Sources of evidence for systematic reviews of interventions in diabetes. Bias due to selective inclusion and reporting of outcomes and analyses in systematic reviews of randomised trials of healthcare interventions. Comparative Effectiveness of Dipeptidylpeptidase-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison 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 The effectiveness of yoga to prevent diabetes mellitus type 2 Do sugar-sweetened beverages cause adverse health outcomes in children? A systematic review protocol Cardiorespiratory Fitness in Childhood and Adolescence Affects Future Cardiovascular Risk Factors: A Systematic Review of Longitudinal Studies Probiotic Therapy of the Irritable Bowel Syndrome: Why Is the Evidence Still Poor and What Can Be Done About It? Reporting of Sex Effects by Systematic Reviews on Interventions for Depression, Diabetes, and Chronic Pain Community pharmacy interventions for public health priorities: protocol for a systematic review of community pharmacy-delivered smoking, alcohol and weight management interventions Systematic reviews in endodontics--examples of GIGO? Empirical Evidence of the Importance of Comparative Studies of Diagnostic Test Accuracy Incorporation of assessments of risk of bias of primary studies in systematic reviews of randomised trials: a cross-sectional study Effectiveness of interventions that assist caregivers to support people with dementia living in the community: a systematic review. A conversation with Joseph Lau. Protocol for an overview of systematic reviews of interventions to reduce unscheduled hospital admissions among adults Checklists of methodological issues for review authors to consider when including non-randomized studies in systematic reviews. Creation of a database to assess effects of omega-3, omega-6 and total polyunsaturated fats on health: methodology for a set of systematic reviews Systematic reviews of evaluations of prognostic variables Common statistical errors in the design and analysis of subfertility trials. How Quickly Do Systematic Reviews Go Out of Date? A Survival Analysis Methodological criteria for the assessment of moderators in systematic reviews of randomised controlled trials: a consensus study Effectiveness of interventions that assist caregivers to support people with dementia living in the community: a systematic review
AIMS To analyse the effect on systematic review s in diabetes interventions of including only trials that are indexed in medline , and to assess the impact of adding trials from other data bases and the grey literature . METHODS All systematic review s of diabetes interventions which included a meta- analysis of r and omized controlled trials , and were published since 1996 , were selected . The impact on the meta- analysis of including only those trials indexed in medline , and the effect of then adding trials from other sources , was assessed . Where possible this was measured quantitatively , by redoing the meta- analysis , otherwise a qualitative estimate was made . RESULTS Forty-four systematic review s met our inclusion criteria . There were 120 articles reporting trial data which were not indexed in medline . These came from 52 % of the review s. In 34 % of the review s , basing a meta- analysis on a search of only medline would miss trials that could affect the result . Sources of non- medline data which had the biggest effect on the meta-analyses were journal articles from central and embase ( mainly in Diabetes , Nutrition and Metabolism ) and unpublished data ( mainly from industry ) . The exceptions were journal articles on herbal medicine , mostly indexed in Chinese language data bases . CONCLUSIONS A search of only the medline data base is insufficient for systematic review s of diabetes , because in about 34 % of review s the missed trials could affect the results of the meta- analysis . It is recommended that central ( on the Cochrane Library ) also be search ed . Scanning meeting abstract s , and seeking unpublished data are also recommended if the intervention has only recently been introduced BACKGROUND Systematic review s may be compromised by selective inclusion and reporting of outcomes and analyses . Selective inclusion occurs when there are multiple effect estimates in a trial report that could be included in a particular meta- analysis ( e.g. from multiple measurement scales and time points ) and the choice of effect estimate to include in the meta- analysis is based on the results ( e.g. statistical significance , magnitude or direction of effect ) . Selective reporting occurs when the reporting of a subset of outcomes and analyses in the systematic review is based on the results ( e.g. a protocol -defined outcome is omitted from the published systematic review ) . OBJECTIVES To summarise the characteristics and synthesis e the results of empirical studies that have investigated the prevalence of selective inclusion or reporting in systematic review s of r and omised controlled trials ( RCTs ) , investigated the factors ( e.g. statistical significance or direction of effect ) associated with the prevalence and quantified the bias . SEARCH METHODS We search ed the Cochrane Methodology Register ( to July 2012 ) , Ovid MEDLINE , Ovid EMBASE , Ovid PsycINFO and ISI Web of Science ( each up to May 2013 ) , and the US Agency for Healthcare Research and Quality ( AHRQ ) Effective Healthcare Program 's Scientific Re source Center ( SRC ) Methods Library ( to June 2013 ) . We also search ed the abstract books of the 2011 and 2012 Cochrane Colloquia and the article alerts for method ological work in research synthesis published from 2009 to 2011 and compiled in Research Synthesis Methods . SELECTION CRITERIA We included both published and unpublished empirical studies that investigated the prevalence and factors associated with selective inclusion or reporting , or both , in systematic review s of RCTs of healthcare interventions . We included empirical studies assessing any type of selective inclusion or reporting , such as investigations of how frequently RCT outcome data is selectively included in systematic review s based on the results , outcomes and analyses are discrepant between protocol and published review or non-significant outcomes are partially reported in the full text or summary within systematic review s. DATA COLLECTION AND ANALYSIS Two review authors independently selected empirical studies for inclusion , extracted the data and performed a risk of bias assessment . A third review author resolved any disagreements about inclusion or exclusion of empirical studies , data extraction and risk of bias . We contacted authors of included studies for additional unpublished data . Primary outcomes included overall prevalence of selective inclusion or reporting , association between selective inclusion or reporting and the statistical significance of the effect estimate , and association between selective inclusion or reporting and the direction of the effect estimate . We combined prevalence estimates and risk ratios ( RRs ) using a r and om-effects meta- analysis model . MAIN RESULTS Seven studies met the inclusion criteria . No studies had investigated selective inclusion of results in systematic review s , or discrepancies in outcomes and analyses between systematic review registry entries and published systematic review s. Based on a meta- analysis of four studies ( including 485 Cochrane Review s ) , 38 % ( 95 % confidence interval ( CI ) 23 % to 54 % ) of systematic review s added , omitted , up grade d or down grade d at least one outcome between the protocol and published systematic review . The association between statistical significance and discrepant outcome reporting between protocol and published systematic review was uncertain . The meta-analytic estimate suggested an increased risk of adding or upgrading ( i.e. changing a secondary outcome to primary ) when the outcome was statistically significant , although the 95 % CI included no association and a decreased risk as plausible estimates ( RR 1.43 , 95 % CI 0.71 to 2.85 ; two studies , n = 552 meta-analyses ) . Also , the meta-analytic estimate suggested an increased risk of downgrading ( i.e. changing a primary outcome to secondary ) when the outcome was statistically significant , although the 95 % CI included no association and a decreased risk as plausible estimates ( RR 1.26 , 95 % CI 0.60 to 2.62 ; two studies , n = 484 meta-analyses ) . None of the included studies had investigated whether the association between statistical significance and adding , upgrading or downgrading of outcomes was modified by the type of comparison , direction of effect or type of outcome ; or whether there is an association between direction of the effect estimate and discrepant outcome reporting . Several secondary outcomes were reported in the included studies . Two studies found that reasons for discrepant outcome reporting were infrequently reported in published systematic review s ( 6 % in one study and 22 % in the other ) . One study ( including 62 Cochrane Review s ) found that 32 % ( 95 % CI 21 % to 45 % ) of systematic review s did not report all primary outcomes in the abstract . Another study ( including 64 Cochrane and 118 non-Cochrane review s ) found that statistically significant primary outcomes were more likely to be completely reported in the systematic review abstract than non-significant primary outcomes ( RR 2.66 , 95 % CI 1.81 to 3.90 ) . None of the studies included systematic review s published after 2009 when reporting st and ards for systematic review s ( Preferred Reporting Items for Systematic review s and Meta-Analyses ( PRISMA ) Statement , and Method ological Expectations of Cochrane Intervention Review s ( MECIR ) ) were disseminated , so the results might not be generalisable to more recent systematic review s. AUTHORS ' CONCLUSIONS Discrepant outcome reporting between the protocol and published systematic review is fairly common , although the association between statistical significance and discrepant