robust evidence.
Multiple studies have been completed and synthesized into a few systematic reviews
on the use of diagnostic tests and adjuncts for diagnosis of oral lesions, which rein-
force the impact of clear evidence-based recommendations.33–36 Still other studies
have discussed the proper approach to lesions found to contain some level of epithe-
lial dysplasia, although consensus on treatment of these lesions has not yet been
established.37 Synthesizing previous recommendations, a recent report from the
American Dental Association provided a Clinical Practice Guideline for evaluation of
potentially malignant oral lesions.38
This guideline reviews the level of evidence supporting various modalities available
for evaluation of a potentially malignant oral disorder. The methods reviewed include
the histopathological testing of lesions, salivary analysis, and use of adjunctive tests,
such as cytologic sampling, oral mucosal staining, autofluorescence, or vital staining
for adults with suspicious lesions in the oral cavity. Using available systematic reviews,
as well as studies dealing with efficacy of adjunctive testing, the expert panel was able
to reach recommendations for the use of these methods, which appear in Box 2.
These carefully compiled and clearly explained guidelines can now be used to
inform the clinical practice of providers in all specialties who manage these pa-
tients.39,40 The clinical evaluation of these lesions will thus be shaped by evidence
on which methods of testing are most reliable.

SALIVARY GLAND DISEASE

The management of salivary gland disease is an area of oral medicine in which existing
treatment recommendations are available to guide expert decisions. As noted

Box 2
Recommendations on the evaluation of potentially malignant oral disorders (PMDs)

 The panel suggests that for adult patients with a clinically evident oral mucosal lesion
considered to be suspicious of a PMD or malignant disorder, or other symptoms, clinicians
should perform a biopsy of the lesion or provide immediate referral to a specialist.
(Conditional recommendation, low-quality evidence.)
 The panel does not recommend cytologic adjuncts for the evaluation of PMDs among adult
patients with clinically evident, seemingly innocuous, or suspicious lesions. Should a patient
decline the clinician’s recommendation for performing a biopsy of the lesion or referral to a
specialist, the clinician can use a cytologic adjunct to provide additional lesion assessment.
(Conditional recommendation, low-quality evidence.)
 A positive or atypical cytologic test result reinforces the need for a biopsy or referral. A
negative cytologic test result indicates the need for periodic follow-up of the patient. If
the clinician detects persistence or progression of the lesion, immediately performing a
biopsy of the lesion or referral to a specialist is indicated.
 The panel does not recommend autofluorescence, tissue reflectance, or vital staining
adjuncts for the evaluation of PMDs among adult patients with clinically evident,
seemingly innocuous, or suspicious lesions. (Conditional recommendation, low-quality
evidence to very low quality evidence.)

From Lingen MW, Abt E, Agrawal N, et al. Evidence-based clinical practice guideline for the
evaluation of potentially malignant disorders in the oral cavity. J Am Dent Assoc
2017;148(10):720; with permission.
88 France & Sollecito

previously, oral medicine practitioners treat both subjective and objective changes to
salivary gland function. Those affected by salivary gland complaints represent a large
and diverse patient population, with varied presentations stemming from a wide range
of causes. Salivary flow rate may be decreased either temporarily or permanently, or
may be unchanged while the consistency of saliva is altered.22 Additionally, salivary
glands may change in size, develop infections, or present with other alterations in
function. Altered salivary flow is particularly prevalent and difficult to treat. Given the
heterogeneous nature of these complaints and the affected population, consensus
recommendations are necessary for appropriate management.
Treatment of decreased salivary flow has been informed by recommendations
formulated as a result of a systematic review performed during the fourth World Work-
shop in Oral Medicine.41 This group synthesized the available evidence through 2005
regarding the treatment of hyposalivation secondary to systemic diseases including
Sjögren syndrome. They combined evidence about which diseases cause salivary
gland dysfunction and about topical and systemic treatments available. After review,
they were able to recommended several agents for treatment (Box 3).
Although the evidence available at the time was insufficient to recommend use of
topical moisturizers or sialogogues, the experts do recommend trial use of these
agents when patient preference and practitioner experience so dictate.
This guideline has materially directed the academic study of salivary gland dysfunc-
tion in oral medicine during the past 10 years. As research into salivary gland disease
has continued, this guideline has served as an evidence base in many systematic and
narrative reviews.42–47 The included recommendations for research have informed the
study of Sjögren syndrome, other causes of xerostomia, and the role that systemic
disease plays in salivary changes. In addition, studies have examined prescription
and nonprescription treatments for patients with xerostomia and hyposalivation.48–51
This guideline has shaped both practice and research focused on patients with sali-
vary gland dysfunction. It allows for oral medicine physicians to provide evidence-
based recommendations and for patients to receive the most effective care and guide
the field in avenues of further research.

