Efficacy of platelet-rich products in preventing cerebrospinal fluid leakage following neurosurgical procedures: A systematic review and meta-analysis

Efficacy of platelet-rich products in preventing cerebrospinal fluid leakage following neurosurgical procedures: A systematic review and meta-analysis | 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 Efficacy of platelet-rich products in preventing cerebrospinal fluid leakage following neurosurgical procedures: A systematic review and meta-analysis Jina Behjati , Mohammadreza Ghasemi , Shaghayegh Karami , Pooya Eini , Arman Keymoradzadeh , Mohammad Ansari , Hassan Reza Mohammadi , Mohsen Koosha , Saeed Oraee-Yazdani doi: https://doi.org/10.1101/2025.05.30.25328644 Jina Behjati a Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences , Tehran, Iran Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: jina.behjati{at}gmail.com Mohammadreza Ghasemi b School of Medicine, Shahid Beheshti University of Medical Sciences , Tehran, Iran Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shaghayegh Karami c School of Medicine, Tehran University of Medical Sciences , Tehran, Iran Find this author on Google Scholar Find this author on PubMed Search for this author on this site Pooya Eini d Toxicological Research Center, Shahid Beheshti University of Medical Sciences , Tehran, Iran Find this author on Google Scholar Find this author on PubMed Search for this author on this site Arman Keymoradzadeh e Department of Neurosurgery, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences , Tehran, Iran Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mohammad Ansari f Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences , Tehran, Iran Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hassan Reza Mohammadi e Department of Neurosurgery, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences , Tehran, Iran Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mohsen Koosha e Department of Neurosurgery, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences , Tehran, Iran Find this author on Google Scholar Find this author on PubMed Search for this author on this site Saeed Oraee-Yazdani a Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences , Tehran, Iran Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: jina.behjati{at}gmail.com Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background and objective Despite advancements in dural closure techniques and materials, cerebrospinal fluid (CSF) leakage remains a major issue for neurosurgeons. This systematic review assesses the efficacy of platelet-rich products in reducing post-operative CSF leakage. Method PubMed, Scopus, Web of Science, EMBASE, Clinicaltrials.gov, and Google Scholar were searched using the following keywords: “platelet-rich products”, “cerebrospinal fluid leak”, “cranial surgery”, and “spinal surgery”. Original studies using platelet-rich products to reduce CSF leaks were included. Meta-analysis used a random-effects model to calculate risk ratios and risk differences. The GRADE tool was used to assess the certainty of evidence. Statistical analyses were performed in STATA 17 and R. Results Eleven studies were included in the qualitative synthesis and five in the quantitative meta-analysis. Leukocyte-rich platelet fibrin (L-PRF) was the most commonly used product (k = 9). Most studies involved endoscopic endonasal skull base surgeries (K = 9). Meta-analysis demonstrated a non-significant effect in CSF leak prevention by relative risk analysis (RR: 1.03, 95% CI: 1.00-1.06, P = 0.06; I² = 0.01%), and risk difference analysis (RD: 0.07, 95% CI: −0.03 to 0.17, P = 0.18; I² = 72.57%). Qualitative analysis showed lower rates of meningitis and improved wound healing in intervention groups, with no serious adverse events attributed to platelet-rich products. Conclusion While platelet-rich products showed promise in preventing CSF leaks and reducing postoperative complications, their effectiveness was not statistically significant. Well-designed randomized controlled trials with larger populations are needed to establish their role in neurosurgical procedures. Introduction Cerebrospinal fluid (CSF) leakage represents a common complication following cranial and spinal surgeries. The incidence varies based on procedure type and lesion location. In cranial procedures, skull base surgeries have an overall rate of 6.2%, with slight variations based on approach: 5.9% for anterior skull base, 6.4% for middle fossa, and 5.2% for transpetrosal approaches 1 . Posterior fossa craniotomies, however, have shown rates up to 32% 2 . When comparing supratentorial versus infratentorial approaches, CSF leaks occur in 2.9% and 5.8% of cases, respectively 1 . In spinal procedures, the rates vary by context: planned intradural surgeries have an 18% incidence, while incidental durotomies during other spinal procedures show rates ranging from 1% to 17% 2 . CSF leaks increase risks of infection, meningitis, hydrocephalus, and CSF fistula formation, which in turn leads to prolonged hospital stays, greater healthcare costs, and increased mortality 1 , 3 . The cornerstone to prevent postoperative CSF leak is watertight dural closure through meticulous surgical reconstruction. However, primary dural closure alone has a CSF leak rate exceeding 40% 4 , necessitating supplementary reinforcement. These include reconstruction with various grafts and flaps (autologous, allogeneic, natural, and synthetic), which can be further enhanced with materials such as polymer hydrogels, liquid fibrin glues, and dural sealant patches 5 , 6 . Recently platelet-rich products have emerged as a promising adjunct to reduce postoperative CSF leaks. These autologous products are