Intermediate repeat alleles at polyglutamine repeat loci in the Indian population

Intermediate repeat alleles at polyglutamine repeat loci in the Indian population | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (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];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Intermediate repeat alleles at polyglutamine repeat loci in the Indian population View ORCID Profile Meghana Janardhanan , View ORCID Profile Akshayaa Ganesh , View ORCID Profile Sowmya Devatha Venkatesh , View ORCID Profile YM Jeevan , Swarna Buddha Nayok , View ORCID Profile Pavithra Jayasankar , View ORCID Profile Vikram Holla , View ORCID Profile Nitish Kamble , View ORCID Profile Biju Viswanath , Ravi Yadav , View ORCID Profile Pramod Pal , Sanjeev Jain , View ORCID Profile Meera Purushottam doi: https://doi.org/10.1101/2025.11.22.25340801 Meghana Janardhanan 1 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences , Bangalore, India (MSc) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Meghana Janardhanan Akshayaa Ganesh 1 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences , Bangalore, India (MSc) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Akshayaa Ganesh Sowmya Devatha Venkatesh 1 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences , Bangalore, India (PhD) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sowmya Devatha Venkatesh YM Jeevan 2 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences , Bangalore (NIMHANS), India (MD) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for YM Jeevan Swarna Buddha Nayok 1 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences , Bangalore, India (MD PhD) Find this author on Google Scholar Find this author on PubMed Search for this author on this site Pavithra Jayasankar 1 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences , Bangalore, India (MD) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Pavithra Jayasankar Vikram Holla 3 Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS) , Hosur Road, Bangalore (MD, DM) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Vikram Holla Nitish Kamble 3 Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS) , Hosur Road, Bangalore (MD, DM) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nitish Kamble Biju Viswanath 1 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences , Bangalore, India (MD, PhD) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Biju Viswanath For correspondence: meera.purushottam{at}gmail.com bijuv1{at}gmail.com Ravi Yadav 3 Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS) , Hosur Road, Bangalore (MD, DM) Find this author on Google Scholar Find this author on PubMed Search for this author on this site Pramod Pal 3 Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS) , Hosur Road, Bangalore (MD, DNB, DM, FRCP) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Pramod Pal Sanjeev Jain 1 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences , Bangalore, India (DPM, MD) Find this author on Google Scholar Find this author on PubMed Search for this author on this site Meera Purushottam 1 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences , Bangalore, India (PhD) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Meera Purushottam For correspondence: meera.purushottam{at}gmail.com bijuv1{at}gmail.com Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF ABSTRACT An expansion of trinucleotide repeats beyond a threshold, at particular loci, is linked to several diseases. The prevalence of these expansion-linked disorders varies across populations, and may be influenced by the prevalence of sub-threshold intermediate alleles, which are prone to expand. The effect of somatic instability of these repeats, adds further complexity to the role of intermediate repeats. We studied the prevalence of intermediate CAG repeat alleles at SCA1, SCA2, SCA3 and HTT in several hundred individuals. These included patients with clinical suspicion of movement disorder (N∼725), those with severe mental illness (N∼ 420), and healthy individuals from the general population (N∼300). Intermediate alleles were defined as those in the range of 36 -38 CAG repeats for ATXN1 , 45 -59 CAG repeats for ATXN3 , 27 - 35 CAG repeats for HTT , and 27-32 CAG repeats for ATXN2 . In those with neuromotor symptoms, we found intermediate alleles in 26 out of 561 (4.6 %) individuals genotyped at ATXN1 , 10 out of 437 (2.2%) individuals at ATXN3 , 16 out of 686 (2.3%) individuals at HTT and 1 out of 484(0.2%) individuals at ATXN2 . In individuals without a diagnosis of movement disorder (patients with SMI and healthy controls), intermediate alleles were detected in 19 out of 725 (2.6%) individuals at ATXN1 and 14 out of 687 (2.0%) individuals at HTT loci. No intermediate alleles were detected at the ATXN2 and ATXN3 loci. The impact of these intermediate