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Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population
review-article
Author(s):
Patricia D. Maglalang
1 ,
Jiali Wen
1 ,
Christoph P. Hornik
2
,
3 ,
Daniel Gonzalez
2
,
4
,
Publication date (Electronic):
15 April 2024
Journal:
Clinical and Translational Science
Publisher:
John Wiley and Sons Inc.
Read this article at
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Abstract
Multiple treatment options exist for children with epilepsy, including surgery, dietary therapies, neurostimulation, and antiseizure medications (ASMs). ASMs are the first line of therapy, and more than 30 ASMs have U.S. Food and Drug Administration (FDA) approval for the treatment of various epilepsy and seizure types in children. Given the extensive FDA approval of ASMs in children, it is crucial to consider how the physiological and developmental changes throughout childhood may impact drug disposition. Various sources of pharmacokinetic (PK) variability from different extrinsic and intrinsic factors such as patients' size, age, drug–drug interactions, and drug formulation could result in suboptimal dosing of ASMs. Barriers exist to conducting clinical pharmacological studies in neonates, infants, and children due to ethical and practical reasons, limiting available data to fully characterize these drugs' disposition and better elucidate sources of PK variability. Modeling and simulation offer ways to circumvent traditional and intensive clinical pharmacology methods to address gaps in epilepsy and seizure management in children. This review discusses various physiological and developmental changes that influence the PK and pharmacodynamic (PD) variability of ASMs in children, and several key ASMs will be discussed in detail. We will also review novel trial designs in younger pediatric populations, highlight the role of extrapolation of efficacy in epilepsy, and the use of physiologically based PK modeling as a tool to investigate sources of PK/PD variability in children. Finally, we will conclude with current challenges and future directions for optimizing the efficacy and safety of these drugs across the pediatric age spectrum.
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Most cited references91
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ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology
The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
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Instruction manual for the ILAE 2017 operational classification of seizure types
Robert Fisher, J. Cross, Carol D'Souza … (2017)
This companion paper to the introduction of the International League Against Epilepsy (ILAE) 2017 classification of seizure types provides guidance on how to employ the classification. Illustration of the classification is enacted by tables, a glossary of relevant terms, mapping of old to new terms, suggested abbreviations, and examples. Basic and extended versions of the classification are available, depending on the desired degree of detail. Key signs and symptoms of seizures (semiology) are used as a basis for categories of seizures that are focal or generalized from onset or with unknown onset. Any focal seizure can further be optionally characterized by whether awareness is retained or impaired. Impaired awareness during any segment of the seizure renders it a focal impaired awareness seizure. Focal seizures are further optionally characterized by motor onset signs and symptoms: atonic, automatisms, clonic, epileptic spasms, or hyperkinetic, myoclonic, or tonic activity. Nonmotor-onset seizures can manifest as autonomic, behavior arrest, cognitive, emotional, or sensory dysfunction. The earliest prominent manifestation defines the seizure type, which might then progress to other signs and symptoms. Focal seizures can become bilateral tonic-clonic. Generalized seizures engage bilateral networks from onset. Generalized motor seizure characteristics comprise atonic, clonic, epileptic spasms, myoclonic, myoclonic-atonic, myoclonic-tonic-clonic, tonic, or tonic-clonic. Nonmotor (absence) seizures are typical or atypical, or seizures that present prominent myoclonic activity or eyelid myoclonia. Seizures of unknown onset may have features that can still be classified as motor, nonmotor, tonic-clonic, epileptic spasms, or behavior arrest. This "users' manual" for the ILAE 2017 seizure classification will assist the adoption of the new system.
