The effect of dysautonomia on motor, behavioral and cognitive fluctuations in Parkinson’s disease

The effect of dysautonomia on motor, behavioral and cognitive fluctuations in Parkinson’s disease | 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 The effect of dysautonomia on motor, behavioral and cognitive fluctuations in Parkinson’s disease View ORCID Profile Abhimanyu Mahajan , Christopher B Morrow , Joseph Seemiller , View ORCID Profile Kelly A Mills , Gregory M Pontone doi: https://doi.org/10.1101/2024.08.26.24312589 Abhimanyu Mahajan 1 Gardner Family Center For Parkinson’s Disease and Movement Disorders, University of Cincinnati , Cincinnati, OH MD, MHS Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Abhimanyu Mahajan Christopher B Morrow 2 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , Baltimore, MD MD, MHS Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joseph Seemiller 3 Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MD MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kelly A Mills 3 Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MD MD, MHS Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kelly A Mills Gregory M Pontone 2 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , Baltimore, MD 4 Division of Aging, Behavioral and Cognitive (ABC) Neurology, Department of Neurology, University of Florida , Gainesville, FL MD, MHS Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: gpontone{at}ufl.edu Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background Motor and non-motor fluctuations adversely impact quality of life in Parkinson’s disease (PD). Dysautonomia, a feature frequently associated with PD and a possible adverse effect of dopaminergic therapy, may be comorbid with fluctuations. Objectives We sought to evaluate the effect of dysautonomia on motor and non-motor fluctuations in PD Methods Two hundred subjects with PD were evaluated in both “on” and “off” dopamine states to assess changes in symptoms related to dopaminergic fluctuations. Multivariable logistic regression was performed to assess the association of dysautonomia with motor, cognitive, and psychiatric worsening from ON to OFF states with adjustment for disease duration, levodopa equivalent daily dosage (LEDD), and dopamine agonist LEDD. Results Subjects with dysautonomia had greater odds of clinically meaningful change in motor features (OR 3.0), cognition (OR 3.4) and anxiety (OR 4.3) compared to those without dysautonomia. Conclusions Dysautonomia may be a contributory mechanism behind fluctuations in PD. The exact nature of this relationship deserves further evaluation. Introduction Dysautonomia, defined as impairment of the autonomic nervous system, is commonly seen in patients with PD. It may also be seen in undiagnosed patients at high-risk for developing motor manifestations of PD. 1 A high prevalence of different aspects of dysautonomia has been reported in patients with PD: 20-60% with urinary or sexual dysautonomia, 10-15% with thermoregulatory dysfunction, 19-50% with gastrointestinal dysfunction, and 10-20% with pupillomotor disorders. 2 - 5 Orthostatic hypotension and supine hypertension may be seen in 20-40% of PD patients with a profound impact on falls, quality of life and a greater need for medical care. 5 , 6 Even if asymptomatic, it may affect overall function and quality of life. 7 A robust response to dopaminergic therapy is a hallmark of idiopathic Parkinson’s disease (PD). However, motor fluctuations in response to treatment may be seen in approximately 40-50% of PD patients 5 years into the disease, with disease duration and treatment dose as predictors. 8 Motor fluctuations typically present as an initial end-of-dose worsening of motor features and may progress to unpredictable fluctuations with a profound impact on quality of life. 9 In addition, PD patients with motor fluctuations may report non-motor fluctuations in anxiety (35.4%), depressive symptoms (34.9%) and feelings of panic (37.1%). 10 - 12 While initially believed to be a consequence of motor fluctuations, noted discordance between severity of fluctuations in motor features and mood led to the acceptance of at least, partial independence between motor and non-motor fluctuations. 13 , 14 Such non-motor fluctuations have an additional, substantive impact on quality of life in PD and might not resolve with treatment of motor fluctuations. 15 Dysautonomia is known to worsen with dopaminergic therapy and may be comorbid with fluctuations. 