Leprosy epidemiology: insights from the Prata Village

Leprosy epidemiology: insights from the Prata Village | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Leprosy epidemiology: insights from the Prata Village Ciane Cristina Oliveira Mackert, Fernando Panissa Lázaro, Márcia Olandowski, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5277338/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Feb, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Leprosy, a chronic infectious disease caused mainly by Mycobacterium leprae ( M. leprae ), is still an important public health problem in countries such as Brazil and India. Here, we estimate key epidemiological parameters in the Prata Village, a unique, hyper-endemic, former leprosy colony isolated in the Brazilian Amazon. This is a population-based study in which the entire Prata Village population has been enrolled. Clinical, socioeconomic, and demographic data were obtained and cross-checked using three independent information sources. Validated data was used for descriptive epidemiological analysis. From a total of 2,005 inhabitants by the time of the enrollment, 1,084 (56.19%) were born in the Village and, therefore, likely under lifelong exposure to leprosy cases. We observed differences between the sub-populations born and not born in the village in the cumulative prevalence of leprosy (5.9% vs. 22.9%, respect.) and the age at diagnosis (15 years vs. 28 years, respect.). In contrast, there was no difference in the distribution of cases between the two sexes. Although extrapolating our findings to more open populations must be done carefully, we believe we used a unique population as a model to provide additional insights into the epidemiology of leprosy. Health sciences/Diseases/Infectious diseases Health sciences/Medical research/Epidemiology leprosy population epidemiology innate susceptibility Figures Figure 1 Figure 2 Introduction Leprosy is a chronic infectious disease caused mainly by Mycobacterium leprae ( M. leprae ), an obligate and highly specialized intracellular parasite that primarily infects skin macrophages and Schwann cells in the peripheral nervous system (1). Leprosy manifests clinically in a spectrum consisting of two polar – tuberculoid and lepromatous – and three intermediate borderline forms (2). According to the latest data from the World Health Organization (WHO), there were 182,815 newly reported cases of leprosy in 2023 (3), mainly concentrated in India and Brazil. The disease is treated through multidrug therapy (MDT) following a WHO protocol considering the number of lesions and the bacillary load (4). The village of Santo Antônio do Prata (the Prata Village) was established in 1898 by Franciscan monks in the Amazon forest of the Northern Brazilian state of Pará. In 1923, the location was designated a compulsory isolation site for individuals diagnosed with leprosy from Brazil's Northern and Northeastern states. Compulsory isolation was lifted in 1962 (5); however, due to the strong social stigma associated with the disease, the emigration of affected individuals and the immigration of non-affected families to the village has been limited over the decades. Consequently, the Prata Village remained socially and geographically isolated until recent years. The population of the village concentrates in an area of around 10 km 2 , and all residents share the same limited social infrastructure, such as a single church, two elementary schools, one social club, and a large central square serving as a communal gathering space for leisure activities such as soccer games and outdoor celebrations. Despite extensive efforts to reduce its incidence, leprosy remains highly prevalent and uniformly distributed throughout the community (6). In 2010, a complex segregation analysis provided evidence of a significant major gene effect controlling susceptibility to leprosy within the Prata population, a finding compatible with the hypothesis that, given the history of the village, genetic risk factors for leprosy are enriched within this population (6). We propose that Prata village can serve as a compelling epidemiological model for leprosy, given that (i) the village is confined in a small, geographically isolated area, (ii) it is a leprosy hyperendemic cluster, (iii) the disease is distributed homogenously across the entire village, (iv) the population shares few social interaction spaces, (v) consequently, exposure to the disease is likely homogeneous and widespread among the community. Finally, (vi) the Prata population is enriched in genetic risk factors controlling leprosy susceptibility. Here, we present a population-based descriptive epidemiological study involving the entire population of the Prata Village. Subjects and Methods Enrollment of the entire population of the Prata Village was performed between 2006 and 2007 for a population-based complex segregation analysis, and a detailed description of the enrollment strategy has been published elsewhere (6). In brief, every household in the village was visited by a research team member, and all adult members of resident families were interviewed; the parents or legal guardians provided information about individuals younger than 18 years old. Socio-economic data has been collected through a questionnaire. All individuals self-reported their present and previous leprosy status as affected or non-affected. All self-reported leprosy cases, active and historical, have been checked using three independent sources available at the village’s health unit: (i) the original medical records, (ii) copies of the compulsory notification forms, and (iii) a logbook containing registries of all cases for treatment follow-up. Self-reported cases confirmed at all three sources were validated as leprosy cases; clinical information was obtained from the medical records upon confirmation. This study was performed following the Declaration of Helsinki and Brazilian research regulations. All subjects enrolled in the study agreed to participate and signed a written informed consent that has been approved along with the research project by the Research Ethics Committee of the Pontifícia Universidade