A systematic review protocol examining the effect of vitamin D supplementation on endothelial function Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer. Evaluation of endothelial function in women with polycystic ovary syndrome. Variations in endothelial function and arterial compliance during the menstrual cycle. Digital Education in Health Professions: The Need for Overarching Evidence Synthesis The impact of cash transfers on social determinants of health and health inequalities in Sub-Saharan Africa: a systematic review protocol Systematic review automation technologies Effect of dark chocolate on arterial function in healthy individuals. How to write an evidence-based clinical review article. Determinants of weight loss maintenance: a systematic review. Seeing the forests and the trees—innovative approaches to exploring heterogeneity in systematic reviews of complex interventions to enhance health system decision-making: a protocol Impact of cocoa flavanol intake on age-dependent vascular stiffness in healthy men: a randomized, controlled, double-masked trial Comparison of sevelamer and calcium carbonate on endothelial function and inflammation in patients on peritoneal dialysis. Effects of sugar-sweetened and sugar-free cocoa on endothelial function in overweight adults. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. Evaluation of the Quality of Prognosis Studies in Systematic Reviews A systematic review of the use of financial incentives and penalties to encourage uptake of healthy behaviors: protocol Predictors of revascularization method and long-term outcome of percutaneous coronary intervention or repeat coronary bypass surgery in patients with multivessel coronary disease and previous coronary bypass surgery. Methods for evidence synthesis in the case of very few studies Issues related to the conduct of systematic reviews: a focus on the nutrition field. Chocolate and Prevention of Cardiovascular Disease: A Systematic Review The Effects of Maternal Supplementation of Polyunsaturated Fatty Acids on Visual, Neurobehavioural, and Developmental Outcomes of the Child: A Systematic Review of the Randomized Trials Effects of therapeutic lifestyle changes on peripheral artery tonometry in patients with abdominal obesity.
Introduction Vitamin D has potential benefits for extraskeletal health . These could include an anti-inflammatory effect as well as a reduction in endothelial dysfunction . We aim to provide quality evidence for the hypothesis that supplementation with vitamin D will improve endothelial function ( EF ) , possibly through the abrogation of systemic inflammation . Methods and analysis We will conduct a systematic review of all r and omised controlled trials on  vitamin D supplementation and EF lasting 12 weeks or more . The search will cover the period 2000–2015 and include studies that describe direct measures of EF  , markers of endothelial cell ( EC ) activation  and if concurrently reported , indicators of systemic inflammation  . Study selection will follow the Preferred Reporting Items for Systematic Review s and Meta-Analyses ( PRISMA ) guidelines and study quality will be assessed by the Jadad score in addition to an evaluation of allocation concealment and data analysis . If sufficient data are available , a meta- analysis will be conducted . The effect sizes will be generated using Hedges ’ g score , for both fixed and r and om effect models . I2 statistics and Galbraith plots will be used to assess heterogeneity and identify their potential sources . Potential publication and small sample size bias will be assessed by visual inspections of funnel plots and also Egger 's test . Meta-regression analysis ( if feasible ) will be conducted with restricted maximum likelihood ( REML ) estimation method , controlling for potential confounders ( demographics , study methods , location , etc ) . A backward elimination process will be applied in the regression modelling procedure . Subgroup analysis , conditional on number of studies retrieved and their sample size , will be stratified on participant disease category , total dose administered , degree of 25(OH)D change and type of supplement used . Ethics and dissemination Formal ethical approval is not required as primary data will not be collected . The results will be disseminated through a peer- review ed publication , conference presentation and the popular press . Trial registration number International Prospect i ve Register for Systematic Review s ( PROSPERO ) number CRD42014013523 BACKGROUND A trial-level surrogate end point for a r and omized clinical trial may allow assessment of the relative benefits of the treatment to be performed at an earlier time point and potentially with a smaller sample size . However , determining whether an end point is a reliable trial-level surrogate based on results of previous trials is not straightforward . The question of trial-level surrogacy is easily confused with the question of individual-level surrogacy , and this confusion can lead to controversy . A recent example concerns the evaluation of pathologic complete response ( pCR ) as a surrogate for event-free survival ( EFS ) and