Box 3
Recommendations for the treatment of patients with salivary gland dysfunction

The World Workshop in Oral Medicine working group recommends the following:
 The use of pilocarpine for [radiation-induced or Sjögren syndrome (SS)-induced xerostomia].
The recommended dosage is 5 mg orally 3 times a day with titration up to 10 mg.
Classification of Recommendation class I, Level of Evidence A.
 Cevimeline 30 mg, 3 times a day orally, is given as a useful treatment for hyposalivation and
xerostomia in primary and secondary SS. Classification of Recommendation class I, Level of
Evidence A.
 150 IU interferon lozenges 3 times daily may enhance salivary secretion in patients with
primary SS. Classification of Recommendation class IIa, Level of Evidence A.
 Anti–tumor necrosis factor-a agents (infliximab, etanercept) are NOT recommended at this
time to treat hyposalivation in patients with SS. Classification of Recommendation class III,
Level of Evidence A.
 Findings suggest that rituximab is effective in the treatment of primary SS. Larger
[randomized controlled] trials are needed to draw any conclusions about the efficacy of
rituximab.

Data from von Bultzingslowen I, Sollecito TP, Fox PC, et al. Salivary dysfunction associated with
systemic diseases: systematic review and clinical management recommendations. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 2007;103:S57.e1-15.
 Evidence-Based Oral Medicine 89

FACIAL PAIN

Facial pain may be the most frequent complaint in an oral medicine practice. This
broad topic is associated with a wide number of distinct etiologies, including odonto-
genic pain, temporomandibular joint (TMJ) pain, neuropathy, headache disorders, and
systemic conditions that present with facial pain, including giant cell arteritis and can-
cers of adjacent structures.52 In these areas, more detailed work is needed based on
each specific diagnosis given the heterogeneity of the causes of facial pain. Each
associated topic will benefit from focused evidence-based reviews that inform and
standardize clinical practice. At this time, literature on these conditions comes mostly
from narrative and opinion-based reviews.53–57 One area in which some evidence
base exists is in the pharmacologic treatment of TMJ-associated pains.
To effectively treat temporomandibular disorders (TMDs), the oral medicine provider
must first formulate an appropriate diagnosis based on history and thorough examina-
tion of all structures in the TMJ complex. Once the cause of the patient’s pain or
dysfunction is elucidated, modalities of treatment can be considered. The oral medi-
cine provider may use multiple treatments, beginning frequently with pharmaco-
therapy, manual manipulation, splint therapy, or trigger point injections, and
progressing later to surgical management as needed.58–60 The most commonly
used method for managing pain due to an arthrogenous or myogenous TMJ disorder
is pharmacotherapy. Numerous medication classes have been used in practice and
proposed in the literature to treat these conditions, including nonsteroidal anti-
inflammatories, corticosteroids, muscle relaxants, benzodiazepines, antidepressants,
anticonvulsants, opioids, and topical formulations of a variety of medications.61–63
Given the wide variation in both medication class and individual agent, it is clear
that synthesis of available evidence is required to direct clinical practice.
Responding to this need, in 2010, Mujakperuo and colleagues64 partnered with the
Cochrane Collaboration to complete a review on the available evidence for pharmaco-
logic treatment of TMJ disorders. They performed a systematic review of available
randomized controlled trials in which a pharmacologic agent was used to treat pain
coming from any TMJ diagnosis. Studies included were required to involve pharmaco-
logic treatment of adults with moderate to severe pain in the TMJ or masticatory mus-
cles that had lasted for at least 3 months. This pain could be associated with
asymmetric or limited movement, as defined by McNeill’s 1997 diagnostic criteria
for TMD.65 The studies were not, however, separated based on the source of the
pain, and largely included small treatment groups and other methodological flaws.
Partially resulting from these limitations, the review found “insufficient evidence to
support or not support the effectiveness of the reported drugs for the management
of pain due to TMD.”64
Lack of definitive recommendation notwithstanding, the clear summary of available
evidence in this review serves as an important resource for clinicians that manage pa-
tients suffering from TMJ disorders. Due to a paucity of evidence, clinicians often use
their own clinical experience and scientific reasoning to shape their practice. Certainly,
some differences in prescribing practice are also due to variation in individual patient
presentation and provider treatment philosophy, and based on evidence from smaller
studies or case series. However, the lack of evidence-based consensus may also
contribute to the significant variability in prescribing habits.
This review highlights the need for use of refined and widely accepted diagnostic
criteria in TMD to allow for direct comparison between studies. For example, the Diag-
nostic Criteria for Temporomandibular Disorders for Clinical and Research Applica-
tions exists to standardize research design.66 With carefully applied diagnostic
90 France & Sollecito

criteria, TMDs can be appropriately separated or compared, and future studies can be
designed to address gaps in knowledge. This will eventually provide sufficient evi-
dence for a Clinical Practice Guideline on temporomandibular disorders that contains
focused treatment recommendations.