Católica do Paraná (51/07/CEP-PUCPR) and the Brazilian National Board for Ethics in Research (222/2006; 25000.001992/2006-17). Of note, only two individuals declined to participate and were not included in the study. Given that this population-based study involved the recruitment of the entire Prata village, no inferential statistics were applied. Descriptive statistics was used to describe and compare two sub-populations: individuals born versus individuals not born in the village, the rationale being that, whereas no information about life conditions pre-Prata was available for the sub-population of individuals not born in the village, individuals born in the village have been living their entire lives in a homogenous environment, hyperendemic for leprosy. Median and mean age at diagnosis were estimated and depicted as Kaplan-Meyer and box plots. Results Of the 2,005 individuals enrolled, 1,672 self-reported as non-affected by leprosy, 319 self-reported as affected, and 14 did not disclose their leprosy status. Data verification confirmed 257 out of the 319 self-reported leprosy cases. For subsequent analyses, 76 individuals with unknown leprosy status (comprised of the 14 individuals who did not disclose their status and an additional 62 individuals with unavailable medical reports) were excluded (see Supplementary Table 01). Consequently, the accumulated prevalence rate of leprosy for the period (including active and historical cases) was calculated as 12.82% (257 cases out of 2,005 individuals), evenly distributed across males and females. When stratifying the affected population by clinical form, 104 (40.5%) cases were lepromatous, 53 (20.6%) were tuberculoid, 53 (20.6%) were borderline, and 47 (18.3%) were indeterminate (suppl. table 3). Therefore, the highest proportion of the Prata patients had a higher bacillary load. The complete demographical, socioeconomic, and clinical characteristics description of the population is provided as supplementary material (suppl. tables 01 to 03). About half of the Prata village population – 1,084 individuals (56.19%) – were born there. Among these, 64 were confirmed leprosy cases, resulting in a cumulative prevalence of 5.9%. Among the individuals not born in the village, the cumulative leprosy prevalence was 22.9% (193 confirmed cases/844 individuals) (Fig. 1 and Tab. Suppl. 02). The median age at diagnosis among the individuals born in the village was 15 years old (mean = 18.17, ranging from 5–75 years old, standard deviation of ± 12.95). In contrast, the median age at diagnosis was 28 years old among the individuals not born in the village (mean = 30.19, ranging from 2–74 years old and standard deviation of ± 15.25) (Fig. 2 and Tab. Suppl. 03). Discussion Here, we present a descriptive, population-based study of a well-controlled, hyperendemic, isolated leprosy-affected community that might bring insights into the epidemiology of this elusive disease. Our most striking findings are the difference between leprosy prevalence and age at diagnosis between two sub-populations of individuals born and not born in the village. We also describe a homogenous distribution of cases across males and females. Leprosy cumulative prevalence among those born and those not born in the village was 5.9% and 22.9%, respectively. It is reasonable to assume that the high cumulative prevalence of leprosy among the population not born in the village is because many of these individuals moved to the village because they had leprosy. In contrast, the much lower cumulative prevalence among the subpopulation born in the village is aligned with previous estimates indicating that approximately 5% of the population is naturally susceptible to leprosy (7,8), a proportion that seems to stand even in a hyperendemic, socially homogenous environment. Of note, previous attempts to determine the proportion of individuals naturally susceptible to leprosy have yielded varied results, ranging from less than 1–12% (5,9). Three factors may contribute to the age-onset difference between the subpopulations born and not born in the village. First, more frequent epidemiological surveys in a village well known for being hyperendemic may lead to earlier detection and diagnosis; second, individuals born in the village are mostly descendants of leprosy-affected individuals and, therefore, likely more genetically susceptible to the disease (6); finally, one intriguing hypothesis is that individuals born in the village are under lifelong exposure to leprosy cases and, thus, more prone to infection. If true, the 15-year average age of diagnosis in this sub-population may indicate the time between early exposure and clinical manifestation of the disease. The occurrence of leprosy cases among children is an indicator of ongoing transmission in the community (10,11), which supports our findings. The leprosy incubation period has been a research subject for several decades. The disease is often characterized by an average incubation period of approximately five years (4,12). An early attempt to estimate the incubation period of leprosy based on patient self-reports reached 8.4 years (13). Data from secondary cases of leprosy among household contacts revealed an average time of disease onset of 4.3 (± 3.3) years, irrespective of the clinical form (14); the authors defined “incubation" as the time between the emergence of an index leprosy patient in a household and the occurrence of a leprosy secondary case in a household contact. It should be noted, however, that the study was performed in a hyper-endemic region; thus, the estimate may be biased by the assumption that exposure occurs only through the index case living in the same household. A study involving 35 military veterans reported a median onset time ranging from 2 to 5 years for tuberculoid and 8 to 12 years for lepromatous leprosy; however, these findings did not reach statistical significance (15). Furthermore, estimates of a 15 to 30-year incubation period in animal models primarily rely on non-human primates, a non-consensus model for leprosy studies (15–17). A screening of the available literature shows that many references of the incubation