derived from patients’ own blood through simple centrifugation, making them cost-effective and eliminating risks of immune reactions 7 . The resulting product is enriched with growth factors and immune cell products such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived factor 4 (PF-4), and transforming growth factor-beta (TGF-β) which have demonstrated accelerated healing properties in various surgical fields 8 – 10 . Among these products, leukocyte-platelet-rich fibrin (L-PRF) is the most widely used in neurosurgery. In addition to its regenerative benefits, leukocyte and platelet components help reduce the risk of infection 11 . Despite the growing clinical use, the efficacy of platelet-rich products in preventing CSF leakage following neurosurgical procedures remains controversial. While some studies suggest reducing CSF leak rates with platelet-rich product applications 8 , others have failed to demonstrate significant benefits over conventional methods 11 , 12 . In this systematic review and meta-analysis, we aim to evaluate the efficacy of platelet-rich products in reducing cerebrospinal fluid (CSF) leakage following cranial and spinal surgeries. We also provide an overview of their current applications in neurosurgery to establish their present role in clinical practice. Methods This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines 13 and was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) under protocol CRD42024619809. Our primary objective was to assess the effectiveness of platelet-rich products in preventing CSF leakage following cranial and spinal procedures. Search strategy A comprehensive search was conducted across multiple databases, including PubMed, Scopus, Web of Science (WOS), EMBASE, Clinicaltrials.gov, and Google Scholar. The search included terms related to platelet-rich products and their variants, combined with terms for cranial and spinal surgical procedures. The initial search was completed on the 4th of December, 2024. An updated search was performed before manuscript submission to ensure inclusion of the most recent literature. Additionally, the reference lists of included studies were manually screened to identify relevant articles. The complete search strategy is detailed in the Supplementary Table 1. Eligibility criteria We included studies that met the following criteria: Patients of all ages undergoing cranial or spinal surgeries where platelet-rich products were used to prevent post-operative CSF leakage Original research articles including randomized controlled trials (RCT), cohort studies, case-control studies, and case series. Studies reporting CSF leakage and associated complications as outcomes Studies were excluded if: The study was published in a language other than English The publication type was a case report, review, book chapter, editorial, comment, or conference abstract The study was conducted on animal subjects or was in vitro The study did not report CSF leak as an outcome Data collection Study selection followed a systematic two-stage screening process. Initially, two independent reviewers (J.B. and Sh.K.) screened the titles and abstracts according to the predefined eligibility criteria. Any disagreements were resolved through discussion or consultation with a third reviewer (M.Gh.). Subsequently, full-text articles that passed initial screening were thoroughly evaluated for eligibility, with any discrepancies resolved through discussion among reviewers. Data extraction was performed using a standardized form including first author’s name, publication year, country of origin, study design, sample size, procedure type, intervention details, control group specifications, follow-up duration, number of patients with and without CSF leakage in the intervention and control groups, and adverse events. All extracted data underwent cross-verification to ensure accuracy, with any inconsistencies resolved through consensus among the authors. Data synthesis Meta-analysis was performed to synthesize the data from included studies. Since our outcome was dichotomous (treatment success), the risk ratio and risk difference with their 95% confidence intervals were calculated based on the number of participants with and without treatment success in the intervention and control groups. Prediction intervals were estimated to determine the range in which the effect size of a potential future study is likely to fall, assuming it is randomly selected from the same population as the studies included in our meta-analysis. Given the heterogeneity among included studies, a random-effects model was applied using the restricted maximum likelihood ratio (REML) method. Heterogeneity was assessed using Cochrane’s Q test I 2 statistics, with the following categories based on I 2 values: 0-25% (low), 25-50% (moderate), 50-75% (substantial), and 75-100% (high) 14 . Doi plots, LFK indexes, and trim- and-fill methods were used to assess the small study effect (publication bias). We used meta-regression to assess the role of moderator variables on the overall effect size and to explore the potential source of heterogeneity. Subgroup analyses were not performed since we did not have more than 10 studies in our meta-analysis. For sensitivity analysis, a leave-one-out method was used to evaluate the impact of each study on the combined effect. All statistical analyses were performed using STATA software, version 17. The Cochrane Risk of Bias 2 (RoB-2) traffic light and summary plots were visualized via R-4.4.2 (R Foundation for Statistical Computing, Vienna, Austria, 2021) robvis package. A two-sided P value of <0.05 was considered statistically significant, except for small study effect tests, where a two-sided P value of <0.1 was considered significant. Quality assessment The quality of studies and potential risk of bias of included studies were independently assessed by two authors (J.B. and Sh.K.), with disagreements resolved through consensus. Multiple validated assessment tools were employed based on study design: the Cochrane Risk of Bias 2 (RoB-2) for randomized trials 15 , the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) for non-randomized studies 15 , 16 , and the Joanna Briggs Institute (JBI) critical appraisal checklist for observational studies 17 , 18 . Additionally, the overall certainty of evidence was evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework 19 . GRADE assesses the quality of evidence across several domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Based on these, evidence quality will be classified as high, moderate, low, or very low. Results Study selection The initial database search yielded 1,210 results. Following duplicate removal, 584 unique articles were left for screening. Based on the title and abstract review, 551 articles were excluded, leaving 33 articles for full-text assessment. After detailed evaluation, 11 studies were included, of which five met the requirements for quantitative synthesis. The study selection process is illustrated in the PRISMA flow diagram ( Figure 1 ). Download figure Open in new tab Figure 1 PRISMA flow diagram Study characteristics and demographics This systematic review included 11 studies published between 2017 and 2024, with 5 studies eligible for meta-analysis 8 , 20 – 23 . The studies originated from diverse geographical locations: three from Egypt, two from Belgium, and one each from the USA, Argentina, Chile, Turkey, India, and Germany ( Table 1 ). Study designs varied, including four randomized controlled trials, two retrospective studies, three prospective studies, one retrospective cohort study, and one case series. Among the 11 studies, only 6 included control groups 8 , 20 – 24 . The total study population encompassed 896 patients, with 543 receiving platelet-rich products. The studies showed a predominance of female patients. The participants in all studies were adults, except for Arabaci et al. which focused on meningocele repair in infants 8 . View this table: View inline View popup Table 1 Characteristics of the included studies Surgical procedures and interventions The majority of procedures (9 out of 11 studies) involved endoscopic endonasal approaches for various skull base pathologies, and the remaining studies examined elective cranial surgery, spine surgery, and meningomyelocele repair ( Table 1 ). Leukocyte-rich platelet fibrin (L-PRF) emerged as the most common platelet-rich product, used in 9 of the 11 studies. The L-PRF was primarily applied as membranes or plugs, with some studies using multiple layers. One study employed a unique three-layer method combining solid membranous PRF (s-PRF) with high-viscosity injectable PRF (i-PRF) 7 . Arabaci et al. used platelet-rich plasma in liquid form applied during and after surgery 8 . Follow-up duration ranged from 21 days to 2 years, with most studies maintaining follow-up for at least 6 months. Clinical outcomes and complications The primary outcome focused on CSF leak occurrence, with adverse events as secondary outcomes. These outcomes are summarized in Table 1 . Platelet-rich products demonstrated favorable results in preventing CSF leaks. In controlled studies, the intervention groups consistently showed lower CSF leak rates compared to control groups. Complication profiles favored platelet-rich product use in multiple studies. Meningitis occurred less frequently in intervention groups, with several studies reporting zero cases compared to multiple occurrences in control groups. Wound healing complications, particularly in endoscopic skull base surgeries, showed improvement with reduced crusting and better mucosal healing in the intervention group 20 . While headache rates remained similar between groups 20 – 22 , other complications such as wound dehiscence and skin necrosis occurred less frequently with platelet-rich products 8 . Notably, no studies reported serious adverse events directly attributed to the use of platelet-rich products. Meta-analysis results Five studies were included in the meta-analysis, with details provided in Table 2 . Analysis of these studies revealed trivial to small effect sizes in CSF leak treatment, as illustrated in the forest plots ( Figure 2 ). The relative risk analysis showed a trivial but marginally significant effect (RR: 1.03, 95% CI: 1.00 to 1.06, P = 0.06), with a prediction interval of 0.981 to 1.074. The risk difference analysis demonstrated a small, non-significant effect (RD: 0.07, 95% CI: −0.03 to 0.17, P = 0.18), with a prediction interval of −0.261 to 0.397. Download figure Open in new tab Figure 2 Efficacy of Platelet-Rich Products in Reducing CSF Leaks Following Cranial and Spinal Surgeries: (a)RR, (b)RD View this table: View inline View popup Download powerpoint Table 2 Characteristics of studies included in the quantitative analysis Heterogeneity assessment showed contrasting results between measures. The relative risk calculation exhibited low heterogeneity (I² = 0.01%, τ² = 0.00, P = 0.13), while the risk difference calculation demonstrated substantial heterogeneity (I² = 72.57%, τ² = 0.01, P = 0.03) and should be interpreted cautiously. Subgroup analysis was not methodologically feasible due to the small number of included studies. For evaluating the source of heterogeneity, we used meta-regression, examining the influence of mean age and female participant percentage, which showed no significant impact on the combined effect measure ( Figure 3 and