outcome reporting is uncertain . Complete reporting of outcomes in systematic review abstract s is associated with statistical significance of the results for those outcomes . Systematic review outcomes and analysis plans should be specified prior to seeing the results of included studies to minimise post-hoc decisions that may be based on the observed results . Modifications that occur once the review has commenced , along with their justification , should be clearly reported . Effect estimates and CIs should be reported for all systematic review outcomes regardless of the results . The lack of research on selective inclusion of results in systematic review s needs to be addressed and studies that avoid the method ological weaknesses of existing research are also needed Objective To compare the safety and efficacy of the dipeptidylpeptidase-4 ( DPP-4 ) inhibitors in patients with type 2 diabetes and inadequate glycemic control . Design Systematic review of r and omized controlled trials ( RCTs ) , health economic evaluation studies , systematic review s , and meta-analyses , followed by primary Bayesian mixed treatment comparison meta-analyses ( MTCs ) , and secondary frequentist direct-comparison meta-analyses using a r and om-effects model . Outcomes were reported as weighted mean change from baseline , or odds ratio ( OR ) with 95 % credible interval . Data sources MEDLINE , MEDLINE In-Process , EMBASE , and BIOSIS via Dialog ProQuest ; Cochrane Central Register of Controlled Trials and Cochrane Data base of Systematic Review s via EBSCO ; four diabetes and two technical congress abstract s ; and health technology assessment organization websites . Eligibility criteria Patients with type 2 diabetes and inadequate glycemic control receiving any pharmacological anti-diabetic treatment . Data extraction and analysis Title/ abstract s were review ed for eligibility , followed by full-text review of publications remaining after first pass . A three-person team filtered articles and an independent review er checked a r and om selection ( 10 % ) of filtered articles . Data extraction and quality assessment of studies were also independently review ed . Five DPP-4 inhibitors ( alogliptin , linagliptin , saxagliptin , sitagliptin , and vildagliptin ) were compared via meta- analysis ( where data were available ) as monotherapy , dual therapy ( plus metformin , sulfonylurea , pioglitazone , or insulin ) , and triple therapy ( plus metformin/sulfonylurea ) . Results The review identified 6,601 articles ; 163 met inclusion criteria and 85 publications from 83 RCTs contained sufficient or appropriate data for analysis . MTCs demonstrated no differences between DPP-4 inhibitors in mean change from baseline in glycosylated hemoglobin ( HbA1c ) or body weight , or the proportions of patients achieving HbA1c < 7 % or experiencing a hypoglycemic event , apart from in patients on alogliptin plus metformin , who achieved HbA1c < 7 % more frequently than those treated with saxagliptin plus metformin [ OR 6.41 ( 95 % CI 3.15–11.98 ) versus 2.17 ( 95 % CI 1.56–2.95 ) ] . Conclusions This systematic review and MTC showed similar efficacy and safety for DPP-4 inhibitors as treatment for type 2 diabetes , either as monotherapy or combination therapy 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. Background : Type 2 diabetes mellitus ( T2DM ) is becoming a leading problem worldwide . Emerging reports reveal alarming evidence of increasing prevalence of T2DM that has reached p and emic levels . Despite the significant incidence , there are limited reliable data re sources and comprehensive systematic review and meta- analysis on the effects of yoga on people who are a prediabetic or high risk for developing T2DM . Objective : The objective of this protocol is to conduct a full-scale systematic review and meta-analyses on the effects of yoga on people who are prediabetes or high risk of developing T2DM . Methods : The articles enrolled in the study will be retrieved from the online data bases between 2002 and the date the search es are executed . The search es will be repeated just before the final analyses and further relevant studies for inclusion . We will conduct a bibliographic search in data bases : Medline / PubMed , Scopus , Cochrane Library , EBSCO , and IndMED using keywords including prediabetes state , high risk for diabetes , metabolic syndrome , and yoga . A defined search strategy will be implemented along with selection criteria to obtain full-text articles of relevant studies . This study protocol was prepared according to the Preferred Reporting Items for Systematic Review s and Meta- Analysis for Protocol s 2015 guidelines . There will be no language restrictions . Ethics and dissemination : The proposed study will be based on published studies and publicly available anonymized data without directly involving human participants and therefore requires neither formal human ethical review nor approval by a human research ethics committee . We published an outline of the protocol in the International Prospect i ve Register of Systematic Review s ( PROSPERO ) in 2018 . We plan to disseminate the findings of this systematic review and meta- analysis through publication in a peer- review ed journal and presentation at relevant conference proceedings . In addition , we believe the results of the systematic review will have implication s for policy and practice . We will prepare policymaker summary using a vali date d format , disseminate through social media and email discussion groups . Review registration number : PROSPERO registration number CRD Background Cardiovascular disease and type 2 diabetes are examples of chronic diseases that impose significant morbidity and mortality in the general population worldwide . Most chronic diseases are associated with underlying preventable risk factors , such as elevated blood pressure , high blood glucose or glucose intolerance , high lipid levels , physical inactivity , excessive sedentary behaviours , and overweight/obesity . The occurrence of intermediate outcomes during childhood increases the risk of disease in adulthood . Sugar-sweetened beverages are known to be significant sources of additional caloric intake , and given recent attention to their contribution in the development of chronic diseases , a systematic review is warranted . We will assess whether the consumption of sugar-sweetened beverages in children is associated with adverse health outcomes and what the potential moderating factors are . Methods / Design Of interest are studies addressing sugar-sweetened beverage consumption , taking a broad perspective . Both direct consumption studies as well as those evaluating interventions that influence consumption ( e.g. school policy , educational ) will be relevant . Non-specific or multi-faceted behavioural , educational , or policy interventions may also be included subject to the level of evidence that exists for the other interventions /exposures . Comparisons of interest and endpoints of interest are pre-specified . We will include r and omized controlled trials , controlled clinical trials , interrupted time series studies , controlled before-after studies , prospect i ve and retrospective comparative cohort studies , case – control studies , and nested case – control design s. The MEDLINE ® , Embase , The Cochrane Library , CINAHL , ERIC , and PsycINFO ® data bases and grey literature sources will be search ed . The processes for selecting studies , abstract ing data , and resolving conflicts are described . We will assess risk of bias using design -specific tools . To determine sets of confounding variables that should be adjusted for , we have developed causal directed acyclic graphs and will use those to inform our risk of bias assessment s. Meta- analysis will be conducted where appropriate ; parameters for exploring statistical heterogeneity and effect modifiers are pre-specified . The Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) approach will be used to determine the quality of evidence for outcomes . Systematic review registration PROSPERO CRD42014009641 Background Although cardiorespiratory fitness ( CRF ) in childhood and adolescence may be linked to future cardiovascular health , there is currently limited evidence for a longitudinal association . Objectives To provide a systematic review on the prospect i ve association between CRF in childhood and adolescence and cardiovascular disease ( CVD ) risk factors at least 2 years later . Methods Using a systematic search of Medline , Embase , and SPORTD iscus , relevant articles were identified by the following criteria : generally healthy children and adolescents between 3 and 18 years of age with CRF assessed at baseline , and a follow-up period of ≥ 2 years . The outcome measures were CVD risk factors . We appraised quality of the included articles with STROBE and QUIPS checklists . Results After screening 7524 titles and abstract s , we included 38 articles , assessing 44,169 children and adolescents followed up for a median of 6 years . Eleven articles were of high quality . There was considerable heterogeneity in methodology , measurement of CRF , and outcomes , which hampered meta- analysis . In approximately half of the included articles higher CRF in childhood and adolescence was associated with lower body mass index ( BMI ) , waist circumference , body fatness and lower prevalence of metabolic syndrome in later life . No associations between CRF in childhood and adolescence and future waist-to-hip ratio , blood pressure , lipid profile , and glucose homeostasis were observed . Conclusion Although about half of the included articles reported inverse associations between CRF in childhood and adolescence and future BMI , body fatness , and metabolic syndrome , evidence for other CVD risk factors was unconvincing . Many articles did not account for important confounding factors such as adiposity . Recommendations for future research include st and ardizing the measurement of CRF , i.e. by reporting VO2max , using