Adenomas Are Frequent in PMS2 Lynch Syndrome patients but Rarely Mismatch Repair Deficient

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Andini , L. Lanjouw , M. Suerink , D. Terlouw , A. Ahadova , S. Aretz , M. Bigirwamungu-Bargeman , H. Bläker , W.H. de Vos Tot Nederveen Cappel , V. Endris , E. Holinski-Feder , M.A.J.M. Jacobs , J.J. Koornstra , A.M.J. Langers , M. Loeffler , A. Lepistö , J.-P. Mecklin , M. Kloor , G. Möslein , P. Peltomäki , K. Pylvänäinen , L. Renkonen-Sinisalo , T.T. Seppälä , C.P. Strassburg , V. Steinke-Lange , M. Morak , R. Hüneburg , S. Redler , C.M.J. Tops , P.C. van de Meeberg , M. van Kouwen , D.B. Vangala , B. Katerberg , M.-L. Verhulst , M. von Knebel Doeberitz , S. Zachariae , C. Engel , H.F.A. Vasen , View ORCID Profile T. van Wezel , H. Morreau , K. Kok , R.H. Sijmons , M. van Leerdam , View ORCID Profile M. Nielsen , G. Kats-Ugurlu , View ORCID Profile S.W. Bajwa-ten Broeke doi: https://doi.org/10.1101/2025.09.01.25334843 K.D. Andini 1 Department of Genetics, University Medical Centre Groningen , Groningen, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site L. Lanjouw 2 Department of Epidemiology, University Medical Centre Groningen , Groningen, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site M. Suerink 3 Department of Clinical Genetics, Leiden University Medical Centre , Leiden, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site D. Terlouw 3 Department of Clinical Genetics, Leiden University Medical Centre , Leiden, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site A. Ahadova 4 Department of Applied Tumour Biology, Institute of Pathology, Heidelberg University Hospital , Heidelberg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site S. Aretz 5 Institute of Human Genetics, University of Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn , Bonn, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site M. Bigirwamungu-Bargeman 6 Department of Gastroenterology & Hepatology , Medisch Spectrum Hospital, Enschede, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site H. Bläker 7 Institute of Pathology, University Hospital Leipzig , Leipzig, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site W.H. de Vos Tot Nederveen Cappel 9 Department of Gastroenterology & Hepatology , Isala Zwolle, Zwolle, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site V. Endris 10 Department of General Pathology, Institute of Pathology, University Hospital Heidelberg , Heidelberg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site E. Holinski-Feder 11 Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München , Munich, Germany ; Center of Medical Genetics , Munich, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site M.A.J.M. Jacobs 13 Department of Gastroenterology & Hepatology, Amsterdam University Medical Center , Amsterdam, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site J.J. Koornstra 14 Department of Gastroenterology & Hepatology, University Medical Centre Groningen, University of Groningen , Groningen, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site A.M.J. Langers 15 Department of Gastroenterology & Hepatology, Leiden University Medical Centre , Leiden, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site M. Loeffler 8 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig , Leipzig, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site A. Lepistö 16 Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki , Helsinki, Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site J.-P. Mecklin 17 Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä , Jyväskylä, Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site M. Kloor 4 Department of Applied Tumour Biology, Institute of Pathology, Heidelberg University Hospital , Heidelberg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site G. Möslein 18 Center for Hereditary Tumors, HELIOS Klinikum Wuppertal, University Witten-Herdecke , Wuppertal, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site P. Peltomäki 19 Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site K. Pylvänäinen 20 The Wellbeing Services County of Central Finland , Jyväskylä, Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site L. Renkonen-Sinisalo 16 Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki , Helsinki, Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site T.T. Seppälä 17 Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä , Jyväskylä, Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site C.P. Strassburg 21 National Center for Hereditary Tumor Syndromes, University Hospital Bonn , Bonn, Germany ; Department of Internal Medicine I, University Hospital Bonn , Bonn, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site V. Steinke-Lange 11 Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München , Munich, Germany ; Center of Medical Genetics , Munich, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site M. Morak 12 LMU Hospital, Campus Innenstadt , Munich, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site R. Hüneburg 5 Institute of Human Genetics, University of Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn , Bonn, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site S. Redler 30 Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University , Düsseldorf, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site C.M.J. Tops 22 Department of Clinical Genetics, Laboratory for Diagnostic Genetic Analysis, Leiden University Medical Center , Leiden, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site P.C. van de Meeberg 23 Department of Gastroenterology & Hepatology , Slingeland Hospital, Doetinchem, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site M. van Kouwen 24 Department of Gastroenterology & Hepatology, Radboud University Medical Centre , Nijmegen, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site D.B. Vangala 25 Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum , Bochum, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site B. Katerberg 9 Department of Gastroenterology & Hepatology , Isala Zwolle, Zwolle, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site M.-L. Verhulst 26 Department of Gastroenterology & Hepatology, Maxima Medical Centre , Eindhoven, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site M. von Knebel Doeberitz 4 Department of Applied Tumour Biology, Institute of Pathology, Heidelberg University Hospital , Heidelberg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site S. Zachariae 8 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig , Leipzig, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site C. Engel 8 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig , Leipzig, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site H.F.A. Vasen 14 Department of Gastroenterology & Hepatology, University Medical Centre Groningen, University of Groningen , Groningen, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site T. van Wezel 27 Department of Pathology, Leiden University Medical Centre , Leiden, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for T. van Wezel H. Morreau 27 Department of Pathology, Leiden University Medical Centre , Leiden, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site K. Kok 1 Department of Genetics, University Medical Centre Groningen , Groningen, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site R.H. Sijmons 1 Department of Genetics, University Medical Centre Groningen , Groningen, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site M. van Leerdam 15 Department of Gastroenterology & Hepatology, Leiden University Medical Centre , Leiden, The Netherlands 28 Department of Gastroenterology , Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site M. Nielsen 3 Department of Clinical Genetics, Leiden University Medical Centre , Leiden, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for M. Nielsen G. Kats-Ugurlu 29 Department of Pathology, University Medical Centre Groningen , Groningen, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site S.W. Bajwa-ten Broeke 1 Department of Genetics, University Medical Centre Groningen , Groningen, the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for S.W. Bajwa-ten Broeke For correspondence: s.w.ten.broeke{at}umcg.nl Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background Lynch syndrome (LS) predisposes carriers to the accelerated development of colorectal cancer (CRC). Pathogenic PMS2 variant (PV) carriers are believed to have the lowest CRC risk and develop MMR deficiency (dMMR) at a later stage of CRC progression. In addition, the PMS2 adenoma incidence rate is considered lowest among all MMR PV carriers. However, neither the exact adenoma incidence nor the prevalence of dMMR among PMS2 PV carriers is known. Method We established a cohort of 171 confirmed PMS2 PV carriers in the Netherlands and collected