Supplementary Table 2). Download figure Open in new tab Figure 3 Meta-regression for the Efficacy of Platelet-Rich Products in Reducing CSF Leaks Following Cranial and Spinal Surgeries: (a)effect of percentage of female participants on RR, (b)effect of mean age on RR, (c)effect of percentage of female participants on RD, (d)effect of mean age on RD Risk of bias assessment The risk of bias assessment was conducted using multiple validated tools based on the study design. The Joanna Briggs Institute (JBI) critical appraisal tool was used for observational studies 17 , 18 . Although the checklist does not establish a minimum threshold for study inclusion, all studies met acceptable quality standards with no significant risk of bias (Supplementary Tables 3 and 4). The ROBINS-I tool was used in one non-randomized trial, showing moderate overall bias due to potential residual confounding, with low risk in all other domains (Supplementary Table 5). The Cochrane RoB-2 tool was used to assess the risk of bias in randomized trials. Only one study demonstrated a low risk of bias (high quality), while the remaining showed a high risk (low quality). Only Coucke et al. clearly described their randomization process and maintained patient blinding 23 . Documentation of follow-up data proved insufficient across studies, with only one study explicitly reporting loss to follow-up. The absence of registered or shared protocols in most studies prevented the evaluation of protocol deviations and selective reporting of results. Detailed risk of bias assessment is presented in Figure 4 . Download figure Open in new tab Figure 4 Risk of Bias Evaluation for the Efficacy of Platelet-Rich Products in Reducing CSF Leaks Following Cranial and Spinal Surgeries: (a) Traffic Light Plot, (b)Weighted Bar Plot Publication bias and sensitivity analysis While traditional funnel plot analysis proved unfeasible due to the small number of studies (<10), alternative methods, including Doi plots, LFK indexes, and trim and fill analyses, revealed no considerable small study effect. Results are shown in Figure 5 , Supplementary Figure 1, and Table 6. Download figure Open in new tab Figure 5 Doi Plots for Small Study Effect (Publication Bias) Assessment for Efficacy of Platelet-Rich Products in Reducing CSF Leaks Following Cranial and Spinal Surgeries: (a) RR, (b) RD Sensitivity analysis using the leave-one-out method confirmed the robustness of our findings, with no single study substantially impacting the overall results. Results are presented in Figure 6 . Download figure Open in new tab Figure 6 Leave-one-out Sensitivity Analysis Results for Efficacy of Platelet-Rich Products in Reducing CSF Leaks Following Cranial and Spinal Surgeries: (a) Risk Ratio, (b) Risk Difference Certainty of evidence The overall certainty of evidence ranged from low to very low, primarily due to the risk of bias, imprecision, and inconsistency across studies. A detailed GRADE assessment is presented in Supplementary Table 7. Discussion To the best of our knowledge, this systematic review and meta-analysis is the first to evaluate the efficacy of platelet-rich products in reducing cerebrospinal fluid leakage following neurosurgical procedures. We found that platelet-rich products did not significantly reduce CSF leak rates. Our quantitative synthesis of five controlled studies showed a relative risk of 1.03 (95% CI: 1.00 to 1.06, P = 0.06) and a risk difference of 0.07 (95% CI: −0.03 to 0.17, P = 0.18), suggesting that while platelet-rich products may offer some benefit in reducing CSF leak rates, this effect does not reach statistical significance. However, our qualitative analysis showed that studies consistently demonstrated lower rates of CSF leakage in groups treated with platelet-rich products than in controls. This warrants further investigation through well-designed clinical trials with larger populations to better understand the potential role of these products in postoperative CSF leak prevention. Various neurosurgical interventions necessitate dural opening, exposing patients to the risk of CSF leakage - a major complication in neurosurgery 1 . This may present as rhinorrhea, otorrhea, or leakage through the surgical incision site 1 . CSF leakage is associated with increased infection risk, elevated intracranial pressure, longer hospital stays, and higher mortality rates 25 . Although reported rates vary across the literature, CSF leaks occur more frequently in skull base surgeries and posterior fossa craniotomies compared to spinal and supratentorial craniotomies 2 . Consequently, diverse management strategies have evolved to address this complication, ranging from advanced surgical techniques to innovative biological and synthetic materials. Among these, platelet concentrates have been investigated as promising adjunctive measures for dural repair and CSF leak prevention. Platelet-rich products have gained widespread attention in different surgical fields such as plastic surgery, otolaryngology, orthopedics, maxillofacial surgery, and neurosurgery 8 , 26 – 28 . This is primarily due to their regenerative properties and ease of use 27 . Different platelet-rich products vary in composition because of differences in preparation methods, and this lack of standardization contributes to the inconsistent efficacy seen across clinical studies 29 . Ehrenfest et al. classified these products based on platelet, leukocyte, and fibrin content into pure PRP (P-PRP), leukocyte-rich PRP (L-PRP), pure platelet-rich fibrin (P-PRF), and leukocyte-rich PRF (L-PRF) 30 . Among these, L-PRF, a second-generation platelet concentrate, was the most commonly used product in neurosurgical cases. One preparation method for L-PRF, as described