16 Whether dysautonomia is associated with, or even potentiates, motor and non-motor fluctuations is poorly understood. Through this effort, we sought to evaluate whether the presence of dysautonomia in persons with PD is associated with the degree to which dopamine replacement affects motor and non-motor function, with specific interest on its impact on changes in mood. Such a relationship, if demonstrated, may suggest aggressive targeting of dysautonomia may impact the experience of motor or non-motor fluctuations. Methods Participants The study protocol 17 included adults 21 years of age or older, diagnosed with idiopathic Parkinson’s disease based on MDS clinical diagnostic criteria 18 . Those in the first year of illness and those diagnosed with dementia were excluded to avoid enrolling individuals with Lewy body dementia. No cognitive cut-off was used to avoid excluding patients with advanced PD who were still able to function independently and did not meet criteria for dementia. Recruitment sites included the Morris K. Udall Parkinson’s Disease Research Center at the Johns Hopkins University School of Medicine, the Johns Hopkins Parkinson’s Disease Research Center, and three outpatient movement disorder neurology clinics. A total of 200 participants completed the study and were included in the analysis. Measures Dysautonomia was defined using the Scales for Outcomes in Parkinson’s Disease – Autonomic Dysfunction (SCOPA-AUT), a well validated scale for measuring symptoms of autonomic dysfunction in PD over the previous month. 19 The established cut-off score of 13.1 was used to define those with dysautonomia. 4 Mood symptoms were measured using the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D), which are well-established measures of anxiety and depressive symptoms commonly used and validated in populations with PD. 20 The HAM-A is a 17-item rating scale that measures the presence and intensity of different anxiety symptom domains. Motor functioning was assessed using the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS III). 21 Cognitive measures were administered and scored according to standard instructions by a trained research assistant. The Symbol Digit Modalities Test (SDMT) and STROOP test were administered in an oral format to avoid motor confounds associated with the written format. Total and dopamine agonist-associated levodopa equivalent daily dosage (LEDD) was calculated for each participant. 11 Procedures Participants were evaluated in both “on” and “off” dopamine states to assess changes in symptoms related to dopaminergic fluctuations. Participants were first evaluated after stopping all dopaminergic medications for a minimum of 12 hours to establish an “off” medication state baseline. Participants then took their typical morning dopaminergic medications and were re-evaluated once they reported being in their best “on” medication state. The change in mood symptoms between “on” and “off” dopamine states was calculated. Assessments were conducted by Movement Disorder Society (MDS) trained clinicians in an outpatient research setting. The Johns Hopkins University Institutional Review Board approved the study protocol, and all participants provided written informed consent before participation. Statistical Analysis Differences in participant characteristics and clinical outcomes were compared using two-sample t-tests for continuous variables and Pearson χ2 tests for categorical variables. We performed multivariable logistic regression to assess the association of dysautonomia with motor, cognitive, and psychiatric worsening from ON to OFF states with adjustment for disease duration, levodopa equivalent daily dosage (LEDD), and dopamine agonist LEDD. Binary outcomes were defined based on established minimally clinically important differences (MCID) –a worsening of 4.63 on the MDS UPDRS III, 4 on the SDMT, 5.5 on thr STROOP test, and 4 on the HAM-D. 22 - 25 There are no widely accepted MCID thresholds for the HAM-A, so we established a threshold of 7.5 which is 0.5 standard deviation beyond the mean change in our population and represents a meaningful increase in clinical anxiety. Alpha was set at 0.05. STATA SE 18 (StataCorp LP, College Station, TX) was used for all analyses. Results Demographic and Clinical Characteristics Table 1 displays demographic, cognitive, motor, and psychiatric symptoms stratified by dysautonomia status for the 200 