st and ardized outcome assessment s , and performing individual patient data meta-analyses Background / Aims Despite numerous r and omized clinical trials and meta-analyses , there is no increased evidence for the efficacy of  probiotics  in the treatment of irritable bowel syndrome ( IBS ) . We review this evidence , identify and analyse the reasons for this lack of evidence and propose method ological improvements for future studies . Methods Based on a literature search , we identified 56 papers that matched the purpose of our analyses . Twenty-seven studies used multi-species bacterial preparations and 29 used single-strain probiotics . They were analysed regarding  patients included , treatment duration , probiotic dosage , and outcome measures . Results Trials in both groups suffered from heterogeneity with respect to probiotic concentration , duration of treatment , and other method ological issues ( crossover design and underpowered studies ) . This heterogeneity did not allow the application of a meta-analytic approach and a systematic review was therefore performed instead . Multi-strain preparations combined 2 to 8 different bacterial subspecies , mostly lactobacilli or bifidobacteria , and used variable lengths of treatments . Overall , more than 50 % of trials presented negative outcomes . The majority of the single-strain probiotic trials employing lactobacilli or Saccharomyces were negative , whereas trials employing bifidobacteria showed positive results . Conclusions The heterogeneity of the studies of probiotics in IBS questions the value of meta-analyses . The use of different bacterial strains and different mixtures of these strains , as well as different dosages , are the main contributors to this heterogeneity . Current data provides limited evidence for the efficacy of a small number of  single-strain probiotics  in IBS ( mostly bifidobacteria ) and sound studies following strict trial guidelines ( Food and Drug Administration and European Medicines Agency guidelines for clinical trials ) are needed . We summarised and proposed some method ological issues for future studies in the field Differences in disease prevalence , clinical manifestations , and health outcomes exist between men and women . Sources for this variation range from biological differentiation at the cellular level to behavioral differences influenced by societal gender norms . Typically , biologically based differences between men and women are called sex differences , whereas gender differences describe health differences related , at least in part , to societal constructs of gender ( 13 ) . For example , biological events unique to women , such as pregnancy and menopause , are probably associated with sex differences in occurrence of certain conditions or in response to some medical therapies ( 48 ) . Gender differences probably exist in health-related perceptions and behaviors for women and men with medical conditions that are prevalent for both sexes ( for example , heart disease and chronic pain ) ( 9 –16 ) . Although sex and gender differences are theoretically distinct , they remain difficult to disentangle when differences between men and women in health outcomes and treatment effectiveness are being examined . For this reason , and for brevity , we hereafter refer to sex and gender differences collectively as sex effects . In the past 2 decades , recognition of the importance of sex effects for health outcomes and treatment heterogeneity has been growing . Beginning in 1993 , the National Institutes of Health has issued policies requiring the inclusion of women and minorities in all clinical research and trial design s with valid analysis of sex effects or differences between racial and ethnic groups ( 17 , 18 ) . Since then , the inclusion of women in clinical trials has increased ( 19 , 20 ) , and sex effects have been identified for medications , such as nicotine replacement therapy , analgesics , and aspirin ( 13 , 14 , 21 ) . Recently , sex effects in adverse reactions led to sex-specific dosage recommendations for a widely used sedative ( 7 ) . Despite this progress , representation of women in clinical studies remains inadequate for many conditions ( 22 ) . Further , published clinical trials infrequently report sex effects or discuss the appropriateness of sex-specific analyses ( 19 , 20 , 23 ) . To advance the clinical evidence base and improve health outcomes for women , clinical research must include adequate numbers of women , appropriately conduct sex-specific analyses , and consistently report sex effects . Systematic review s ( SRs ) are a key source of information for clinicians , research ers , and guideline panels . By synthesizing the overall body of evidence for key clinical and research questions , SRs could potentially make a unique contribution to the evaluation of sex effects . To our knowledge , however , the reporting of sex effects by SRs has not been previously examined . Here , we use evidence mapping to systematic ally evaluate the reporting of sex effects by SRs examining a diverse set of interventions for chronic conditions common to women ( that is , depression , diabetes , and chronic pain ) . Evidence mapping is an emerging approach that describes key characteristics of studies for a broad area of medicine ( 2426 ) . Our evidence map addresses the volume and characteristics of eligible SRs , including the representation of women in primary studies , whether and how review s reported sex effects , and findings about sex effects . Methods This work was part of a larger report for the Veterans Health Administration ( VHA ) Evidence -based Synthesis Program ( ESP ) . The complete technical report is available online ( www.hsrd . research .va.gov/publications/esp ) and includes additional information on our methods . We focused on SRs to determine the reporting of sex effects , provide high-level information about the volume of current clinical evidence , and summarize information about actual sex effects . Prioritization of Conditions for Inclusion We used forced-ranking prioritization ( 27 ) with our VHA stakeholders to determine our conditions of interest . These stakeholders included representatives from the Health Services Research & Development Center for the Study of Healthcare Innovation , Implementation and Policy ; Health Services Research & Development Women 's Health Research Network ; Women 's Health Research in the Office of Research & Development ; Women 's Health Services ; and Mental Health Services . We initially selected 34 conditions ( Appendix Table 1 ) based on disease prevalence in women , disease burden in women , availability and breadth of effective treatments for men or women , and women veterans ' priorities for gender-specific care . Stakeholders ranked this initial set of conditions , discussed the rankings , and reranked conditions that initially received intermediate priority rankings . After 2 rounds of iterative prioritization , the following conditions were selected : depressive disorders , type 2 diabetes mellitus , and chronic pain ( that is , chronic low back pain , fibromyalgia , and chronic knee pain due to osteoarthritis ) . Appendix Table 1 . Conditions Presented to Stakeholders for Prioritization * Data Sources and Search es In collaboration with an expert reference librarian , we search ed PubMed and Cochrane Data base of Systematic Review s to identify eligible SRs published after 1 October 2009 through 31 October 2014 for depression , 13 February 2015 for diabetes , and 27 February 2015 for chronic pain . Search strategies used Medical Subject Headings and free-text terms for the conditions of interest , eligible interventions , and SRs ( Appendix Table 2 ) . We restricted the search to the past 6 years because SRs are typically out date d within 5 years of publication ( 28 ) , and our goal was to describe the current state of the clinical literature . In addition to electronic search ing , we screened published review s of review s for eligible articles . Appendix Table 2 . Search Strategies Study Selection and Quality Assessment Eligible SRs evaluated interventions in several broad categories ( that is , medications , behavioral interventions , supervised exercise , and quality improvement or organizational interventions ) . We also included condition-specific interventions , such as bariatric surgery for diabetes . Review s that evaluated mixed conditions or multiple interventions must have reported results separately for at least 1 eligible condition or intervention . We included review s of interventions in any setting , with any type of active or inactive comparator , and with any duration of follow-up . Detailed inclusion and exclusion criteria are provided in Appendix Table 3 . Appendix Table 3 . Detailed Inclusion and Exclusion Criteria for Review Eligibility Two investigators screened citations for eligibility , and citations that were considered to be relevant by either person were retained for full-text review . Full-text articles were review ed by 2 investigators , and disagreements were resolved through discussion or adjudicated by a third person . Formal assessment of review quality was beyond the scope of this project . However , we noted whether review s originated from organizations known for high- quality review s ( that is , Cochrane Collaboration , Agency for Healthcare Research and Quality Evidence -based Practice Centers , and VHA ESP ) . For review s reporting sex effects , we also assessed industry funding and whether statistical power was considered . Data Abstract ion Data were abstract ed by 1 investigator and review ed by a second person . Disagreements were resolved by discussion or by a third review er . Abstract ed data included the analysis method ( that is , qualitative synthesis , meta- analysis , network meta- analysis , or individual-patient data [ IPD ] meta- analysis ) ; clinical conditions ; interventions ; main outcomes ; number and design of primary studies ( for example , r and omized , controlled trials [ RCTs ] or observational