Outpatient Treatment of Confirmed COVID-19: A Living, Rapid Evidence Review for the American College of Physicians (Version 2).

BACKGROUND: Clinicians and patients want to know the benefits and harms of outpatient treatment options for the Omicron variant of SARS-CoV-2. PURPOSE: To assess the benefits and harms of 22 different COVID-19 treatments. DATA SOURCES: The Epistemonikos COVID-19 L·OVE platform, the iSearch COVID-19 portfolio, and the World Health Organization (WHO) COVID-19 Research Database from 26 November 2021 to 2 March 2023. STUDY SELECTION: Two reviewers independently screened abstracts and full texts against a priori-defined criteria. DATA EXTRACTION: One reviewer extracted the data and assessed the risk of bias and certainty of evidence (COE). A second reviewer verified the data abstraction and assessments. DATA SYNTHESIS: Two randomized controlled trials and 6 retrospective cohort studies were included. Nirmatrelvir-ritonavir was associated with a reduction in hospitalization due to COVID-19 (for example, 0.7% vs. 1.2%; moderate COE) and all-cause mortality (for example, <0.1% vs. 0.2%; moderate COE). Molnupiravir led to a higher recovery rate (31.8% vs. 22.6%; moderate COE) and reduced time to recovery (9 vs. 15 median days; moderate COE) but had no effect on all-cause mortality (0.02% vs. 0.04%; moderate COE) and the incidence of serious adverse events (0.4% vs. 0.3%; moderate COE). Ivermectin had no effect on time to recovery (moderate COE) and resulted in no difference in adverse events compared with placebo (low COE). Sotrovimab resulted in no difference in all-cause mortality compared with no treatment (low COE). No eligible studies for all other treatments of interest were identified. LIMITATION: Evidence for nirmatrelvir-ritonavir and sotrovimab is based on nonrandomized studies only. CONCLUSION: Nirmatrelvir-ritonavir and molnupiravir probably improve outcomes for outpatients with mild to moderate COVID-19. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42023406456).

Outpatient Treatment of Confirmed COVID-19: A Living, Rapid Review for the American College of Physicians.

BACKGROUND: Clinicians and patients want to know the benefits and harms of outpatient treatment options for SARS-CoV-2 infection. PURPOSE: To assess the benefits and harms of 12 different COVID-19 treatments in the outpatient setting. DATA SOURCES: Epistemonikos COVID-19 L·OVE Platform, searched on 4 April 2022. STUDY SELECTION: Two reviewers independently screened abstracts and full texts against a priori-defined criteria. Randomized controlled trials (RCTs) that compared COVID-19 treatments in adult outpatients with confirmed SARS-CoV-2 infection were included. DATA EXTRACTION: One reviewer extracted data and assessed risk of bias and certainty of evidence (COE). A second reviewer verified data abstraction and assessments. DATA SYNTHESIS: The 26 included studies collected data before the emergence of the Omicron variant. Nirmatrelvir-ritonavir and casirivimab-imdevimab probably reduced hospitalizations (1% vs. 6% [1 RCT] and 1% vs. 4% [1 RCT], respectively; moderate COE). Nirmatrelvir-ritonavir probably reduced all-cause mortality (0% vs. 1% [1 RCT]; moderate COE), and regdanvimab probably improved recovery (87% vs. 72% [1 RCT]; moderate COE). Casirivimab-imdevimab reduced time to recovery by a median difference of 4 days (10 vs. 14 median days [1 RCT]; high COE). Molnupiravir may reduce all-cause mortality, sotrovimab may reduce hospitalization, and remdesivir may improve recovery (low COE). Lopinavir-ritonavir and azithromycin may have increased harms, and hydroxychloroquine may result in lower recovery rates (low COE). Other treatments had insufficient evidence or no statistical difference in efficacy and safety versus placebo. LIMITATION: Many outcomes had few events and small samples. CONCLUSION: Some antiviral medications and monoclonal antibodies may improve outcomes for outpatients with mild to moderate COVID-19. However, the generalizability of the findings to the currently dominant Omicron variant is limited. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42022323440).

