Search

Purpose A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies. Methods Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364). Results Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30–1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias. Conclusion The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research.

Background: Smoking cessation is an effective secondary prevention measure after acute coronary syndrome (ACS). We conducted a systematic review with the aim to better understand which patients have a greater propensity to quit smoking and the risk factors for continued smoking after ACS. Methods: We searched MEDLINE and EMBASE for studies that evaluated smoking cessation after ACS. The pooled rate of smoking cessation across included studies was performed. Random effects meta-analysis for different variables and their association with smoking cessation was conducted. Results: A total of 39 studies with 11 228 patients were included in this review. The pooled rate of smoking cessation following ACS across 38 studies was 45.0%. Factors associated with greater likelihood of smoking cessation were attendance at cardiac rehabilitation (OR 1.90 95% CI 1.44-2.51), married/not alone (OR 1.68 95% CI 1.32-2.13), intention/attempt to quit smoking (OR 1.27 95% CI 1.11-1.46), diabetes mellitus (OR 1.24 95% CI 1.03-1.51) and hospitalised duration (OR 1.09 95% CI 1.02-1.15). Variables associated with a lower likelihood of smoking cessation were depression (OR 0.57 95% CI 0.43-0.75), chronic obstructive pulmonary disease/lung disease (OR 0.73 95% CI 0.57-0.93), previous admission with acute myocardial infarction/cardiac admission (OR 0.61 95% CI 0.47-0.80), cerebrovascular disease/transient ischaemic attack (OR 0.42 95% CI 0.30-0.58) and unemployment (OR 0.37 95% CI 0.17-0.80). Conclusions: The majority of smokers with an ACS continue to smoke after admission. Patients attending cardiac rehabilitation show increased odds of quitting while people who are depressed and those with chronic lung disease were less likely to quit smoking and should be targeted for intensive smoking cessation interventions.

Objectives Methodological research has been undertaken to investigate the many challenges in searching for adverse effects data. It is imperative that the search approach adopted in systematic reviews is based on the best available evidence. We provide a detailed summary of the results and implications of the current evidence base to assist future searches for adverse effects. Study Design and Setting This article is a narrative review from the authors of the Cochrane Handbook chapter on adverse effects. Results The specified search strategy must be based on the population, intervention, comparator, outcome(s) format for question formulation and appropriate study designs for adverse effects data. Search filters and suggested search terms are available for the adverse effects of drug, medical devices, and surgical interventions. The use of generic adverse effects terms (such as harms and complications) as text words and indexing terms and specific adverse effects terms (such as rash and wound infection) are warranted. Searching databases beyond MEDLINE has proven useful, as well as the use of nondatabase sources. Conclusion This article provides the most up-to-date evidence-based guidance in identifying adverse effects data in the literature. It will support searchers and researchers evaluating the potential for harm of medical interventions in systematic reviews.

Background Objectively derived search filters for adverse drug effects and complications in surgery have been developed but not for medical device adverse effects. Objective To develop and validate search filters to retrieve evidence on medical device adverse effects from ovid medline and embase. Methods We identified systematic reviews from Epistemonikos and the Health Technology Assessment (hta) database. Included studies within these reviews that reported on medical device adverse effects were randomly divided into three test sets and one validation set of records. Using word frequency analysis from one test set, we constructed a sensitivity maximising search strategy. This strategy was refined using two other test sets, then validated. Results From 186 systematic reviews which met our inclusion criteria, 1984 unique included studies were available from medline and 1986 from embase. Generic adverse effects searches in medline and embase achieved 84% and 83% sensitivity. Recall was improved to over 90%, however, when specific adverse effects terms were added. Conclusion We have derived and validated novel search filters that retrieve over 80% of records with medical device adverse effects data in medline and embase. The addition of specific adverse effects terms is required to achieve higher levels of sensitivity.

Background Despite the availability of tests to diagnose acute myocardial infarction (AMI), cases are still missed. Methods We systematically reviewed the literature to determine how missed AMI has been defined, the reported rates of misdiagnosed AMI, the outcomes patients with misdiagnosed AMI have, what diagnosis was initially suspected in missed AMI cases, and what factors are associated with misdiagnosed AMI. We searched MEDLINE and EMBASE in September 2020 for studies that evaluated missed AMI. Data were extracted from studies that met the inclusion criteria and the results were narratively synthesized. Results A total of 15 studies were included in this review. The number of patients with missed AMI in individual studies ranged from 64 to 4707. There was no consistently used definition for misdiagnosed AMI, but most studies reported rates of approximately 1%-2%. Compared with AMI that was recognized, 1 study found no difference in mortality for misdiagnosed AMI at 30 days and 1 year. The common initial misdiagnoses that subsequently had AMI were ischemic heart disease, nonspecific chest pain, gastrointestinal disease, musculoskeletal pain, and arrhythmias. Reasons for missed AMI include incorrect electrocardiogram interpretation and failure to order appropriate diagnostic tests. Hospitals in rural areas and those with a low proportion of classical chest pain patients that turned out to have AMI were at greater risk of missed AMI. Conclusions Misdiagnosed AMI is an unfortunate part of everyday clinical practice and better training in electrocardiogram interpretation, and education about atypical presentations of AMI may reduce the number of misdiagnosed AMIs.

Objectives This systematic review (PROSPERO CRD42019115918) compared the evidence behind anticholinergic burden (ACB) measures and their ability to predict changes in older people's physical function and quality of life. Design Eligible cohort or case-control studies were identified systematically using comprehensive search terms and a validated search filter for prognostic studies. Medline (OVID), EMBASE (OVID), CINAHL (EMBSCO), and PsycINFO (OVID) databases were searched. Risk of bias, using Quality in Prognosis Studies tool, and quality of evidence, using the Grading of Recommendations, Assessment, Development and Evaluation, were assessed. Setting and Participants People aged 65 years and older from any clinical setting. Measures Any ACB measures were accepted (including the anticholinergic domain of the Drug Burden Index). Any global/multidimensional measure for physical function and/or quality of life was accepted for outcome. Results Thirteen studies reporting associations between ACB and physical function (n = 10) or quality of life (n = 4) were included. Exposure measures included Anticholinergic Cognitive Burden Scale, Anticholinergic Drug Scale, Anticholinergic Risk Scale, Clinician Rated Anticholinergic Score, and the anticholinergic domain of the Drug Burden Index. All studies were rated moderate risk of bias in ≥2 Quality in Prognosis Studies categories with 5 rated high risk in ≥1 categories. Seven of 10 studies (5251 of 7569 participants) reported significant decline in physical function with increased burden. All 4 studies (2635 participants) reporting quality of life demonstrated similar association with increased burden. High risk of biases and inadequate data reporting restricted analysis. There was no evidence to support one measure being superior to another. Conclusions and Implications The evidence supports association between increased ACB and future impairments in physical function and quality of life. No conclusion can be made regarding which ACB measure has the best prognostic value. Well-designed longitudinal studies are required to address this. Clinicians should be aware of patient's anticholinergic burden and consider alternative medications where appropriate.