alleles on risk of disease in future generations, and prevalence of disease, needs to be evaluated. Introduction Tandem repeats are common, multi-allelic, highly mutable, and polymorphic sequences in the genome. Expansion of CAG trinucleotide repeats is linked to neurodegenerative syndromes, including Huntington’s disease (HD; Huntingtin HTT ), Spinocerebellar Ataxia type 1 (SCA1; Ataxin-1, ATXN1 ), SCA2 ( ATXN2 ), and SCA3 ( ATXN3 ). These disorders are inherited in an autosomal dominant pattern, and often show anticipation which is perhaps driven by instability and expansion of the repeat sequence ( 1 ). Their prevalence varies significantly across populations. HD is more frequent in the European population (4.5-8.9 per 100,000), than in Africa (0.02-2.6 per 100,000) and varies considerably in the South American population ( 2 ). This variation in prevalence may be influenced by the average CAG repeat length and frequency of different HTT gene haplotypes in the general population ( 3 ). According to de Mattei et al., (2023), SCA1 accounts for a significant portion of ataxia syndromes in some parts of Europe; Greece (12%), France (14.1–17.4%), Germany (9%), Finland (4%), the Netherlands (6.2%), and Portugal (2.2%), while in Italy the prevalence varied with geographic origin of probands ( 4 ). Elsewhere, SCA1 had a lower relative frequency, being absent or infrequent (0-2%) in United Kingdom, Czech Republic, and Norway, but detected in approximately 5% in Spain. In the case of SCA2, France, Spain and Italy, Eastern European countries, such as Serbia (13%), Poland (11.3%), and Czech Republic (11%), exhibit a relatively high prevalence. SCA3 is the most common spinocerebellar ataxia (SCA) worldwide and is detected in 20-50% of families with SCA. It is the most common SCA in Portugal (58-74%), Brazil (69-92%), China (48-49%), the Netherlands (44%), Germany (42%), and Japan (28-63%) among tested SCA cases, but is quite rare in Italy (1%), and South Africa (4%) ( 5 ). In Brazil, its high frequency is particularly notable in regions with strong Portuguese ancestry and remains restricted to a few haplotypes when encountered in other parts of the world ( 6 , 7 ). In India too, SCA1 and SCA2 are more common, while SCA3 is more frequent in areas with Portuguese or European admixture ( 8 , 9 ) Intermediate alleles (IA) are unstable repeats that usually do not cause disease but may expand, while pathogenic repeat alleles manifest clinically. Since these alleles are inherently unstable, large IAs in the population may act as a reservoir for pathogenic expansions in a subsequent generation, and contribute to the varying prevalence as described earlier. These IAs are observed in a significant proportion of the general population, often at ATXN1 and HTT loci ( 10 ). In a systematic literature review, IAs in the HTT region ranged from 0.45% - 8.7% in the general population, and 0.05% - 5.1% in individuals with a family history of HD ( 11 ). Specific haplogroups (A1 and A2 variants) associated with European HD populations are also detected in those with IAs ( 12 ). This suggests that IAs may be more likely to expand upon transmission in particular haplogroups. IAs might also be linked to the risk of other psychiatric and neurological symptoms. Intermediate alleles at the HTT locus were more frequent in those diagnosed with Multi-System Atrophy (8.8%) when compared to controls (3.9%) ( 13 ). IAs in HTT, ATXN1 , and ATXN2 loci also seem to increase the risk of Alzheimer’s Disease (AD), and Fronto-Temporal Dementia (FTD)( 14 ). Low-penetrance HTT repeat expansions were detected in 0.3% of Parkinson’s Disease patients and 0.19% of healthy controls ( 13 ). IAs may also have a role in the risk of polymorphic symptoms and severe mental illness (SMI), like schizophrenia and mood disorders ( 15 – 17 ). To examine these issues further, there is a need to carry out a systematic evaluation of IAs in the general population, and in individuals with SMI. We studied the prevalence of IAs at ATXN1, ATXN2 and ATXN3 and HTT loci in patients with clinical evidence of movement disorder, and also in patients with severe mental illness, as well as individuals from the general population. Methodology We describe the occurrence of IAs in two sets of samples. The first set included individuals referred to the Genetic Counselling and Testing (GCAT) Clinic, with a suspected diagnosis of movement disorder (ataxia or HD, Group1) (N∼686). The other sets had persons with no symptoms of ataxia or movement disorder, population controls (N∼300, Group 2), and those with a severe mental illness (SMI) (N∼420, Group 3) (either schizophrenia or bipolar disorder, diagnosed according to ICD 10). The size of the CAG repeats at HTT, ATXN1, ATXN2 and ATXN3 loci was determined following standard protocols (Venkatesh et al., 2018). The Institutional Ethics Committee approved the study and