period refer to a book Chap. (18), describing it as being between 2–5 years; careful analysis of the references used in the book revealed that the information is based on studies of different experimental designs, resulting in findings ranging from 2–30 years. More recently, a case report was published about a male individual with an incubation period of 50 years before symptom onset (19). Together, these studies emphasize the variability in the data related to the incubation period of leprosy. One final interesting observation is the distribution of leprosy across sexes in the Prata population. While it is commonly reported that leprosy is more prevalent in males compared to females (20,21), we found that this difference is not clear among sub-populations born and not born in the Prata Village. The proportions of males and females among both sub-populations were similar, with 51.5% males and 48.5% females among those born in the village and 48.9% males and 51.1% females among those not born in the village. Given that the disease is incorporated into the culture of the village and is thus more naturally perceived by the population, our data suggests that the sex effect on leprosy distribution may be more influenced by behavioral factors rather than inherent biological differences between males and females. As a final note: if the population in the Prata Village indeed has increased natural susceptibility to leprosy, it is expected to have a higher incidence of reinfection/relapse cases. This is supported by a recent study that reported high rates of leprosy recurrence in the village, along with a high prevalence of drug-resistant strains of M. leprae (22). These observations suggest that the Prata Village population is more susceptible to leprosy and permanently exposed to resistant bacteria, creating an ideal environment for the persistence of leprosy hyper-endemicity. We are aware of the limitations of our study. For example, as we are confident in our strategy of cross-checking clinical records of different sources to characterize a case, we are also aware that clinical examination would be interesting, particularly for the self-reported non-affected population. However, examining the entire population of the village would be an enormous task; also, we believe that the risk of a self-reported non-affected individual being affected is reduced by (i) the fact that the village is maintained under constant surveillance, with an MD dermatologist visiting the village on regular basis, and (ii) because leprosy is widespread and part of the local culture, the stigma associated with the status of affected is reduced amongst the villagers, favoring seeking for medical help. Our observations also suggest that some villagers may perceive being diagnosed with leprosy as a positive outcome, as they may become eligible for financial governmental support (23). Another limitation, particularly regarding our arguments on the proportion of naturally susceptible individuals and the disease's incubation period, is that one must assume equal and permanent exposure of all newborn individuals to M. leprae throughout their lives, which is impossible to prove. For example, our approach does not consider the exact clinical form of each leprosy case and the presence or absence of an index case within the household of a new case (24). On the other hand, the Prata village presents (i) a high prevalence of leprosy (12.82%), (ii) most of the cases of high bacillary load (40.5% were lepromatous), and (iii) a homogenous environment with a low degree of social isolation between leprosy affected and non-affected individuals. These observations favor the assumption that the Prata population is under constant high exposure. In conclusion, although extrapolating our findings to more open populations must be done carefully, we believe we used a unique population as a model to provide additional insights into the epidemiology of leprosy. Declarations Additional Information The authors declare that the research was conducted without any commercial or financial relationships that could potentially create a conflict of interest. Author Contribution CCOM, FPL, and MBX: collected the data; MO: performed the statistical analysis; HRSD, PVUS, RSAR, and GC: performed the statistical analysis and wrote the article; AMS: wrote the article; ES, AA, and MTM: designed the study, provided senior supervision, and reviewed and wrote the article. Acknowledgement We thank all Prata Village populations for their acceptance in participating in the study. This study was supported by grants of Unicef/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), MCT/CNPq/MS-SCTIE-DECIT 35/2005 – “Estudos da Hanseníase” and MCT/CNPq/MS-SCTIE-DECIT 25/2006 – “Estudo de Doenças Negligenciadas”. Data Availability The authors state that all data produced in the study are available. Data requests can be made to the corresponding author via this email: [email protected] . References Britton WJ, Lockwood DNJ. Leprosy. The Lancet. 2004;363:1209–19. Ridley, D.S; Jopling WH. Classification of Leprosy According to Immunity. A five-group system. Internacional Journal of Leprosy. 1966;34:255–72. World Health Organization. Global leprosy (Hansen disease) update, 2023: Elimination of leprosy disease is possible – Time to act!. 2024. Available from: https://www.who.int/publications/i/item/who-wer9937-501-521 World Health Organization. Guidelines for the Diagnosis, Treatment and Prevention of Leprosy. New Delhi: World Health Organization, Regional Office for South-East Asia; 2018. Rosa Maciel L, Oliveira MLW del R, Gallo MEN, Damasco MS. Memories and history of Hansen’s disease in Brazil told by witnesses (1960–2000). História, Ciências, Saúde - Manguinhos. 2003;10:308–36. Lázaro FP, Werneck RI, Mackert CCO, Cobat A, Prevedello FC, Pimentel RP, et al. A major gene controls leprosy susceptibility in a hyperendemic isolated population from north of Brazil. Journal of Infectious Diseases. 2010;201(10):1598–605. Massone C, Nunzi E. Pathogenesis of Leprosy. In: Nunzi E, Massone C, Portaels F, editors. Leprosy and Buruli Ulcer - A Practical Guide. 