participants. Of the 200 participants, 106 exhibited symptoms of dysautonomia (SCOPA-AUT ≥ 13.1) constituting 53% of the study sample. Given the known relationship between dopamine replacement therapy and orthostatic hypotention, a sensitivity analysis excluding SCOPA-AUT items associated with orthostasis (questions 14-18) was conducted but did not materially alter the results. As such, symptoms related to orthostatic hypotension alone were not thought to be responsible for the relationship. SCOPA-AUT scores were calculated using all questions. There were no statistically significant differences in age, sex, or race in those with or without dysautonomia. There were no statistically significant cognitive differences between the groups. Duration of disease (8.2 versus 5.0, p<0.001), LEDD (877.6 versus 723.6, p<0.001), and dopamine-agonist LEDD (113.9 versus 61.3, p = 0.008) were all higher in the dysautonomia group. View this table: View inline View popup Table 1: Demographic, Cognitive, Behavioral, and Motor Symptoms by Dysautonomia Status The magnitude of improvement in motor (MDS UPDRS III change of -14.3 versus -12.2, p = 0.045) and anxiety symptoms (HAM-A change -6.0 versus -4.0, p<0.001) between on and off states was greater in the dysautonomia group relative to the non-dysautonomia group. There was no evidence of a difference in depressive symptom change between the groups. The odds of clinically meaningfully worsening in those with dysautonomia versus those without dysautonomia was 3.0 (95% CI 1.0 – 8.8) for motor symptoms, 3.4 (95% CI 1.5-7.9) for SDMT, and 4.3 (95% CI 1.9 – 9.9) for anxiety symptoms ( Table 2 , Supplementary data). Additional assessment of the relationship using linear regression models led to similar conclusions. An increase in SCOPA scores was associated with a significant difference in STROOP scores with medication. [-0.17 (0.07), p = 0.03) (Supplementary data: SupplementaryTable 1) View this table: View inline View popup Table 2: Odds of motor and non-motor fluctuations in Parkinson’s disease with dysautonomia Discussion Early reports of fluctuations with dopaminergic therapy included the co-prevalence of dysautonomia and behavioral/ cognitive features with descriptions of flushing, sweating, fear and confusion, along with mood swings. 14 , 26 In our sample of 200 patients with systematically collected data before and after dopaminergic treatment, the presence of dysautonomia over the last month was associated with greater odds of clinically-relevant change in anxiety, cognition (SDMT: psychomotor speed, attention, visual scanning and tracking, and working memory) 27 and motor features. Motor fluctuations are thought to represent the combined effect of pulsatile dopaminergic stimulation and disease progression, leading to a reduction in dopamine synthesis and presynaptic dopaminergic terminal storage. 14 , 28 , 29 Additionally, post-synaptic changes, as a consequence of disease and treatment, likely contribute. 14 Despite shared risk factors of disease duration, treatment dose and duration, and PD progression, non-motor fluctuations are not entirely explained by the kinetics of dopamine repletion as it relates to motor function. 13 , 14 Thus, other mechanisms may affect the relationship between dopamine replacement and non-motor symptom changes. Our data may suggest that, accounting for disease duration and dopamine replacement dose as surrogates of overall disease severity, the presence of dysautonomia may predispose individuals to experience greater differences in anxiety with dopamine repletion. In support of this notion, several other studies suggest a causal role of dysautonomia in the experience of anxiety in PD. Dysautonomia has been reported to be an independent predictor of anxiety in PD. 30 Greater dysautonomia, especially gastrointestinal and thermoregulatory symptoms, has been associated with greater mood related symptom burden longitudinally in early PD. 31 A technique called heart rate variability biofeedback, involving self-regulation of a physiological dysregulated vagal nerve function, especially when combined with cognitive behavioral therapy has been reported to improve anxiety. 32 While a possible explanation is that manifestations of dysautonomia (tachycardia, reduced heart rate variability) overlap with self-reported anxiety, 30 , 33 the role of the autonomic nervous system in anxiety is well established with substantial reductions in heart rate variability (poor vagal control) noted across psychiatric disorders in medication-free individuals. 