1.1 Background Greater anticholinergic burden (ACB) increases the risk of mortality in older individuals, yet the strength of this association varies between studies. One possible explanation for this variance is the use of different approaches to quantify ACB. This systematic review (PROSPERO number CRD42019115918) assessed the prognostic utility of ACB-specific measures on mortality in older individuals. 1.2 Methods Multiple cross-disciplinary databases were searched from 2006-2018. Observational studies assessing the association between ACB and mortality utilizing ≥1 ACB measure, involving persons aged ≥65 years were included. Screening and data extraction were performed by two independent reviewers, with disagreements resolved by a third independent reviewer. Risk of bias and quality of evidence were assessed using Quality in Prognosis Studies (QUIPS) and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria. Meta-analysis was conducted where appropriate. 1.3 Results Of 19,224 titles, 20 articles describing 18 cohort studies involving 498,056 older individuals were eligible. Eight anticholinergic-specific measures were identified; the Anticholinergic Cognitive Burden Scale (ACBS, n=9) and Anticholinergic Risk scale (ARS, n=8) were most frequently reported. The evidence base was of poor quality, with moderate to high risk of bias. Meta-analysis showed increased mortality risk. 1.4 Conclusions There was a modest association between some ACB measures and mortality, with most evidence derived from the ACBS. Studies comparing different measures within the same population were lacking. Analysis was limited by poor generalizability between studies, specifically regarding heterogeneity in methodology and reporting, as well as high risk of bias for most studies in the evidence base.

Background Search filter development for adverse effects has tended to focus on retrieving studies of drug interventions. However, a different approach is required for surgical interventions. Objective To develop and validate search filters for medline and Embase for the adverse effects of surgical interventions. Methods Systematic reviews of surgical interventions where the primary focus was to evaluate adverse effect(s) were sought. The included studies within these reviews were divided randomly into a development set, evaluation set and validation set. Using word frequency analysis we constructed a sensitivity maximising search strategy and this was tested in the evaluation and validation set. Results Three hundred and fifty eight papers were included from 19 surgical intervention reviews. Three hundred and fifty two papers were available on medline and 348 were available on Embase. Generic adverse effects search strategies in medline and Embase could achieve approximately 90% relative recall. Recall could be further improved with the addition of specific adverse effects terms to the search strategies. Conclusion We have derived and validated a novel search filter that has reasonable performance for identifying adverse effects of surgical interventions in medline and Embase. However, we appreciate the limitations of our methods, and recommend further research on larger sample sizes and prospective systematic reviews.

Authors and indexers are increasingly including terms for adverse drug effects in the titles, abstracts or indexing of records in MEDLINE and Embase. However, it is not clear if this is the same for studies with non-drug adverse effects data. We therefore assessed the feasibility of using adverse effects terms when searching MEDLINE or Emabse to retrieve papers of non-drug adverse effects. A collection of papers that reported data on non-drug adverse effects was sought from included studies of systematic reviews. Each included study was analysed to ascertain whether the corresponding record in MEDLINE and Embase included adverse effects terms in the title, abstract or indexing. From 9,129 records screened from DARE (Database of Abstracts of Reviews of Effects), 30 reviews evaluating non-drug adverse effects met our inclusion criteria. From these, 635 unique papers were included in our analysis. Sensitive searches for adverse effects required generic and specific named adverse effects terms using the title, abstract and indexing. Records relating to surgical interventions were more likely to contain adverse effects terms than records relating to non-surgical interventions. Using any adverse effects terms in the title, abstract or indexing in MEDLINE and Embase would have identified an average of 94% of papers on surgical adverse effect interventions per systematic review and 72% of papers on non-surgical adverse effects per systematic review. Hence, while a generic non-drug adverse effect search filter may not yet be feasible, a filter for the adverse effects of surgical interventions may be within reach.

Background Metabolomics refers to study of the metabolome, the entire set of metabolites produced by a biological system. The application of metabolomics to exhaled breath samples - breathomics - is a rapidly growing field with potential application to asthma diagnosis and management. Objectives We aimed to review the adult asthma breathomic literature and present a comprehensive list of volatile organic compounds identified by asthma breathomic models. Methods We undertook a systematic search for literature on exhaled volatile organic compounds in adult asthma. We assessed the quality of studies and performed a qualitative synthesis. Results We identified twenty studies; these were methodologically heterogenous with a variable risk of bias. Studies almost universally reported breathomics to be capable of differentiating - with moderate or greater accuracy - between samples from healthy controls and those with asthma; and to be capable of phenotyping disease. However, there was little concordance in the compounds upon which discriminatory models were based. Conclusion Results to-date are promising but validation in independent prospective cohorts is needed. This may be challenging given the high levels of inter-individual variation. However, large-scale, multi-centre studies are underway and validation efforts have been aided by the publication of technical standards likely to increase inter-study comparability. Successful validation of breathomic models for diagnosis and phenotyping would constitute an important step towards personalised medicine in asthma.

Aim We conducted a systematic review of the use of continuous glucose monitoring (CGM) in older patients, in order to consolidate the growing evidence base in this area. Methods Our protocol was registered on PROSPERO (CRD42017068523). We searched SCI Web of Science, Ovid SP MEDLINE and EMBASE from January 2010 to June 2017 for observational studies and randomized controlled trial of CGM in older patients (mean age 65 or older) with diabetes. We excluded studies that involved only hospitalized patients. Two reviewers independently extracted data blood sugar values (in particular, hypoglycemic episodes) captured with the use of CGM. We also assessed adverse events and acceptability of CGM. Results After screening 901 abstracts, we included nine studies with a total of 989 older patients with diabetes. The CGM studies reveal that hypoglycemic episodes were occurring in a sizeable proportion (28–65%) of participants. Most (80–100%) of these episodes were asymptomatic, with some patients spending nearly 2 h per day in the hypoglycemic range. Older people with diabetes found CGM acceptable and experienced improved health-related well-being. Conclusion CGM frequently picks up asymptomatic hypoglycemic episodes in older patients with diabetes. Users of CGM report improved well-being, and reduction of diabetes-related stress.

World Health Organization Responds to Concerns about Surgical Site Infection Prevention Recommendations.

Plain English summary If people can read, understand and act on health information to better their health and reduce illness, they are thought to have “adequate” health literacy. Poor health literacy can mean people are less able to access health care and manage their health. Health literacy tends to worsen as adults get older, and is especially poor in adults age 65 and over. Ideally, health literacy interventions target people before age 65, to establish good skills and habits before people have many health problems associated with ageing. It is also good if researchers consult ordinary people, including patients and the public (PPI) when planning a programme to try to improve health literacy. This may help ensure individual needs are catered for. We therefore looked for studies that described any role of patient or public representatives in the research planning stages. We explored how the representatives contributed to each project. We found only 20 studies that included people other than the research team. Lack of reporting and consultation with patient and public representatives may contribute to less success when public health programmes are undertaken. Abstract Background Health literacy is the ability to understand, access and use health care and is a critical mediating factor that affects the health of older adults. Patient and public involvement in health and social care research, policy and design of care delivery is one mechanism that can promote production of better health literacy. This mapping review looks for and describes practices, concepts and methods that have been reported involving patients and public in the development and design of health literacy interventions for older people. Methods Studies for the present review were selected from an inventory of health behaviour studies published between 2003 and 2013. The inventory was created by systematic searches on bibliographic databases (Medline, CINAHL, Scopus, Google) for health literacy interventions involving older people (50+ years) and resulted in screening of 5561 articles, of which 1097 met study inclusion criteria. For the research described in this article 96 of the 1097 studies specifically focused on health literacy and were independently screened by two reviewers to assess involvement of stakeholders other than investigators and participants. Results Twenty studies included patient and/or public involvement in at least one research domain: design, management or evaluation. Involvement included volunteers, older people, patients, and/or community representatives. Conclusions Patient and public involvement were rarely reported in studies on health literacy interventions for older people. Future intervention development needs high quality PPI, which is well reported to develop the evidence base and inform practice.