2 Edition. Springer; 2022. p. 1–570. Lastória JC, de Abreu MAMM. Leprosy: Review of the epidemiological, clinical, and etiopathogenic aspects - Part 1. An Bras Dermatol. 2014;89(2):205–18. Sharma R, Singh P, Loughry WJ, Lockhart JM, Inman WB, Duthie MS, et al. Zoonotic leprosy in the southeastern United States. Emerg Infect Dis. 2015 Dec 1;21(12):2127–34. Lockwood DNJ, Suneetha S. Leprosy: too complex a disease for a simple elimination paradigm. Vol. 83, Bulletin of the World Health Organization. 2005. World Health Organization. Weekly epidemiological record. Global leprosy (Hansen disease) update, 2022: new paradigm – control to elimination [Internet]. 2023. Available from: https://population.un.org/wpp/, Schreuder PAM, Noto S, Richardus JH. Epidemiologic trends of leprosy for the 21st century. Clin Dermatol. 2016 Jan 1;34(1):24–31. Bechelli LM. O tempo de incubação da lepra. 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American Journal of Case Reports. 2024;25. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy - A population-based cohort study in Indonesia. Lepr Rev. 2006 Mar;77(1):48–61. Pescarini JM, Strina A, Nery JS, Skalinski LM, Andrade KVF de, Penna MLF, et al. Socioeconomic risk markers of leprosy in high-burden countries: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2018 Jul 9;12(7). Rosa PS, D’Espindula HRS, Melo ACL, Fontes ANB, Finardi AJ, Belone AFF, et al. Emergence and transmission of drug-/multidrug-resistant mycobacterium leprae in a former leprosy colony in the brazilian amazon. Clinical Infectious Diseases. 2020;70(10):2054–61. Alves LC, Sanchez MN, Hone T, Pinto LF, Nery JS, Tauil PL, et al. The association between a conditional cash transfer programme and malaria incidence: a longitudinal ecological study in the Brazilian Amazon between 2004 and 2015. BMC Public Health. 2021 Dec 29;21(1):1253. Fine PE, Sterne JA, Pönnighaus JM, Bliss L, Saui J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in northern Malawi. Am J Epidemiol. 1997 Jul 1;146(1):91–102. Additional Declarations No competing interests reported. Supplementary Files SUPPLEMENTMATEpiPrata291024.doc Cite Share Download PDF Status: Published Journal Publication published 19 Feb, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 24 Dec, 2024 Reviews received at journal 19 Dec, 2024 Reviewers agreed at journal 11 Dec, 2024 Reviews received at journal 27 Nov, 2024 Reviewers agreed at journal 17 Nov, 2024 Reviewers invited by journal 14 Nov, 2024 Editor assigned by journal 05 Nov, 2024 Editor invited by journal 04 Nov, 2024 Submission checks completed at journal 30 Oct, 2024 First submitted to journal 16 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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16:08:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5277338/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5277338/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-90399-0","type":"published","date":"2025-02-19T15:57:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69912633,"identity":"1e2f0bbe-e0f1-4e1f-ac3a-3c49fbda42e2","added_by":"auto","created_at":"2024-11-26 14:05:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":17091,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eThe proportion of affected individuals in the total population and the sub-populations of individuals born and not born at the Prata village. Numbers inside the bars: total number of individuals and proportion in %.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5277338/v1/81f9bac9cde6f1c043017884.png"},{"id":69912619,"identity":"5c53d3fd-b834-4016-a9ce-05b7d8d00d46","added_by":"auto","created_at":"2024-11-26 14:05:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":150398,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eKaplan-Meyer plot for age at diagnosis among affected individuals of the Prata Village, according to the place of birth (born vs. not born at the village). Not born in Prata (blue): sub-population of individuals that have not been born at the Prata village; Born in Prata (red): sub-population of individuals that have been born at the Prata Village. Kaplan-Meyer plot: Y-axis: the cumulative proportion of non-affected individuals; Median: median age at diagnosis. Box plot: the back bands inside the boxes are the median; the bottom and top of the boxes represent the first and third quartiles respectively; the ends of the whiskers represent the 10th and the 90th percentile.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage247.png","url":"https://assets-eu.researchsquare.com/files/rs-5277338/v1/b2331d11554d8b89ef092f8e.png"},{"id":77058232,"identity":"3fd8824e-75eb-4e27-9d92-3954aac44a70","added_by":"auto","created_at":"2025-02-24 16:55:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":540360,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5277338/v1/1e5cea28-7f56-46c9-b67f-63b2d885b4ff.pdf"},{"id":69912634,"identity":"ec7001fe-7d0e-4976-8937-b58b43987a12","added_by":"auto","created_at":"2024-11-26 14:05:35","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":252928,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTMATEpiPrata291024.doc","url":"https://assets-eu.researchsquare.com/files/rs-5277338/v1/ea42051522a1768c5078055e.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Leprosy epidemiology: insights from the Prata Village","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLeprosy is a chronic infectious disease caused mainly by \u003cem\u003eMycobacterium leprae\u003c/em\u003e (\u003cem\u003eM. leprae\u003c/em\u003e), an obligate and highly specialized intracellular parasite that primarily infects skin macrophages and Schwann cells in the peripheral nervous system (1). Leprosy manifests clinically in a spectrum consisting of two polar \u0026ndash; tuberculoid and lepromatous \u0026ndash; and three intermediate borderline forms (2). According to the latest data from the World Health Organization (WHO), there were 182,815 newly reported cases of leprosy in 2023 (3), mainly concentrated in India and Brazil. The disease is treated through multidrug therapy (MDT) following a WHO protocol considering the number of lesions and the bacillary load (4).