34 A recent study offered preliminary evidence of cardiac sympathetic denervation explaining ∼20% of pure anxiety variance in PD, independent of sex, dopaminergic impairment, and anxiolytic treatments. 35 As such, dysautonomia may be postulated as a cause of poor response to anti-anxiety medications in some individuals. 36 A similar relationship has been proposed with cognition. 37 A review of relevant studies with direct and indirect evidence reported a relationship between dysautonomia and cognitive impairment. 38 Dysautonomia, manifesting as early orthostatic hypotension, is shown to predict greater cognitive dysfunction. 39 PD patients with orthostatic hypotension decline faster in executive function compared to those with normal blood pressures. 40 The relationship between OH and cognitive decline may be explained by widespread peripheral and central noradrenergic loss. 37 Noradrenaline modulates cognition, specifically attention and working memory. 41 Alpha-synuclein burden in Locus Coeruleus, a key source of noradrenaline, precedes and is noted to be of a greater magnitude than substantia nigra. 42 Dysautonomia-mediated cerebral hypoperfusion has also been postulated as a contributing mechanism. 38 Fluctuations in cognition have been associated with blood pressure fluctuation with clinical presentation 43 and results of neuropsychological testing 44 in PD. Improvement in orthostatic hypotension has been postulated as a mechanism of clinical benefit seen with use of Rivastigmine in cognitively impaired PD patients. 45 Our study results, suggesting a contribution of dysautonomia to clinically-relevant fluctuations in anxiety in a robust sample of subjects with PD, are consistent with this literature. While linear regression modeling showed a statistically significant effect of dysautonomia on STROOP and SDMT scores, logistic regression modeling (with an additional focus on clinically-meaningful significance) only showed a relationship between dysautonomia and SDMT. An effect of dopaminergic treatment on SDMT performance has been demonstrated using the same data set and is thought to be potentially related to excess dopaminergic stimulation along circuits innervating the pre-frontal cortex. 46 These conflicting results are consistent with literature with previous studies showing no effect of dopaminergic medications on STROOP test. 47 - 49 Both SDMT and STROOP are tests that measure processing speed, workingmemory, attention, and impulse suppression. However, subtle differences remain including the assessment of speed of visual search, word reading and color naming. The effect of dysautonomia on cognitive fluctuations needs additional, nuanced assessment. Our study sample with a mean age of 65.2 years (SD. 7.7 years), mean disease duration of 9.1 years (SD. 5.8 years) and LEDD of 805.2 mg (SD. 498.7 mg) is a reasonable representation of PD in the clinic. Our model accounted for dopamine-agonist dose which may disproportionately impact studied outcomes. The use of clinically relevant change in outcomes, representative of clinical impact, is a strength of our analysis. Our study has several limitations. On and Off states were defined based on withdrawal of dopaminergic medication. A rationale of this approach is its use for determination of candidacy for deep brain stimulation in PD. 50 However, this manufactured off-state may differ from spontaneous or unpredictable fluctuations as any uncertainty associated with such fluctuations may be associated with greater anxiety. Moreover, our battery to assess non-motor features was limited given sample size constraints. The use of HAM-A and HAM-D to assess changes in the on- and off-states in PD has not been validated. Similarly, SDMT and STROOP scales have not been validated for this purpose. Genetic status of included subjects was not available. As such, the differential effect of genetic mutations on dysautonomia, and motor and non-motor fluctuations and their relationship cannot be accounted for. Regardless, the study design allows for a robust assessment of the impact of dysautonomia, a common manifestation in idiopathic PD, on dopamine-replacement association changes in motor and non-motor manifestations. In addition to offering a potential insight into a mechanism behind the reported relationship, it offers a potential therapeutic avenue for management of motor and non-motor