clinical excerpts to establish adenoma incidence. We also collected 123 paraffin blocks from PMS2 PV carriers and investigated PMS2 and MLH1 expression with immunohistochemistry (IHC). Results We collected 123 paraffin blocks containing adenomatous lesions from PMS2 PV carriers removed who underwent surveillance colonoscopy between 2018-2023. Of the 123 IHC-stained lesions 109 were tubular adenomas, 86.2% of which (n=94/109) retained PMS2 protein expression. All specimens showed intact MLH1 staining. Conclusion Adenomas are frequent in PMS2 PV carriers, although the majority of PMS2-associated adenomas retained MMR-proficiency. The result of our study corroborates the late involvement of PMS2 deficiency in the evolution of to PMS2 associated CRC. Research Letter Lynch syndrome (LS) predisposes carriers of a germline heterozygous pathogenic variant (PV) in one of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 or PMS2 , to the development of mainly colorectal and endometrial carcinomas 1 . Previous studies reported a relatively low risk of colorectal cancer (CRC) among PMS2 PV carriers. This has resulted in an underreporting of PMS2 PV carriers in Lynch syndrome cohorts reported in literature due to clinical recognition and ascertainment, as evidenced by a much higher prevalence of 1:714 of PMS2 variants in the general population compared to other MMR genes 2 , 3 , 4 . This suggests that many PMS2-LS families remain undetected by clinical selection criteria. The variation in cancer risk associated with the different subtypes of Lynch syndrome is likely due to differences in molecular pathogenesis of PMS2 -CRC. Recent reports based on IHC and molecular testing have highlighted three pathways of LS colorectal carcinogenesis 5 . Carriers of MLH1, MSH2 , and in part MSH6 PVs may develop LS-associated CRC through MMR-deficient early lesions, such as MMR-deficient crypt foci or MMR-deficient adenomas. In contrast, we have previously reported that PMS2 -CRC likely develops through MMR-proficient adenoma that transforms into MMR-deficient CRC over time 6 ( Figure 1A ). However, our knowledge on PMS2 carcinogenesis is still limited, since data regarding incidence and characteristics of early PMS2- associated adenomas are sparse. Our current study addresses the cumulative incidence and immunohistochemical features of adenomas in PMS2 PV carriers based on surveillance colonoscopy data on confirmed germline PMS2 PV carriers registered in the Netherlands. Download figure Open in new tab Figure 1. A) PMS2 Lynch syndrome carcinogenesis pathway, in which MMR capacity is lost over time as the adenoma progresses into colorectal cancer, B) Cumulative incidence of adenomas among four Lynch syndrome-associated genes (left) and after adjusting for age at first colonoscopy (right), and C) Immunohistochemical staining patterns of adenomatous lesions: PMS2-proficient tubular adenoma, PMS2-deficient tubular adenoma with PMS2-DCF, PMS2-deficient colorectal cancer The Dutch PMS2 cohort consists of 171 individuals, its clinical characteristics summarized in Table 1 . A total of 576 colonoscopies were performed between 1987 and 2023, representing 1769 years of follow-up. The cumulative incidence of PMS2 -associated adenomas 10 years after index colonoscopy was 58% (39.2%-81.2%), highest among the four MMR genes followed by MSH2 , as demonstrated in Figure 1B (left panel). A previous report by Engel et al. 7 demonstrated adenoma incidence rates of 44.2% for MSH2 , 38.4% for MSH6 , and 32.2% for MLH1 . We were able to merge this data with our PMS2 cohort, allowing us to compare the different Lynch syndrome subtypes. Because of differences in mean age at index colonoscopy ( Table 1 ) which could impact the time until the occurrence of an adenoma, we performed a Cox regression analysis. Age at first surveillance was indeed associated with the risk of developing adenomas in all MMR gene mutation carriers (HR = 1.027, 95% CI: 1.022-1.32, p <0.001). Additionally, we added gender to the analysis and found that female mutation carriers have a lower hazard of adenoma development compared to males (HR = 0.781, 95% CI: 0.689-0.879 p <0.001). The analyses showed similar directional trends for the cumulative incidence across gene groups in both Kaplan-Meier analysis and the adjusted Cox regression model, with the highest risk for MSH2 PV carriers, followed by PMS2- and the lowest risk for MSH6 - and MLH1 - PV carriers ( Figure 1B , right panel). View this table: View inline View popup Download powerpoint Table 1. Clinical and histopathological characteristics of Dutch PMS2 cohort Next, we set out to investigate the prevalence of PMS2 deficiency in (early) lesions detected in the PMS2-cohort and conducted immunohistochemical (IHC) staining for anti-MLH1 and anti-PMS2 antibodies on 123 paraffin blocks containing lesions removed during colonoscopy between 2018-2023. See supplementary data for a detailed description of the methods. The morphological features of the lesions are described in Table 1 . Of the 123 IHC-stained lesions 109 were tubular adenomas, 86.2% of which (n=94/109) retained PMS2 protein expression. As expected for germline PMS2 PV carriers, MLH1 staining remained intact in all adenomas. The finding that only 13.8% of adenomas removed in our PMS2 cohort were MMR deficient is in striking contrast with a meta-analysis involving 640 adenomas from MLH1, MSH2 , and MSH6 PV carriers of which 76.7% of dysplastic adenomas were already MMR-deficient (n = 491, 95% CI: 73.3–79.8%) 5 . Our observations support the notion that loss of the PMS2 wildtype allele, and thus occurrence of PMS2-defiency, may occur later in the adenoma-carcinoma evolution in PMS2 PV carriers. Our analyses also demonstrated that despite rare occurrence of PMS2 -CRC among our cohort (n=2), 58% of PMS2 variant carriers developed adenomas within 10 years of first colonoscopy. This means that most adenomas in patients with PMS2-LS likely do not (rapidly) progress to CRC. Furthermore, the high cumulative PMS2 adenoma incidence, coupled with low PMS2-CRC occurrence, suggests that routine surveillance colonoscopy was successful to prevent almost all occurrences of CRC. Our current data combining epidemiological and IHC analyses corroborate the preference of an “accelerated” adenoma-carcinoma sequence in PMS2-Lynch syndrome: early PMS2 adenomas are MMR-proficient and a minority progressively lose MMR capacity over time which sets the acceleration in motion. An intriguing observation is that the incidence of adenomas in PMS2 PV carriers appears similar to that of MSH2 PV carriers, despite the hypothesis that the latter subtype develops CRC from MMRd crypt foci through an intermittent adenoma phase. This alternative route may contribute to the relatively high adenoma incidence seen in MSH2-versus MLH1-associated Lynch syndrome patients, as MSH2-deficency drives the development of an adenoma. A possible explanation for the comparable adenoma incidence observed in PMS2 PV carriers could be the presence of additional, non-MMR-related risk factors in our clinically-ascertained cohort, indirectly increasing their risk of CRC. Beside the underlying germline PMS2 PV, such factors that innately confer higher risk (both external and internal) of adenoma development remain to be investigated. Additionally, the older age of our cohort of PMS2 PV carriers may also increase the risk of adenoma detection due to mutations that accumulate in the colonic epithelium over time, although the age-related mutation accumulation is not enough to induce the loss of PMS2 heterozygosity as demonstrated by the overwhelming majority of PMS2-proficient adenomas among our cohort. To the best of our knowledge, our study is the first to thoroughly assess adenoma morphology and PMS2 deficiency status based on immunohistochemistry. Our data can be combined with similar PMS2-focused data from other countries, as well as sequencing data from both normal-looking crypts and adenomas of PMS2 PV carriers, in order to paint a complete picture of its early-stage carcinogenesis. Future studies should investigate the varying “mutational evolution” of events leading to MMR deficiency, adenoma development, and/or progression into LS-CRC. By understanding the early molecular alterations for each LS-associated gene, prevention approaches (e.g. neoantigen-based vaccinations 9 or NSAID-based chemoprevention 10 ) can be tailored to each molecular pathway. In conclusion, PMS2-deficiency is rare in (early) adenomas of PMS2 PV carriers, despite frequent adenoma detection after index colonoscopy. Adenoma formation in this Lynch syndrome subtype thus appears largely independent of PMS2 loss, highlighting the need to uncover other key drivers to guide effective prevention. Data Availability All data produced in the present study are available in the manuscript, otherwise will be made