\u003c/p\u003e \u003cp\u003eThe village of \u003cem\u003eSanto Ant\u0026ocirc;nio do Prata\u003c/em\u003e (the Prata Village) was established in 1898 by Franciscan monks in the Amazon forest of the Northern Brazilian state of Par\u0026aacute;. In 1923, the location was designated a compulsory isolation site for individuals diagnosed with leprosy from Brazil's Northern and Northeastern states. Compulsory isolation was lifted in 1962 (5); however, due to the strong social stigma associated with the disease, the emigration of affected individuals and the immigration of non-affected families to the village has been limited over the decades. Consequently, the Prata Village remained socially and geographically isolated until recent years. The population of the village concentrates in an area of around 10 km\u003csup\u003e2\u003c/sup\u003e, and all residents share the same limited social infrastructure, such as a single church, two elementary schools, one social club, and a large central square serving as a communal gathering space for leisure activities such as soccer games and outdoor celebrations. Despite extensive efforts to reduce its incidence, leprosy remains highly prevalent and uniformly distributed throughout the community (6). In 2010, a complex segregation analysis provided evidence of a significant major gene effect controlling susceptibility to leprosy within the Prata population, a finding compatible with the hypothesis that, given the history of the village, genetic risk factors for leprosy are enriched within this population (6).\u003c/p\u003e \u003cp\u003eWe propose that Prata village can serve as a compelling epidemiological model for leprosy, given that (i) the village is confined in a small, geographically isolated area, (ii) it is a leprosy hyperendemic cluster, (iii) the disease is distributed homogenously across the entire village, (iv) the population shares few social interaction spaces, (v) consequently, exposure to the disease is likely homogeneous and widespread among the community. Finally, (vi) the Prata population is enriched in genetic risk factors controlling leprosy susceptibility. Here, we present a population-based descriptive epidemiological study involving the entire population of the Prata Village.\u003c/p\u003e"},{"header":"Subjects and Methods","content":"\u003cp\u003eEnrollment of the entire population of the Prata Village was performed between 2006 and 2007 for a population-based complex segregation analysis, and a detailed description of the enrollment strategy has been published elsewhere (6). In brief, every household in the village was visited by a research team member, and all adult members of resident families were interviewed; the parents or legal guardians provided information about individuals younger than 18 years old. Socio-economic data has been collected through a questionnaire. All individuals self-reported their present and previous leprosy status as affected or non-affected. All self-reported leprosy cases, active and historical, have been checked using three independent sources available at the village\u0026rsquo;s health unit: (i) the original medical records, (ii) copies of the compulsory notification forms, and (iii) a logbook containing registries of all cases for treatment follow-up. Self-reported cases confirmed at all three sources were validated as leprosy cases; clinical information was obtained from the medical records upon confirmation. This study was performed following the Declaration of Helsinki and Brazilian research regulations. All subjects enrolled in the study agreed to participate and signed a written informed consent that has been approved along with the research project by the Research Ethics Committee of the Pontif\u0026iacute;cia Universidade Cat\u0026oacute;lica do Paran\u0026aacute; (51/07/CEP-PUCPR) and the Brazilian National Board for Ethics in Research (222/2006; 25000.001992/2006-17). Of note, only two individuals declined to participate and were not included in the study.\u003c/p\u003e \u003cp\u003eGiven that this population-based study involved the recruitment of the entire Prata village, no inferential statistics were applied. Descriptive statistics was used to describe and compare two sub-populations: individuals born versus individuals not born in the village, the rationale being that, whereas no information about life conditions pre-Prata was available for the sub-population of individuals not born in the village, individuals born in the village have been living their entire lives in a homogenous environment, hyperendemic for leprosy. Median and mean age at diagnosis were estimated and depicted as Kaplan-Meyer and box plots.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 2,005 individuals enrolled, 1,672 self-reported as non-affected by leprosy, 319 self-reported as affected, and 14 did not disclose their leprosy status. Data verification confirmed 257 out of the 319 self-reported leprosy cases. For subsequent analyses, 76 individuals with unknown leprosy status (comprised of the 14 individuals who did not disclose their status and an additional 62 individuals with unavailable medical reports) were excluded (see Supplementary Table\u0026nbsp;01). Consequently, the accumulated prevalence rate of leprosy for the period (including active and historical cases) was calculated as 12.82% (257 cases out of 2,005 individuals), evenly distributed across males and females.\u003c/p\u003e \u003cp\u003eWhen stratifying the affected population by clinical form, 104 (40.5%) cases were lepromatous, 53 (20.6%) were tuberculoid, 53 (20.6%) were borderline, and 47 (18.3%) were indeterminate (suppl. table 3). Therefore, the highest proportion of the Prata patients had a higher bacillary load. The complete demographical, socioeconomic, and clinical characteristics description of the population is provided as supplementary material (suppl. tables 01 to 03).\u003c/p\u003e \u003cp\u003eAbout half of the Prata village population \u0026ndash; 1,084 individuals (56.19%) \u0026ndash; were born there. Among these, 64 were confirmed leprosy cases, resulting in a cumulative prevalence of 5.9%. Among the individuals not born in the village, the cumulative leprosy prevalence was 22.9% (193 confirmed cases/844 individuals) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Tab. Suppl. 