cohorts ) ; proportion of women in the included primary studies ; and if sex effects were part of the study aims , analysis plan , or results . For review s reporting sex effects , we also recorded the number of primary studies used for sex-specific analyses , effect estimates , and the method used ( for example , metaregression , subgroup analysis , or IPD meta- analysis ) . All eligible review s on depressive disorders and chronic pain conditions were fully abstract ed . All diabetes review s of nonpharmacologic interventions were also fully abstract ed . For eligible diabetes medication review s ( n= 120 ) , we applied an additional prioritization procedure before full abstract ion . We prioritized review s that examined multiple classes of medications or evaluated a single class of medications when 6 or fewer eligible review s were identified . For SRs evaluating a single class ( > 6 eligible review s were identified ) , we used additional prioritization criteria ( for example , the most recent review published in a high-impact journal or work done by an organization known for high- quality review s ) . The remaining unselected but eligible review s ( n= 58 ) had a keyword text search for sex effects and were fully abstract ed only when this search yielded positive results ( n= 13 ) . Data Synthesis and Analysis of SRs We grouped eligible review s by intervention category and described the overall volume of clinical literature for interventions addressing each condition of interest . We also determined the number of review s reporting sex effects and summarized these results . Time trends for the proportion of these review s were examined for depression and diabetes . Examination of Primary RCTs for Selected Interventions We anticipated that some interventions for each condition would have few or no eligible SRs that addressed sex effects . Thus , for a subset of interventions for each condition , we evaluated primary RCTs to determine the feasibility of conducting a future review to evaluate sex effects . Specifically , we examined  quality improvement interventions and psychotherapy for depression ; diet , physical activity , and culturally tailored psychoeducation for diabetes ; behavioral interventions for chronic low back pain ; and exercise interventions Background Community pharmacists can deliver health care advice at an opportunistic level , related to prescription or non-prescription medicines and as part of focused services design ed to reduce specific risks to health . Obesity , smoking and excessive alcohol intake are three of the most significant modifiable risk factors for morbidity and mortality in the UK , and interventions led by community pharmacists , aim ed at these three risk factors , have been identified by the government as public health priorities . In 2008 , the Department of Health for Engl and stated that ‘ a sound evidence base that demonstrates how pharmacy delivers effective , high quality and value for money services is needed ’ ; this systematic review aims to respond to this requirement . Methods / design We will search the data bases MEDLINE , Embase , CINAHL , PsycINFO , Social Sciences Citation Index , ASSIA , IBSS , Sociological Abstract s , Scopus and NHS Economic Evaluation Data base for studies that have evaluated interventions based on community pharmacies that aim to target weight management , smoking cessation and alcohol misuse . We will include all r and omised controlled trials ( RCTs ) , non-r and omised controlled trials ( N RCTs ) , controlled before-after studies ( CBAs ) and interrupted time series ( ITS ) and repeated measures studies . Data from included studies will be extracted by two independent review ers and will include study details methods , results , intervention implementation/costs and method ological quality . Meta- analysis will be conducted if appropriate ; if not , the synthesis will be restricted to a narrative overview of individual studies looking at the same question . Discussion The review aims to summarise the evidence base on the effectiveness of community pharmacy interventions on health and health behaviours in relation to weight management , smoking cessation and alcohol misuse . It will also explore if , and how , socio-economic status , gender , ethnicity and age moderate the effect of the interventions and will describe how the interventions included in the review have been organised , implemented and delivered , since context is an important factor governing the success of public health interventions . The findings from this review will have an impact on the commissioning of public health services aim ing to promote healthy weight , smoking cessation and prevent excessive alcohol consumption . Systematic review registration The review has been registered with PROSPERO ( registration no. CRD42013005943 ) . Available at : http://www.crd.york.ac.uk/ prospero /display_record.asp?ID = CRD42013005943 In many areas of medicine the amount of published information is increasing at an exponential rate , making it difficult for the clinician to condense the data to a manageable amount of valuable and useful information . Systematic review s have been suggested as a remedy for this information overload . Such review s are regarded as the highest level of evidence . Certain statistical methods , e.g. , meta- analysis , have also been introduced for the calculation of a more comprehensive summation of the compiled results from studies with small sample sizes . These findings would then serve as an authoritarian guide for evidence -based practice . Endodontists have lately jumped on the b and wagon of systematic review s and meta-analyses , and papers on various topics are being published . Well done , such comprehensive information would be very useful and authoritative for the practitioner . Alarmingly , the quality of these recent publications is negatively correlated to the frequency . This can have serious consequences in the clinical arena if spurious information is given a seal of approval when communicated as facts in refereed journals . A systematic literature review is design ed to focus on a single question and to synthesize all high- quality research reports relevant to the question . In these studies , however , sources of bias are often not controlled . Therefore , even the best review and meta- analysis becomes useless if it is based on poorly design ed research . Furthermore , these review s are mostly based on published data which are too often biased toward studies that show significant differences in results and /or outcome . “ Uninteresting ” conclusions tend not to be published . Endodontic literature , thus far , is short on well design ed and executed r and omized clinical trials . Furthermore , clinical protocol s often have many important “ proprietary ” modifications that make comparison difficult . This makes it very hard to undertake a systematic review to answer a narrow question . Such GIGO ( garbage in , garbage out ) can easily lead to biased conclusions and reinforce already existing biased comclusions . An example of such bias can be illustrated by a meta- analysis recently published . The study focused on assessing if there were differences in outcome between 1 and 2 treatment visits when treating teeth with apical periodontitis . Relevant publications on this topic are rare , and with the narrow inclusion criteria only 3 investigations were available for the review . However , the only factors connecting these 3 studies was the words “ single ” and “ two visits ” in the title . Beyond that , the selected studies are too different and inadequate for the study . Only 1 study is somewhat demonstrably r and omized , and outcome assessment s are based on 3 vastly different criteria . Two of the studies use calcium hydroxide as intracanal dressing , whereas the third uses no intervisit medication . Complexity of initial pathology and healing time are also clearly factors of great importance but not controlled . In addition , sample sizes in the component studies as well as the final cohort are all too small for the conclusions that there was no significant difference between 1or 2-visit treatment protocol s. To undertake and publish a meta- analysis on such an incomplete sample is counterproductive . Although the publication noted its numerous limitations , it will still communicate erroneous conclusions with a poor scientific foundation to the less informed reader . There are other examples of recently published systematic review s that are very ambiguous and tend to communicate spurious facts . One of these studies looks at the effect of smear-layer removal on sealing ability of root canal obturation . The study is entirely limited to laboratory experiments , with the majority of evaluations using dye leakage which is generally considered to be unreliable . This is an example of review ers lacking content expertise . The authors draw the conclusion , using defective review material , that removal of smear layer enhances the seal of the root filling . We may generally believe that this is the truth BACKGROUND Systematic review s that " compare " the accuracy of 2 or more tests often include different sets of studies for each test . PURPOSE To investigate the availability of direct comparative studies of test accuracy and to assess whether summary estimates of accuracy differ between meta-analyses of noncomparative and comparative studies . DATA SOURCES Systematic review s in any language from the Data base of Abstract s of Review s of Effects and the Cochrane Data base of Systematic Review s from 1994 to October 2012 . STUDY SELECTION 1 of 2 assessors selected review s that evaluated at least 2 tests and identified meta-analyses that included both noncomparative studies and comparative studies . DATA EXTRACTION 1 of 3 assessors extracted data about review and study characteristics and test performance . DATA SYNTHESIS 248 review s compared test accuracy ; of the 6915 studies , 2113 ( 31 % ) were comparative . Thirty-six review s ( with 