available upon reasonable request to the authors. Funding The LYNCH-GPS project is funded by the Dutch Cancer Society Young Investigator Grant (KWF 2019-12570). We also thank (patients who voluntarily participate in LYNCH-GPS study, PALGA, MSc. Biomedical Sciences intern A.M. Reilly, pathology archive manager H.J. Hilbrands, pathology technicians, external collaborators from various hospitals in the Netherlands) for providing the FFPE material and assisting us in sample storage and/or processing. Ethical statement This study was carried out following the ethical approval issued by the Institutional Review Board of Leiden University Medical Centre (No. P01.019) in a previous project. Conflict of interest The authors declare no competing conflicts of interest. REFERENCES ↵ Lynch , H. T. , Snyder , C. L. , Shaw , T. G. , Heinen , C. D. & Hitchins , M. P. 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OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted September 02, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Adenomas Are Frequent in PMS2 Lynch Syndrome patients but Rarely Mismatch Repair Deficient Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Adenomas Are Frequent in PMS2 Lynch Syndrome patients but Rarely Mismatch Repair Deficient K.D. Andini , L. Lanjouw , M. Suerink , D. Terlouw , A. Ahadova , S. Aretz , M. Bigirwamungu-Bargeman , H. Bläker , W.H. de Vos Tot Nederveen Cappel , V. Endris , E. Holinski-Feder , M.A.J.M. Jacobs , J.J. Koornstra , A.M.J. Langers , M. Loeffler , A. Lepistö , J.-P. Mecklin , M. Kloor , G. Möslein , P. Peltomäki , K. Pylvänäinen , L. Renkonen-Sinisalo , T.T. Seppälä , C.P. Strassburg , V. Steinke-Lange , M. Morak , R. Hüneburg , S. Redler , C.M.J. Tops , P.C. van de Meeberg , M. van Kouwen , D.B. Vangala , B. Katerberg , M.-L. Verhulst , M. von Knebel Doeberitz , S. Zachariae , C. Engel , H.F.A. Vasen , T. van Wezel , H. Morreau , K. Kok , R.H. Sijmons , M. van Leerdam , M. Nielsen , G. Kats-Ugurlu , S.W. Bajwa-ten Broeke medRxiv 2025.09.01.25334843; doi: https://doi.org/10.1101/2025.09.01.25334843 Share This Article: Copy Citation Tools Adenomas Are Frequent in PMS2 Lynch Syndrome patients but Rarely Mismatch Repair Deficient K.D. Andini , L. Lanjouw , M. Suerink , D. Terlouw , A. Ahadova , S. Aretz , M. Bigirwamungu-Bargeman , H. Bläker , W.H. de Vos Tot Nederveen Cappel , V. Endris , E. Holinski-Feder , M.A.J.M. Jacobs , J.J. Koornstra , A.M.J. Langers , M. Loeffler , A. Lepistö , J.-P. Mecklin , M. Kloor , G. Möslein , P. Peltomäki , K. Pylvänäinen , L. Renkonen-Sinisalo , T.T. Seppälä , C.P. Strassburg , V. Steinke-Lange , M. Morak , R. Hüneburg , S. Redler , C.M.J. Tops , P.C. van de Meeberg , M. van Kouwen , D.B. Vangala , B. Katerberg , M.-L. Verhulst , M. von Knebel Doeberitz , S. Zachariae , C. Engel , H.F.A. Vasen , T. van Wezel , H. Morreau , K. Kok , R.H. Sijmons , M. van Leerdam , M. Nielsen , G. Kats-Ugurlu , S.W. Bajwa-ten Broeke medRxiv 2025.09.01.25334843; doi: https://doi.org/10.1101/2025.09.01.25334843 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Gastroenterology Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (297) Cardiovascular Medicine (4420) Dentistry and Oral Medicine (443) Dermatology (381) Emergency Medicine (606) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1507) Epidemiology (15212) Forensic Medicine (30) Gastroenterology (1120) Genetic and Genomic Medicine (6581) Geriatric Medicine (667) Health Economics (996) Health Informatics (4519) Health Policy (1366) Health Systems and Quality Improvement (1611) Hematology (538) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15906) Intensive Care and Critical Care Medicine (1103) Medical Education (620) Medical Ethics (144) Nephrology (667) Neurology (6580) Nursing (345) Nutrition (998) Obstetrics and Gynecology (1141) Occupational and Environmental Health (956) Oncology (3323) Ophthalmology (970) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (663) Pediatrics (1689) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5429) Public and Global Health (9212) Radiology and Imaging (2192) Rehabilitation Medicine and Physical Therapy (1368) Respiratory Medicine (1194) Rheumatology (593) Sexual and Reproductive Health (709) Sports Medicine (529) Surgery (709) Toxicology (99) Transplantation (288) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9fefeaff1808e2c5',t:'MTc3OTMyODA5Nw=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();