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).

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.

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.

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.

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.

Comparative effectiveness of second-generation antidepressants for accompanying anxiety, insomnia, and pain in depressed patients: a systematic review.

BACKGROUND: Patients with major depressive disorder (MDD) often suffer from accompanying symptoms that influence the choice of pharmacotherapy with second-generation antidepressants (SGAs). We conducted a systematic review to determine the comparative effectiveness of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, desvenlafaxine, duloxetine, venlafaxine, bupropion, mirtazapine, nefazodone, and trazodone, for accompanying anxiety, insomnia, and pain in patients with MDD. METHODS: We conducted searches in multiple databases including MEDLINE®, Embase, the Cochrane Library, International Pharmaceutical Abstracts, and PsycINFO, from 1980 through August 2011 and reviewed reference lists of pertinent articles. We dually reviewed abstracts, full-text articles, and abstracted data. We included randomized, head-to-head trials of SGAs of at least 6 weeks' duration. We grouped SGAs into three classes for the analysis: selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, and others. We graded the strength of the evidence as high, moderate, low, or very low based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group (GRADE) approach. RESULTS: We located 19 head-to-head trials in total: 11 on anxiety, six on insomnia, and four on pain. For the majority of comparisons, the strength of the evidence was moderate or low: evidence is weakened by inconsistency and imprecision. For treating anxiety, insomnia, and pain moderate evidence suggests that the SSRIs do not differ. CONCLUSIONS: Evidence guiding the selection of an SGA based on accompanying symptoms of depression is limited. Very few trials were designed and adequately powered to answer questions about accompanying symptoms; analyses were generally of subgroups in larger MDD trials.

How should primary care doctors select which antidepressants to administer?

Clinicians can choose among various second-generation antidepressants for treating depressive disorders, such as major depressive disorder, subsyndromal depression, or dysthymia. Systematic reviews indicate that available drugs differ in frequency of administration, costs, and the risks of some adverse events but have similar efficacy for treating major depressive disorder. Furthermore, evidence does not support the choice of one antidepressant over another based on accompanying symptoms, such anxiety, insomnia, or pain. Available studies provide little guidance for clinicians about the benefits of second-generation antidepressants for treating dysthymia and subsyndromal depression. Evidence is also unclear about the comparative risks of serious adverse events, such as suicidality, seizures, fractures, increased bleeding, or serotonin syndrome. This article summarizes the best available evidence regarding comparative benefits and harms of second-generation antidepressants for treating depressive disorders.

Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis.

BACKGROUND: Second-generation antidepressants dominate the management of major depressive disorder (MDD), but evidence on the comparative benefits and harms of these agents is contradictory. PURPOSE: To compare the benefits and harms of second-generation antidepressants for treating MDD in adults. DATA SOURCES: English-language studies from PubMed, Embase, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts from 1980 to August 2011 and reference lists of pertinent review articles and gray literature. STUDY SELECTION: 2 independent reviewers identified randomized trials of at least 6 weeks' duration to evaluate efficacy and observational studies with at least 1000 participants to assess harm. DATA EXTRACTION: Reviewers abstracted data about study design and conduct, participants, and interventions and outcomes and rated study quality. A senior reviewer checked and confirmed extracted data and quality ratings. DATA SYNTHESIS: Meta-analyses and mixed-treatment comparisons of response to treatment and weighted mean differences were conducted on specific scales to rate depression. On the basis of 234 studies, no clinically relevant differences in efficacy or effectiveness were detected for the treatment of acute, continuation, and maintenance phases of MDD. No differences in efficacy were seen in patients with accompanying symptoms or in subgroups based on age, sex, ethnicity, or comorbid conditions. Individual drugs differed in onset of action, adverse events, and some measures of health-related quality of life. LIMITATIONS: Most trials were conducted in highly selected populations. Publication bias might affect the estimates of some comparisons. Mixed-treatment comparisons cannot conclusively exclude differences in efficacy. Evidence within subgroups was limited. CONCLUSION: Current evidence does not warrant recommending a particular second-generation antidepressant on the basis of differences in efficacy. Differences in onset of action and adverse events may be considered when choosing a medication. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

[Clinical outcomes, health-related quality of life, and cost-effectiveness of a 6-month community- based lifestyle program for adults at increased cardiovascular risk in lower Austria]. / Klinische Ergebnisse, gesundheitsbezogene Lebensqualität und Kosten-Effektivität eines 6-monatigen Programms zur Lebensstilmodifikation bei Personen mit erhöhtem kardioväskularen Risiko in Niederösterreich.

AIM: To investigate lifestyle intervention effects and cost-effectiveness of a structured 6-month exercise and nutrition program for individuals at high risk for cardiovascular disease. METHODS: Uncontrolled before and after study with assessments at baseline and six months. Adults without existing cardiovascular disease (CVD) but at increased CVD risk were eligible. The analysis was done by intention-to-treat (last-observation-carried-forward). Incremental cost-effectiveness analysis was performed. Main outcome measures were changes in cardiovascular risk-factors (blood pressure, weight, body-mass index, serum lipids, blood glucose, smoking cessation, and exercise) and health-related quality of life. RESULTS: A total of 356 adults (70.5% female; mean age 48.9 years; mean body mass index 32.4; drop-out 10.4%) participated. At 6 months significant favorable effects were observed in several cardiovascular risk outcomes, exercise behaviour and health related quality of life. At an average incremental cost per life year saved for the ITT-population of 22.474 the program can be considered cost-effective.

Antidepressants for the treatment of abdominal pain-related functional gastrointestinal disorders in children and adolescents.