by Soldatova, involves collecting blood in anticoagulant-free tubes and centrifuging it at 2700 rpm for 12–18 minutes (adjusted based on coagulation status), which will activate the coagulation cascade 31 . During this process, a fibrin clot is formed above the red blood cell layer. The clot is extracted and put in an Xpression™ preparation box and compressed to form a 1-mm thick membrane 31 . Within two hours, the L-PRF membrane is ready for application, maintaining its biological potency for tissue regeneration and surgical repair. Since L-PRF is prepared in parallel with surgery, it does not extend the overall operative time, allowing integration into the surgical workflow 7 , 32 . The fibrin scaffold embedded with viable autologous cells and concentrated growth factors - such as transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF)-promotes tissue regeneration through enhanced angiogenesis and vasculogenesis 10 . Also, its platelet and leukocyte components provide bactericidal effects 33 . The autologous nature of these products eliminates immunological concerns and transmission risks 23 . Intraoperative measures to prevent CSF leakage following neurosurgical procedures rely on multiple layers of repair, including dural closure, bone and soft tissue reconstruction, as well as CSF diversion when necessary, typically using lumbar drains 34 . Complete dural closure is of paramount importance, but when primary closure is impossible due to dural damage or shrinkage, particularly in prolonged surgeries in some anatomical regions, dural grafts become necessary 35 . Dural grafts are available in two categories: biological and synthetic. Biological options include autologous grafts like fascia lata and pericranium, as well as commercial products such as DuraGen ® (bovine) and TissuDura ® (equine), which are type I collagen matrices derived from Achilles tendons 6 . Synthetic alternatives include expanded polytetrafluoroethylene (Teflon) and polyglycolic acid 6 , 36 . These grafts are often reinforced with dural sealants such as TachoSil ® , which is FDA-approved for dural repair reinforcement, and Tisseel ® , a widely used two-component fibrin sealant, used off-label for this purpose 23 . In skull base procedures, particularly in high-flow CSF leaks with large defects, vascularized flaps (e.g., nasoseptal, middle or inferior turbinate flaps) and the gasket seal technique (a method using a fascia lata graft secured by a rigid buttress to create a watertight closure) are also used for soft tissue and bone reconstruction 37 , 38 . In the following sections, we explore the role of platelet-rich products in each step of CSF leak prevention described across different neurosurgical contexts. Endoscopic skull base surgery Soldatova et al. first used L-PRF in 2016 to prevent CSF leaks in endoscopic endonasal procedures 31 . Their reconstruction techniques consisted of a collagen matrix or L-PRF membrane for the intradural layer, followed by a mucoperiosteal graft or flap for the extradural layer, and eventually, covering the borders of the reconstruction by L-PRF membranes 31 . Other studies have adopted a similar approach, incorporating L-PRF membranes into their reconstruction techniques 10 , 12 , 20 , 21 , 32 , 39 . Multiple studies specifically compared patients who received L-PRF membranes to those who underwent the same reconstruction without L-PRF 20 , 21 , 24 . While CSF leak rates were lower in the L-PRF group, the difference did not reach statistical significance. In a subsequent study, Ibrahim et al. introduced an innovative approach combining liposuction-harvested fat with L-PRF and thrombin to create a fat-enhanced L-PRF membrane, which served as both intradural and extradural grafting material 22 . In a recent study, Shah et al. developed a comprehensive multi-layer technique incorporating solid PRF and injectable PRF 7 . They placed an intradural layer of solid PRF at the sella floor, followed by injectable PRF as a bioadhesive, topped with a second solid PRF membrane layer, and secured with a hemostatic gelatin sponge 7 . This approach achieved 95% success rate in preventing CSF leaks 7 . Cranial surgery Coucke et al. conducted a non-inferiority study comparing L-PRF membranes and liquid L-PRF glue against TachoSil ® and Tisseel ® in elective craniotomies 23 . They placed L-PRF membrane over sutured dura while using L-PRF glue to reinforce dural closure, and in cases involving bone defects, L-PRF was combined with bone fragments to enhance reconstruction 23 . They found L-PRF to be non-inferior with significant cost advantages (€11.41 versus €208.10 for commercial sealants) 23 . Their study showed lower risk ratios for CSF leakage in both infratentorial and supratentorial approaches with L-PRF, though the differences were not statistically significant 23 . The marked cost advantage of L-PRF over commercial dural products, with their comparable efficacy, supports their adoption in cost-sensitive healthcare environments. Theys et al. examined the use of L-PRF in cranial procedures in 11 cases including 9 microvascular decompressions, one petrotentorial meningioma removal, and one supratentorial skull base surgery 39 . In these cases L-PRF membranes were used as graft, either sutured or placed extradurally to support dural repair 39 . In MVD cases only, they also used commercial sealants to assist Teflon patch placement and reintegrate bone fragments 39 . No complications, such as CSF leaks or surgical site hemorrhage were reported in their cases 39 . Spine surgery Platelet-rich plasma has been applied in various aspects of spine surgery, such as treating discogenic back pain, lumbar disc herniation, spinal cord injuries, ligament injuries, spinal