fluctuations by addressing dysautonomia to target non-motor fluctuations in mood. This direction must be explored further in clinical studies. Data Availability All data produced in the present study are available upon reasonable request to the authors Financial disclosures AM: Dr. Mahajan has received funding from Parkinson’s foundation, Sunflower Parkinson’s disease foundation and Dystonia Medical Research Foundation outside of the submitted work. CBM: Dr. Morrow has received funding from the National Institutes of Health (KL2TR003099, L30AG083912). JS: Dr. Seemiller has received funding from the Parkinson’s Foundation. KAM: Dr. Mills has received funding from Parkinson’s Foundation, Michael J. Fox Foundation, and NINDS/NIH (R21NS128391-01A1). He receives clinical trial research support from UCB Pharma. He has done consulting with Tilosia, LLC. GMP: Dr. Pontone was funded by 5K23AG044441 during the completion of this work and is now funded by 1R01MH123552. GMP has done consulting with Acadia Pharmaceuticals Inc and GE Healthcare. Conflict of Interest The authors declare that there are no conflicts of interest relevant to this work. Funding sources Dr. Greg Pontone and the study described in this manuscript was funded by the NIH/NIA as part of a K23 award (K23 AG044441-01A1). Ethical Compliance Statement The Johns Hopkins University Institutional Review Board approved the study protocol. The research team obtained written consent from all participants prior to their participation. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Author Contributions Research project: A. Conception, B. Organization, C. Execution; Statistical Analysis: A. Design, B. Execution, C. Review and Critique; Manuscript: A. Writing of the first draft, B. Review and Critique. AM: 1A, 1B, 1C, 2A, 2C, 3A, 3B CBM: 1B, 1C, 2A, 2B, 2C, 3B JS: 2C, 3B KAM: 2A, 2C, 3B GMP: 1B, 1C, 2C, 3B Disclosures Financial disclosures from the last 12 months The authors declare that there are no additional relevant disclosures to report Acknowledgement We would like to thank the subjects for participating in this study. References 1. ↵ Liepelt-Scarfone I , Pilotto A , Müller K , et al. Autonomic dysfunction in subjects at high risk for Parkinson’s disease . J Neurol . 2015 Dec ; 262 ( 12 ): 2643 – 52 . 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Share The effect of dysautonomia on motor, behavioral and cognitive fluctuations in Parkinson’s disease Abhimanyu Mahajan , Christopher B Morrow , Joseph Seemiller , Kelly A Mills , Gregory M Pontone medRxiv 2024.08.26.24312589; doi: https://doi.org/10.1101/2024.08.26.24312589 Share This Article: Copy Citation Tools The effect of dysautonomia on motor, behavioral and cognitive fluctuations in Parkinson’s disease Abhimanyu Mahajan , Christopher B Morrow , Joseph Seemiller , Kelly A Mills , Gregory M Pontone medRxiv 2024.08.26.24312589; doi: https://doi.org/10.1101/2024.08.26.24312589 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 Neurology Subject Areas All Articles Addiction Medicine (574) Allergy and Immunology (865) Anesthesia (304) Cardiovascular Medicine (4460) Dentistry and Oral Medicine (445) Dermatology (383) Emergency Medicine (611) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1517) Epidemiology (15250) Forensic Medicine (31) Gastroenterology (1132) Genetic and Genomic Medicine (6621) Geriatric Medicine (669) Health Economics (1002) Health Informatics (4563) Health Policy (1372) Health Systems and Quality Improvement (1617) Hematology (544) HIV/AIDS (1272) Infectious Diseases (except HIV/AIDS) (15936) Intensive Care and Critical Care Medicine (1107) Medical Education (624) Medical Ethics (147) Nephrology (670) Neurology (6640) Nursing (346) Nutrition (1001) Obstetrics and Gynecology (1148) Occupational and Environmental Health (957) Oncology (3350) Ophthalmology (981) Orthopedics (369) Otolaryngology (421) Pain Medicine (436) Palliative Medicine (130) Pathology (665) Pediatrics (1698) Pharmacology and Therapeutics (693) Primary Care Research (714) Psychiatry and Clinical Psychology (5464) Public and Global Health (9258) Radiology and Imaging (2211) Rehabilitation Medicine and Physical Therapy (1372) Respiratory Medicine (1198) Rheumatology (598) Sexual and Reproductive Health (716) Sports Medicine (533) Surgery (715) Toxicology (100) 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:'a03889ea6abd8650',t:'MTc4MDA4OTU4MQ=='};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())}}}})();