02).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe median age at diagnosis among the individuals born in the village was 15 years old (mean\u0026thinsp;=\u0026thinsp;18.17, ranging from 5\u0026ndash;75 years old, standard deviation of \u0026plusmn;\u0026thinsp;12.95). In contrast, the median age at diagnosis was 28 years old among the individuals not born in the village (mean\u0026thinsp;=\u0026thinsp;30.19, ranging from 2\u0026ndash;74 years old and standard deviation of \u0026plusmn;\u0026thinsp;15.25) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Tab. Suppl. 03).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHere, we present a descriptive, population-based study of a well-controlled, hyperendemic, isolated leprosy-affected community that might bring insights into the epidemiology of this elusive disease. Our most striking findings are the difference between leprosy prevalence and age at diagnosis between two sub-populations of individuals born and not born in the village. We also describe a homogenous distribution of cases across males and females.\u003c/p\u003e \u003cp\u003eLeprosy cumulative prevalence among those born and those not born in the village was 5.9% and 22.9%, respectively. It is reasonable to assume that the high cumulative prevalence of leprosy among the population not born in the village is because many of these individuals moved to the village because they had leprosy. In contrast, the much lower cumulative prevalence among the subpopulation born in the village is aligned with previous estimates indicating that approximately 5% of the population is naturally susceptible to leprosy (7,8), a proportion that seems to stand even in a hyperendemic, socially homogenous environment. Of note, previous attempts to determine the proportion of individuals naturally susceptible to leprosy have yielded varied results, ranging from less than 1\u0026ndash;12% (5,9).\u003c/p\u003e \u003cp\u003eThree factors may contribute to the age-onset difference between the subpopulations born and not born in the village. First, more frequent epidemiological surveys in a village well known for being hyperendemic may lead to earlier detection and diagnosis; second, individuals born in the village are mostly descendants of leprosy-affected individuals and, therefore, likely more genetically susceptible to the disease (6); finally, one intriguing hypothesis is that individuals born in the village are under lifelong exposure to leprosy cases and, thus, more prone to infection. If true, the 15-year average age of diagnosis in this sub-population may indicate the time between early exposure and clinical manifestation of the disease. The occurrence of leprosy cases among children is an indicator of ongoing transmission in the community (10,11), which supports our findings. The leprosy incubation period has been a research subject for several decades. The disease is often characterized by an average incubation period of approximately five years (4,12). An early attempt to estimate the incubation period of leprosy based on patient self-reports reached 8.4 years (13). Data from secondary cases of leprosy among household contacts revealed an average time of disease onset of 4.3 (\u0026plusmn;\u0026thinsp;3.3) years, irrespective of the clinical form (14); the authors defined \u0026ldquo;incubation\" as the time between the emergence of an index leprosy patient in a household and the occurrence of a leprosy secondary case in a household contact. It should be noted, however, that the study was performed in a hyper-endemic region; thus, the estimate may be biased by the assumption that exposure occurs only through the index case living in the same household. A study involving 35 military veterans reported a median onset time ranging from 2 to 5 years for tuberculoid and 8 to 12 years for lepromatous leprosy; however, these findings did not reach statistical significance (15). Furthermore, estimates of a 15 to 30-year incubation period in animal models primarily rely on non-human primates, a non-consensus model for leprosy studies (15\u0026ndash;17). A screening of the available literature shows that many references of the incubation period refer to a book Chap.\u0026nbsp;(18), describing it as being between 2\u0026ndash;5 years; careful analysis of the references used in the book revealed that the information is based on studies of different experimental designs, resulting in findings ranging from 2\u0026ndash;30 years. More recently, a case report was published about a male individual with an incubation period of 50 years before symptom onset (19). Together, these studies emphasize the variability in the data related to the incubation period of leprosy.\u003c/p\u003e \u003cp\u003eOne final interesting observation is the distribution of leprosy across sexes in the Prata population. While it is commonly reported that leprosy is more prevalent in males compared to females (20,21), we found that this difference is not clear among sub-populations born and not born in the Prata Village. The proportions of males and females among both sub-populations were similar, with 51.5% males and 48.5% females among those born in the village and 48.9% males and 51.1% females among those not born in the village. Given that the disease is incorporated into the culture of the village and is thus more naturally perceived by the population, our data suggests that the sex effect on leprosy distribution may be more influenced by behavioral factors rather than inherent biological differences between males and females.\u003c/p\u003e \u003cp\u003eAs a final note: if the population in the Prata Village indeed has increased natural susceptibility to leprosy, it is expected to have a higher incidence of reinfection/relapse cases. This is supported by a recent study that reported high rates of leprosy recurrence in the village, along with a high prevalence of drug-resistant strains of \u003cem\u003eM. leprae\u003c/em\u003e (22). These observations suggest that the Prata Village population is more susceptible to leprosy and permanently exposed to resistant bacteria, creating an ideal environment for the persistence of leprosy hyper-endemicity.