Background Laparoscopic appendectomy is amongst the most common general surgical procedures performed in the developed world. Arguably, the most critical part of this procedure is effective closure of the appendix stump to prevent catastrophic intra-abdominal complications from a faecal leak into the abdominal cavity. A variety of methods to close the appendix stump are used worldwide; these can be broadly divided into traditional ligatures (such as intracorporeal or extracorporeal ligatures or Roeder loops) and mechanical devices (such as stapling devices, clips, or electrothermal devices). However, the optimal method remains unclear. Objectives To compare all surgical techniques now used for appendix stump closure during laparoscopic appendectomy. Search methods In June 2017, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 6) in the Cochrane Library, MEDLINE Ovid (1946 to 14 June 2017), Embase Ovid (1974 to 14 June 2017), Science Citation Index - Expanded (14 June 2017), China Biological Medicine Database (CBM), the World Health Organization International Trials Registry Platform search portal, ClinicalTrials.gov, Current Controlled Trials, the Chinese Clinical Trials Register, and the EU Clinical Trials Register (all in June 2017). We searched the reference lists of relevant publications as well as meeting abstracts and Conference Proceedings Citation Index to look for additional relevant clinical trials. Selection criteria We included all randomised controlled trials (RCTs) that compared mechanical appendix stump closure (stapler, clips, or electrothermal devices) versus ligation (Endoloop, Roeder loop, or intracorporeal knot techniques) for uncomplicated appendicitis. Data collection and analysis Two review authors identified trials for inclusion, collected data, and assessed risk of bias independently. We performed the meta-analysis using Review Manager 5. We calculated the odds ratio (OR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CIs). Main results We included eight randomised studies encompassing 850 participants. Five studies compared titanium clips versus ligature, two studies compared an endoscopic stapler device versus ligature, and one study compared an endoscopic stapler device, titanium clips, and ligature. In our analyses of primary outcomes, we found no differences in total complications (OR 0.97, 95% CI 0.27 to 3.50, 8 RCTs, very low-quality evidence), intraoperative complications (OR 0.93, 95% CI 0.34 to 2.55, 8 RCTs, very low-quality evidence), or postoperative complications (OR 0.80, 95% CI 0.21 to 3.13, 8 RCTs, very low-quality evidence) between ligature and all types of mechanical devices. However, our analyses of secondary outcomes revealed that use of mechanical devices saved approximately nine minutes of total operating time when compared with use of a ligature (mean difference (MD) -9.04 minutes, 95% CI -12.97 to -5.11 minutes, 8 RCTs, very low-quality evidence). However, this finding did not translate into a clinically or statistically significant reduction in inpatient hospital stay (MD 0.02 days, 95% CI -0.12 to 0.17 days, 8 RCTs, very low-quality evidence). Available information was insufficient for reliable comparison of total hospital costs and postoperative pain/quality of life between the two approaches. Overall, evidence across all analyses was of very low quality, with substantial potential for confounding factors. Given the limitations of all studies in terms of bias and the low quality of available evidence, a clear conclusion regarding superiority of any one particular type of mechanical device over another is not possible. Authors' conclusions Evidence is insufficient at present to advocate omission of conventional ligature-based appendix stump closure in favour of any single type of mechanical device over another in uncomplicated appendicitis.

Background although variation in stroke service provision and outcomes have been previously investigated, it is less well known what service characteristics are associated with reduced short- and medium-term mortality. Methods data from a prospective multicentre study (2009–12) in eight acute regional NHS trusts with a catchment population of about 2.6 million were used to examine the prognostic value of patient-related factors and service characteristics on stroke mortality outcome at 7, 30 and 365 days post stroke, and time to death within 1 year. Results a total of 2,388 acute stroke patients (mean (standard deviation) 76.9 (12.7) years; 47.3% men, 87% ischaemic stroke) were included in the study. Among patients characteristics examined increasing age, haemorrhagic stroke, total anterior circulation stroke type, higher prestroke frailty, history of hypertension and ischaemic heart disease and admission hyperglycaemia predicted 1-year mortality. Additional inclusion of stroke service characteristics controlling for patient and service level characteristics showed varying prognostic impact of service characteristics on stroke mortality over the disease course during first year after stroke at different time points. The most consistent finding was the benefit of higher nursing levels; an increase in one trained nurses per 10 beds was associated with reductions in 30-day mortality of 11–28% (P < 0.0001) and in 1-year mortality of 8–12% (P < 0.001). Conclusions there appears to be consistent and robust evidence of direct clinical benefit on mortality up to 1 year after acute stroke of higher numbers of trained nursing staff over and above that of other recognised mortality risk factors.

Non-randomized studies of the effects of interventions are critical to many areas of health care evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomized Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomization to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomized studies.

Background We performed a systematic review to assess whether we can quantify the underreporting of adverse events (AEs) in the published medical literature documenting the results of clinical trials as compared with other nonpublished sources, and whether we can measure the impact this underreporting has on systematic reviews of adverse events. Methods and Findings Studies were identified from 15 databases (including MEDLINE and Embase) and by handsearching, reference checking, internet searches, and contacting experts. The last database searches were conducted in July 2016. There were 28 methodological evaluations that met the inclusion criteria. Of these, 9 studies compared the proportion of trials reporting adverse events by publication status. The median percentage of published documents with adverse events information was 46% compared to 95% in the corresponding unpublished documents. There was a similar pattern with unmatched studies, for which 43% of published studies contained adverse events information compared to 83% of unpublished studies. A total of 11 studies compared the numbers of adverse events in matched published and unpublished documents. The percentage of adverse events that would have been missed had each analysis relied only on the published versions varied between 43% and 100%, with a median of 64%. Within these 11 studies, 24 comparisons of named adverse events such as death, suicide, or respiratory adverse events were undertaken. In 18 of the 24 comparisons, the number of named adverse events was higher in unpublished than published documents. Additionally, 2 other studies demonstrated that there are substantially more types of adverse events reported in matched unpublished than published documents. There were 20 meta-analyses that reported the odds ratios (ORs) and/or risk ratios (RRs) for adverse events with and without unpublished data. Inclusion of unpublished data increased the precision of the pooled estimates (narrower 95% confidence intervals) in 15 of the 20 pooled analyses, but did not markedly change the direction or statistical significance of the risk in most cases. The main limitations of this review are that the included case examples represent only a small number amongst thousands of meta-analyses of harms and that the included studies may suffer from publication bias, whereby substantial differences between published and unpublished data are more likely to be published. Conclusions There is strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study. The inclusion of unpublished data can also reduce the imprecision of pooled effect estimates during meta-analysis of adverse events., In a systematic review, Su Golder and colleagues study the completeness of adverse event reporting, mainly associated with pharmaceutical interventions, in published articles as compared with other information sources., Author Summary Why Was This Study Done? Research on medical treatments provides information on the efficacy of such treatments, and on side effects. The balance between efficacy and side effects is important in assessing the overall benefit of a new treatment. How much information on the side effects of medical treatments that is currently not published in journal articles is not known. What Did the Researchers Do and Find? We searched several databases and other sources, and found 28 studies that provided information on the amount of data on side effects in published journal articles as compared to other sources (such as websites, conferences, and industry-held data). The 28 studies found that a lower percentage of published studies than unpublished studies contain information on side effects of treatments. A lower number of side effects are generally reported in published than unpublished studies, and a wider range of named side effects are reported in unpublished than published studies. Including unpublished data in research leads to more precise conclusions. What Do These Findings Mean? These findings suggest that researchers should search beyond journal publications for information on side effects of treatments. These findings also support the need for the drug industry to release full data on side effects so that a complete picture can be given to health professionals, policy makers, and patients.