Type I Interferon as cardiovascular risk factor in systemic and cutaneous lupus erythematosus: A systematic review.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have a high burden of cardiovascular disease (CVD) of multifactorial origin. The aim of this systematic review is to analyze the role of the interferon I (IFN-I) signature and fibroblast growth factor-23 (FGF-23) in patients with SLE or cutaneous lupus erythematosus (CLE) herein. MATERIALS AND METHODS: We conducted a systematic literature search in PubMed and Scopus using keywords for major adverse cardiovascular events (MACE) and intermediate outcomes (endothelial dysfunction, subclinical atherosclerosis, platelet activation) associated with IFN-I or FGF-23 in patients with SLE and CLE. RESULTS: 4745 citations were screened, of which 12 studies were included. IFN-I was associated with MACE in two third of the studies and the association was strongest for cardiac events. An association of IFN-I was found in all studies investigating impaired vascular function, but only in 50% (respectively 40%) of reports examining the relation of IFN-I and platelet activation (respectively subclinical atherosclerosis). Altogether the reports were of variable bias and quality due to high variability of examined IFN-I biomarkers and inconsistent results for different outcome measures. No studies investigating the cardiovascular risk of circulating IFN-I in CLE, nor FGF-23 in SLE or CLE were found. CONCLUSION: Clinical studies measuring the association between IFN-I and direct / intermediate measures of CVD are rare and ambiguous in SLE and nonexistent in CLE, hampering a definite conclusion.

Second-generation antidepressants for treatment of seasonal affective disorder.

BACKGROUND: Seasonal affective disorder (SAD) is a seasonal pattern of recurrent depressive episodes that is often treated with second-generation antidepressants (SGAs), light therapy, or psychotherapy. OBJECTIVES: To assess the efficacy and safety of second-generation antidepressants (SGAs) for the treatment of seasonal affective disorder (SAD) in adults in comparison with placebo, light therapy, other SGAs, or psychotherapy. SEARCH METHODS: This is an update of an earlier review first published in 2011. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) in the Cochrane Library (all years), Ovid MEDLINE, Embase, and PsycINFO (2011 to January 2020), together with the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all available years), for reports of randomised controlled trials (RCTs). We hand searched the reference lists of all included studies and other systematic reviews. We searched ClinicalTrials.gov for unpublished/ongoing trials. We ran a separate update search for reports of adverse events in the Ovid databases.  SELECTION CRITERIA: For efficacy we included RCTs of SGAs compared with other SGAs, placebo, light therapy, or psychotherapy in adult participants with SAD. For adverse events we also included non-randomised studies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and full-text publications against the inclusion criteria. Data extraction and 'Risk of bias' assessment were conducted individually. We pooled data for meta-analysis where the participant groups were similar, and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment. MAIN RESULTS: In this update we identified no new RCT on the effectiveness of SGAs in SAD patients. We included 2 additional single-arm observational studies that reported on adverse events of SGAs.  For efficacy we included three RCTs of between five and eight weeks' duration with a total of 204 participants. For adverse events we included two RCTs and five observational (non-randomised) studies of five to eight weeks' duration with a total of 249 participants. All participants met the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for SAD. The average age ranged from 34 to 42 years, and the majority of participants were female (66% to 100%). Results from one trial with 68 participants showed that fluoxetine (20/36) was numerically superior to placebo (11/32) in achieving clinical response; however, the confidence interval (CI) included both a potential benefit as well as no benefit of fluoxetine (risk ratio (RR) 1.62, 95% CI 0.92 to 2.83, very low-certainty evidence). The number of adverse events was similar in both groups (very low-certainty evidence). Two trials involving a total of 136 participants compared fluoxetine versus light therapy. Meta-analysis showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24, low-certainty evidence), RR of remission 0.81 (95% CI 0.39 to 1.71, very low-certainty evidence). The number of adverse events was similar in both groups (low-certainty evidence). We did not identify any eligible study comparing SGA with another SGA or with psychotherapy. Two RCTs and five non-randomised studies reported adverse event data on a total of 249 participants who received bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, reboxetine, light therapy, or placebo. We were only able to obtain crude rates of adverse events, therefore caution is advised regarding interpretation of this information. Between 0% and 100% of participants who received an SGA suffered an adverse event, and between 0% and 25% of participants withdrew from the study due to adverse events. AUTHORS' CONCLUSIONS: Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo showing a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy suggesting equivalence between the two interventions. The lack of available evidence precluded us from drawing any overall conclusions on the use of SGAs for SAD. Further, larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs. Data on adverse events were sparse, and a comparative analysis was not possible. The data we obtained on adverse events is therefore not robust, and our confidence in the data is limited. Overall, up to 25% of participants treated with SGAs for SAD withdrew from the study early due to adverse events.