fusion, intervertebral disc regeneration, and preventing epidural fibrosis 29 . However, similar to craniotomies, their application in spinal surgeries to enhance dural repair has been limited. In one study, Theys et al. investigated L-PRF for dural repair in two patients with chronic CSF leaks after multiple failed spine surgeries 39 . In one case, a 3-cm dural defect was sutured with L-PRF, while in the other, L-PRF was layered as an extradural graft to reinforce closure 39 . They also used TachoSil® in both cases for extra support 39 . While the second patient improved, the first experienced CSF leak recurrence 39 . In a different application, Arabaci et al. explored the use of platelet-rich plasma (PRP) in repairing meningomyelocele in infants, applying it directly to the dura and wound edges while also infusing it under the skin flap and along the wound line post-closure 8 . This led to significantly lower rates of CSF leak, meningitis, and hydrocephalus in the PRP group compared to the control 8 . Clinical implication These products offer surgeons a versatile tool that can be adapted to various surgical scenarios - from complex skull base reconstructions to cranial and spinal dural repairs. The autologous nature of these products not only ensures safety but also allows for immediate availability during surgery. Also, their dual mechanism of action - promoting tissue regeneration while providing antimicrobial protection - makes them particularly valuable in preventing both CSF leaks and post-operative infections 33 . The cost-effectiveness and straightforward preparation protocols make these products a practical addition to the neurosurgical armamentarium. Limitations Several limitations should be considered when interpreting our findings. First, the small number of included studies (11 total, with only five suitable for meta-analysis) limited our ability to perform subgroup analyses. Second, the certainty of our evidence is low to very low, indicating the need for future studies with high methodological quality in order. Most studies lacked proper documentation of follow-up data and registered protocols, making it difficult to evaluate protocol deviations and selective reporting. Therefore, we recommend that future researchers ensure their studies are conducted using pre-registered protocols. The heterogeneity assessment showed contrasting results between measures, with substantial heterogeneity in the risk difference calculation requiring cautious interpretation. Furthermore, the varying surgical approaches (endoscopic skull base, craniotomy, spine, and meningomyelocele repair), preparation methods, populations (adults vs. infants), and application techniques across studies make it challenging to establish standardized protocols. While our sensitivity analysis confirmed the robustness of our findings, the overall limitations in study quality and quantity suggest the need for more rigorous, well-designed trials to strengthen the evidence base for platelet-rich products in neurosurgical applications. Conclusion Our systematic review and meta-analysis demonstrated that while these products show favorable trends in preventing CSF leaks and reducing complications, the statistical analysis revealed no significant difference. The intervention groups consistently showed lower rates of complications, especially meningitis and wound healing issues, with no reported serious adverse events. While these findings are encouraging, the overall low to very low quality of evidence necessitates the need for well-designed randomized controlled trials with larger sample sizes to establish the efficacy of these products in neurosurgical procedures. Future studies should focus on standardizing protocols and comparing different techniques to optimize clinical outcomes. Funding There are no funds allocated for our project. Conflict of interest We have no conflicts of interest Data availability The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Acknowledgment None Footnotes ↵ † These authors share senior authorship References 1. ↵ Coucke B , Van Gerven L , De Vleeschouwer S , Van Calenbergh F , van Loon J , Theys T . The incidence of postoperative cerebrospinal fluid leakage after elective cranial surgery: a systematic review . Neurosurg Rev . 2022 ; 45 ( 3 ): 1827 – 1845 . doi: 10.1007/s10143-021-01641-y OpenUrl CrossRef PubMed 2. ↵ Rapisarda A , Orlando V , Izzo A , et al. New Tools and Techniques to Prevent CSF Leak in Cranial and Spinal Surgery . Surg Technol Int . 2022 ; 40 : 399 – 403 . doi: 10.52198/22.STI.40.NS1577 OpenUrl CrossRef PubMed 3. ↵ Lasica N , Lesha E , Beckfort NS , Arnautovic KI . Does the crafted abdominal fat grafting technique completely eliminate risk of postoperative CSF leak in endonasal pituitary surgery? Technical note and preliminary clinical outcome . Published online February 1, 2025 . doi: 10.3171/2024.11.FOCUS24665 OpenUrl CrossRef 4. ↵ Yoshimoto T , Sawamura Y , Houkin K , Abe H . Effectiveness of fibrin glue for preventing postoperative extradural fluid leakage . Neurol Med Chir (Tokyo) . 1997 ; 37 ( 12 ): 886 – 889 ; discussion 889-890. doi: 10.2176/nmc.37.886 OpenUrl CrossRef PubMed 5. ↵ Lasica N , Djilvesi D , Papic V , et al. Venous thromboembolic and hemorrhagic events after meningioma surgery: A single-center retrospective cohort study of risk factors . PLoS One . 2022 ; 17 ( 8 ): e0273189 . doi: 10.1371/journal.pone.0273189 OpenUrl CrossRef PubMed 6. ↵ Shah R , Huda S , Ward M , D’Amico RS , Caridi J , Ben-Shalom N . The use of dural sealant patches for reinforcement of durotomy repair: a systematic review . Published online February 1, 2025 . doi: 10.3171/2024.12.FOCUS24705 OpenUrl CrossRef 7. ↵ Shah MJ , Argiti K , Nakagawa JM , et al. Platelet rich fibrin three-layer reconstruction of the sellar floor after endoscopic endonasal transsphenoidal approach: technical note and initial experience . Front Surg . 