\u003c/p\u003e \u003cp\u003eWe are aware of the limitations of our study. For example, as we are confident in our strategy of cross-checking clinical records of different sources to characterize a case, we are also aware that clinical examination would be interesting, particularly for the self-reported non-affected population. However, examining the entire population of the village would be an enormous task; also, we believe that the risk of a self-reported non-affected individual being affected is reduced by (i) the fact that the village is maintained under constant surveillance, with an MD dermatologist visiting the village on regular basis, and (ii) because leprosy is widespread and part of the local culture, the stigma associated with the status of affected is reduced amongst the villagers, favoring seeking for medical help. Our observations also suggest that some villagers may perceive being diagnosed with leprosy as a positive outcome, as they may become eligible for financial governmental support (23).\u003c/p\u003e \u003cp\u003eAnother limitation, particularly regarding our arguments on the proportion of naturally susceptible individuals and the disease's incubation period, is that one must assume equal and permanent exposure of all newborn individuals to \u003cem\u003eM. leprae\u003c/em\u003e throughout their lives, which is impossible to prove. For example, our approach does not consider the exact clinical form of each leprosy case and the presence or absence of an index case within the household of a new case (24). On the other hand, the Prata village presents (i) a high prevalence of leprosy (12.82%), (ii) most of the cases of high bacillary load (40.5% were lepromatous), and (iii) a homogenous environment with a low degree of social isolation between leprosy affected and non-affected individuals. These observations favor the assumption that the Prata population is under constant high exposure.\u003c/p\u003e \u003cp\u003eIn conclusion, although extrapolating our findings to more open populations must be done carefully, we believe we used a unique population as a model to provide additional insights into the epidemiology of leprosy.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eAdditional Information\u003c/h2\u003e \u003cp\u003eThe authors declare that the research was conducted without any commercial or financial relationships that could potentially create a conflict of interest.\u003c/p\u003e \u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eCCOM, FPL, and MBX: collected the data; MO: performed the statistical analysis; HRSD, PVUS, RSAR, and GC: performed the statistical analysis and wrote the article; AMS: wrote the article; ES, AA, and MTM: designed the study, provided senior supervision, and reviewed and wrote the article.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank all Prata Village populations for their acceptance in participating in the study. This study was supported by grants of Unicef/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), MCT/CNPq/MS-SCTIE-DECIT 35/2005 \u0026ndash; \u0026ldquo;Estudos da Hansen\u0026iacute;ase\u0026rdquo; and MCT/CNPq/MS-SCTIE-DECIT 25/2006 \u0026ndash; \u0026ldquo;Estudo de Doen\u0026ccedil;as Negligenciadas\u0026rdquo;.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe authors state that all data produced in the study are available. Data requests can be made to the corresponding author via this email: [email protected].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBritton WJ, Lockwood DNJ. Leprosy. The Lancet. 2004;363:1209\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRidley, D.S; Jopling WH. Classification of Leprosy According to Immunity. A five-group system. Internacional Journal of Leprosy. 1966;34:255\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. Global leprosy (Hansen disease) update, 2023: Elimination of leprosy disease is possible \u0026ndash; Time to act!. 2024. Available from: https://www.who.int/publications/i/item/who-wer9937-501-521\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. Guidelines for the Diagnosis, Treatment and Prevention of Leprosy. New Delhi: World Health Organization, Regional Office for South-East Asia; 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosa Maciel L, Oliveira MLW del R, Gallo MEN, Damasco MS. Memories and history of Hansen\u0026rsquo;s disease in Brazil told by witnesses (1960\u0026ndash;2000). Hist\u0026oacute;ria, Ci\u0026ecirc;ncias, Sa\u0026uacute;de - Manguinhos. 2003;10:308\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eL\u0026aacute;zaro FP, Werneck RI, Mackert CCO, Cobat A, Prevedello FC, Pimentel RP, et al. A major gene controls leprosy susceptibility in a hyperendemic isolated population from north of Brazil. Journal of Infectious Diseases. 2010;201(10):1598\u0026ndash;605.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMassone C, Nunzi E. Pathogenesis of Leprosy. In: Nunzi E, Massone C, Portaels F, editors. Leprosy and Buruli Ulcer - A Practical Guide. 2 Edition. Springer; 2022. p. 1\u0026ndash;570.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLast\u0026oacute;ria JC, de Abreu MAMM. Leprosy: Review of the epidemiological, clinical, and etiopathogenic aspects - Part 1. An Bras Dermatol. 2014;89(2):205\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharma R, Singh P, Loughry WJ, Lockhart JM, Inman WB, Duthie MS, et al. Zoonotic leprosy in the southeastern United States. Emerg Infect Dis. 2015 Dec 1;21(12):2127\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLockwood DNJ, Suneetha S. Leprosy: too complex a disease for a simple elimination paradigm. Vol. 83, Bulletin of the World Health Organization. 2005.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. Weekly epidemiological record. Global leprosy (Hansen disease) update, 2022: new paradigm \u0026ndash; control to elimination [Internet]. 2023. Available from: https://population.un.org/wpp/,\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchreuder PAM, Noto S, Richardus JH. Epidemiologic trends of leprosy for the 21st century. Clin Dermatol. 