Combining abbreviated literature searches with single-reviewer screening: three case studies of rapid reviews.

BACKGROUND: Decision-makers increasingly request rapid answers to clinical or public health questions. To save time, personnel, and financial resources, rapid reviews streamline the methodological steps of the systematic review process. We aimed to explore the validity of a rapid review approach that combines a substantially abbreviated literature search with a single-reviewer screening of abstracts and full texts using three case studies. METHODS: We used a convenience sample of three ongoing Cochrane reviews as reference standards. Two reviews addressed oncological topics and one addressed a public health topic. For each of the three topics, three reviewers screened the literature independently. Our primary outcome was the change in conclusions between the rapid reviews and the respective Cochrane reviews. In case the rapid approach missed studies, we recalculated the meta-analyses for the main outcomes and asked Cochrane review authors if the new body of evidence would change their original conclusion compared with the reference standards. Additionally, we assessed the sensitivity of the rapid review approach compared with the results of the original Cochrane reviews. RESULTS: For the two oncological topics (case studies 1 and 2), the three rapid reviews each yielded the same conclusions as the Cochrane reviews. However, the authors would have had less certainty about their conclusion in case study 2. For case study 3, the public health topic, only one of the three rapid reviews led to the same conclusion as the Cochrane review. The other two rapid reviews provided insufficient information for the authors to draw conclusions. Using the rapid review approach, the sensitivity was 100% (3 of 3) for case study 1. For case study 2, the three rapid reviews identified 40% (4 of 10), 50% (5 of 10), and 60% (6 of 10) of the included studies, respectively; for case study 3, the respective numbers were 38% (8 of 21), 43% (9 of 21), and 48% (10 of 21). CONCLUSIONS: Within the limitations of these case studies, a rapid review approach that combines abbreviated literature searches with single-reviewer screening may be feasible for focused clinical questions. For complex public health topics, sensitivity seems to be insufficient.

Comparative Risk of Harm Associated With the Use of Targeted Immunomodulators: A Systematic Review.

OBJECTIVE: To systematically compare the risk of adverse events (AEs) for 13 targeted immunomodulators (TIMs) indicated for ankylosing spondylitis (AS), inflammatory bowel diseases, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis (PsA), or rheumatoid arthritis (RA). METHODS: We searched electronic databases through July 2015 to retrieve randomized controlled trials (RCTs) and observational studies comparing AEs between 2 or more TIMs head-to-head. We reported on the following outcomes: number of AEs, discontinuation due to AEs, serious AEs, mortality, serious infections, tuberculosis, herpes zoster, and malignancies. We qualitatively synthesized the literature and conducted random-effects meta-analyses if 3 or more studies provided data for an outcome. RESULTS: Ten head-to-head RCTs and 51 observational studies were included in this systematic review. A majority of the studies (70%) were conducted in RA patients. Risk of treatment discontinuation due to AEs was higher with infliximab than with adalimumab or etanercept in RA, PsA, and AS. A higher risk for serious infections was noted with infliximab than with abatacept, adalimumab, or etanercept in RA. Risk for treatment discontinuation due to AEs, serious infections, and tuberculosis was lower with etanercept than with adalimumab in RA. Limited evidence suggested no comparative differences in risk for mortality, malignancies, and herpes zoster for adalimumab, etanercept, and infliximab in RA. CONCLUSION: Important differences were noted in the safety profile of TIMs in RA, generally favoring abatacept, adalimumab, and etanercept over infliximab. Head-to-head comparative evidence for other TIMs and non-RA populations was insufficient to draw conclusions for most of the safety outcomes.