OBJECTIVE: To review the relationship between health literacy and adherence to cardiovascular/diabetes medication. DATA SOURCES: We searched EMBASE (1974-February 2012) and MEDLINE (1948-February 2012). Search terms included health literacy, numeracy, health education and related terms, health literacy measurement tools, and medication adherence. STUDY SELECTION AND DATA EXTRACTION: English-language articles of all study designs were considered. Articles were included if they had a measurement of health literacy and medication adherence and if participants were older adults taking drugs for cardiovascular illness or diabetes mellitus. DATA SYNTHESIS: A total of 1310 citations were reviewed, including 9 articles that reported on 7 research studies. Most studies were retrospective, and all were based in the US. Because there was considerable diversity in measurements, participant characteristics, and outcome measures, we conducted a narrative synthesis rather than a meta-analysis. In assessing study validity, we looked at participant selection, method of measuring health literacy and medication adherence, missing data or losses, and adjustment for confounders. Of the 7 included studies, only 1 found a demonstrable association between health literacy and refill adherence. One clinical trial failed to show significant improvements in medication adherence after an intervention to improve health literacy. CONCLUSIONS: The current evidence does not show a definite association between health literacy and medication adherence in older adults with cardiovascular disease or diabetes mellitus. In the absence of a definite link, efforts to develop interventions to improve health literacy would not necessarily improve adherence to cardiovascular medications. There is an urgent need for robust studies outside of the US, with wider, generalized recruitment of participants.

Objectives: The aim of this study is to determine the relative value and contribution of searching different sources to identify adverse effects data.Methods: The process of updating a systematic review and meta-analysis of thiazolidinedione-related fractures in patients with type 2 diabetes mellitus was used as a case study. For each source searched, a record was made for each relevant reference included in the review noting whether it was retrieved with the search strategy used and whether it was available but not retrieved. The sensitivity, precision, and number needed to read from searching each source and from different combinations of sources were also calculated.Results: There were 58 relevant references which presented sufficient numerical data to be included in a meta-analysis of fractures and bone mineral density. The highest number of relevant references were retrieved from Science Citation Index (SCI) (35), followed by BIOSIS Previews (27) and EMBASE (24). The precision of the searches varied from 0.88% (Scirus) to 41.67% (CENTRAL). With the search strategies used, the minimum combination of sources required to retrieve all the relevant references was; the GlaxoSmithKline (GSK) website, Science Citation Index (SCI), EMBASE, BIOSIS Previews, British Library Direct, Medscape DrugInfo, handsearching and reference checking, AHFS First, and Thomson Reuters Integrity or Conference Papers Index (CPI).Conclusions: In order to identify all the relevant references for this case study a number of different sources needed to be searched. The minimum combination of sources required to identify all the relevant references did not include MEDLINE

One of the key difficulties in conducting specific searches for adverse effects stems from the absence of adverse effects terms in the title, abstract, and indexing of relevant articles. In 2001, Derry et al. evaluated articles that reported adverse effects data from clinical trials and found that about 23% of such articles had no adverse effects terms (either generic or specific) in the title, abstract, or indexing of records in MEDLINE or EMBASE [1]. Hence, electronic searches based on specific adverse effect–related terms could miss nearly a quarter of relevant papers. Current guidance on systematic reviews of adverse effects emphasizes the use of nonspecific searches (without relying on adverse effects terms) as well as the need to check full-text versions of retrieved articles to ensure a complete search [2]. Unfortunately, implementation of such guidance is onerous and time consuming compared to running more specific adverse effects–based searches. However, methodological developments in the past decade might have changed the situation since Derry et al.'s study [1]. In 2003, ten new recommendations about the reporting of harms were added to the Consolidated Standards of Reporting Trials (CONSORT), including a recommendation that if the study collected data on harms, the title or abstract should state this [3]. Additionally, the Cochrane Adverse Effects Methods Group , which was formed in 2007, as well as many other authors, called for improved reporting of adverse effects [4–32]. However, it is unclear if these developments have had a meaningful impact on the prevalence of adverse effects terms in the title, abstract, or indexing of relevant adverse effects papers. This study collected a large, diverse, and contemporaneous cohort of articles with adverse effects data so that the presence or absence of specific adverse effects terms could be assessed [1].

Background: Search filters can potentially improve the efficiency of searches involving electronic databases such as medline and embase. Although search filters have been developed for identifying records that contain adverse effects data, little is known about the sensitivity of such filters. Objectives: This study measured the sensitivity of using available adverse effects filters to retrieve papers with adverse effects data. Methods: A total of 233 included studies from 26 systematic reviews of adverse effects were used for analysis. Search filters from medline and embase were tested for their sensitivity in retrieving the records included in these reviews. In addition, the sensitivity of each individual search term used in at least one search filter was measured. Results: Subheadings proved the most useful search terms in both medline and embase. No indexing terms in medline achieved over 12% sensitivity. The sensitivity of published search filters varied in medline from 3% to 93% and in embase from 57% to 97%. Whether this level of sensitivity is acceptable will be dependent on the purpose of the search. Conclusions: Although no adverse effects search filter captured all the relevant records, high sensitivity could be achieved. Search filters may therefore be useful in retrieving adverse effects data.

Background: Search filters have been developed in MEDLINE and EMBASE to help overcome the challenges of searching electronic databases for information on adverse effects. However, little evaluation of their effectiveness has been carried out. Objectives: To measure the sensitivity and precision of available adverse effects search filters in MEDLINE and EMBASE. Methods: A case study systematic review of fracture related adverse effects associated with the use of thiazolidinediones was used. Twelve MEDLINE search strategies and three EMBASE search strategies were tested. Results: Nineteen relevant references from MEDLINE and 24 from EMBASE were included in the review. Four search filters in MEDLINE achieved high sensitivity (95 or 100%) with an improved level of precision from searches without any adverse effects filter. High precision in MEDLINE could also be achieved (up to 53%) using search filters that rely on Medical Subject Headings. No search filter in EMBASE achieved high precision (all were under 5%) and the highest sensitivity in EMBASE was 83%. Conclusions: Adverse effects search filters appear to be effective in MEDLINE for achieving either high sensitivity or high precision. Search filters in EMBASE, however, do not appear as effective, particularly in improving precision.