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National and State Estimates of the Numbers of Adults and Children with Active Epilepsy — United States, 2015
Matthew M. Zack, Rosemarie Kobau (2017)
Epilepsy, a brain disorder leading to recurring seizures, has garnered increased public health focus because persons with epilepsy experience pronounced and persistent health and socioeconomic disparities despite treatment advances, public awareness programs, and expanded rights for persons with disabilities ( 1 , 2 ). For almost all states, epilepsy prevalence estimates do not exist. CDC used national data sources including the 2015 National Health Interview Survey (NHIS) for adults (aged ≥18 years), the 2011–2012 National Survey of Children’s Health (NSCH), and the 2015 Current Population Survey data, describing 2014 income levels, to estimate prevalent cases of active epilepsy, overall and by state, to provide information for state public health planning. In 2015, 1.2% of the U.S. population (3.4 million persons: 3 million adults and 470,000 children) reported active epilepsy (self-reported doctor-diagnosed epilepsy and under treatment or with recent seizures within 12 months of interview) or current epilepsy (parent-reported doctor-diagnosed epilepsy and current epilepsy). Estimated numbers of persons with active epilepsy, after accounting for income and age differences by state, ranged from 5,900 in Wyoming to 427,700 in California. NHIS data from 2010–2015 indicate increases in the number of persons with active epilepsy, probably because of population growth. This study provides updated national and modeled state-specific numbers of active epilepsy cases. Public health practitioners, health care providers, policy makers, epilepsy researchers, and other epilepsy stakeholders, including family members and people with epilepsy, can use these findings to ensure that evidence-based programs meet the complex needs of adults and children with epilepsy and reduce the disparities resulting from it. Epilepsy has been assessed only intermittently in population surveys ( 1 , 2 ). Before 2010, the last U.S. national estimate of epilepsy prevalence was based on 1986–1990 data using one question assessing the occurrence of epilepsy or repeated seizures, convulsions, or blackouts in any household family members ( 3 ). Other recent estimates based on limited U.S. and international geographic regions, clinical samples, and decades-old data are not representative of the current U.S. population ( 2 , 4 ). Data from the 2010 and 2013 NHIS using a validated case definition indicate approximately 1% of the U.S. population had active epilepsy ( 5 ). A study using 2005 Behavioral Risk Factor Surveillance System data employing similar epilepsy case-ascertainment questions* provided state-level estimates of a history of epilepsy for 19 states (1.65%) and active epilepsy for 13 states (0.84%) ( 6 ). No substantial differences among states in the prevalence of a history of epilepsy or active epilepsy were detected ( 6 ). A third study, which extrapolated 2007–2011 administrative claims data from multiple states to the overall U.S. population found an epilepsy prevalence estimate of 0.84% ( 4 ). For almost all states, epilepsy prevalence estimates do not exist. Groups interested in reducing epilepsy prevalence need updated estimates of the numbers of persons living with epilepsy nationally and within their states. This study aims to provide updated national and modeled state-specific estimates of active epilepsy prevalence based on the latest data available to provide information for public health action to reduce epilepsy burden. To estimate the number of prevalent cases of active epilepsy among adults aged ≥18 years, CDC analyzed three questions on epilepsy from the 2015 Sample Adult component of NHIS, an annual, cross-sectional household survey of the civilian, noninstitutionalized U.S. population. Adults classified as having “active epilepsy” reported a history of doctor-diagnosed epilepsy and were taking medication to control it, had