MEDICALLY COMPLEX CARE

Dental treatment of medically complex patients is by definition broad, as it requires a

thorough assessment of the patient to determine fitness to undergo dental proced-
ures, as well as determination of the necessary modifications, if any, to treatment.
This subject matter falls under the purview of oral medicine, given the field’s unique
position as both a medical and dental discipline. This dual identity means that oral
medicine providers possess a thorough understanding of both the nature of dental
treatment and the intricacies of a patient’s medical condition. Modifying dental care
is also a topic that relies on evidence-based recommendation, as patient safety during
dental treatment must be carefully protected. Dental care for medically complex pa-
tients requires a review of available evidence and creation of Clinical Practice Guide-
lines to protect societal well-being.
Evidence-based reviews are necessary to inform clinical management of the inter-
play between medical morbidities and dental care. Many medical conditions have
been reviewed in the dental literature over several decades, with investigators
addressing what possible complications may arise for these patients during dental
treatment and how best to approach their care.67–71 These include, notably, guidelines
for the use of antibiotic prophylaxis before dental treatment for patients at risk of
developing bacterial endocarditis,72–75 and recommendations against the discontinu-
ation of anticoagulation before invasive dental procedures.76–79
An area that has received significant attention is the question of whether patients
who have previously undergone various surgical procedures require antibiotic prophy-
laxis before dental treatment.80–82 Most notably, much study has focused on whether
prophylactic antibiotic therapy before dental treatment will lower the risk of prosthetic
joint infection in patients who have previously undergone prosthetic joint replacement.
To address this question, the American Dental Association created a definitive
evidence-based Clinical Practice Guideline for use of antibiotic prophylaxis in patients
with prosthetic joint replacements.83 This review compiled all available evidence from
both dental and orthopedic literature on the incidence and sequelae of prosthetic joint
infection after dental treatment. Based on available literature, the expert panel “judged
with moderate certainty that there is no association between dental procedures and the
occurrence of [prosthetic joint infection]s.”81 Although data were only available relating
to infections in prosthetic hip and knee joints, the lack of association between dental
treatment and joint infections was judged to be applicable to all joint replacements given
the anatomic similarity between joints. With this evidence, the panel opined that “in gen-
eral, for patients with prosthetic joint implants, prophylactic antibiotics are not recom-
mended prior to dental procedures to prevent prosthetic joint infection.”81
The findings of this Clinical Practice Guideline, discouraging across-the-board use
of prophylactic antibiotics for patients after prosthetic joint replacement, ensures pa-
tient safety. In addition, limiting prescriptions of antibiotics benefits both individual pa-
tients and the general population by combatting the growing problems of antibiotic
resistance. These guidelines have shaped dental practice since their publication.
They provide one clear example of the ways in which creation of a Clinical Practice
Guideline benefits the practice of dentistry, the care of individual patients, and society
at large.
 Evidence-Based Oral Medicine 91

SUMMARY

The field of oral medicine concentrates on patients with oral lesions, mucosal disease,
salivary gland dysfunction, facial pain conditions, and complex medical histories.
Through treating affected patients and advising on these complex conditions, oral
medicine practitioners serve as leaders in dentistry, and their connection to both med-
icine and dentistry provides oral medicine with a unique perspective on health care
and patient well-being. The intricate clinical conditions and patient presentations
encountered in oral medicine necessitate that patient care be approached in a clear
and organized fashion. Evidence-based Clinical Practice Guidelines provide this
clarity by compiling all available scientific evidence and providing recommendations
on diagnosis and treatment.
Although much of dentistry, including oral medicine, continues to be informed by
provider experience and training, the standards in the field have adapted according
to the information available as Clinical Practice Guidelines have been produced. As
illustrated here, guidelines produced on a variety of subjects have helped to guide clin-
ical practice in oral medicine. Existing guidelines have limited the prescription of anti-
biotics by recommending against their use in patients with prosthetic joint
replacements. Expert recommendations have also shaped both research and practice
in treatment of salivary gland disease. New guidelines on the treatment of PMDs will
direct future evaluation of suspicious lesions. In facial pain, existing evidence high-
lights the need for definitive diagnostic criteria that directs future study. Through
this spread of information, general dentistry practice has and will continue to demon-
strate improved understanding of difficult patient presentations and appropriate eval-
uation, management, and referrals. For those areas and subjects currently without
clear guidelines, further study and synthesis of information will lead to improved pa-
tient care.

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