overall survival ( OS ) in early-stage breast cancer . MATERIAL S AND METHODS The differences between individual-level surrogacy ( i.e. for patients receiving a specific treatment , the surrogate end point predicts the definitive end point ) and trial-level surrogacy ( the results of the trial for the surrogate end point predict the results of the trial for the definitive end point ) are discussed . Trial-level data used in two previous meta-analyses evaluating pCR as a trial-level surrogate for EFS and OS were re-analyzed using methods that appropriately account for the variability in pCR rates as well as the variability in the hazard ratios for EFS and OS . RESULTS There is no evidence that pCR is a trial-level surrogate for EFS or OS , nor is there evidence that pCR could be used reliably to screen out nonpromising agents from further drug development . CONCLUSIONS At present , neoadjuvant RCTs should continue to follow patients to observe EFS and OS to assess clinical benefit , and they should be design ed with sufficient sample size to reliably assess EFS . However , one can not rule out the possibility that future meta-analyses involving more trials and in which the patient population or class of treatments is restricted could suggest the validity of pCR as a trial-level surrogate for EFS or OS in some focused setting OBJECTIVES Previous studies have suggested that vascular reactivity may be altered in women with polycystic ovary syndrome ( PCOS ) . We sought to evaluate the vascular reactivity specifically the endothelial function ( EF ) in women with PCOS and to study the effect of metformin on their EF . STUDY DESIGN Thirty-one women diagnosed with PCOS and 33 healthy controls underwent evaluation of EF using a post-ischemia reactive hyperemia technique ( Endo-PAT ) . EF was quantitatively determined as the ratio between the arterial pulse wave amplitude following a 5min arterial occlusion in the forearm to the pre-occlusion value . Oral metformin 850 mg bid was administered to PCOS patients . After 3 months of treatment EF was reassessed using the same technique . RESULTS The average endothelial function was 1.48+/-0.32 in the PCOS group versus 2.00+/-0.51 in the controls ( P<0.001 ) . There were no significant changes in the EF among the 18 patients who were treated with metformin  , EF index pre- and post-treatment was 1.42 versus 1.43 , respectively . CONCLUSIONS Endothelial dysfunction is more likely to occur among PCOS patients than in healthy controls . These preliminary results suggest that metformin treatment for 3 months in PCOS patients does not improve endothelial function Female sex hormones have been implicated in the cardioprotection of premenopausal women . However , the cardiovascular actions of these hormones and the effects of their natural fluctuations during the menstrual cycle are not fully understood . We studied changes in vascular function during the menstrual cycle in 15 healthy premenopausal women . Four noninvasive procedures were performed during the early follicular ( EF ) , late follicular ( LF ) , early luteal ( EL ) , and late luteal ( LL ) phases : flow-mediated dilatation ( FMD ) of the brachial artery during reactive hyperemia , laser Doppler velocimetry ( LDV ) with direct current iontophoresis of acetylcholine ( ACh ) and nitroprusside , whole body arterial compliance ( WBAC ) , and pulse wave velocity . Hormone levels were consistent with predicted cycle phase and showed that all subjects ovulated during the cycle studied . FMD , LDV with ACh , and WBAC varied cyclically , with significant increases from the F to LF phase , sharp falls in the EL phase , and significant recoveries in the LL phase . These changes were most marked for FMD [ EF , 8.8 + /- 0.6 % ( mean + /- SEM ) ; LF , 10.0 + /- 0.7 ; EL , 4.2 + /- 0.6 ; LL , 8.6 + /- 0.9 ] and the LDV response to ACh ( EF , 2.7 + /- 0.2 V/min ; LF , 3.3 + /- 0.4 ; EL , 1.8 + /- 0.3 ; LL , 2.7 + /- 0.4 ) . WBAC changed similarly ( EF , 0.58 + /- 0.08 arbitrary units ; LF , 0.84 + /- 0.06 ; EL , 0.65 + /- 0.05 ; LL , 0.68 + /- 0.06 ) . Sodium nitroprusside-induced vasodilatation decreased significantly from EF to EL , with no other significant difference , and pulse wave velocity did not vary significantly over the four time points . Conductance and resistance artery endothelial reactivity and smooth muscle sensitivity to nitric oxide and arterial compliance are modulated significantly in response to the changing hormonal patterns of the menstrual cycle . These findings emphasize the importance of menstrual phase in the interpretation of data on endothelial function and may provide insights into the mechanisms underlying sex differences in cardiovascular risk and other disease processes in premenopausal women Synthesizing evidence from r and omized controlled trials of  digital health education  poses some challenges . These include a lack of clear categorization of digital health education in the literature ; constantly evolving concepts , pedagogies , or theories ; and a multitude of methods , features , technologies , or delivery setting s. The Digital Health Education Collaboration was established to evaluate