52 meta-analyses ) had adequate studies to compare results of noncomparative and comparative studies by using a hierarchical summary receiver-operating characteristic meta-regression model for each test comparison . In 10 meta-analyses , noncomparative studies ranked tests in the opposite order of comparative studies . A total of 25 meta-analyses showed more than a 2-fold discrepancy in the relative diagnostic odds ratio between noncomparative and comparative studies . Differences in accuracy estimates between noncomparative and comparative studies were greater than expected by chance ( P < 0.001 ) . LIMITATION A paucity of comparative studies limited exploration of direction in bias . CONCLUSION Evidence derived from noncomparative studies often differs from that derived from comparative studies . Robustly design ed studies in which all patients receive all tests or are r and omly assigned to receive one or other of the tests should be more routinely undertaken and are preferred for evidence to guide test selection . PRIMARY FUNDING SOURCE National Institute for Health Research ( United Kingdom ) Objective We examined how assessment s of risk of bias of primary studies are carried out and incorporated into the statistical analysis and overall findings of a systematic review . Design A cross-sectional review . Sample We assessed 200 systematic review s of r and omised trials published between January and March 2012 ; Cochrane ( n=100 ) , non-Cochrane ( Data base of Review s of Effects ) ( n=100 ) . Main outcomes Our primary outcome was a descriptive analysis of how assessment s of risk of bias are carried out , the methods used , and the extent to which such assessment s were incorporated into the statistical analysis and overall review findings . Results While Cochrane review s routinely reported the method of risk of bias assessment and presented their results either in text or table format , 20 % of non-Cochrane review s failed to report the method used and 39 % did not present the assessment results . Where it was possible to evaluate the individual results of the risk of bias assessment ( n=154 ) , 75 % ( n=116/154 ) of review s had ≥1 trial at high risk of bias ; the median proportion of trials per review at high risk of bias was 50 % ( IQR 31 % to 89 % ) . Despite this , only 56 % ( n=65/116 ) incorporated the risk of bias assessment into the interpretation of the results in the abstract and 41 % ( n=47/116 ) ( 49 % ; n=40/81 Cochrane and 20 % ; n=7/35 non-Cochrane ) incorporated the risk of bias assessment into the interpretation of the conclusions . Of the 83 % ( n=166/200 ) systematic review s which included a meta- analysis , only 11 % ( n=19/166 ) incorporated the risk of bias assessment into the statistical analysis . Conclusions Cochrane review s were more likely than non-Cochrane review s to report how risk of bias assessment s of primary studies were carried out ; however , both frequently failed to take such assessment s into account in the statistical analysis and conclusions of the systematic review OBJECTIVES The objective of this review was to assess the effectiveness of interventions that assist caregivers to provide support for people living with dementia in the community . INCLUSION CRITERIA Types of participants Adult caregivers who provide support for people with dementia living in the community ( non-institutional care).Types of interventions Interventions design ed to support caregivers in their role such as skills training , education to assist in caring for a person living with dementia and support groups/programs . Interventions of formal approaches to care design ed to support caregivers in their role , care planning , case management and specially design ated members of the healthcare team - for example dementia nurse specialist or volunteers trained in caring for someone with dementia . Types of studies This review considered any meta-analyses , systematic review s , r and omised control trials , quasi-experimental studies , cohort studies , case control studies and observational studies without control groups that addressed the effectiveness of interventions that assist caregivers to provide support for people living with dementia in the community . SEARCH STRATEGY The search sought to identify published studies from 2000 to 2005 through the use of electronic data bases . Only studies in English were considered for inclusion . The initial search was conducted of the data bases , CINAHL , MEDLINE and PsychINFO using search strategies adapted from the Cochrane Dementia and Cognitive Improvement Group . A second more extensive search was then conducted using the appropriate Medical Subject Headings ( MeSH ) and keywords for other available data bases . Finally , h and search ing of reference lists of articles retrieved and of core dementia , geriatric and psycho geriatric journals was undertaken . ASSESSMENT OF QUALITY Method ological quality of each of the articles was assessed by two independent review ers using appraisal checklist developed by the Joanna Briggs Institute and based on the work of the Cochrane Collaboration and Centre for Review s and Dissemination . DATA COLLECTION AND ANALYSIS St and ardised mean differences or weighted mean differences and their 95 % confidence intervals were calculated for each included study reported in the meta- analysis . Results from comparable groups of studies were pooled in statistical meta- analysis using Review Manager Software from the Cochrane Collaboration . Heterogeneity between combined studies was tested using st and ard chi-square test . Where statistical pooling was not appropriate or possible , the findings are summarised in narrative form . RESULTS A comprehensive search of relevant data bases , h and search ing and cross referencing found 685 articles that were assessed for relevance to the review . Eighty-five papers appeared to meet the inclusion criteria based on title and abstract , and the full paper was retrieved . Of the 85 full papers review ed , 40 were accepted for inclusion , three were systematic review s , three were meta- analysis , and the remaining 34 were r and omised controlled trials . For the r and omised controlled trials that were able to be included in a meta- analysis , st and ardised mean differences or weighted mean differences and their 95 % confidence intervals were calculated for each . Results from comparable groups of studies were pooled in statistical meta- analysis using Review Manager Software and heterogeneity between combined studies was assessed by using the chi-square test . Where statistical pooling was not appropriate or possible , the findings are summarised in narrative form . The results are discussed in two main sections . Firstly it was possible to assess the effectiveness of different types of caregiver interventions on the outcome categories of depression , health , subjective well-being , self-efficacy and burden . Secondly , results are reported by main outcome category . For each of these sections , meta- analysis was conducted where it was possible ; otherwise , a narrative summary describes the findings . EFFECTIVENESS OF INTERVENTION TYPE Four categories of intervention were included in the review - psycho-educational , support , multi-component and other . Psycho-educational Thirteen studies used  psycho-educational interventions  , and all but one showed positive results across a range of outcomes . Eight studies were entered in a meta- analysis . No significant impact of psycho-educational interventions was found for the outcome categories of subjective well-being , self-efficacy or health . However , small but significant results were found for the categories of depression and burden . Support Seven studies discussed support only interventions and two of these showed significant results . These two studies were suitable for meta- analysis and demonstrated a small but significant improvement on caregiver burden . Multi-component Twelve of the studies report multi-component interventions and 10 of these report significant outcomes across a broad range of outcome measures including self-efficacy , depression , subjective well-being and burden . Unfortunately because of the heterogeneity of study design s and outcome measures , no meta- analysis was possible . Other interventions Other interventions included the use of exercise or nutrition which result ed in improvements in psychological distress and health benefits . Case management and a computer aided support intervention provided mixed results . One cognitive behavioural therapy study reported a reduction in anxiety and positive impacts on patient behaviour . EFFECTIVENESS OF INTERVENTIONS USING SPECIFIC OUTCOME CATEGORIES In addition to analysis by type of intervention it was possible to analyse results based on some outcome categories that were used across the studies . In particular the impact of interventions on caregiver depression was available for meta- analysis from eight studies . This indicated that multi-component and psycho-educational interventions showed a small but significant positive effect on caregiver depression . Five studies using the outcome category of caregiver burden  were entered into a meta- analysis and findings indicated that there were no significant effects of any of interventions . No meta- analysis was possible for the outcome categories of health , self-efficacy or subjective well-being . IMPLICATION S FOR PRACTICE From this review there is evidence to support the use of well- design ed psycho-educational or multi-component interventions for caregivers of people with dementia who live in the community . Factors that appear to positively contribute to effective interventions are those which : Factors which do not appear to have benefit in interventions are those which Dr. Joseph Lau is a world-leading expert in meta- analysis and systematic review s. Currently a professor in the Department of Health Services , Policy and Practice and co-director of the Center for Evidence -based Medicine at Brown University , Professor Lau has applied evidence -based methods to a variety of clinical , biomedical and healthcare topics ; has developed reliable and efficient methods and tools to conduct systematic review s and meta-analyses ; and has advanced an underst and ing on the impact of factors that may contribute to differences of results in scientific studies . His past research includes cumulative meta- analysis of r and omized controlled trials , comparison of results from large trials and meta-analyses of small trials , effect of baseline risk in the interpretation of clinical trial results , and empirical evaluation of existing methods of combining data . His current focus is on a Web-based repository of systematic review data , review s of diagnostic tests , nutrition , clinical practice guidelines , and dissemination of evidence -based methods to varied health-care disciplines . This report is a conversation from an adapted version of an interview , more or less chronologically arranged , between Joseph C. Cappelleri as interviewer and Joseph Lau as interviewee , with Meghan Ingerick recording and transcribing the interview Introduction Unscheduled hospital admissions are an increasing burden on health systems worldwide . To date , initiatives to reduce admissions have had limited success as it is unclear which strategies effectively reduce admissions and are supported by a strong evidence -base . Therefore , we will conduct an overview to find , assess and summarise all published peer- review ed systematic review s of r and omised controlled trials that examine the effect of an intervention on  unplanned admissions among adults . Methods and analysis This is a protocol for a systematic overview of review s. We will search four data bases : Ovid MEDLINE , PubMed , Cochrane Data base of Systematic Review s and the Cochrane Data base of Abstract s of Review s of Effects . We will consider systematic review s and meta-analyses of r and omised controlled trials in adults ( ≥16 years old ) evaluating the effect of any intervention on unscheduled hospital admissions including those to treat , monitor , diagnose or prevent a health problem . We will only include review s that identified unscheduled hospitalisations as a prespecified outcome . Two authors will independently screen articles for inclusion using a priori criteria . We will assess the quality of included review s and extract ratings of the quality of evidence from within each review . We will create a hierarchical list of interventions based on estimates of absolute admission reductions and the quality of the evidence . Presentation of results will align with guidelines in the Cochrane H and book of Systematic Review s of Interventions and the Preferred Reporting Items for Systematic Review s and Meta- Analysis statement . Ethics and dissemination Ethics approval is not required . We will su bmi t the results of this study for peer- review publication . The results will inform future research and could be used by healthcare managers , administrators and policymakers to guide re source allocation decisions and inform local implementation and optimisation of interventions to reduce unscheduled hospital admissions BACKGROUND There is increasing interest from review authors about including  non-r and omized studies  ( NRS ) in their systematic review s of health care interventions . This series from the Ottawa Non-R and omized Studies Workshop consists of six papers identifying method ological issues when doing this . AIM To format the guidance from the preceding papers on study design and bias , confounding and meta- analysis , selective reporting , and applicability/directness into checklists of issues for review authors to consider when including NRS in a systematic review . CHECKLISTS Checklists were devised providing frameworks to describe/assess : ( 1 ) study design s based on study design features ; ( 2 ) risk of residual confounding and when to consider meta-analysing data from NRS ; ( 3 ) risk of selective reporting based on the Cochrane framework for detecting selective outcome reporting in trials but extended to selective reporting of analyses ; and ( 4 ) directness of evidence contributed by a study to aid integration of NRS findings into summary of findings tables . SUMMARY The checklists described will allow review groups to operationalize the inclusion of NRS in systematic review s in a more consistent way . The next major step is extending the existing Cochrane Risk of Bias tool so that it can assess the risk of bias to NRS included in a review . Copyright © 2013 John Wiley & Sons , Objective To create a data base of long-term r and omised controlled trials ( RCTs ) comparing higher with lower omega-3 , omega-6 or total polyunsaturated fatty acid ( PUFA ) , regardless of reported outcomes , and to develop methods to assess effects of increasing omega-6 , alpha-linolenic acid ( ALA ) , long-chain omega-3 ( LCn3 ) and total PUFA on health outcomes . Design Systematic review search , methodology and meta-analyses . Data sources Medline , Embase , CENTRAL , WHO International Clinical Trials Registry Platform , Clinical trials.gov and trials in relevant systematic review s. Eligibility criteria RCTs of ≥24 weeks ' duration assessing effects of increasing ALA , LCn3 , omega-6 or total PUFAs , regardless of outcomes reported . Data synthesis Methods included r and om-effects meta-analyses and sensitivity analyses . Funnel plots were examined , and subgrouping assessed effects of intervention type , replacement , baseline diabetes risk and use of diabetic medications , trial duration and dose . Quality of evidence was assessed using Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) . Results Electronic search es generated 37 810 hits , de-duplicated to 19 772 titles and abstract s. We assessed 2155 full-text papers , conference abstract s and trials registry entries independently in duplicate . Included studies were grouped into 363 RCTs comparing higher with lower omega-3 , omega-6 and /or total PUFA intake of at least 6 months ’ duration —the Data base . Of these 363 included RCTs , 216 RCTs were included in at least one of our review s of health outcomes , data extracted and risk of bias assessed in duplicate . Ninety five RCTs were included in the Data base but not included in our current review s. Of these 311 completed trials , 27 altered ALA intake , 221 altered LCn3 intake and 16 trials altered omega-3 intake without specifying whether ALA or LCn3 . Forty one trials altered omega-6 and 59 total PUFA.The remaining 52 trials are ongoing though 13 ( 25 % ) appear to be outst and ing , or constitute missing data . Conclusions This extensive data base of trials is available to allow assessment of further health outcomes This is the last in a series of four articles Prognostic studies include clinical studies of variables predictive of future events as well as epidemiological studies of aetiological risk factors . As multiple similar studies accumulate it becomes increasingly important to identify and evaluate all of the relevant studies to develop a more reliable overall assessment . For prognostic studies this is not straightforward . Box 1 summarises the clinical importance of information on prognostic factors . Many of the issues discussed are also relevant to aetiological studies , especially cohort ones . Some features of prognostic studies lead to particular difficulties for the systematic review er . Firstly , in most clinical prognostic studies the outcome of primary interest is the time to an event , often death . Meta- analysis of such studies is rather more difficult than that for binary data or continuous measurements . Secondly , in many context s the prognostic variable of interest is often one of several prognostic variables . When examining a variable of interest research ers should consider other prognostic variables with which it might be correlated . Thirdly , many prognostic factors are continuous variables , for which research ers use a wide variety of methods of analysis . # # # # Summary points Systematic review s are applicable to all types of research design , and studies of prognostic variables are an important additional area where appropriate methodology should be applied Prognostic variables should be evaluated in a representative sample of patients assembled at a common point in the course of their disease — ideally they should all have received the same medical treatment or been in a r and omised trial When examined critically , a high proportion of prognostic studies are found to be method ologically poor Meta- analysis of published data is hampered by difficulties in extraction of data and variation in the characteristics of the study and patients The poor quality of the published literature is a strong argument in favour BACKGROUND The quality of clinical trials has received increasing attention with the growth of evidence -based medicine and systematic review s. We aim ed to identify whether errors and omissions commonly encountered when undertaking Cochrane review s in this field are still passing peer review . METHODS We undertook a review of trials published in 2001 by two major journals . We selected from Medline only trials in which authors compared pregnancy rates under two interventions by allocating women to different groups . RESULTS We identified 39 trials meeting our criteria . Six trials were fatally flawed by design , either by inappropriate use of a cross-over design or by systematic allocation described by the authors as ' r and om ' . Only six reports cl aim ed to apply the intention-to-treat principle , and the principle was misunderstood by four of these . Only five trials reported live birth rates sufficiently to allow valid meta- analysis . Most trials ( 82 % ) included at least one ' unit of analysis ' error . CONCLUSIONS We selected simple trials from respected journals , assuming that our sample would represent trials of highest method ological quality in the field . Nevertheless , the st and ards of design , analysis and reporting