Average effect estimates remain similar as evidence evolves from single trials to high-quality bodies of evidence: a meta-epidemiologic study.

OBJECTIVES: The objective of our study was to use a diverse sample of medical interventions to assess empirically whether first trials rendered substantially different treatment effect estimates than reliable, high-quality bodies of evidence. STUDY DESIGN AND SETTING: We used a meta-epidemiologic study design using 100 randomly selected bodies of evidence from Cochrane reports that had been graded as high quality of evidence. To determine the concordance of effect estimates between first and subsequent trials, we applied both quantitative and qualitative approaches. For quantitative assessment, we used Lin's concordance correlation and calculated z-scores; to determine the magnitude of differences of treatment effects, we calculated standardized mean differences (SMDs) and ratios of relative risks. We determined qualitative concordance based on a two-tiered approach incorporating changes in statistical significance and magnitude of effect. RESULTS: First trials both overestimated and underestimated the true treatment effects in no discernible pattern. Nevertheless, depending on the definition of concordance, effect estimates of first trials were concordant with pooled subsequent studies in at least 33% but up to 50% of comparisons. The pooled magnitude of change as bodies of evidence advanced from single trials to high-quality bodies of evidence was 0.16 SMD [95% confidence interval (CI): 0.12, 0.21]. In 80% of comparisons, the difference in effect estimates was smaller than 0.5 SMDs. In first trials with large treatment effects (>0.5 SMD), however, estimates of effect substantially changed as new evidence accrued (mean change 0.68 SMD; 95% CI: 0.50, 0.86). CONCLUSION: Results of first trials often change, but the magnitude of change, on average, is small. Exceptions are first trials that present large treatment effects, which often dissipate as new evidence accrues.

The predictive validity of quality of evidence grades for the stability of effect estimates was low: a meta-epidemiological study.

OBJECTIVE: To determine the predictive validity of the U.S. Evidence-based Practice Center (EPC) approach to GRADE (Grading of Recommendations Assessment, Development and Evaluation). STUDY DESIGN AND SETTING: Based on Cochrane reports with outcomes graded as high quality of evidence (QOE), we prepared 160 documents which represented different levels of QOE. Professional systematic reviewers dually graded the QOE. For each document, we determined whether estimates were concordant with high QOE estimates of the Cochrane reports. We compared the observed proportion of concordant estimates with the expected proportion from an international survey. To determine the predictive validity, we used the Hosmer-Lemeshow test to assess calibration and the C (concordance) index to assess discrimination. RESULTS: The predictive validity of the EPC approach to GRADE was limited. Estimates graded as high QOE were less likely, estimates graded as low or insufficient QOE more likely to remain stable than expected. The EPC approach to GRADE could not reliably predict the likelihood that individual bodies of evidence remain stable as new evidence becomes available. C-indices ranged between 0.56 (95% CI, 0.47 to 0.66) and 0.58 (95% CI, 0.50 to 0.67) indicating a low discriminatory ability. CONCLUSION: The limited predictive validity of the EPC approach to GRADE seems to reflect a mismatch between expected and observed changes in treatment effects as bodies of evidence advance from insufficient to high QOE.

Information overload in healthcare: too much of a good thing?

The rapidly growing production of healthcare information - both scientific and popular - increasingly leads to a situation of information overload affecting all actors of the healthcare system and threatening to impede the adoption of evidence-based practice. In preparation for the 2015 Cochrane Colloquium in Vienna, we discuss the issues faced by three major actors of this system: patients, healthcare practitioners, and systematic reviewers. We analyze their situation through the concept of "filter failure", positing that the main problem is not that there is "too much information", but that the traditional means of managing and evaluating information are ill-suited to the realities of the digital age. Some of the major instances of filter failure are inadequate information retrieval systems for point-of-care settings, the problem of identifying all relevant evidence in an exceedingly diverse landscape of information resources, and the very basic lack of health information literacy, concerning not only the general public. Finally, we give an overview of proposed solutions to the problem of information overload. These new or adapted filtering systems include adapting review literature to the specific needs of practitioners or patients, technological improvements to information systems, strengthening the roles of intermediaries, as well as improving health literacy.