the evidence on digital education in health professions ; inform policymakers , educators , and students ; and ultimately , change the way in which these professionals learn and are taught . The aim of this paper is to present the overarching methodology that we use to synthesize evidence across our digital health education review s and to discuss challenges related to the process . For our research , we followed Cochrane recommendations for the conduct of systematic review s ; all review s are reported according to the PRISMA ( Preferred Reporting Items for Systematic Review s and Meta-Analyses ) guidance . This included assembling experts in various digital health education fields ; identifying gaps in the evidence base ; formulating focused research questions , aims , and outcome measures ; choosing appropriate search terms and data bases ; defining inclusion and exclusion criteria ; running the search es jointly with librarians and information specialists ; managing abstract s ; retrieving full-text versions of papers ; extracting and storing large data sets , critically appraising the quality of studies ; analyzing data ; discussing findings ; drawing meaningful conclusions ; and drafting research papers . The approach used for synthesizing evidence from digital health education trials is commonly regarded as the most rigorous benchmark for conducting systematic review s. Although we acknowledge the presence of certain biases ingrained in the process , we have clearly highlighted and minimized those biases by strictly adhering to scientific rigor , method ological integrity , and st and ard operating procedures . This paper will be a valuable asset for research ers and method ologists undertaking systematic review s in digital health education Background There is increasing pressure to address the social determinants of health ( SDoH ) and health inequities through the implementation of culturally acceptable interventions particularly in Sub-Saharan Africa ( SSA ) where health outcomes are generally poor . Available evaluation research on cash transfers ( CTs ) suggests that the programs may influence the wider determinants of health in SSA ; yet , there has been no attempt to synthesize the evidence regarding their contribution to tackling the SDoH and health inequalities . To date , nearly all the review s on CTs ' impact on health have predominantly featured evidence from Latin America with limited transferability to the social , cultural , and political environments in SSA . Therefore , the aim of this study is to undertake a systematic review to assess the role of CTs in tackling the wider determinants of health and health inequalities in SSA . Methods / design A systematic review of published and unpublished literature on CTs ’ impact on health and health determinants covering the period 2000–2016 will be undertaken . Studies will be considered for inclusion if they present quantitative or qualitative data , including all relevant study design s. The SDoH conceptual framework will be used to guide the data extraction process . EPPI Review er software will be used for data management and analysis . Studies included in the review will be analyzed by narrative synthesis and /or meta- analysis as appropriate for the nature of the data retrieved . Discussion This review will provide empirical evidence on the impact of CTs on SDoH to inform CT policy , implementation , and research in SSA . The protocol follows the Preferred Reporting Items for Systematic Review and Meta- Analysis Protocol s ( PRISMA -P ) . Systematic review registration This protocol has been registered with the PROSPERO international prospect i ve register of systematic review s , reference CRD42015025015 Systematic review s , a cornerstone of evidence -based medicine , are not produced quickly enough to support clinical practice . The cost of production , availability of the requisite expertise and timeliness are often quoted as major contributors for the delay . This detailed survey of the state of the art of information systems design ed to support or automate individual tasks in the systematic review , and in particular systematic review s of r and omized controlled clinical trials , reveals trends that see the convergence of several parallel research projects . We surveyed literature describing informatics systems that support or automate the processes of systematic review or each of the tasks of the systematic review . Several projects focus on automating , simplifying and /or streamlining specific tasks of the systematic review . Some tasks are already fully automated while others are still largely manual . In this review , we describe each task and the effect that its automation would have on the entire systematic review process , summarize the existing information system support for each task , and highlight where further research is needed for realizing automation for the task . Integration of the systems that automate systematic review tasks may lead to a revised systematic review workflow . We envisage the optimized workflow will lead to system in which each systematic review is described as a computer program that automatically retrieves relevant trials , appraises them , extracts and synthesizes data , evaluates the risk of bias , performs meta- analysis calculations , and produces a report in real time BACKGROUND Epidemiologic studies suggest that high flavonoid intake confers a benefit on cardiovascular outcome . Endothelial function , arterial stiffness , and wave reflections are important determinants of cardiovascular performance and are predictors of cardiovascular risk . METHODS The effect of flavonoid-rich dark chocolate ( 100 g ) on endothelial function , aortic stiffness , wave reflections , and oxidant status were studied for 3 h in 17 young healthy volunteers according to a r and omized , single-blind , sham procedure-controlled , cross-over protocol .  