***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more CONTEXT We wanted to investigate vitamin D in low-risk prostate cancer . OBJECTIVES The objective of the study was to determine whether vitamin D(3 ) supplementation at 4000 IU/d for 1 yr is safe and would result in a decrease in serum levels of prostate-specific antigen ( PSA ) or in the rate of progression . DESIGN In this open-label clinical trial ( Investigational New Drug 77,839 ) , subjects were followed up until repeat biopsy . SETTING All subjects were enrolled through the Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center , both in Charleston , SC . PATIENTS AND OTHER PARTICIPANTS All subjects had a diagnosis of low-risk prostate cancer . Fifty-two subjects were enrolled in the study , 48 completed 1 yr of supplementation , and 44 could be analyzed for both safety and efficacy objectives . INTERVENTION The intervention included vitamin D(3 ) soft gels ( 4000 IU ) . MAIN OUTCOME MEASURES Adverse events were monitored throughout the study . PSA serum levels were measured at entry and every 2 months for 1 yr . Biopsy procedures were performed before enrollment ( for eligibility ) and after 1 yr of supplementation . RESULTS No adverse events associated with vitamin D(3 ) supplementation were observed . No significant changes in PSA levels were observed . However , 24 of 44 subjects ( 55 % ) showed a decrease in the number of positive cores or decrease in Gleason score ; five subjects ( 11 % ) showed no change ; 15 subjects ( 34 % ) showed an increase in the number of positive cores or Gleason score .  CONCLUSION Patients with low-risk prostate cancer under active surveillance may benefit from vitamin D(3 ) supplementation at 4000 IU/d Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation  to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies Objective A small r and omized controlled trial suggested that vitamin D might increase the production of testosterone in men , which is supported by experimental studies in animals and a cross‐sectional study showing positive associations between plasma 25‐hydroxyvitamin D [ 25(OH)D ] and testosterone and concordant seasonal variation of both biomarkers The male reproductive tract has been identified as a target tissue for vitamin D , and previous data suggest an association of 25-hydroxyvitamin D [ 25(OH)D ] with testosterone levels in men . We therefore aim ed to evaluate whether vitamin D supplementation influences testosterone levels in men . Healthy overweight men undergoing a weight reduction program who participated in a r and omized controlled trial were analyzed for testosterone levels . The entire study included 200 nondiabetic subjects , of whom 165 participants ( 54 men ) completed the trial . Participants received either 83 μg ( 3,332 IU ) vitamin D daily for 1 year ( n = 31 ) or placebo ( n = 2 3 ) . Initial 25(OH)D concentrations were in the deficiency range ( < 50 nmol/l ) and testosterone values were at the lower end of the reference range ( 9.09 - 55.28 nmol/l for males aged 20 - 49 years ) in both groups . Mean circulating 25(OH)D concentrations increased significantly by 53.5 nmol/l in the vitamin D group , but remained almost constant in the placebo group . Compared to baseline values , a significant increase in total testosterone levels ( from 10.7 ± 3.9 nmol/l to 13.4 ± 4.7 nmol/l ; p < 0.001 ) , bioactive testosterone ( from 5.21 ± 1.87 nmol/l to 6.25 ± 2.01 nmol/l ; p = 0.001 ) , and free testosterone levels ( from 0.222 ± 0.080 nmol/l to 0.267 ± 0.087 nmol/l ; p = 0.001 ) were observed in the vitamin D supplemented group . By contrast , there was no significant change in any testosterone measure in the placebo group . Our results suggest that vitamin D supplementation might increase testosterone levels . Further r and omized controlled trials are warranted to confirm this hypothesis Background Systematic Review s ( SRs ) of experimental animal studies are not yet common practice , but awareness of the merits of conducting such SRs is steadily increasing . As animal intervention studies differ from r and omized clinical trials ( RCT ) in many aspects , the methodology for SRs of clinical trials needs to be adapted and optimized for animal intervention studies . The Cochrane Collaboration developed a Risk of Bias ( RoB ) tool to establish consistency and avoid discrepancies in assessing the method ological quality of RCTs . A similar initiative is warranted in the field of animal experimentation . Methods We provide an RoB tool for animal intervention studies ( SYRCLE ’s RoB tool ) . This tool is based on the Cochrane RoB tool and has been adjusted for aspects of bias that play a specific role in animal intervention studies . To enhance transparency and applicability , we formulated signalling questions to facilitate judgment . Results The result ing RoB tool  for animal studies contains 10 entries . These entries are related to selection bias , performance bias , detection bias , attrition bias , reporting bias and other biases . Half these items are in agreement with the items in the Cochrane RoB tool . Most of the variations between the two tools are due to differences in design between RCTs and animal studies . Shortcomings in , or unfamiliarity with , specific aspects of experimental design of animal studies compared to clinical studies also play a role . Conclusions SYRCLE ’s RoB tool is an adapted version of the Cochrane RoB tool . Widespread adoption and implementation of this tool will facilitate and improve critical appraisal of evidence from animal studies . This may subsequently enhance the efficiency of translating animal research into clinical practice and increase awareness of the necessity of improving the method ological quality of animal studies 
    Output:
    
Discussion To our knowledge , this will be the first systematic synthesis of the evidence underpinning the vitamin D-testosterone-prostate cancer mechanistic pathway .