2016 Jan 1;34(1):24\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBechelli LM. O tempo de incuba\u0026ccedil;\u0026atilde;o da lepra. Rev Bras Leprol. 1936;4:355\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrasad K, Ali P. Incubation Period of Leprosy. Indian J Med Res. 1967;55(1):29\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFine PEM. Leprosy: the epidemiology of a slow bacterium. Epidemiol Rev. 1982;4:161\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWaters MFR, Bin B, Isa HJ, Rees RJW, McDougall AC. Experimental lepromatous leprosy in the white-handed gibbon (Hylobatus lar): successful inoculation with leprosy bacilli of human origin. Br J exp Path. 1978;59:551.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuzuki K, Udono T, Fujisawa M, Tanigawa K, Idani G, Ishii N. Infection during infancy and long incubation period of leprosy suggested in a case of a chimpanzee used for medical research. J Clin Microbiol. 2010 Sep;48(9):3432\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoordeen SK. Elimination of leprosy as a public health problem: progress and prospects*. Bull World Health Organ. 1995;73(1):1\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajani AJ, Raval DM, Chitale RA, Kempaiah P, Elwasila SM, Durvasula R, et al. Half a Century in Hiding: A Unique Case of Tuberculoid Leprosy with an Unprecedented Incubation Period. American Journal of Case Reports. 2024;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy - A population-based cohort study in Indonesia. Lepr Rev. 2006 Mar;77(1):48\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePescarini JM, Strina A, Nery JS, Skalinski LM, Andrade KVF de, Penna MLF, et al. Socioeconomic risk markers of leprosy in high-burden countries: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2018 Jul 9;12(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosa PS, D\u0026rsquo;Espindula HRS, Melo ACL, Fontes ANB, Finardi AJ, Belone AFF, et al. Emergence and transmission of drug-/multidrug-resistant mycobacterium leprae in a former leprosy colony in the brazilian amazon. Clinical Infectious Diseases. 2020;70(10):2054\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlves LC, Sanchez MN, Hone T, Pinto LF, Nery JS, Tauil PL, et al. The association between a conditional cash transfer programme and malaria incidence: a longitudinal ecological study in the Brazilian Amazon between 2004 and 2015. BMC Public Health. 2021 Dec 29;21(1):1253.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFine PE, Sterne JA, P\u0026ouml;nnighaus JM, Bliss L, Saui J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in northern Malawi. Am J Epidemiol. 1997 Jul 1;146(1):91\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"leprosy, population, epidemiology, innate susceptibility","lastPublishedDoi":"10.21203/rs.3.rs-5277338/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5277338/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLeprosy, a chronic infectious disease caused mainly by \u003cem\u003eMycobacterium leprae\u003c/em\u003e (\u003cem\u003eM. leprae\u003c/em\u003e), is still an important public health problem in countries such as Brazil and India. Here, we estimate key epidemiological parameters in the Prata Village, a unique, hyper-endemic, former leprosy colony isolated in the Brazilian Amazon. This is a population-based study in which the entire Prata Village population has been enrolled. Clinical, socioeconomic, and demographic data were obtained and cross-checked using three independent information sources. Validated data was used for descriptive epidemiological analysis. From a total of 2,005 inhabitants by the time of the enrollment, 1,084 (56.19%) were born in the Village and, therefore, likely under lifelong exposure to leprosy cases. We observed differences between the sub-populations born and not born in the village in the cumulative prevalence of leprosy (5.9% vs. 22.9%, respect.) and the age at diagnosis (15 years vs. 28 years, respect.). In contrast, there was no difference in the distribution of cases between the two sexes. Although extrapolating our findings to more open populations must be done carefully, we believe we used a unique population as a model to provide additional insights into the epidemiology of leprosy.\u003c/p\u003e","manuscriptTitle":"Leprosy epidemiology: insights from the Prata Village","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-26 14:05:30","doi":"10.21203/rs.3.rs-5277338/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-24T17:56:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-19T14:31:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"324760670216229557292983591434031246857","date":"2024-12-11T14:56:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-27T17:39:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218695942402859607437015168536971605921","date":"2024-11-17T10:20:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-14T20:06:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-05T14:03:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-11-05T03:01:40+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-30T06:42:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-10-16T16:01:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"982c437b-01f3-4dff-8732-b0df331a9a3d","owner":[],"postedDate":"November 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":39893384,"name":"Health sciences/Diseases/Infectious diseases"},{"id":39893385,"name":"Health sciences/Medical research/Epidemiology"}],"tags":[],"updatedAt":"2025-02-24T16:55:16+00:00","versionOfRecord":{"articleIdentity":"rs-5277338","link":"https://doi.org/10.1038/s41598-025-90399-0","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-02-19 15:57:51","publishedOnDateReadable":"February 19th, 2025"},"versionCreatedAt":"2024-11-26 14:05:30","video":"","vorDoi":"10.1038/s41598-025-90399-0","vorDoiUrl":"https://doi.org/10.1038/s41598-025-90399-0","workflowStages":[]},"version":"v1","identity":"rs-5277338","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5277338","identity":"rs-5277338","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}