Background The effect of inhaled corticosteroids (ICS) on fracture risk in patients with chronic obstructive pulmonary disease (COPD) remains uncertain. The aim of this study was to evaluate the association between ICS and fractures in COPD. Methods MEDLINE, EMBASE, regulatory documents and company registries were searched up to August 2010. Randomised controlled trials (RCTs) of budesonide or fluticasone versus control treatment for COPD (≥24 weeks duration) and controlled observational studies reporting on fracture risk with ICS exposure vs no exposure in COPD were included. Peto OR meta-analysis was used for fracture risk from RCTs while ORs from observational studies were pooled using the fixed effect inverse variance method. Dose–response analysis was conducted using variance-weighted least squares regression in the observational studies. Heterogeneity was assessed using the I 2 statistic. Results Sixteen RCTs (14 fluticasone, 2 budesonide) with 17 513 participants, and seven observational studies (n=69 000 participants) were included in the meta-analysis. ICSs were associated with a significantly increased risk of fractures (Peto OR 1.27; 95% CI 1.01 to 1.58; p=0.04; I 2 =0%) in the RCTs. In the observational studies, ICS exposure was associated with a significantly increased risk of fractures (OR 1.21; 95% CI 1.12 to 1.32; p 2 =37%), with each 500 μg increase in beclomethasone dose equivalents associated with a 9% increased risk of fractures, OR 1.09 (95% CI 1.06 to 1.12; p Conclusion Among patients with COPD, long-term exposure to fluticasone and budesonide is consistently associated with a modest but statistically significant increased likelihood of fractures.

ObjectiveTo evaluate homocysteine (Hcy) levels in patients with peripheral arterial disease (PAD) as compared to unaffected controls, and to review the clinical effects of therapy aimed at lowering homocysteine in PAD patients.MethodsMEDLINE, EMBASE and Cochrane databases were searched from 1950 to December 2007. We selected observational studies and trials that evaluated Hcy levels in patients with PAD compared to unaffected controls. We also included trials on the effect of Hcy-lowering therapy (folate supplementation) in PAD patients. Continuous outcomes were pooled in a random effects meta-analysis of the weighted mean difference between comparator groups.ResultsWe retrieved 33 potentially suitable articles from our search. Meta-analysis of 14 relevant studies showed that Hcy was significantly elevated (pooled mean difference +4.31μmoll; 95% C.I. 1.71, 6.31, p

Our aim was to review systematically the literature on educational interventions to improve prescribing by medical students and junior doctors. MEDLINE, EMBASE, Educational Resource Information Center, British Education Index, PsycINFO, CINAHL, TIMELIT, Cochrane Trials Database and grey literature were searched. Inclusion criteria were: educational interventions to improve medical student and/or junior doctors' prescribing, in primary or secondary care settings, and published after 1990. After screening 3189 records, we retrieved 11 controlled and four 'before-and-after' trials. Ten controlled trials showed improvements in the scores of the intervention group on written scenarios or clinical examination stations, but one study in junior doctors showed no effect on real-life prescription errors. Only one intervention [the World Health Organization (WHO) Good Prescribing Guide, in six randomized trials] had been tested in a variety of international settings and across a range of students at different levels. All four 'before-and-after' trials reported significant improvements in written tests or clinical stations. However, most studies tested only small numbers of participants and were affected by a range of methodological flaws. There is only moderate evidence in the literature to inform medical schools about how to prepare medical students for the challenges of prescribing. The WHO Good Prescribing Guide is the only model that has been widely used and shown to improve prescribing. Although it is based on sound principles, there is a need for further development. Robust methods of assessment are required to show clearly whether particular teaching interventions are successful.

Background— The prognostic impact of site-specific major bleeding complications after percutaneous coronary intervention (PCI) has yielded conflicting data. The aim of this study is to provide an overview of site-specific major bleeding events in contemporary PCI and study their impact on mortality and major adverse cardiovascular event outcomes. Methods and Results— We conducted a meta-analysis of PCI studies that evaluated site-specific periprocedural bleeding complications and their impact on major adverse cardiovascular events and mortality outcomes. A systematic search of MEDLINE and Embase was conducted to identify relevant studies and random effects meta-analysis was used to estimate the risk of adverse outcomes with site-specific bleeding complications. Twenty-five relevant studies including 2 400 645 patients that underwent PCI were identified. Both non–access site (risk ratio [RR], 4.06; 95% confidence interval [CI], 3.21–5.14) and access site (RR, 1.71; 95% CI, 1.37–2.13) related bleeding complications were independently associated with an increased risk of periprocedural mortality. The prognostic impact of non–access site–related bleeding events on mortality related to the source of anatomic bleeding, for example, gastrointestinal RR, 2.78; 95% CI, 1.25 to 6.18; retroperitoneal RR, 5.87; 95% CI, 1.63 to 21.12; and intracranial RR, 22.71; 95% CI, 12.53 to 41.15. Conclusions— The prognostic impact of bleeding complications after PCI varies according to anatomic source and severity. Non–access site-related bleeding complications have a similar prevalence to those from the access site but are associated with a significantly worse prognosis partly related to the severity of the bleed. Clinicians should minimize the risk of major bleeding complications during PCI through judicious use of bleeding avoidance strategies irrespective of the access site used.

Objective To determine whether anecdotal reports of suspected adverse drug reactions are valuable early warning signals. Design Systematic literature survey Data sources We evaluated all case reports of adverse drug reactions published in 1997 in five medical journals. Reports were excluded if the adverse reaction had previously been described in earlier publications and was already listed in the product information of the drug reference source (the British National Formulary (BNF) or the Medicines Compendium). We used the Web of Knowledge Citation Index and Medline for 2003 to identify follow-up studies. Main outcome measures Primary: the number of suspected adverse reactions subjected to formal validation studies and the findings of these studies. Secondary: the number of instances in which the warning from the case report was incorporated into the product information. Results We evaluated 63 suspected adverse reactions and found that most (52/63, 83%) had not yet been subjected to further detailed evaluation. Data from controlled studies that supported the postulated link between the drug and the adverse event were available in only three cases. Of the 48 agents listed in the drug reference sources, details of the suspected reaction were subsequently added to the Medicines Compendium in 15 instances, and to the BNF in seven instances. In each case, only one reaction had been confirmed. Conclusions Published case reports of suspected adverse reactions are of limited value as suspicions are seldom subjected to confirmatory investigation. Furthermore, these alerts are not incorporated into drug reference sources in a systematic manner.