[Practical experience with overviews of reviews--valuable decision aid or academic exercise?]. / Praxiserfahrungen mit Overviews of Reviews--wertvolle Entscheidungsunterstützung oder wissenschaftliche Fingerübung?

The "overview of reviews" has evolved as a method to aggregate information from systematic reviews. Based on research projects conducted by two Austrian institutions, this article aims to point out methods and perceived strengths and limitations of overviews of reviews and to discuss their application and constraints for different healthcare settings. The six analysed projects differed in their objectives as well as in the corresponding methodology. We identified the following strengths of the overviews of reviews performed: the overview of the evidence base on an issue, the rapid detection of the results of numerous reviews, the demonstration of evidence gaps and potential savings in time and resources. At the same time, the methodology could lead to a loss of information, limited relevance and to uncertainties regarding the robustness of the overall results. However, the heterogeneity of the methods used shows that the development of methods for overviews of reviews is still ongoing. Whether overviews of reviews provide valuable decision support depends on the research question and realistic expectations towards the method.

Socioeconomic inequalities in non-communicable diseases and their risk factors: an overview of systematic reviews.

BACKGROUND: Non-communicable diseases (NCDs) are the largest cause of premature death worldwide. Socioeconomic inequalities contribute to a disparity in the burden of NCDs among disadvantaged and advantaged populations in low (LIC), middle (MIC), and high income countries (HIC). We conducted an overview of systematic reviews to systematically and objectively assess the available evidence on socioeconomic inequalities in relation to morbidity and mortality of NCDs and their risk factors. METHODS: We searched PubMed, The Cochrane Library, EMBASE, SCOPUS, Global Health, and Business Source Complete for relevant systematic reviews published between 2003 and December 2013. Two authors independently screened abstracts and full-text publications and determined the risk of bias of the included systematic reviews. RESULTS: We screened 3302 abstracts, 173 full-text publications and ultimately included 22 systematic reviews. Most reviews had major methodological shortcomings; however, our synthesis showed that having low socioeconomic status (SES) and/or living in low and middle income countries (LMIC) increased the risk of developing cardiovascular diseases (CVD), lung and gastric cancer, type 2 diabetes, and chronic obstructive pulmonary disease (COPD). Furthermore, low SES increased the risk of mortality from lung cancer, COPD, and reduced breast cancer survival in HIC. Reviews included here indicated that lower SES is a risk factor for obesity in HIC, but this association varied by SES measure. Early case fatalities of stroke were lower and survival of retinoblastoma was higher in MIC compared to LIC. CONCLUSIONS: The current evidence supports an association between socioeconomic inequalities and NCDs and risk factors for NCDs. However, this evidence is incomplete and limited by the fairly low methodological quality of the systematic reviews, including shortcomings in the study selection and quality assessment process.

Inadequate use and regulation of interventions against publication bias decreases their effectiveness: a systematic review.

OBJECTIVES: To determine the effectiveness of interventions designed to prevent or reduce publication and related biases. STUDY DESIGN AND SETTING: We searched multiple databases and performed manual searches using terms related to publication bias and known interventions against publication bias. We dually reviewed citations and assessed risk of bias. We synthesized results by intervention and outcomes measured and graded the quality of the evidence (QoE). RESULTS: We located 38 eligible studies. The use of prospective trial registries (PTR) has increased since 2005 (seven studies, moderate QoE); however, positive outcome-reporting bias is prevalent (14 studies, low QoE), and information in nonmandatory fields is vague (10 studies, low QoE). Disclosure of financial conflict of interest (CoI) is inadequate (five studies, low QoE). Blinding peer reviewers may reduce geographical bias (two studies, very low QoE), and open-access publishing does not discriminate against authors from low-income countries (two studies, very low QoE). CONCLUSION: The use of PTR and CoI disclosures is increasing; however, the adequacy of their use requires improvement. The effect of open-access publication and blinding of peer reviewers on publication bias is unclear, as is the effect of other interventions such as electronic publication and authors' rights to publish their results.