all patients gave written informed consent for the study. The gnomADv3.1.2 which has STR data for the general population was examined for IAs at the four loci studied, in other world populations of interest (Supplementary table 1a and 1b). ( https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3 ) Results In group1 we detected 53 chromosomes, with an intermediate repeat size in at least one of the genes that were analyzed. These included IAs in 26/561(4.6%) individuals at ATXN1 , 1/484(0.2%) individual at ATXN2 , 10/437(2.3%) individuals at ATXN3 , and 16/686 (2.3%) individuals at the HTT locus ( Table 1 ). In a few instances of those with neuromotor symptoms, (3 cases out of 561, in SCA1; 4 out of 437, in SCA3; 5 out of 686, in HD) an IA was detected along with an expanded allele, at the same locus. View this table: View inline View popup Table 1: Number of individuals within the normal, intermediate and pathological ranges in individuals with a suspected diagnosis of movement disorder In group 2 and 3, IAs were detected in 19/725 (2.6%) individuals (9/308 population controls and 10/417 SMI) at ATXN1 . Similarly, 14/687(2.0%) individuals (6/302 population controls and 8/377patients with SMI) at HTT locus, carried IAs ( Table 2 ). No IAs were observed at the ATXN2 and ATXN3 loci. View this table: View inline View popup Download powerpoint Table 2: Number of individuals within the normal, intermediate and pathological ranges in individuals without a primary diagnosis of ataxia or movement disorder (population controls and individuals with severe mental illness) In summary, IAs were observed in 15/300 controls (4.9%) in group 2, and in group 3, we detected 18 persons with IAs (4.3%). The occurrence of IA did not differ between those with SMI and controls. Moreover, we did not detect any correlation between the age at onset in bipolar disorder (n=187), and CAG upper repeat alleles at any locus. An examination of population wise STR frequencies in the gnomADv3.1.2 also showed negligible occurrence of IAs at the ATXN2 and ATXN3 loci (Supplementary table 1a). IAs are detected in ATXN1 and HTT in about 5% of the global population. At the ATXN1 locus the IA are seen in less than 1% of those of mid-eastern origin, but in almost 6% of non-Finnish Europeans and 3.5% in the SAS population. At the HTT locus too, IAs seem to be undetected in the Amish, but occur in about 5-6% Europeans, and in more than 10% of mid-Eastern samples. (Supplementary table 1b). Discussion A significant proportion of the general population (3-5%) seems to harbor intermediate alleles which seems to be relatively common. Intermediate alleles at the ATXN1 were also found along with a pathogenic expansion in four SCA2, and two SCA3 positive individuals. Expansions of alleles on both chromosomes have been detected occasionally, in our laboratory in those with ataxia or HD ( 20 ) and at other centers ( 9 ), and may contribute to more severe disease. Such instances suggest a more generalized defect in DNA replication, leading to slippage of repeat sequences during cell division, perhaps contributing to the occurrence of instability at multiple loci. Previous studies on brain, sperm and blood tissues have also reported somatic instability in both SCA1 and HD, invoking a common mechanism for tissue-specific allele heterogeneity ( 18 ). Recent work from our center has also reported regional CAG repeat instability in the PPP2R2B locus in samples of postmortem SCA12 brain ( 19 ). In a few HD patients and in some siblings and parents of HD patients we found instances of intermediate alleles ( 20 ). The presence of IA in DNA from leucocytes could sometimes correspond to pathogenic repeat sizes in other tissues (such as the brain), and thus account for some of the polymorphic phenotypes reported for IAs ( 17 ). The ATXN2 CAG allele in the normal population is almost mono-allelic to a very large extent, suggesting that the repeat length at this locus is quite invariable. At the ATXN3 locus, the specific haplotype associations suggest founder effects. We did not find IAs in the ATXN2 and ATXN3 loci in the non-ataxia population. Associated haplotypes might include sequences that provide structural stability and prevent slippage. Particular DNA sequences might also attract proteins that provide stability. For instance, a unique 17bp sequence upstream of the fgf14 gene is not found in expanded GAA alleles that cause SCA27B ( 21 ). Such protective phenomena could deter the generation of IAs at particular loci, as observed in the current study. The worldwide allele frequencies of IA might also influence the prevalence of disease in the population, at both the HTT and ATXN1 loci. Though the middle Eastern haplotypes are believed to be of African origin, the prevalence of HD is much lower in Africa. In Alzheimer’s disease, a protective SNP was seen to overcome the risk for