SummaryIntroductionThe initial prognostic assessment of patients with community-acquired pneumonia (CAP) has important clinical implications. We hypothesized that midregional proadrenomedullin (MR-proADM) is a valuable test for the prediction of outcomes in patients with CAP.MethodsWe performed a systemic review of the literature and a meta-analysis to evaluate the prognostic value of MR-proADM for short and long-term mortality in patients with CAP.ResultsTwelve studies were included in the systematic review. Elevated MR-proADM was associated with an increase in short-term mortality (OR = 6.8; 95% CI: 4.65–10.13; P value

Background Dietary interventions are an important component of cardiovascular risk factor management although their impact on cardiovascular risk and mortality remains uncertain. We have studied influence of a vegetarian diet on cardiovascular risk and mortality. Methods We searched MEDLINE and EMBASE for comparative studies that evaluated clinical outcomes associated with vegetarian diet as compared to non-vegetarian controls or the general population. Relevant studies were pooled using random effects meta-analysis for risk of death, ischaemic heart disease (IHD) and cerebrovascular disease. We conducted subgroup analysis according to specific type of cohort (e.g. Seventh Day Adventist [SDA]) and gender. Results Eight studies met the inclusion criteria with 183,321 participants (n=183,321). There was significant heterogeneity in all the meta-analyses, particularly evident with the studies of SDA. In all instances, we found that SDA studies showed greater effect size as compared to non-SDA studies: death (RR 0.68 95% CI 0.45–1.02 vs RR 1.04 95% CI 0.98–1.10), ischaemic heart disease (IHD) (RR 0.60 95% CI 0.43–0.80 vs RR 0.84 95% CI 0.74–0.96) and cerebrovascular disease (RR 0.71 95% CI 0.41–1.20 vs RR 1.05 95% CI 0.89–1.24). Sex specific analyses showed that IHD was significantly reduced in both genders but risk of death and cerebrovascular disease was only significantly reduced in men. Conclusions Data from observational studies indicates that there is modest cardiovascular benefit, but no clear reduction in overall mortality associated with a vegetarian diet. This evidence of benefit is driven mainly by studies in SDA, whereas the effect of vegetarian diet in other cohorts remains unproven.

In recent years, clinical trials and observational studies have raised concerns about the potential adverse effects of inhaled corticosteroids (ICS) such as pneumonia, cataract, fractures and hyperglycaemia, which are of particular concern for older patients.We conducted a meta-review by searching electronic databases (MEDLINE, EMBASE, PubMed) for systematic reviews and meta-analyses of ICS use and the adverse effects of interest. We also evaluated new primary studies that reported information beyond that available from previously published meta-analyses. Two reviewers independently extracted data on measures of associated harm with ICS use.We identified five relevant meta-analyses for inclusion in this meta-review, and also three new studies of ICS and pneumonia. We found consistent evidence of a dose-response relationship between ICS use and serious adverse effects such as fractures and pneumonia. The estimated number needed to treat for harm due to fracture with ICS was 83 with 3-years use, and 60 per year for pneumonia. Both asthma and chronic obstructive pulmonary disease (COPD) users of ICS were at risk of pneumonia, with fluticasone appearing to confer higher risk than budesonide. There is also some suggestion that ICS use is associated with cataracts in a dose-response manner but the evidence is less robust here. Equally, the influence of ICS on diabetes mellitus remains uncertain.In view of the dose-response relationship seen between ICS use and important adverse effects such as fractures and pneumonia, clinicians needs to carefully balance the benefits of ICS versus the harms in older patients receiving long-term high-dose ICS.

Objective: About half of medical and health related studies are not published. We conducted a systematic review of reports on reasons given by investigators for not publishing their studies in peer-reviewed journals. Methods: MEDLINE, EMBASE, PsycINFO, and SCOPUS (until 13/09/2013), and references of identified articles were searched to identify reports of surveys that provided data on reasons given by investigators for not publishing studies. The proportion of non-submission and reasons for non-publication was calculated using the number of unpublished studies as the denominator. Because of heterogeneity across studies, quantitative pooling was not conducted. Exploratory subgroup analyses were conducted. Results: We included 54 survey reports. Data from 38 included reports were available to estimate proportions of at least one reason given for not publishing studies. The proportion of non-submission among unpublished studies ranged from 55% to 100%, with a median of 85%. The reasons given by investigators for not publishing their studies included: lack of time or low priority (median 33%), studies being incomplete (median 15%), study not for publication (median 14%), manuscript in preparation or under review (median 12%), unimportant or negative result (median 12%), poor study quality or design (median 11%), fear of rejection (median 12%), rejection by journals (median 6%), author or co-author problems (median 10%), and sponsor or funder problems (median 9%). In general, the frequency of reasons given for non-publication was not associated with the source of unpublished studies, study design, or time when a survey was conducted. Conclusions: Non-submission of studies for publication remains the main cause of non-publication of studies. Measures to reduce non-publication of studies and alternative models of research dissemination need to be developed to address the main reasons given by investigators for not publishing their studies, such as lack of time or low priority and fear of being rejected by journals.

Background. Several models have been developed to predict the risk of mortality in community-acquired pneumonia (CAP). This study aims to systematically identify and evaluate the performance of published risk prediction models for CAP.Methods. We searched MEDLINE, EMBASE, and Cochrane library in November 2011 for initial derivation and validation studies for models which predict pneumonia mortality. We aimed to present the comparative usefulness of their mortality prediction.Results. We identified 20 different published risk prediction models for mortality in CAP. Four models relied on clinical variables that could be assessed in community settings, with the two validated models BTS1 and CRB-65 showing fairly similar balanced accuracy levels (0.77 and 0.72, resp.), while CRB-65 had AUROC of 0.78. Nine models required laboratory tests in addition to clinical variables, and the best performance levels amongst the validated models were those of CURB and CURB-65 (balanced accuracy 0.73 and 0.71, resp.), with CURB-65 having an AUROC of 0.79. The PSI (AUROC 0.82) was the only validated model with good discriminative ability among the four that relied on clinical, laboratorial, and radiological variables.Conclusions. There is no convincing evidence that other risk prediction models improve upon the well-established CURB-65 and PSI models.

Search filters can potentially improve the efficiency of searches involving electronic databases such as medline and embase. Although search filters have been developed for identifying records that contain adverse effects data, little is known about the sensitivity of such filters. This study measured the sensitivity of using available adverse effects filters to retrieve papers with adverse effects data. A total of 233 included studies from 26 systematic reviews of adverse effects were used for analysis. Search filters from medline and embase were tested for their sensitivity in retrieving the records included in these reviews. In addition, the sensitivity of each individual search term used in at least one search filter was measured. Subheadings proved the most useful search terms in both medline and embase. No indexing terms in medline achieved over 12% sensitivity. The sensitivity of published search filters varied in medline from 3% to 93% and in embase from 57% to 97%. Whether this level of sensitivity is acceptable will be dependent on the purpose of the search. Although no adverse effects search filter captured all the relevant records, high sensitivity could be achieved. Search filters may therefore be useful in retrieving adverse effects data.

Search filters have been developed in MEDLINE and EMBASE to help overcome the challenges of searching electronic databases for information on adverse effects. However, little evaluation of their effectiveness has been carried out.To measure the sensitivity and precision of available adverse effects search filters in MEDLINE and EMBASE.A case study systematic review of fracture related adverse effects associated with the use of thiazolidinediones was used. Twelve MEDLINE search strategies and three EMBASE search strategies were tested.Nineteen relevant references from MEDLINE and 24 from EMBASE were included in the review. Four search filters in MEDLINE achieved high sensitivity (95 or 100%) with an improved level of precision from searches without any adverse effects filter. High precision in MEDLINE could also be achieved (up to 53%) using search filters that rely on Medical Subject Headings. No search filter in EMBASE achieved high precision (all were under 5%) and the highest sensitivity in EMBASE was 83%.Adverse effects search filters appear to be effective in MEDLINE for achieving either high sensitivity or high precision. Search filters in EMBASE, however, do not appear as effective, particularly in improving precision.