2024 ; 11 : 1500158 . doi: 10.3389/fsurg.2024.1500158 OpenUrl CrossRef PubMed 8. ↵ Arabacı Ö , Akyol ME , Çelikkaleli E , Sönmez B , Çetin E , Beger B . A randomized trial of the effects of platelet-rich plasma on postoperative complications after meningomyelocele sac repair . Eur Rev Med Pharmacol Sci . 2023 ; 27 ( 12 ): 5552 – 5558 . doi: 10.26355/eurrev_202306_32792 OpenUrl CrossRef PubMed 9. Araki J , Jona M , Eto H , et al. Optimized preparation method of platelet-concentrated plasma and noncoagulating platelet-derived factor concentrates: maximization of platelet concentration and removal of fibrinogen . Tissue Eng Part C Methods . 2012 ; 18 ( 3 ): 176 – 185 . doi: 10.1089/ten.TEC.2011.0308 OpenUrl CrossRef PubMed 10. ↵ Yadav R , Chaudhary AK , Gupta DK , Saroj SK , Singh V , Kumar R . Use of Autologous Leukocyte-Platelet Rich Fibrin (L-PRF) in Endoscopic Anterior Skull Base Defect Repair-A Newer Graft Material: Name of Authors . Indian J Otolaryngol Head Neck Surg . 2024 ; 76 ( 6 ): 5618 – 5622 . doi: 10.1007/s12070-024-05046-3 OpenUrl CrossRef PubMed 11. ↵ Ibrahim AA , Mandour Z , A. Abo Elwafa R , Abdelnaby MM , Yoneis AMAMI. Application of Leukocyte and platelet-rich fibrin as a sealing material in endoscopic reconstruction of spontaneous CSF leaks . Egyptian Journal of Ear, Nose, Throat and Allied Sciences . 2022 ; 23 ( 23 ): 1 – 7 . doi: 10.21608/ejentas.2022.112908.1452 OpenUrl CrossRef 12. ↵ Constanzo F , Pinto J , Ledermann C , Schmidt T . Leukocyte-Rich and Platelet-Rich Fibrin for Skull Base Reconstruction After Endoscopic Endonasal Skull Base Surgery . Neurosurgery . 2023 ; 92 ( 4 ): 787 – 794 . doi: 10.1227/neu.0000000000002270 OpenUrl CrossRef PubMed 13. ↵ Page MJ , McKenzie JE , Bossuyt PM , et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews . BMJ . Published online March 29, 2021 : n71 . doi: 10.1136/bmj.n71 OpenUrl FREE Full Text 14. ↵ Higgins JPT , Thompson SG . Quantifying heterogeneity in a meta-analysis . Stat Med . 2002 ; 21 ( 11 ): 1539 – 1558 . doi: 10.1002/sim.1186 OpenUrl CrossRef PubMed Web of Science 15. ↵ Sterne JAC , Savović J , Page MJ , et al. RoB 2: a revised tool for assessing risk of bias in randomised trials . BMJ . 2019 ; 366 : l4898 . doi: 10.1136/bmj.l4898 OpenUrl FREE Full Text 16. ↵ Sterne JA , Hernán MA , Reeves BC , et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions . BMJ (Clinical Research Edition) . 2016 ; 355 . doi: 10.1136/bmj.i4919 OpenUrl FREE Full Text 17. ↵ Munn Z , Barker TH , Moola S , et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool . JBI Evid Synth . 2020 ; 18 ( 10 ): 2127 – 2133 . doi: 10.11124/JBISRIR-D-19-00099 OpenUrl CrossRef PubMed 18. ↵ Barker TH , Hasanoff S , Aromataris E , et al. The revised JBI critical appraisal tool for the assessment of risk of bias for cohort studies . JBI Evid Synth . 2025 ; 23 ( 3 ): 441 – 453 . doi: 10.11124/JBIES-24-00103 OpenUrl CrossRef PubMed 19. ↵ Guyatt GH , Oxman AD , Vist GE , et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations . BMJ . 2008 ; 336 ( 7650 ): 924 – 926 . doi: 10.1136/bmj.39489.470347.AD OpenUrl FREE Full Text 20. ↵ Ibrahim AA , Mandour Z , Abo Elwafa RA , Abdelnaby MM , Yoneis A . Application of Leukocyte and platelet-rich fibrin as a sealing material in endoscopic reconstruction of spontaneous CSF leaks . Egyptian Journal of Ear, Nose, Throat and Allied Sciences . 2022 ; 23 ( 23 ). doi: 10.21608/ejentas.2022.112908.1452 OpenUrl CrossRef 21. ↵ Khafagy YW , Abd Elfattah AM , Moneir W , Salem EH . Leukocyte- and platelet-rich fibrin: a new graft material in endoscopic repair of spontaneous CSF leaks . Eur Arch Otorhinolaryngol . 2018 ; 275 ( 9 ): 2245 – 2252 . doi: 10.1007/s00405-018-5048-7 OpenUrl CrossRef PubMed 22. ↵ Ibrahim AA , Yoneis A , Elsakka A , Elwany S . Fat enhanced leukocyte-platelet-rich fibrin versus fascia lata in endoscopic reconstruction of CSF leaks . Eur Arch Oto-Rhino-Laryngol . 2023 ; 280 ( 9 ): 4141 – 4147 . doi: 10.1007/s00405-023-08010-z OpenUrl CrossRef PubMed 23. ↵ Coucke B , De Vleeschouwer S , van Loon J , et al. Leukocyte- and platelet-rich fibrin in cranial surgery: a single-blinded, prospective, randomized controlled noninferiority trial . J Neurosurg . Published online February 23, 2024 : 1 – 9 . doi: 10.3171/2023.12.JNS232125 OpenUrl CrossRef 24. ↵ Costanzo R , Rosetti V , Tomassini A , et al. Hypothalamic Hemangioma-like Pilocytic Astrocytoma in an Adult Patient: A Systematic Review with a Focus on Differential Diagnosis and Neurological Presentation . J Clin Med . 2024 ; 13 ( 12 ). doi: 10.3390/jcm13123536 OpenUrl CrossRef 25. ↵ Chae JK , Rosen K , Zappi K , et al. Cranial and Spinal Cerebrospinal Fluid Leaks: Foundations of Identification and Management . World Neurosurg . 2024 ; 187 : 288 – 293 . doi: 10.1016/j.wneu.2024.03.111 OpenUrl CrossRef PubMed 26. ↵ Hasiba-Pappas SK , Tuca AC , Luze H , et al. Platelet-Rich Plasma in Plastic Surgery: A Systematic Review . Transfus Med Hemother . 2022 ; 49 ( 3 ): 129 – 142 . doi: 10.1159/000524353 OpenUrl CrossRef PubMed 27. ↵ Sharifi A , Kouhi A , Patel ZM . Utilization and efficacy of platelet-rich plasma and platelet-rich fibrin in otolaryngology: a systematic evidence-based review . Eur Arch Otorhinolaryngol . 2024 ; 281 ( 10 ): 5091 – 5110 . doi: 10.1007/s00405-024-08763-1 OpenUrl CrossRef PubMed 28. ↵ Marx RE . Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant Dent . 2001 ; 10 ( 4 ): 225 – 228 . doi: 10.1097/00008505-200110000-00002 OpenUrl CrossRef PubMed 29. ↵ Wang H , Zhu J , Xia Y , Li Y , Fu C . Application of platelet-rich plasma in spinal surgery . Front Endocrinol (Lausanne) . 