had one or more seizures in the past year, or both (Table 1) ( 5 , 6 ). Validation of survey questions for surveillance of active epilepsy yielded sensitivity and specificity exceeding 80% and 99%, respectively, with a positive predictive value of 74% similar to validation estimates seen in surveillance of other chronic disorders ( 5 ). Only 0.07% of adults in 2015 refused to answer or did not know if they had doctor-diagnosed active epilepsy. To estimate prevalent cases of active epilepsy among children aged 0–17 years, CDC analyzed data from the 2011–2012 NSCH, † a cross-sectional telephone survey of households with at least one resident child aged 0–17 years at interview. NSCH asks parents or guardians if a doctor or health care provider ever told them that their child had epilepsy or seizure disorder, and if so, if their child currently has epilepsy or seizure disorder (current epilepsy) (Table 1). Only 0.03% of parents or guardians refused to answer or did not know if a doctor had ever told them their child had epilepsy or a seizure disorder. Prevalence of current epilepsy among children based on NSCH data was estimated to be 6.3 per 1,000, similar to estimates from administrative data ( 7 , 8 ). TABLE 1 Epilepsy surveillance case ascertainment questions, by survey Survey Questions Possible responses National Health Interview Survey (2015) 1. Have you ever been told by a doctor or other health professional that you have a seizure disorder or epilepsy? 1) Yes, 2) No, 7) Refused, 8) Not ascertained, 9) Don’t know 2. Are you currently taking any medicine to control your seizure disorder or epilepsy? 1) Yes, 2) No, 7) Refused, 8) Not ascertained, 9) Don’t know 3. Today is . Think back to last year about the same time. About how many seizures of any type have you had in the past year? 0) None, 1) One, 2) Two or three, 3) Between four and ten, 4) More than 10, 7) Refused, 8) Not ascertained, 9) Don’t know National Survey of Children’s Health (2011–2012) 1. Has a doctor or health care provider ever told you that your child has epilepsy or a seizure disorder? 1) Yes, 2) No, 7) Refused, 8) Not ascertained, 9) Don’t know 2. Does your child currently have epilepsy or a seizure disorder? 1) Yes, 2) No, 7) Refused, 8) Not ascertained, 9) Don’t know Obtaining state-level estimates required using the best available data to confirm that epilepsy prevalence did not differ significantly across states ( 6 ). Epilepsy prevalence and state populations do differ by age and income distribution. NHIS and NSCH data was used to calculate the prevalence (proportion) of active epilepsy for three age groups (0–17 years, 18–64 years, and ≥65 years) stratified by three family income groups (0%–99%, 100%–199%, ≥200% of poverty thresholds). Data for 2014 was obtained for the three age groups and three family income groups among civilian and military noninstitutionalized populations for each state from the U.S. Census's Current Population Survey 2015 Annual Social and Economic Supplement. § Multiplying the age- and income-specific active epilepsy prevalence estimates by the population estimates for each of the three age and income groups yielded state-level estimates of active epilepsy, indirectly standardized for age and income. ¶ Adding these standardized estimates for both groups from each data set produced total estimated numbers of cases with active epilepsy. Combining the variance estimates of both adults and children with epilepsy from each survey and of these age- and income-specific population estimates as the variance of the product of these two random variables yielded 95% confidence intervals for these total estimates.