Introduction: There is considerable debate surrounding the clinical relevance of an adverse interaction between clopidogrel and proton pump inhibitors (PPIs). Some studies have indicated that PPIs may attenuate the antiplatelet efficacy of clopidogrel, thus leading to increased risk of thrombotic cardiovascular events. Areas covered: From a literature search of MEDLINE and EMBASE, the authors critically appraised data from systematic reviews, randomised controlled trials and observational studies that evaluated platelet function and clinical outcomes in patients receiving concomitant clopidogrel and PPIs. Expert opinion: The evidence from platelet function and cardiovascular outcome studies is highly inconsistent. Higher quality data from randomised trials indicate that use of PPI therapy for up to 6 months is unlikely to cause any adverse interaction with clopidogrel, and there are gastrointestinal benefits with PPI use.

OBJECTIVES: To estimate the prevalence of low health literacy, and evaluate the impact of low health literacy on outcomes in patients with chronic musculoskeletal conditions.DATA SOURCES: We searched Embase, Pubmed, PsycInfo, and CINAHL in January 2011 for relevant studies, restricted to English-language articles.STUDY SELECTION AND DATA EXTRACTION: Studies were included if they measured health literacy and/or reported on the link between outcomes and health literacy levels in patients with osteoporosis, osteoarthritis, or rheumatoid arthritis. We assessed risk of bias from participant selection, methods of measuring health literacy and functional outcomes, missing data, and potential for confounding.DATA SYNTHESIS: We reviewed 1863 citations and judged 8 studies to be relevant. Most were cross-sectional in nature, and five were based in the United States. Diversity in measurements, participant characteristics, and settings meant that results had to be synthesized narratively. Prevalence of low health literacy varied from 7% to 42%. Of the five studies that reported on musculoskeletal outcomes, only one showed an association (unadjusted) between low health literacy and greater pain and limitations in physical functioning. However, other studies, including those with multivariate analyses, found no significant relationship between health literacy and measures of pain or disease specific questionnaires. One clinical trial found short-term improvements in the mental health of patients with musculoskeletal conditions after an intervention to improve health literacy.LIMITATIONS: Most of the studies were cross-sectional in nature, which precludes interpretation of a causal relationship. The sample sizes may not have been sufficiently large to enable detection of significant associations.CONCLUSIONS: The current evidence does not show a consistent association between low health literacy and poorer functional outcomes in patients with chronic musculoskeletal conditions. In the absence of a definite link, efforts to develop interventions to improve health literacy would not necessarily improve health service or patient-related outcomes.

See related research article on page [E21][1] and at [www.cmaj.ca/lookup/doi/10.1503/cmaj.140848][2] In a linked research paper, Gillies and colleagues present a systematic review and meta-analyses showing a favourable safety profile for amoxicillin.[1][3] Their findings are important for

Aim To conduct a systematic review in order to compare adverse effects (AE) and the reporting of harm in randomised controlled trials (RCTs) and non-RCTs evaluating intravitreal ranibizumab and bevacizumab in age-related macular degeneration. Methods Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. Studies which compared bevacizumab or ranibizumab as monotherapy with any other control group were included. Case series were included if they met predefined quality standards. Results The 2 year results of phase III trials evaluating ranibizumab show that the rates of serious ocular AE were low (≤2.1%) but indicate major safety concerns (RR 3.13, 95% CI 1.10 to 8.92). A possible signal with regard to thromboembolic events (RR 1.35, 95% CI 0.66 to 2.77) and a significant increase in non-ocular haemorrhage (RR 1.62, 95% CI 1.03 to 2.55) were also noted. In contrast to ranibizumab trials, the RCTs evaluating bevacizumab are of limited value. The main shortcomings are small sample sizes and an apparent lack of rigorous monitoring for AE. A critical assessment of the large number of published case series evaluating bevacizumab also shows that no reliable conclusions on safety can be drawn using this study design. Therefore, any perception that intravitreal bevacizumab injections are not associated with major ocular or systemic AE are not supported by reliable data. Conclusion The bevacizumab studies show too many methodological limitations to rule out any major safety concerns. Higher evidence from ranibizumab trials suggests signals for an increased ocular and systemic vascular and haemorrhagic risk which warrants further investigation.

Systematic reviews can provide accurate and timely information on adverse effects. An essential part of the systematic review process is a thorough search of the literature. This often requires searching many different sources. However, it is unclear which sources are most effective at providing information on adverse effects.To identify and summarise studies that have evaluated sources of information on adverse effects.Studies were located by searching in 10 databases as well as by reference checking, hand searching, citation searching and contacting experts.A total of 6218 citations were retrieved yielding 19 studies which met the inclusion criteria. The included studies tended to focus on the adverse effects of drug interventions and compare the relative value of different sources using the number of relevant references retrieved from searches of each source. However, few studies were conducted recently with a large sample of references.This review suggests that embase, Derwent Drug File, medline and industry submissions may potentially provide the greatest number of relevant references for information on adverse effects of drugs. However, a systematic evaluation of the current value of different sources of information for adverse effects is urgently required.

Objectives To identify and appraise empirical studies on publication and related biases published since 1998; to assess methods to deal with publication and related biases; and to examine, in a random sample of published systematic reviews, measures taken to prevent, reduce and detect dissemination bias. Data sources The main literature search, in August 2008, covered the Cochrane Methodology Register Database, MEDLINE, EMBASE, AMED and CINAHL. In May 2009, PubMed, PsycINFO and OpenSIGLE were also searched. Reference lists of retrieved studies were also examined. Review methods In Part I, studies were classified as evidence or method studies and data were extracted according to types of dissemination bias or methods for dealing with it. Evidence from empirical studies was summarised narratively. In Part II, 300 systematic reviews were randomly selected from MEDLINE and the methods used to deal with publication and related biases were assessed. Results Studies with significant or positive results were more likely to be published than those with non-significant or negative results, thereby confirming findings from a previous HTA report. There was convincing evidence that outcome reporting bias exists and has an impact on the pooled summary in systematic reviews. Studies with significant results tended to be published earlier than studies with non-significant results, and empirical evidence suggests that published studies tended to report a greater treatment effect than those from the grey literature. Exclusion of non-English-language studies appeared to result in a high risk of bias in some areas of research such as complementary and alternative medicine. In a few cases, publication and related biases had a potentially detrimental impact on patients or resource use. Publication bias can be prevented before a literature review (e.g. by prospective registration of trials), or detected during a literature review (e.g. by locating unpublished studies, funnel plot and related tests, sensitivity analysis modelling), or its impact can be minimised after a literature review (e.g. by confirmatory large-scale trials, updating the systematic review). The interpretation of funnel plot and related statistical tests, often used to assess publication bias, was often too simplistic and likely misleading. More sophisticated modelling methods have not been widely used. Compared with systematic reviews published in 1996, recent reviews of health-care interventions were more likely to locate and include non-English-language studies and grey literature or unpublished studies, and to test for publication bias. Conclusions Dissemination of research findings is likely to be a biased process, although the actual impact of such bias depends on specific circumstances. The prospective registration of clinical trials and the endorsement of reporting guidelines may reduce research dissemination bias in clinical research. In systematic reviews, measures can be taken to minimise the impact of dissemination bias by systematically searching for and including relevant studies that are difficult to access. Statistical methods can be useful for sensitivity analyses. Further research is needed to develop methods for qualitatively assessing the risk of publication bias in systematic reviews, and to evaluate the effect of prospective registration of studies, open access policy and improved publication guidelines.