disease conferred by ApoeE4 in Africa ( 22 ). A focused understanding of the surrounding gene sequences and preserved haplotypes might be needed to uncover such genetic effects in TNRs. Whole genome data from diverse populations such as India should be examined for occurrence of intermediate alleles in conjunction with other functional DNA repair pathway variants which might influence somatic variation and hence disease presentation. Intermediate alleles that occur alongside pathogenic alleles in the same locus, or at alternate TNR loci (as identified in our study), could also act as disease modifiers in some instances. This kind of data analysis for repeat loci is best carried out using long read sequencing data using increasingly affordable newer technologies, which provide better quality sequence data. Thus, repeat instability may lead to generation of intermediate alleles in the population which ultimately progress to pathogenic alleles in some tissues in an individual patient. The study of genetic epidemiology of intermediate alleles, its impact on both germline and somatic instability, and correlations with phenotypes, might help explain prevalence of the linked diseases across populations, as well as disease biology. Data Availability All data produced in the present study are available upon reasonable request to the authors Footnotes Funding: This work was supported by grant from Scientific Knowledge for Ageing and Neurological Ailments (SKAN) trust project ‘Genetics of bipolar disorder and related illnesses: a study of intermediate alleles in candidate genes with repeat expansion loci’ (SKAN/002/208/2021/01480), Accelerator program for Discovery in Brain disorders using Stem cells (ADBS) (jointly funded by the Department of Biotechnology, Government of India, and the Pratiksha Trust; Grant BT/PR17316/MED/31/326/2015), and the Centre for Brain and Mind (CBM) grant of the Rohini Nilekani Philanthropies. BV is also supported by The Wellcome Trust DBT India Alliance Intermediate (Clinical and Public Health) Fellowship (IA/CPHI/20/1/505266). References 1. ↵ Apolinário , T.A. , Paiva , C.L.A. and Agostinho , L.A. 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Available at : doi: 10.1002/ggn2.202100078 . OpenUrl CrossRef PubMed 22. ↵ Venkatesh , S.D. et al. ( 2018 ) “ Genetic testing for clinically suspected spinocerebellar ataxias: report from a tertiary referral centre in India ,” Journal of Genetics , 97 ( 1 ), pp. 219 – 224 . Available at : doi: 10.1007/s12041-018-0911-2 . OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted November 25, 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. 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Share Intermediate repeat alleles at polyglutamine repeat loci in the Indian population Meghana Janardhanan , Akshayaa Ganesh , Sowmya Devatha Venkatesh , YM Jeevan , Swarna Buddha Nayok , Pavithra Jayasankar , Vikram Holla , Nitish Kamble , Biju Viswanath , Ravi Yadav , Pramod Pal , Sanjeev Jain , Meera Purushottam medRxiv 2025.11.22.25340801; doi: https://doi.org/10.1101/2025.11.22.25340801 Share This Article: Copy Citation Tools Intermediate repeat alleles at polyglutamine repeat loci in the Indian population Meghana Janardhanan , Akshayaa Ganesh , Sowmya Devatha Venkatesh , YM Jeevan , Swarna Buddha Nayok , Pavithra Jayasankar , Vikram Holla , Nitish Kamble , Biju Viswanath , Ravi Yadav , Pramod Pal , Sanjeev Jain , Meera Purushottam medRxiv 2025.11.22.25340801; doi: https://doi.org/10.1101/2025.11.22.25340801 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 Genetic and Genomic Medicine Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4435) Dentistry and Oral Medicine (444) Dermatology (382) Emergency Medicine (608) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1509) Epidemiology (15227) Forensic Medicine (30) Gastroenterology (1124) Genetic and Genomic Medicine (6597) Geriatric Medicine (668) Health Economics (997) Health Informatics (4534) Health Policy (1368) Health Systems and Quality Improvement (1613) Hematology (540) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15916) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (146) Nephrology (667) Neurology (6599) Nursing (346) Nutrition (998) Obstetrics and Gynecology (1144) Occupational and Environmental Health (957) Oncology (3332) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (663) Pediatrics (1693) Pharmacology and Therapeutics (691) Primary Care Research (711) Psychiatry and Clinical Psychology (5447) Public and Global Health (9230) Radiology and Imaging (2198) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (593) Sexual and Reproductive Health (712) Sports Medicine (530) Surgery (712) Toxicology (99) Transplantation (289) 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:'a003f0f17b70aa64',t:'MTc3OTUzODA1NQ=='};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())}}}})();