Flow-mediated dilation ( FMD ) of the brachial artery , aortic augmentation index ( AIx ) , and carotid-femoral pulse wave velocity ( PWV ) were used as measures of endothelial function , wave reflections , and aortic stiffness , respectively . Plasma oxidant status was evaluated with measurement of plasma malondialdehyde ( MDA ) and total antioxidant capacity ( TAC ) . RESULTS Chocolate led to a significant increase in resting and hyperemic brachial artery diameter throughout the study ( maximum increase by 0.15 mm and 0.18 mm , respectively , P < .001 for both ) . The FMD increased significantly at 60 min ( absolute increase 1.43 % , P < .05 ) . The AIx was significantly decreased with chocolate throughout the study ( maximum absolute decrease 7.8 % , P < .001 ) , indicating a decrease in wave reflections , whereas PWV did not change to a significant extent . Plasma MDA and TAC did not change after chocolate , indicating no alterations in plasma oxidant status . CONCLUSIONS Our study shows for the first time that consumption of dark chocolate acutely decreases wave reflections , that it does not affect aortic stiffness , and that it may exert a beneficial effect on endothelial function in healthy adults .  Chocolate consumption may exert a protective effect on the cardiovascular system ; further studies are warranted to assess any long-term effects Traditional clinical review articles , also known as up date s , differ from systematic review s and meta-analyses . Up date s selectively review the medical literature while discussing a topic broadly . Non-quantitative systematic review s comprehensively examine the medical literature , seeking to identify and synthesize all relevant information to formulate the best approach to diagnosis or treatment . Meta-analyses ( quantitative systematic review s ) seek to answer a focused clinical question , using rigorous statistical analysis of pooled research studies . This article presents guidelines for writing an evidence -based clinical review article for American Family Physician . First , the topic should be of common interest and relevance to family practice . Include a table of the continuing medical education objectives of the review . State how the literature search was done and include several sources of evidence -based review s , such as the Cochrane Collaboration , BMJ 's Clinical Evidence , or the InfoRetriever Web site . Where possible , use evidence based on clinical outcomes relating to morbidity , mortality , or quality of life , and studies of primary care population s. In articles su bmi tted to American Family Physician , rate the level of evidence for key recommendations according to the following scale : level A ( r and omized controlled trial [ RCT ] , meta- analysis ) ; level B ( other evidence ) ; level C ( consensus/expert opinion ) . Finally , provide a table of key summary points BACKGROUND Discerning the determinants of weight loss maintenance is important in the planning of future interventions and policies regarding overweight and obesity . We have therefore systematic ally synthesized recent literature on determinants of weight loss maintenance for individuals with overweight and obesity . METHODS With the use of the Preferred Reporting Items for Systematic Review s and Meta-Analyses statement , prospect i ve studies were identified from search es in PubMed and PsycINFO from 2006 to 2016 . We included articles investigating adults with overweight and obesity undergoing weight loss without surgery or medication .  Included articles were scored on their method ological quality , and a best- evidence synthesis was applied to summarize the results . RESULTS Our search result ed in 8,222 articles of which 67 articles were selected . In total , 124 determinants were identified of which 5 were demographic , 59 were behavioural , 51 were psychological/cognitive and 9 were social and physical environmental determinants . We found consistent evidence that demographic determinants were not predictive of weight loss maintenance . Behavioural and cognitive determinants that promote a reduction in energy intake , an increase in energy expenditure and monitoring of this balance are predictive determinants . CONCLUSION This review identifies key determinants in weight loss maintenance . However , more research regarding cognitive and environmental determinants of weight loss maintenance is needed to advance