Objective To evaluate the measures taken to deal with publication bias across different categories of systematic reviews published in 2006 and to compare these with reviews published in 1996. Study Design and Setting PubMed was searched for systematic reviews published in 2006; 100 treatment effect, 50 diagnostic accuracy, 100 risk factor, and 50 gene–disease association reviews were randomly selected. Results The use of MEDLINE increased from 74% to 95%; checking references increased from 42% to 73%; use of Cochrane Library increased from 5% to 58%; and use of CINAHL increased from 8% in 1996 to 24% in treatment reviews, 20% in diagnostic reviews, 18% in risk factor reviews, and 0% in genetic reviews published in 2006. A 20% increase was observed for explicit searching of non–English-language studies in all reviews published in 2006. Efforts to search for unpublished studies increased to 61% from 35% in treatment reviews published in 1996. Twenty-six percent of the reviews used funnel plots or related methods to test for publication bias compared with less than 6% in earlier reviews. Conclusion Recent reviews show a significant improvement in the measures taken to prevent publication bias. However, few methods exist to deal with publication bias in the nonquantitative findings of systematic reviews.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Industry-funded studies tend to emphasize favourable beneficial effects of the sponsor's product, but we do not know if reports of adverse effects are downplayed. • Pharmaceutical companies are required to collate and accurately report adverse effects data in order to fulfil regulatory requirements. WHAT THIS STUDY ADDS • The bias found in the studies looking at the association between industry funding and reporting of beneficial effects may not be as prominent when considering adverse effects data. • Industry-funded studies do not appear to differ from non-industry-funded studies in reporting the raw adverse effects data, but the interpretation and conclusions may be slanted to favour the sponsor's product. • Readers of industry-funded studies should critically examine the raw safety data themselves rather than be swayed by the authors' interpretation. AIM To investigate whether adverse effects data for the sponsor's product are presented more favourably in pharmaceutical industry-funded studies than in non-industry-funded studies. METHODS We conducted a systematic review of methodological evaluations that had assessed the relationship between industry funding and the reported risk of adverse effects. Searches were undertaken in 10 databases and supplemented with other sources of information such as handsearching, citation searching, checking conference proceedings and discussion with experts. Two reviewers independently screened the records and carried out data extraction for potentially relevant papers. We included studies that compared the results and interpretation of the adverse effects data according to funding source (e.g. adverse effects data in pharmaceutical industry research vs. data from nonprofit organizations, or from one manufacturer vs. another). Methodological evaluations were excluded if categories of funding source were not explicitly specified by the researchers, and if we were uncertain that industry-funded studies were present in the evaluation. RESULTS The search strategy yielded 4069 hits, of which six methodological evaluations met our inclusion criteria. One survey of 370 trials covering a wide range of topics found that trials with industry sponsors had more complete reporting of adverse effects compared with non-industry-funded trials, whereas another survey of 504 inhaled corticosteroid studies showed no apparent difference after confounding factors were adjusted for. In contrast, we found evidence from post hoc subgroup analyses involving two products where the likelihood of harm was of a lower magnitude in manufacturer-funded studies compared with nonmanufacturer-funded studies. There is also evidence from four methodological evaluations that authors with industry funding were more likely than authors without pharmaceutical funding to interpret and conclude that a drug was safe, even among studies that did find a statistically significant increase in adverse effects for the sponsored product. CONCLUSIONS Our review indicates that industry funding may not be a major threat to bias in the reporting of the raw adverse effects data. However, we are concerned about potential bias in the interpretation and conclusions of industry-funded authors and studies.

Introduction For any health intervention, accurate knowledge of both benefits and harms is needed. Systematic reviews often compound poor reporting of harms in primary studies by failing to report harms or doing so inadequately. While the PRISMA statement (Preferred Reporting Items for Systematic reviews and MetaAnalyses) helps systematic review authors ensure complete and transparent reporting, it is focused mainly on efficacy. Thus, a PRISMA harms checklist has been developed to improve harms reporting in systematic reviews, promoting a more balanced assessment of benefits and harms. Methods A development strategy, endorsed by the EQUATOR Network and existing reporting guidelines (including the PRISMA statement, PRISMA for abstracts, and PRISMA for protocols), was used. After the development of a draft checklist of items, a modified Delphi process was initiated. The Delphi consisted of three rounds of electronic feedback followed by an in-person meeting. Results The PRISMA harms checklist contains four essential reporting elements to be added to the original PRISMA statement to improve harms reporting in reviews. These are reported in the title (“Specifically mention ‘harms’ or other related terms, or the harm of interest in the review”), synthesis of results (“Specify how zero events were handled, if relevant”), study characteristics (“Define each harm addressed, how it was ascertained (eg, patient report, active search), and over what time period”), and synthesis of results (“Describe any assessment of possible causality”). Additional guidance regarding existing PRISMA items was developed to demonstrate relevance when synthesising information about harms. Conclusions The PRISMA harms checklist identifies a minimal set of items to be reported when reviewing adverse events. This guideline extension is intended to improve harms reporting in systematic reviews, whether harms are a primary or secondary outcome.

We conducted a systematic review of genetic association studies for osteoarthritis of the peripheral joints (OA) and spinal degenerative disease (SDD). Electronic searches were carried out for any English language article reporting on a gene association study for either OA or SDD published up until the end of 2006. A team of seven reviewers used a standardised template to extract data in duplicate. In all, 90 studies fulfilled our inclusion criteria, reporting a total of 94 significant associations from 83 different genes. We found relatively few instances in which a specific gene–disease association had been analysed by more than one study, and there were 14 cases in which significant associations were replicated in independent studies (at joints associated with the AGC1, ASPN, COL9A2, COL9A3, COL11A2, ESR1, FZRB, HFE, IL1A, IL1RN, PTGS2 and VDR genes). Methodological and reporting problems were widespread, including failure to report full results, missing population details, multiple testing, and over-reliance on subgroup analysis. In summary, the complex phenotypes of OA and SDD may have made it difficult for researchers to focus their efforts. The field is dominated by isolated analyses of disparate potential associations, a problem that is amplified by the frequent analysis of different polymorphisms within individual genes. Flaws in study methodology and interpretation undoubtedly increase the risk of publication bias. Closer adherence to published recommendations (in particular those produced by HuGENet) will help to ensure that future studies are well-designed and build on current understanding, rather than simply adding to the growing bank of potential associations.