** In 2015, 1.2% (95% confidence interval = 1.1–1.4) of the U.S. population was classified as having active epilepsy (3.4 million; 3 million adults and 470,000 children). Among adults, the estimated number of cases of active epilepsy ranged from 5,100 in Wyoming to 367,900 in California (Table 2). Among children, the estimated number of cases of current epilepsy ranged from 800 in Wyoming to 59,800 in California. The number of persons estimated to have active epilepsy was <14,000 in nine states and the District of Columbia, 14,000–32,799 in 11 states, 32,800–56,799 in nine states, 56,800–92,699 in 10 states, and ≥92,700 persons in 11 states. (Table 2). TABLE 2 Estimated numbers of active epilepsy cases, by state and age group — United States, 2015 Geographic area Age group (yrs) All ages <18* ≥18† No. (95% CI§) No. (95% CI) No. (95% CI) United States 3,439,600 (3,009,100–3,870,100) 471,900 (392,600–551,200) 2,967,700 (2,544,500–3,390,800) Alabama 54,100 (46,400–61,900) 7,500 (5,900–9,200) 46,600 (39,000–54,200) Alaska 7,200 (6,100–8,300) 1,100 (800–1,400) 6,100 (5,000–7,200) Arizona 77,000 (66,400–87,500) 11,200 (8,900–13,600) 65,700 (55,400–76,000) Arkansas 32,800 (28,000–37,600) 4,900 (3,700–6,100) 28,000 (23,300–32,600) California 427,700 (372,600–482,900) 59,800 (49,000–70,600) 367,900 (313,800–422,000) Colorado 56,800 (48,300–65,300) 7,800 (6,000–9,600) 49,000 (40,700–57,300) Connecticut 35,900 (30,400–41,400) 4,500 (3,400–5,700) 31,400 (26,000–36,800) Delaware 9,700 (8,200–11,100) 1,300 (900–1,600) 8,400 (7,000–9,900) District of Columbia 7,500 (6,300–8,800) 800 (600–1,100) 6,700 (5,500–7,900) Florida 223,900 (194,100–253,800) 27,300 (21,900–32,800) 196,600 (167,200–225,900) Georgia 110,200 (94,900–125,500) 16,700 (13,200–20,100) 93,500 (78,600–108,500) Hawaii 14,000 (11,900–16,100) 2,000 (1,500–2,400) 12,000 (10,000–14,100) Idaho 16,800 (14,200–19,300) 2,600 (2,000–3,200) 14,200 (11,700–16,600) Illinois 136,600 (117,900–155,400) 18,600 (14,900–22,400) 118,000 (99,700–136,400) Indiana 69,500 (59,600–79,400) 10,600 (8,300–13,000) 58,900 (49,200–68,500) Iowa 31,400 (26,800–36,100) 4,400 (3,400–5,400) 27,000 (22,500–31,600) Kansas 29,900 (25,500–34,300) 4,400 (3,400–5,400) 25,500 (21,200–29,900) Kentucky 49,500 (42,000–57,000) 6,800 (4,900–8,700) 42,700 (35,500–50,000) Louisiana 54,900 (46,600–63,200) 7,900 (6,200–9,700) 47,000 (38,900–55,100) Maine 14,100 (11,900–16,300) 1,700 (1,200–2,200) 12,400 (10,300–14,600) Maryland 59,900 (50,700–69,100) 7,900 (6,200–9,700) 52,000 (42,900–61,000) Massachusetts 71,600 (60,900–82,300) 8,400 (6,500–10,300) 63,200 (52,600–73,700) Michigan 108,900 (93,300–124,500) 13,600 (10,800–16,400) 95,300 (79,900–110,600) Minnesota 53,700 (45,700–61,700) 7,400 (5,900–9,000) 46,300 (38,400–54,100) Mississippi 35,700 (30,600–40,700) 5,100 (3,900–6,300) 30,600 (25,700–35,500) Missouri 61,200 (52,400–70,000) 8,300 (6,500–10,100) 52,900 (44,200–61,600) Montana 10,800 (9,100–12,600) 1,400 (1,000–1,800) 9,400 (7,700–11,100) Nebraska 19,600 (16,600–22,500) 2,800 (2,200–3,500) 16,700 (13,800–19,600) Nevada 31,600 (26,800–36,400) 4,400 (3,300–5,400) 27,200 (22,500–31,900) New Hampshire 13,100 (11,100–15,200) 1,500 (1,100–1,900) 11,600 (9,600–13,700) New Jersey 92,700 (79,100–106,200) 12,000 (9,500–14,500) 80,600 (67,300–93,900) New Mexico 23,200 (19,800–26,500) 3,400 (2,600–4,200) 19,800 (16,400–23,100) New York 215,200 (186,300–244,000) 26,600 (21,600–31,500) 188,600 (160,200–217,100) North Carolina 110,100 (94,700–125,500) 15,200 (11,800–18,500) 94,900 (79,900–110,000) North Dakota 7,300 (6,200–8,500) 1,000 (700–1,200) 6,400 (5,300–7,500) Ohio 126,400 (109,300–143,400) 16,900 (13,600–20,300) 109,400 (92,700–126,200) Oklahoma 41,100 (34,900–47,300) 6,400 (5,000–7,900) 34,700 (28,700–40,700) Oregon 42,900 (36,300–49,400) 5,400 (4,100–6,800) 37,400 (31,000–43,900) Pennsylvania 133,000 (114,600–151,400) 16,900 (13,500–20,200) 116,100 (98,000–134,200) Rhode Island 11,100 (9,300–12,900) 1,300 (900–1,700) 9,800 (8,100–11,500) South Carolina 53,400 (45,500–61,300) 7,100 (5,500–8,700) 46,300 (38,500–54,000) South Dakota 8,900 (7,400–10,400) 1,300 (900–1,600) 7,600 (6,200–9,100) Tennessee 73,900 (62,900–84,800) 10,000 (7,800–12,300) 63,800 (53,100–74,600) Texas 292,900 (255,400–330,300) 47,200 (38,500–56,000) 245,600 (209,200–282,000) Utah 29,300 (24,900–33,600) 5,300 (4,100–6,500) 24,000 (19,800–28,200) Vermont 6,300 (5,300–7,300) 700 (500–900) 5,600 (4,700–6,600) Virginia 84,800 (72,600–97,000) 11,000 (8,800–13,200) 