Grades for quality of evidence were associated with distinct likelihoods that treatment effects will remain stable.

OBJECTIVES: We sought to determine whether producers or users of systematic reviews using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach or a close variation give the same meanings to terms intended to convey uncertainty about treatment effects when interpreting grades for the quality or strength of evidence. STUDY DESIGN AND SETTING: Following exploratory interviews with stakeholders and user testing, we conducted an international Web-based survey among producers and users of systematic reviews. For each quality grade (high, moderate, low, very low/insufficient), we asked participants to assign a minimum likelihood that treatment effects will not change substantially as new studies emerge. Using multivariate analysis of covariance, we tested whether the estimated likelihoods differed between producers and users. RESULTS: In all, 244 participants completed the survey. The associated minimum likelihoods that treatment effects will not change substantially for high, moderate, and low grades of quality of evidence (QOE) were 86% [95% confidence interval (CI): 85%, 87%], 61% (95% CI: 59%, 63%), and 34% (95% CI: 32%, 36%), respectively (very low was preset at 0%). Likelihoods for each grade were similar between producers and users of systematic reviews (P > 0.05 for all comparisons). CONCLUSION: GRADE is, in general, a suitable method to convey uncertainties for systematic review producers to users. The wide ranges of likelihoods associated with GRADE terms suggest that current definitions of levels of QOE that rely exclusively on qualitative certainty expressions should be augmented by numerical predictions once such data are available.

SAMURAI: Sensitivity analysis of a meta-analysis with unpublished but registered analytical investigations (software).

BACKGROUND: The non-availability of clinical trial results contributes to publication bias, diminishing the validity of systematic reviews and meta-analyses. Although clinical trial registries have been established to reduce non-publication, the results from over half of all trials registered in ClinicalTrials.gov remain unpublished even 30 months after completion. Our goals were i) to utilize information available in registries (specifically, the number and sample sizes of registered unpublished studies) to gauge the sensitivity of a meta-analysis estimate of the effect size and its confidence interval to the non-publication of studies and ii) to develop user-friendly open-source software to perform this quantitative sensitivity analysis. METHODS: The open-source software, the R package SAMURAI, was developed using R functions available in the R package metafor. The utility of SAMURAI is illustrated with two worked examples. RESULTS: Our open-source software SAMURAI, can handle meta-analytic datasets of clinical trials with two independent treatment arms. Both binary and continuous outcomes are supported. For each unpublished study, the dataset requires only the sample sizes of each treatment arm and the user predicted 'outlook' for the studies. The user can specify five outlooks ranging from 'very positive' (i.e., very favorable towards intervention) to 'very negative' (i.e., very favorable towards control).SAMURAI assumes that control arms of unpublished studies have effects similar to the effect across control arms of published studies. For each experimental arm of an unpublished study, utilizing the user-provided outlook, SAMURAI randomly generates an effect estimate using a probability distribution, which may be based on a summary effect across published trials. SAMURAI then calculates the estimated summary treatment effect with a random effects model (DerSimonian & Laird method), and outputs the result as a forest plot. CONCLUSIONS: To our knowledge, SAMURAI is currently the only tool that allows systematic reviewers to incorporate information about sample sizes of treatment groups in registered but unpublished clinical trials in their assessment of the potential impact of publication bias on meta-analyses. SAMURAI produces forest plots for visualizing how inclusion of registered unpublished studies might change the results of a meta-analysis. We hope systematic reviewers will find SAMURAI to be a useful addition to their toolkit.

Glycoprotein 130 polymorphism predicts soluble glycoprotein 130 levels.