of many subfertility trials are not sufficient to allow reliable interpretation of results , or inclusion in meta-analyses Context Clinicians rely on systematic review s for current , evidence -based information . Contribution This survival analysis of 100 meta-analyses indexed in ACP Journal Club from 1995 to 2005 found that new evidence that substantively changed conclusions about the effectiveness or harms of therapies arose frequently and within relatively short time periods . The median survival time without substantive new evidence for the meta-analyses was 5.5 years . Significant new evidence was already available for 7 % of the review s at the time of publication and became available for 23 % within 2 years . Implication Clinical ly important evidence that alters conclusions about the effectiveness and harms of treatments can accumulate rapidly . The Editors Systematic review s have become increasingly common in recent years ( 1 ) and are recommended by many as the best sources of evidence to guide both clinical decisions ( 2 ) and health care policy ( 3 ) . For systematic review s to fulfill these roles , their findings must remain relatively stable for at least several years or effective mechanisms must exist for alerting end users to important changes in evidence . Yet , surprisingly little research has assessed the extent to which systematic review s become out of date or the rate at which this occurs ( 47 ) . Some organizations , such as the Cochrane Collaboration , recommend updating systematic review s every 2 years , but few empirical data guide this or other recommendations about updating . We sought to determine how quickly systematic review s meet explicitly defined criteria for changes in evidence of sufficient importance to warrant updating . We also sought to identify predictors of survival time , the time to such important changes in evidence . Survival time might vary depending on many factors , including the type of question posed by the original review ( for example , therapeutic or diagnostic ) , the types of studies included ( for example , r and omized trials or observational studies ) , and whether the systematic review provided quantitative synthesis . To limit such variation , we focused on systematic review s of r and omized , controlled trials that evaluated therapeutic benefit or harm by providing quantitative synthesis ( meta- analysis ) for at least 1 outcome . Methods Study Design and Sample We used a quasi-r and om process ( alphabetical sort order by author ) to select 100 systematic review s that were indexed in ACP Journal Club with an accompanying commentary between January 1995 and December 2005 ( with a search date no later than 31 December 2004 to ensure at least 1 full year for new evidence to appear ) . We chose this sampling frame because ACP Journal Club selects systematic review s that meet explicit quality st and ards and are deemed directly relevant to clinical practice ( 8) . We regarded the sample size of 100 as sufficiently large to achieve suitably narrow confidence intervals and to permit evaluation of up to 5 potential predictors of survival . Eligibility Criteria Eligible review s evaluated the benefit or harm of a specific drug , class of drug , device , or procedure ( invasive procedure or surgery ) and included r and omized or quasi-r and omized , controlled trials . We excluded evaluations of alternative and complementary medicines because the stability of review s of such therapies might differ substantially from review s of conventional therapies . We required that review s provide a point estimate and 95 % confidence interval for at least 1 outcome in the form of a relative risk , odds ratio , or absolute risk difference for binary outcomes and weighted mean differences for continuous outcomes . We excluded meta-analyses of individual-patient data , meta-regressions , and indirect meta-analyses because of the difficulty of determining whether new data would alter previous quantitative results . Two team members independently assessed eligibility , with disagreements resolved by consensus involving a third review er . When more than 1 review on the same topic was identified , only the earliest was included . Search ing For each review , search es for new trials included identifying new systematic review s on the same topic , su bmi tting relevant content terms to the Clinical Queries function in Ovid , applying the Related Articles function in PubMed to the 3 largest and the 3 most recent trials in the original review ( up to 6 trials in total ) , and using Scopus ( www . scopus .com/ scopus /home.url ) to identify new r and omized trials that cited the original review . When these search strategies yielded no eligible new trials , we conducted more comprehensive electronic search es and review ed relevant chapters in such sources as Clinical Evidence and UpTo Date to ensure that we had not missed new trials . Team members who had background s in both medicine and clinical research screened citations retrieved by the preceding methods to identify trials that would have met the inclusion criteria in the original review . Retrieved articles were screened in chronological order to ascertain quantitative or qualitative signals for the need for updating . The review protocol stopped when any criteria for updating were met . Each systematic review was discussed in detail , with the final statussignal for updating was or was not detectedadjudicated by consensus ( Figure 1 ) . Figure 1 . Overall process for determining updating status . ACP Journal Club Signals for the Need to Up date Systematic Review s In design ing criteria for comparing new findings with those in a previous review , we adapted methods used by other investigators to address similar problems with comparing 2 sets of results relating to the same question ( 913 ) , such as r and omized and nonr and omized studies of the same intervention . These investigators identified conflicting findings among different publications using a combination of quantitative thresholds for differences in effect magnitude and qualitative judgments about the language used to describe the results . We have similarly conceptualized quantitative and qualitative signals of potential changes in evidence that are sufficiently important to warrant updating previous systematic review s. Quantitative Signals Quantitative signals consisted of a change in statistical significance or relative change in effect magnitude of at least 50 % . We restricted these changes to those involving 1 of the primary outcomes of the original review or any mortality outcome . We also ignored trivial changes in statistical significance when the original and up date d meta-analytic results both had P values between 0.04 and 0.06so that quantitative signals of changes in evidence would represent robust indicators of the need to up date previous review s. Quantitative signals were detected by combining data from eligible new trials with the previous results using a fixed-effects approach . Use of fixed-effect models allowed pooling of the new trials with the previous meta-analytic result , as opposed to having to obtain original data from all of the included trials in each of 100 systematic review s. Although r and om-effects models are usually preferred to avoid spurious precision in the face of heterogeneity , our goal was to detect potential changes in evidence that would warrant a formal up date , not produce exact estimates of the up date d results . Qualitative Signals Qualitative signals included new information about harm sufficient to affect clinical decision making , important caveats to the original results , emergence of a superior alternate therapy , and important changes in certainty or direction of effect . Qualitative signals were detected by using explicit criteria for comparing the language in the original review with descriptions of findings in new systematic review s that addressed the same topic , pivotal trials , clinical practice guidelines , or recent editions of major textbooks ( for example , UpTo Date ) . Pivotal trials were defined as trials that had a sample size at least 3 times larger than that of the previous largest trial or were published in 1 of the 5 highest-impact general medical journals ( The New Engl and Journal of Medicine , Lancet , Journal of the American Medical Association , Annals of Internal Medicine , and the British Medical Journal ) . We defined 2 levels of importance for qualitative signals : potentially invalidating changes in evidence , which would make one no longer want clinicians or policymakers to base decisions on the original findings ( such as a pivotal trial that characterized treatment effectiveness in terms opposite of those in the original systematic review ) , and major changes in evidence , which would affect clinical decision making in important ways without invalidating the previous results ( such as the identification of patient population s for whom treatment is more or less beneficial ) . Major changes also included differing characterizations of effectiveness that were less extreme than those for potentially invalidating signals but that would still affect clinical decision making ( for example , a change from possibly beneficial to definitely beneficial ) . Of importance , such characterizations as possibly effective , probably effective , and promising , were all categorized as possibly effective . Thus , qualitative signals for changes in evidence captured substantive differences in the characterization of treatment effects , not merely semantic differences . Full definitions for each of the specific signals can be found at www.ohri.ca/UpdatingSystRevs . Data Collection For each review , we characterized the clinical content area , eligibility criteria for included trials , definitions of reported outcomes , number of included trials and participants , meta-analytic result for each outcome , identification of statistical heterogeneity , and excerpted quotations of the authors ' characterizations of