73,800 (61,800–85,800) Washington 74,600 (64,000–85,200) 10,200 (8,100–12,300) 64,400 (54,000–74,800) West Virginia 21,500 (18,100–25,000) 2,500 (1,900–3,100) 19,000 (15,600–22,500) Wisconsin 59,600 (50,800–68,300) 7,900 (6,300–9,500) 51,700 (43,100–60,300) Wyoming 5,900 (5,000–6,800) 800 (600–1,000) 5,100 (4,200–6,000) Abbreviation: CI = confidence interval. * Active epilepsy cases in children are estimated from the current epilepsy prevalence in children (2011–2012 National Survey of Children's Health) and the population of children, accounting for the ratios of family income to poverty thresholds. † Active epilepsy cases in adults are estimated from the prevalence of active epilepsy (taking medication, having had a seizure in the past year, or both) in adults (2015 National Health Interview Survey) and the population of adults, accounting for the ratios of family income to poverty thresholds. The total population estimates come from the 2014 weighted person counts of the Current Population Survey, 2015 Annual Social and Economic Supplement of the civilian noninstitutionalized population living in houses and military population living in houses. § Confidence interval represents only sampling uncertainty from the sampling uncertainties in the prevalence estimates and in the state-specific and age-specific ratios of family income to poverty thresholds. Discussion This study provides updated national and estimated state-specific numbers of the active epilepsy cases. Affecting 3.4 million U.S. residents, epilepsy is not a rare condition. Epilepsy poses substantial individual and societal burdens that require heightened public health action ( 1 , 2 ). As a complex condition varying in severity and impact, it affects persons of all ages and racial and ethnic groups, especially those with the lowest incomes ( 2 , 5 , 9 ). Persons with epilepsy often have multiple co-occurring conditions (e.g., stroke, heart disease, depression, or developmental delay) that complicate their epilepsy management, impair life goals, and contribute to early mortality ( 1 , 2 ). Among five chronic conditions in children and adolescents selected because of their adverse impact on academic and health outcomes, epilepsy is the costliest and the second most common ( 8 ). Children with seizures are more likely to live in poverty, and their parents more frequently report food insecurity ( 9 ). Direct yearly health care costs per person with epilepsy ranged from $10,192 to $47,862 (2013 U.S. dollars) and were higher for persons with uncontrolled seizures ( 10 ). Medicaid recipients have a higher prevalence of epilepsy, especially among adults aged 20–64 years (3.4%) ( 4 ); this study adjusted for income to account for this confounder. The estimated 3 million U.S. adults with active epilepsy and 470,000 U.S. children with current epilepsy in 2015 exceed the estimated 2.3 million U.S. adults in 2010 ( 5 ) and the 450,000 U.S. children with current epilepsy in 2007 ( 7 ). The estimated increase in numbers of persons with epilepsy is not explained by age or income, because this study controlled for these known confounders. The increase is likely because of population growth over the past decade, or other unknown factors (e.g., an increased willingness to disclose one has epilepsy). The number of prevalent cases of active epilepsy by state generally mirrors the states’ population distributions. The 2015 NHIS epilepsy prevalence estimate (1.2%) in this study is roughly consistent with the BRFSS estimate from 13 states (0.84% [95% confidence interval = 0.74–0.96]) that used a slightly more conservative approach assessing a 3-month seizure recall period versus 12 months ( 6 ). The findings in this report are subject to at least four limitations. First, because these estimates depend on self-report, they might be subject to reporting bias. Second, these state estimates do not account for possible differences in seizure type, severity, or etiology. Third, underreporting associated with perceived repercussions in disclosing epilepsy (e.g., stigma or driver’s