OBJECTIVE: Interleukin-6 (IL-6) is a key cytokine in inflammatory diseases. It exerts its biological function via binding to a homodimer of its signal transducer glycoprotein 130 (gp130). Soluble gp130 (sgp130) is the natural inhibitor of IL-6 trans-signalling. The aim of this study was to test a possible influence of the gp130 genotype on sgp130 serum levels. MATERIAL AND METHODS: In two separate populations, subjects were genotyped for the gp130 polymorphism G148C. Sgp130, IL-6 and soluble interleukin-6 receptor (sIL-6R) levels were measured. The OSLO population consisted of 546 male subjects at high risk for CAD. The VIENNA population consisted of 299 male subjects with angiographically proven CAD. RESULTS: In the OSLO population, 124 (22.7%) subjects were hetero- or homozygote for the rare C allele. Individuals carrying the polymorphism had significantly higher levels of sgp130. In a multivariate linear regression model this association remained significant (adjusted p=0.001). In the VIENNA population, 48 (16.1%) subjects were hetero- or homozygote for the rare C allele. Consistent with the former study, sgp130 levels were significantly higher in carriers of the polymorphism compared to wildtype carriers (adjusted p=0.038). In the VIENNA population, sgp130 levels were significantly higher in diabetic patients. In the OSLO population, sgp130 was higher in patients with increased body mass index and in smokers (p<0.05). CONCLUSIONS: Sgp130 serum levels are significantly higher in subjects carrying the gp130 polymorphism G148C compared to wildtype carriers. This finding proposes a possible genetical influence on sgp130 levels which may alter individual coping mechanisms in inflammatory diseases.

Barriers to and facilitators of interventions to counter publication bias: thematic analysis of scholarly articles and stakeholder interviews.

BACKGROUND: When the nature and direction of research results affect their chances of publication, a distortion of the evidence base - termed publication bias - results. Despite considerable recent efforts to implement measures to reduce the non-publication of trials, publication bias is still a major problem in medical research. The objective of our study was to identify barriers to and facilitators of interventions to prevent or reduce publication bias. METHODS: We systematically reviewed the scholarly literature and extracted data from articles. Further, we performed semi-structured interviews with stakeholders. We performed an inductive thematic analysis to identify barriers to and facilitators of interventions to counter publication bias. RESULTS: The systematic review identified 39 articles. Thirty-four of 89 invited interview partners agreed to be interviewed. We clustered interventions into four categories: prospective trial registration, incentives for reporting in peer-reviewed journals or research reports, public availability of individual patient-level data, and peer-review/editorial processes. Barriers we identified included economic and personal interests, lack of financial resources for a global comprehensive trial registry, and different legal systems. Facilitators identified included: raising awareness of the effects of publication bias, providing incentives to make data publically available, and implementing laws to enforce prospective registration and reporting of clinical trial results. CONCLUSIONS: Publication bias is a complex problem that reflects the complex system in which it occurs. The cooperation amongst stakeholders to increase public awareness of the problem, better tailoring of incentives to publish, and ultimately legislative regulations have the greatest potential for reducing publication bias.

A case study of pooled-studies publications indicated potential for both valuable information and bias.

OBJECTIVES: Pooled-studies publications (PSPs) present statistical analyses of multiple randomized controlled trials without a systematic literature search or critical appraisal. We explored the characteristics of PSPs and their potential impact on a systematic review (SR). STUDY DESIGN AND SETTING: We systematically evaluated PSPs excluded from an SR of second-generation antidepressants. We analyzed their basic characteristics, risk of bias, and the effect of new data on review conclusions. RESULTS: We identified 57 PSPs containing a median of five trials (range, 2-11) and 1,233 patients (range, 117-2,919). Ninety-six percent of PSPs were industry funded, and 49% of PSPs contained unpublished data. The median number of citations for PSPs was 29 (range, 0-549). Only 7% planned pooling a priori, and 19% combined trials with identical protocols. Fifty-nine percent of PSPs eligible for general efficacy provided no new data. For some subgroups and accompanying symptoms (e.g., anxiety, insomnia, melancholia, fatigue, sex, and race), more than 30% of PSPs presented entirely new data or data that could alter the strength of the evidence available in the SR. CONCLUSION: In this case study, PSPs provided new information on subgroups and secondary outcomes; however, guidance for reviewers and development of a system to assess their susceptibility to bias are required.