2023 ; 14 : 1138255 . doi: 10.3389/fendo.2023.1138255 OpenUrl CrossRef PubMed 30. ↵ Dohan Ehrenfest DM , Rasmusson L , Albrektsson T. Classification of platelet concentrates: from pure platelet-rich plasma (P-PRP) to leucocyte- and platelet-rich fibrin (L-PRF) . Trends Biotechnol . 2009 ; 27 ( 3 ): 158 – 167 . doi: 10.1016/j.tibtech.2008.11.009 OpenUrl CrossRef PubMed Web of Science 31. ↵ Soldatova L , Campbell RG , Elkhatib AH , et al. Role of Leukocyte-Platelet-Rich Fibrin in Endoscopic Endonasal Skull Base Surgery Defect Reconstruction . J Neurol Surg B Skull Base . 2017 ; 78 ( 1 ): 59 – 62 . doi: 10.1055/s-0036-1584894 OpenUrl CrossRef PubMed 32. ↵ Rasmussen J , Ruggeri C , Ciraolo C , Baccanelli M , Yampolsky C , Ajler P . Application of Fibrin Rich in Leukocytes and Platelets in the Reconstruction of Endoscopic Approaches to the Skull Base . World Neurosurg . 2018 ; 118 : 32 – 41 . doi: 10.1016/j.wneu.2018.06.180 OpenUrl CrossRef PubMed 33. ↵ Yadav G , Choupoo S , Das SK , et al. Evaluating the role of flupirtine for postcraniotomy pain and compare it with diclofenac sodium: A prospective, randomized, double blind, placebo-controlled study . Journal of Neurosurgical Anesthesiology . 2014 ; 26 ( 1 ): 32 – 36 . doi: 10.1097/ANA.0b013e31829a04ad OpenUrl CrossRef PubMed 34. ↵ Pereira EAC , Grandidge CA , Nowak VA , Cudlip SA . Cerebrospinal fluid leaks after transsphenoidal surgery - Effect of a polyethylene glycol hydrogel dural sealant . J Clin Neurosci . 2017 ; 44 : 6 – 10 . doi: 10.1016/j.jocn.2017.06.016 OpenUrl CrossRef PubMed 35. ↵ Aldahash HA , Ansary MA , Hallak HM , Alhuthayl MR , Alotaibi FA . Hemopatch® as a primary dural sealant in cranial neurosurgery: Technical note and a retrospective study . Neurosciences (Riyadh) . 2024 ; 29 ( 2 ): 128 – 132 . doi: 10.17712/nsj.2024.2.20230109 OpenUrl Abstract / FREE Full Text 36. ↵ Burkett CJ , Patel S , Tabor MH , Padhya T , Vale FL . Polyethylene glycol (PEG) hydrogel dural sealant and collagen dural graft matrix in transsphenoidal pituitary surgery for prevention of postoperative cerebrospinal fluid leaks . J Clin Neurosci . 2011 ; 18 ( 11 ): 1513 – 1517 . doi: 10.1016/j.jocn.2011.04.005 OpenUrl CrossRef PubMed 37. ↵ Mughal Z , Martinez-Devesa P , Boukas A , Jeyaretna S , Qureishi A . Contemporary Management of Cerebrospinal Fluid Rhinorrhoea: A Review of the Literature . J Clin Med . 2025 ; 14 ( 3 ): 995 . doi: 10.3390/jcm14030995 OpenUrl CrossRef PubMed 38. ↵ Garcia-Navarro V , Anand VK , Schwartz TH . Gasket seal closure for extended endonasal endoscopic skull base surgery: efficacy in a large case series . World Neurosurg . 2013 ; 80 ( 5 ): 563 – 568 . doi: 10.1016/j.wneu.2011.08.034 OpenUrl CrossRef PubMed 39. ↵ Theys T , Van Hoylandt A , Broeckx CE , et al. Plasma-rich fibrin in neurosurgery: a feasibility study . Acta Neurochir (Wien) . 2018 ; 160 ( 8 ): 1497 – 1503 . doi: 10.1007/s00701-018-3579-8 OpenUrl CrossRef PubMed 40. Constanzo F , Pinto J , Ledermann C , Schmidt T . Leukocyte-Rich and Platelet-Rich Fibrin for Skull Base Reconstruction After Endoscopic Endonasal Skull Base Surgery . Neurosurgery . 2023 ; 92 ( 4 ): 787 – 794 . doi: 10.1227/neu.0000000000002270 OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted May 31, 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 Efficacy of platelet-rich products in preventing cerebrospinal fluid leakage following neurosurgical procedures: A systematic review and meta-analysis 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 Efficacy of platelet-rich products in preventing cerebrospinal fluid leakage following neurosurgical procedures: A systematic review and meta-analysis Jina Behjati , Mohammadreza Ghasemi , Shaghayegh Karami , Pooya Eini , Arman Keymoradzadeh , Mohammad Ansari , Hassan Reza Mohammadi , Mohsen Koosha , Saeed Oraee-Yazdani medRxiv 2025.05.30.25328644; doi: https://doi.org/10.1101/2025.05.30.25328644 Share This Article: Copy Citation Tools Efficacy of platelet-rich products in preventing cerebrospinal fluid leakage following neurosurgical procedures: A systematic review and meta-analysis Jina Behjati , Mohammadreza Ghasemi , Shaghayegh Karami , Pooya Eini , Arman Keymoradzadeh , Mohammad Ansari , Hassan Reza Mohammadi , Mohsen Koosha , Saeed Oraee-Yazdani medRxiv 2025.05.30.25328644; doi: https://doi.org/10.1101/2025.05.30.25328644 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 Surgery Subject Areas All Articles Addiction Medicine (569) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4442) Dentistry and Oral Medicine (444) Dermatology (383) Emergency Medicine (609) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1511) Epidemiology (15230) Forensic Medicine (30) Gastroenterology (1126) Genetic and Genomic Medicine (6610) Geriatric Medicine (668) Health Economics (998) Health Informatics (4542) Health Policy (1370) Health Systems and Quality Improvement (1613) Hematology (543) HIV/AIDS (1266) Infectious Diseases (except HIV/AIDS) (15923) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (147) Nephrology (668) Neurology (6607) Nursing (346) Nutrition (999) Obstetrics and Gynecology (1146) Occupational and Environmental Health (957) Oncology (3337) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (664) Pediatrics (1693) Pharmacology and Therapeutics (692) Primary Care Research (712) Psychiatry and Clinical Psychology (5448) Public and Global Health (9238) Radiology and Imaging (2202) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (596) Sexual and Reproductive Health (714) 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:'a01ca4d988783517',t:'MTc3OTc5NzA4Mw=='};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())}}}})();