our knowledge on determinants of weight loss maintenance Background To improve quality of care and patient outcomes , health system decision-makers need to identify and implement effective interventions . An increasing number of systematic review s document the effects of quality improvement programs to assist decision-makers in developing new initiatives . However , limitations in the reporting of primary studies and current meta- analysis methods ( including approaches for exploring heterogeneity ) reduce the utility of existing syntheses for health system decision-makers . This study will explore the role of innovative meta- analysis approaches and the added value of enriched and up date d data for increasing the utility of systematic review s of complex interventions . Methods / Design We will use the data set from our recent systematic review of 142 r and omized trials of diabetes quality improvement programs  to evaluate novel approaches for exploring heterogeneity . These will include exploratory methods , such as multivariate meta-regression analyses and all-subsets combinatorial meta- analysis . We will then up date our systematic review to include new trials and enrich the data set by surveying authors of all included trials . In doing so , we will explore the impact of variables not , reported in previous publications , such as details of study context , on the effectiveness of the intervention . We will use innovative analytical methods on the enriched and up date d data set to identify key success factors in the implementation of  quality improvement interventions  for diabetes . Decision-makers will be involved throughout to help identify and prioritize variables to be explored and to aid in the interpretation and dissemination of results . Discussion This study will inform future systematic review s of complex interventions and describe the value of enriching and updating data for exploring heterogeneity in meta- analysis . It will also result in an up date d comprehensive systematic review of diabetes quality improvement interventions that will be useful to health system decision-makers in developing interventions to improve outcomes for people with diabetes . Systematic review registration PROSPERO registration no. Increased vascular stiffness , endothelial dysfunction , and isolated systolic hypertension are hallmarks of vascular aging . Regular cocoa flavanol ( CF ) intake can improve vascular function in healthy young and elderly at-risk individuals . However , the mechanisms underlying CF bioactivity remain largely unknown . We investigated the effects of CF intake on cardiovascular function in healthy young and elderly individuals without history , signs , or symptoms of cardiovascular disease by applying particular focus on functional endpoints relevant to cardiovascular aging . In a r and omized , controlled , double-masked , parallel-group dietary intervention trial , 22 young ( < 35 years ) and 20 elderly ( 50–80 year ) healthy , male non-smokers consumed either a CF-containing drink ( 450 mg CF ) or nutrient-matched , CF-free control drink bi-daily for 14 days . The primary endpoint was endothelial function as measured by flow-mediated vasodilation ( FMD ) . Secondary endpoints included cardiac output , vascular stiffness , conductance of conduit and resistance arteries , and perfusion in the microcirculation . Following 2 weeks of CF intake , FMD improved in young ( 6.1 ± 0.7 vs. 7.6 ± 0.7 % , p < 0.001 ) and elderly ( 4.9 ± 0.6 vs. 6.3 ± 0.9 % , p < 0.001 ) . Secondary outcomes demonstrated in both groups that CF  intake decreased pulse wave velocity and lowered total peripheral resistance , and increased arteriolar and microvascular vasodilator capacity , red cell deformability , and diastolic blood pressure , while cardiac output remained affected . In the elderly , baseline systolic blood pressure was elevated , driven by an arterial-stiffness-related augmentation . CF intake decreased aortic augmentation index ( −9 % ) and thus systolic blood pressure ( −7 mmHg ; Clinical trials.gov : NCT01639781 ) . CF intake reverses age-related burden of cardiovascular risk in healthy elderly , highlighting the potential of dietary flavanols to maintain cardiovascular health BACKGROUND Hyperphosphataemia is a known independent risk factor for cardiovascular mortality . The objective of the study was to compare the effects of two phosphate binders , sevelamer carbonate and calcium carbonate on endothelial function ( EF ) and inflammation in patients on peritoneal dialysis ( PD ) with Type 2 diabetes mellitus ( T2DM ) . METHODS Fifteen subjects with hyperphosphataemia discontinued all phosphate binders to undergo a two-week washout and were assigned to sevelamer carbonate or calcium carbonate treatments for eight weeks . After a second two-week washout period , subjects crossed over to either of the alternate treatments for another eight weeks . At the beginning and end of each treatment , biomarkers of EF , pro-inflammatory cytokines , serum albumin , calcium , phosphate and lipids were measured . RESULTS Sevelamer carbonate significantly improved lipid profile compared with calcium carbonate . Amongst the EF and pro-inflammatory biomarkers , sevelamer carbonate decreased serum endothelin-1 , plasminogen activator inhibitor-1 , C-reactive protein and interleukin-6 . Both phosphate binders were effective in decreasing serum phosphate but sevelamer had a positive effect on EF . CONCLUSIONS Treatment with sevelamer carbonate has beneficial effects compared with calcium carbonate in decreasing inflammation and improving EF in patients with T2DM on PD BACKGROUND Studies of cocoa suggest an array of cardiovascular benefits ; however , the effects of daily intake of sugar-free and sugar-sweetened cocoa beverages on endothelial function ( EF ) have yet to be established . METHODS 44 adults ( BMI 25 - 35 kg/m2 ) participated in a r and omized , controlled , crossover trial . Participants were r and omly assigned to a treatment sequence : sugar-free cocoa beverage , sugar-sweetened cocoa beverage , and sugar-sweetened cocoa-free placebo . Treatments were administered daily for 6 weeks , with a 4-week washout period . RESULTS Cocoa ingestion improved EF measured as flow-mediated dilation ( FMD ) compared to placebo ( sugar-free cocoa : change , 2.4 % [ 95 % CI , 1.5 to 3.2 ] vs. -0.8 % [ 95 % CI , -1.9 to 0.3 ] ; difference , 3.2 % [ 95 % CI , 1.8 to 4.6 ] ; p<0.001 and sugar-sweetened cocoa : change , 1.5 % [ 95 % CI , 0.6 to 2.4 ] vs. -0.8 % [ 95 % CI , -1.9 to 0.3 ] ; difference , 2.3 % [ 95 % CI , 0.9 to 3.7 ] ; p=0.002 ) . The magnitude of improvement in FMD after consumption of sugar-free versus sugar-sweetened cocoa was greater , but not significantly . Other biomarkers of cardiac risk did not change appreciably from baseline . BMI remained stable throughout the study . CONCLUSIONS Daily cocoa ingestion improves EF independently of other biomarkers of cardiac risk , and does not cause weight gain . Sugar-free preparations may further augment endothelial function Allopurinol ameliorates endothelial dysfunction and arterial stiffness among patients without chronic kidney disease ( CKD ) , but it is unknown if it has similar effects among patients with CKD . Furthermore , because arterial stiffness increases left ventricular afterload , any allopurinol-induced improvement in arterial compliance might also regress left ventricular hypertrophy ( LVH ) . We conducted a r and omized , double-blind , placebo-controlled , parallel-group study in patients with stage 3 CKD and LVH . We r and omly assigned 67 subjects to allopurinol  at 300 mg/d  or placebo for 9 months ; 53 patients completed the study . We measured left ventricular mass index ( LVMI ) with cardiac magnetic resonance imaging ( MRI ) , assessed endothelial function by flow-mediated dilation ( FMD ) of the brachial artery , and evaluated central arterial stiffness by pulse-wave analysis . Allopurinol significantly reduced LVH ( P=0.036 ) , improved endothelial function ( P=0.009 ) , and improved the central augmentation index ( P=0.015 ) . This study demonstrates that allopurinol can regress left ventricular mass and improve endothelial function among patients with CKD . Because LVH and endothelial dysfunction associate with prognosis , these results call for further trials to examine whether allopurinol reduces cardiovascular events in patients with CKD and LVH Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items Background The use of financial incentives and penalties to encourage uptake of healthy behaviors is increasingly seen as a viable intervention in developed countries . Previous review s of the effectiveness of financial incentives and penalties for encouraging the uptake of healthy behaviors have focused on individual behaviors making it difficult to draw overall conclusions about the effectiveness of such interventions . This systematic review will explore the effectiveness of financial incentives and penalties for encouraging a wide range of behaviors , including : smoking cessation , increased physical activity , healthier dietary intake , sensible patterns of alcohol consumption , safe sun , safe sex , and primary preventive clinical behaviors . Methods Systematic methods will be used to search existing literature and screen studies for inclusion . All studies that meet the following inclusion criteria will be included in the review : participants were 18 years old or older and living in high-income countries ; interventions included cash or cash-like incentives to promote the uptake of healthy behaviors , or cash or cash-like penalties to discourage unhealthy behaviors ; the comparator was usual care or no intervention ; study design was r and omized controlled trial , cluster r and omized controlled trial , controlled before and after study , or interrupted time series analysis . Two review ers will independently screen the publications to ensure they meet the inclusion criteria . Quality will be assessed by two research ers , working independently , using the Cochrane risk of bias tool . Meta- analysis will be conducted , if appropriate . Any studies identified as at ‘ high risk of bias ’ will be excluded from meta- analysis . Discussion This systematic review will provide policy-relevant recommendations for the use of