Adjunct ultrasonography for breast cancer screening in women at average risk: a systematic review.

BACKGROUND: Screening with mammography has the ability to detect breast cancer at an early stage but misses some cancers. Supporters of adjunct ultrasonography to the screening regimen argue that it might be a safe and inexpensive approach to reduce the false-negative rates of screening. Critics are concerned that adjunct ultrasonography will also increase the rate of false-positive findings and can lead to unnecessary biopsies and treatments in women at average risk. AIMS: The purpose of this review was to systematically assess the comparative benefits and harms of mammography with adjunct breast ultrasonography and mammography only in breast cancer screening. METHODS: We searched multiple electronic databases and the Cochrane Breast Cancer Group's Specialised Register (from 1995 to February 2012). To detect ongoing or unpublished studies, we searched trial registries and multiple sources of grey literature. Two researchers independently reviewed all abstracts and full-text articles against pre-defined eligibility criteria. We dually rated the risk of bias of studies and the strength of evidence based on established guidance. RESULTS: We did not detect any controlled studies that provide evidence for (or against) the use of adjunct ultrasonography for screening in women at average risk for breast cancer. Extrapolations of results from women at elevated risk for breast cancer indicate that the false-positive rates in women at average risk who were recalled because of positive ultrasonographies will exceed 98%. In women with dense or very dense breast tissue, the evidence regarding the use of adjunct ultrasonography is not conclusive. CONCLUSIONS: No methodologically sound evidence is available justifying the routine use of ultrasonography as an adjunct screening tool in women at average risk for breast cancer. IMPLICATIONS FOR PRACTICE: Clinicians should not use ultrasonography as a screening tool for breast cancer screening on a routine basis. The use should be limited to women with dense breasts for whom the accuracy of mammography is low, or for diagnostic purposes.

Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk.

BACKGROUND: Breast cancer is the most common malignant disease diagnosed in women worldwide. Screening with mammography has the ability to detect breast cancer at an early stage. The diagnostic accuracy of mammography screening largely depends on the radiographic density of the imaged breasts. In radiographically dense breasts, non-calcified breast cancers are more likely to be missed than in fatty breasts. As a consequence, some cancers are not detected by mammography screening. Supporters of adjunct ultrasonography to the screening regimen for breast cancer argue that it might be a safe and inexpensive approach to reduce the false negative rates of the screening process. Critics, however, are concerned that performing supplemental ultrasonography on women at average risk will also increase the rate of false positive findings and can lead to unnecessary biopsies and treatments. OBJECTIVES: To assess the comparative effectiveness and safety of mammography in combination with breast ultrasonography versus mammography for breast cancer screening for women at average risk of breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialised Register, MEDLINE (via OvidSP) and EMBASE up until February 2012.To detect ongoing or unpublished studies, we searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov and the National Cancer Institute's clinical trial database until June 2012. In addition, we conducted grey literature searches using the following sources: OpenGrey; National Institute of Health RePORTER; Health Services Research Projects in Progress (HSRPROJ); Hayes, Inc. Health Technology Assessment; The New York Academy of Medicine's Grey Literature Index and Conference Papers Index. SELECTION CRITERIA: For efficacy, we considered randomised controlled trials (RCTs), with either individual or cluster randomisation, and prospective, controlled non-randomised studies with a low risk of bias and a sample size of at least 500 participants.In addition to studies eligible for efficacy, we considered any controlled, non-randomised study with a low risk of bias and a study size of at least 500 participants for the assessment of harms.Our population of interest were women between the ages of 40 and 75 years who were at average risk for breast cancer. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts and full-text publications against the inclusion criteria. None of the studies met our inclusion criteria. MAIN RESULTS: Our review did not detect any controlled studies on the use of adjunct ultrasonography for screening in women at average risk for breast cancer. One ongoing randomised controlled trial was identified (J-START, Japan). AUTHORS' CONCLUSIONS: Presently, there is no methodologically sound evidence available justifying the routine use of ultrasonography as an adjunct screening tool in women at average risk for breast cancer.