license restrictions) ( 2 ) and the exclusion of institutionalized adults from the NHIS and the Census might underestimate epilepsy prevalence. Fourth, the assumption of applying national estimates to states is based on findings from 13 geographically disparate states indicating no differences in epilepsy prevalence, after accounting for multiple comparisons and sample size limitations ( 6 ). Although adjusting for age and income might account for some of the variation in prevalence across all states in this study, without available direct surveillance data on epilepsy, these estimates of active epilepsy cases in states need empirical confirmation. Public health practitioners, health care providers, policy makers, epilepsy researchers, and other epilepsy stakeholders, including family members and people with epilepsy, can use these findings to ensure that evidence-based programs meet the complex needs of adults and children with epilepsy and reduce the disparities resulting from it. Summary What is already known about this topic? Epilepsy is a common neurologic disorder resulting in substantial health, social, and mortality disparities. What is added by this report? In 2015, approximately 3 million U.S. adults and 470,000 children had active epilepsy. For almost all states, epilepsy prevalence estimates do not exist. Estimated numbers of active epilepsy ranged from 5,900 persons with epilepsy in Wyoming to more than 427,000 in California. The number of persons with active epilepsy increased compared with earlier years, likely because of population growth. What are the implications for public health practice? This study provides updated national estimates and the first modeled estimates of active epilepsy cases for all States. Public health practitioners, health care providers, policy makers, epilepsy researchers, and other epilepsy stakeholders including family members and people with epilepsy, can use these findings to ensure that evidence-based programs meet the complex needs of adults and children with epilepsy and reduce the disparities resulting from it.
Author and article information
Contributors
Daniel Gonzalez:
ORCID: https://orcid.org/0000-0001-5522-5686
daniel.gonzalez@duke.edu
Journal
Journal ID (nlm-ta): Clin Transl Sci
Journal ID (iso-abbrev): Clin Transl Sci
Journal ID (doi): 10.1111/(ISSN)1752-8062
Journal ID (publisher-id): CTS
Title:
Clinical and Translational Science
Publisher:
John Wiley and Sons Inc.
(Hoboken
)
ISSN
(Print):
1752-8054
ISSN
(Electronic):
1752-8062
Publication date
(Electronic):
15
April
2024
Publication date Collection:
April
2024
Volume: 17
Issue: 4
(
doiID:
10.1111/cts.v17.4
)
Electronic Location Identifier: e13793
Affiliations
Author notes
[*]
[*
]
Correspondence
Daniel Gonzalez, Duke Clinical Research Institute, PO Box 17969, Durham, NC, 27715, USA.
Email: daniel.gonzalez@ 123456duke.edu
Daniel Gonzalez, Duke Clinical Research Institute, PO Box 17969, Durham, NC, 27715, USA.
Email: daniel.gonzalez@ 123456duke.edu
Author information
Patricia D. Maglalang
https://orcid.org/0000-0003-1628-7408
Jiali Wen
https://orcid.org/0000-0002-9173-9665
Christoph P. Hornik
https://orcid.org/0000-0001-7056-8759
Daniel Gonzalez
https://orcid.org/0000-0001-5522-5686
Article
Publisher ID: CTS13793 Other ID: CTS-2023-0113CDOI: 10.1111/cts.13793
PMC ID: 11017206
PubMed ID: 38618871
SO-VID: f6b46d52-13d5-4388-87d1-aac77587743d
Copyright © © 2024 The Authors.
Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology
and Therapeutics.
License:
This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
History
Date
revision received
: 08
March
2024
Date
received
: 26
January
2024
Date
accepted
: 25
March
2024
Page count
Figures: 2,
Tables: 3,
Pages: 18,
Words: 11120
Categories
Subject:
Review
Subject:
Reviews
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cover-date April 2024
details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.4.0 mode:remove_FC converted:15.04.2024
ScienceOpen disciplines: Medicine
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ScienceOpen disciplines: Medicine