financial incentives and penalties as a method of encouraging uptake of healthy behaviors AIMS The optimal revascularization strategy in patients with symptomatic multivessel coronary artery disease ( CAD ) and previous coronary artery bypass grafting ( CABG )  remains unknown . METHODS AND RESULTS We evaluated all patients with previous CABG undergoing isolated , non-emergency multivessel revascularization between 1 January 1995 and 31 December 2000 . The analysis concentrated on the independent predictors of the revascularization method , as well as on long-term mortality and its predictors , after calculating a propensity score for the method of revascularization . There were 2191 patients ( 1487 with reoperation and 704 with percutaneous coronary intervention , PCI ) in the study . The most important factors in choosing reoperation were presence of more diseased or occluded grafts , previous infa rct ion , lower ejection fraction ( EF ) , longer interval from first CABG , and more total occlusions of native arteries , as well as absence of a patent mammary graft . The distribution of the propensity score was skewed towards the two extremes . At 5 years , the unadjusted cumulative survival was 79.5 % for CABG and 75.3 % for PCI , P=0.008 . After adjustment for the propensity score for PCI vs. CABG , PCI was associated with a hazard ratio of 1.47 ( 0.94 - 2.28 ) , P=0.09 . The most powerful predictors of mortality were higher age and lower EF . CONCLUSION The choice of the revascularization method in patients with previous CABG  is dictated mostly by anatomical considerations and less by clinical characteristics . In contrast , clinical characteristics predominantly affect long-term outcome , whereas the method of revascularization has a limited effect . A r and omized clinical trial addressing this important segment of the population with ischaemic heart disease is warranted In systematic review s , meta‐analyses are routinely applied to summarize the results of the relevant studies for a specific research question . If one can assume that in all studies the same true effect is estimated , the application of a meta‐ analysis with common effect ( commonly referred to as fixed‐effect meta‐ analysis ) is adequate . If between‐ study heterogeneity is expected to be present , the method of choice is a meta‐ analysis with r and om effects . The widely used DerSimonian and Laird method for meta‐analyses with r and om effects has been criticized due to its unfavorable statistical properties , especially in the case of very few studies . A working group of the Cochrane Collaboration recommended the use of the Knapp‐Hartung method for meta‐analyses with r and om effects . However , as heterogeneity can not be reliably estimated if only very few studies are available , the Knapp‐Hartung method , while correctly accounting for the corresponding uncertainty , has very low power . Our aim is to summarize possible methods to perform meaningful evidence syntheses in the situation with only very few ( ie , 2‐4 ) studies . Some general recommendations are provided on which method should be used when . Our recommendations are based on the existing literature on methods for meta‐ analysis with very few studies and consensus of the authors . The recommendations are illustrated by 2 examples coming from dossier assessment s of the Institute for Quality and Efficiency in Health Care Systematic review s ( SRs ) are an increasingly popular evidence -based tool and are often used to answer complex research questions across many different research domains . Early SR methodology was advanced by social scientists , and the term meta- analysis was coined by a social scientist who also conducted research in psychology . SRs have recently become popular in healthcare and are likely to be beneficial in any field . The aim of this report is to highlight issues in SR conduct with a focus on the field of nutrition and to make recommendations on improving SR conduct in this area . Development of the research question is probably the most important step in conducting an SR . The 4 main components of an answerable question are 1 ) the patient , population , or problem ; 2 ) the intervention , independent variable , or exposure ; 3 ) the comparators ; and 4 ) the dependent variables or outcomes of interest . The question will be used to determine the optimal methods for conducting the SR . SRs often include study design s beyond r and omized trials and do not always include a meta- analysis of the results . Other topics explored include underst and ing and interpreting discordant review s and the importance of reporting tools [ eg , QUality Of Reporting Of Meta-analyses ( QUOROM Statement ) or CONsoli date d St and ards Of Reporting of Trials ( CONSORT Statement ) ] . Recommendations are then provided , such as developing a capacity-building program , search ing the primary literature for research gaps , and extending reporting tools such as the QUOROM Statement to the field of nutrition Background Consumption of chocolate has been often hypothesized to reduce the risk of cardiovascular disease ( CVD ) due to chocolate 's high levels of stearic