the main results . We also abstract ed whether a given outcome was explicitly identified as 1 of the primary or main outcomes . We discounted identification of more than 3 such outcomes as inconsistent with the Background Current method ological guidelines provide advice about the assessment of sub-group analysis within RCTs , but do not specify explicit criteria for assessment . Our objective was to provide research ers with a set of criteria that will facilitate the grading of evidence for moderators , in systematic review s. Method We developed a set of criteria from method ological manuscripts ( n = 18 ) using snowballing technique , and electronic data base search es . Criteria were review ed by an international Delphi panel ( n = 21 ) , comprising authors who have published method ological papers in this area , and research ers who have been active in the study of sub-group analysis in RCTs . We used the Research ANd Development/University of California Los Angeles appropriateness method to assess consensus on the quantitative data . Free responses were coded for consensus and disagreement . In a subsequent round additional criteria were extracted from the Cochrane Review ers ' H and book , and the process was repeated . Results The recommendations are that meta-analysts report both confirmatory and exploratory findings for sub-groups analysis . Confirmatory findings must only come from studies in which a specific theory/ evidence based a-priori statement is made . Exploratory findings may be used to inform future/subsequent trials . However , for inclusion in the meta- analysis of moderators , the following additional criteria should be applied to each study : Baseline factors should be measured prior to r and omisation , measurement of baseline factors should be of adequate reliability and validity , and a specific test of the interaction between baseline factors and interventions must be presented . Conclusions There is consensus from a group of 21 international experts that method ological criteria to assess moderators within systematic review s of RCTs is both timely and necessary . The consensus from the experts result ed in five criteria divided into two groups when synthesis ing evidence : confirmatory findings to support hypotheses about moderators and exploratory findings to inform future research . These recommendations are discussed in reference to previous recommendations for evaluating and reporting moderator studies Objectives The objective of this review was to assess the effectiveness of interventions that assist caregivers to provide support for people living with dementia in the community . Inclusion criteria Types of participants Adult caregivers who provide support for people with dementia living in the community ( non‐institutional care ) . Types of interventions Interventions design ed to support caregivers in their role such as skills training , education to assist in caring for a person living with dementia and support groups/programs . Interventions of formal approaches to care design ed to support caregivers in their role , care planning , case management and specially design ated members of the healthcare team ‐ for example dementia nurse specialist or volunteers trained in caring for someone with dementia . Types of studies This review considered any meta‐analyses , systematic review s , r and omised control trials , quasi‐experimental studies , cohort studies , case control studies and observational studies without control groups that addressed the effectiveness of interventions that assist caregivers to provide support for people living with dementia in the community . Search strategy The search sought to identify published studies from 2000 to 2005 through the use of electronic data bases . Only studies in English were considered for inclusion . The initial search was conducted of the data bases , CINAHL , MEDLINE and PsychINFO using search strategies adapted from the Cochrane Dementia and Cognitive Improvement Group . A second more extensive search was then conducted using the appropriate Medical Subject Headings ( MeSH ) and keywords for other available data bases . Finally , h and search ing of reference lists of articles retrieved and of core dementia , geriatric and psycho geriatric journals was undertaken . Assessment of quality Method ological quality of each of the articles was assessed by two independent review ers using appraisal checklist developed by the Joanna Briggs Institute and based on the work of the Cochrane Collaboration and Centre for Review s and Dissemination . Data collection and analysis St and ardised mean differences or weighted mean differences and their 95 % confidence intervals were calculated for each included study reported in the meta‐ analysis . Results from comparable groups of studies were pooled in statistical meta‐ analysis using Review Manager Software from the Cochrane Collaboration . Heterogeneity between combined studies was tested using st and ard chi‐square test . Where statistical pooling was not appropriate or possible , the findings are summarised in narrative form . Results A comprehensive search of relevant data bases , h and search ing and cross referencing found 685 articles that were assessed for relevance to the review . Eighty‐five papers appeared to meet the inclusion criteria based on title and abstract , and the full paper was retrieved . Of the 85 full papers review ed , 40 were accepted for inclusion , three were systematic review s , three were meta‐ analysis , and the remaining 34 were r and omised controlled trials . For the r and omised controlled trials that were able to be included in a meta‐ analysis , st and ardised mean differences or weighted mean differences and their 95 % confidence intervals were calculated for each . Results from comparable groups of studies were pooled in statistical meta‐ analysis using Review Manager Software and heterogeneity between combined studies was assessed by using the chi‐square test . Where statistical pooling was not appropriate or possible , the findings are summarised in narrative form . The results are discussed in two main sections . Firstly it was possible to assess the effectiveness of different types of caregiver interventions on the outcome categories of depression , health , subjective well‐being , self‐efficacy and burden . Secondly , results are reported by main outcome category . For each of these sections , meta‐ analysis was conducted where it was possible ; otherwise , a narrative summary describes the findings . Effectiveness of intervention type Four categories of intervention were included in the review ‐ psycho‐educational , support , multi‐component and other . Psycho‐educational Thirteen studies used  psycho‐educational interventions , and all but one showed positive results across a range of outcomes . Eight studies were entered in a meta‐ analysis . No significant impact of psycho‐educational interventions was found for the outcome categories of subjective well‐being , self‐efficacy or health . However , small but significant results were found for the categories of depression and burden . Support Seven studies discussed support only interventions and two of these showed significant results . These two studies were suitable for meta‐ analysis and demonstrated a small but significant improvement on caregiver burden . Multi‐component Twelve of the studies report multi‐component interventions and 10 of these report significant outcomes across a broad range of outcome measures including self‐efficacy , depression , subjective well‐being and burden . Unfortunately because of the heterogeneity of study design s and outcome measures , no meta‐ analysis was possible . Other interventions Other interventions included the use of exercise or nutrition which result ed in improvements in psychological distress and health benefits .  Case management and a computer aided support intervention provided mixed results . One cognitive behavioural therapy study reported a reduction in anxiety and positive impacts on patient behaviour . Effectiveness of interventions using specific outcome categories In addition to analysis by type of intervention it was possible to analyse results based on some outcome categories that were used across the studies . In particular the impact of interventions on  caregiver depression was available for meta‐ analysis from eight studies . This indicated that multi‐component and psycho‐educational interventions showed a small but significant positive effect on caregiver depression . Five studies using the outcome category of caregiver burden  were entered into a meta‐ analysis and findings indicated that there were no significant effects of any of interventions . No meta‐ analysis was possible for the outcome categories of health , self‐efficacy or subjective well‐being . Implication s for practice From this review there is evidence to support the use of well‐ design ed psycho‐educational or multi‐component interventions for caregivers of people with dementia who live in the community . Factors that appear to positively contribute to effective interventions are those which : Provide opportunities within the intervention for the person with dementia as well as the caregiver to be involved Encourage active participation in educational interventions for caregivers Offer individualised programs rather than group sessions Provide information on an ongoing basis , with specific information about services and coaching regarding their new role Target the care recipient particularly by reduction in behaviours Factors which do not appear to have benefit in interventions are those which : Simply refer caregivers to support groups Only provide self help material s Only offer peer
Conclusions : Probiotics may have beneficial effects on the reduction of glucose , insulin and HbA1c for diabetes , especially for T2DM mellitus patients
Abstract Background : A systematic review and meta- analysis was design ed to evaluate the effect of probiotics  on diabetes and its associated risk factors .