acid and antioxidant flavonoids . However , debate still lingers regarding the true long term beneficial cardiovascular effects of chocolate overall . Methods We review ed English- language MEDLINE publications from 1966 through January 2005 for experimental , observational , and clinical studies of relations between cocoa , cacao , chocolate , stearic acid , flavonoids ( including flavonols , flavanols , catechins , epicatechins , and procynadins ) and the risk of cardiovascular disease ( coronary heart disease ( CHD ) , stroke ) . A total of 136 publications were selected based on relevance , and quality of design and methods . An up date d meta- analysis of flavonoid intake and CHD mortality was also conducted . Results The body of short-term r and omized feeding trials suggests cocoa and chocolate may exert beneficial effects on cardiovascular risk via effects on lowering blood pressure , anti-inflammation , anti-platelet function , higher HDL , decreased LDL oxidation . Additionally , a large body of trials of stearic acid suggests it is indeed cholesterol-neutral . However , epidemiologic studies of serum and dietary stearic acid are inconclusive due to many method ologic limitations . Meanwhile , the large body of prospect i ve studies of flavonoids suggests the flavonoid content of chocolate may reduce risk of cardiovascular mortality . Our up date d meta- analysis indicates that intake of flavonoids may lower risk of CHD mortality , RR = 0.81 ( 95 % CI : 0.71–0.92 ) comparing highest and lowest tertiles . Conclusion Multiple lines of evidence from laboratory experiments and r and omized trials suggest stearic acid may be neutral , while flavonoids are likely protective against CHD mortality . The highest priority now is to conduct larger r and omized trials to definitively investigate the impact of chocolate consumption on long-term cardiovascular outcomes Polyunsaturated fatty acid ( PUFA ) use in pregnancy has been promoted as beneficial for visual and neurobehavioural development in the fetus . However , no systematic review of the r and omized trials has been conducted . The objective of this review was to evaluate potential advantages of this regiment by review ing all r and omized trials in pregnancy . Methods . Systematic review of r and omized controlled studies comparing cognitive and visual achievements among infants whose mothers were treated and untreated with PUFA during gestation . Results . Nine studies met the inclusion criteria , three focusing on  visual and six on neurobehavioural development . Due to differing outcome measurements in the infants , the studies could not be combined into a formal meta- analysis . Synthesizing the existing data , for both visual and neurobehavioural development , most studies could not show sustained benefits to infant cognition or visual development . Conclusion . At the present time a recommendation to change practice and supplement all expecting mothers with PUFA  to improve offspring vision or neurobehavioural function is not supported by existing evidence BACKGROUND AND AIMS Abdominal obesity ( AO ) is associated with endothelial function ( EF ) alteration and increased global cardiovascular ( CV ) risk .  Therapeutic lifestyle changes ( TLSC ) reduce CV risk , but the impact on EF assessed by peripheral artery tonometry ( PAT ) is unknown . In this study , we aim ed to prospect ively assess the effects of TLSC on EF measured by PAT in increased CV risk patients with AO . METHODS AND RESULTS 150 patients with AO and moderate CV risk were r and omized to groups receiving a one-year intervention of either conventional medical care ( control group , CG ) or an intensive TLSC program ( intervention group , IG ) . Vascular studies ( EF by PAT , intima-media thickness ( IMT ) ) and lifestyle ( LS ) assessment were performed before and after intervention . The PAT ratio improved in the IG and worsened in the CG . The global CV risk was reduced ( P = 0.017 ) in the IG due to a significant decrease in systolic blood pressure ( P < 0.001 ) , increase in HDL cholesterol and ApolipoproteinA1 ( P = 0.013 ) . More individuals in the IG than in the CG quit smoking ( P = 0.001 ) and increased their physical activity ( P = 0.014 ) . The improvement in at least two LS components was associated with a PAT ratio increase ( 2.44 IC : 95 % 0.99 - 6.00 , P = 0.051 ) . The PAT ratio increase determined less IMT progression ( -1.1 IC : 95 % 0.91 - 1.00 , P = 0.053 ) . CONCLUSIONS Good adherence to a TLSC program reduces global CV risk and determines PAT ratio improvement . The PAT ratio increase is the main determinant of lower IMT progression
Conclusion : The results from this meta- analysis suggest a beneficial short-term effect of coffee intake on EF as measured by FMD .
Base on systematic review results acute and chronic intake of coffee products may exerts an unfavorable effect on AS .
Background : Endothelial function ( EF ) and arterial stiffness ( AS ) are predictors of cardiovascular disease .
As previous research concerning the effect of coffee intake on EF and AS was controversial , we conducted a systematic review and meta- analysis to synthesize research .