BACKGROUND: Abdominal pain-related functional gastrointestinal disorders (FGIDs) are among the most common medical problems in paediatric medicine. Frequently, physicians prescribe antidepressants as a second-line treatment for children and adolescents with FGIDs. To date, the evidence on the benefits and harms of antidepressants for the treatment of abdominal pain-related FGIDs has not been assessed systematically. OBJECTIVES: The primary objectives were to conduct a systematic review to evaluate the efficacy and safety of antidepressants for the treatment of abdominal pain-related FGIDs in children and adolescents. SEARCH STRATEGY: We searched The Cochrane Library, PubMed, EMBASE, IPA, CINAHL, PsycINFO, ISI Web of Science, Biosis Previews and the International Clinical Trials Registry Platform of the World Health Organization with appropriate filters (from inception to January 31, 2011). SELECTION CRITERIA: For efficacy we included double-blind, randomised controlled trials (RCTs) of antidepressants for treatment of abdominal pain-related FGIDs in children and adolescents 18 years or younger. Open-label and uncontrolled experimental studies, as well as observational studies were eligible for the assessment of harms. The minimum study duration was 4 weeks. The minimum study size was 30 participants. DATA COLLECTION AND ANALYSIS: Two authors independently assessed all abstracts and full text articles, and rated the risk of bias for included studies. Data were extracted independently by one author and checked for accuracy by another author. Data were analysed using RevMan 5. MAIN RESULTS: Two RCTs (123 participants), both using amitriptyline, met the pre-specified inclusion criteria. These studies provided mixed findings on the efficacy of amitriptyline for the treatment of abdominal pain-related FGIDs. The larger, publicly-funded study reported no statistically significant difference in efficacy between amitriptyline and placebo in 90 children and adolescents with FGIDs after 4 weeks of treatment. On intention-to-treat (ITT)- analysis, 59% of the children reported feeling better in the amitriptyline group compared with 53% in the placebo group (RR 1.12; 95% CI: 0.77 to 1.63; P = 0.54). The risk of bias for this study was rated as low.The second RCT enrolled 33 adolescents with irritable bowel syndrome. Patients receiving amitriptyline experienced greater improvements in the primary outcome, overall quality of life, at weeks 6, 10, and 13 compared with those on placebo (P= 0.019, 0.004, and 0.013, respectively). No effect estimates were calculated for the quality of life outcome because mean quality of life scores and standard deviations were not reported. For most secondary outcomes no statistically significant differences between amitriptyline and placebo could be detected. The risk of bias for this study was rated as unclear for most items. However, it was rated as high for other bias due to multiple testing. The results of this study should be interpreted with caution due to the small number of patients and multiple testing.The larger study reported mild adverse events including fatigue, rash and headache and dizziness. On ITT analysis, 4% of the amitriptyline group experienced at least one adverse event compared to 2% of the placebo group. There was no statistically significant difference in the proportion of patients who experienced at least one adverse event (RR 1.91; 95% CI 0.18 to 20.35; P = 0.59). The smaller study reported no adverse events. The methods of adverse effects assessment was poorly reported in both studies and no clear conclusions on the risks of harms of amitriptyline can be drawn. AUTHORS' CONCLUSIONS: Clinicians must be aware that for the majority of antidepressant medications no evidence exists that supports their use for the treatment of abdominal pain-related FGIDs in children and adolescents. The existing randomised controlled evidence is limited to studies on amitriptyline and revealed no statistically significant differences between amitriptyline and placebo for most efficacy outcomes. Amitriptyline does not appear to provide any benefit for the treatment of FGIDs in children and adolescents. Studies in children with depressive disorders have shown that antidepressants can lead to substantial, sometimes life-threatening adverse effects. Until better evidence evolves, clinicians should weigh the potential benefits of antidepressant treatment against known risks of antidepressants in paediatric patients.

Second-generation antidepressants for 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 SGAs for the treatment of SAD in adults in comparison with placebo, light therapy, other SGAs or psychotherapy. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neuorosis Review Group's specialised register (CCDANCTR) on the 26 August 2011. The CCDANCTR contains reports of relevant randomised controlled trials from The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). In addition, we searched pharmaceutical industry trials registers via the Internet to identify unpublished trial data. Furthermore, we searched OVID MEDLINE, MEDLINE In-process, EMBASE and PsycINFO to 27July 2011 for publications on adverse effects (including non-randomised studies). SELECTION CRITERIA: For efficacy we included randomised trials of SGAs compared with other SGAs, placebo, light therapy or psychotherapy in adult participants with SAD. For adverse effects we also included non-randomised studies. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts and full-text publications against the inclusion criteria. Data abstraction and risk of bias assessment were conducted by one reviewer and checked for accuracy and completeness by a second. 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: For efficacy we included three randomised trials of between five and eight weeks duration with a total of 204 participants. For adverse effects we included two randomised trials and three observational (non-randomised) studies of five to eight weeks duration with a total of 225 participants. Overall, the randomised trials had low-to-moderate risk of bias, and the observational studies had a high risk of bias (due to small size and high attrition). The participants in the studies all met DSM (Diagnostic and Statistics Manual of Mental Disorders) criteria for SAD. The average age was approximately 40 years and 70% of the participants were female.Results from one trial with 68 participants showed that fluoxetine was not significantly more effective than placebo in achieving clinical response (risk ratio (RR) 1.62, 95% confidence interval (CI) 0.92 to 2.83). The number of adverse effects were similar between the two groups.We located two trials that contained a total of 136 participants for the comparison fluoxetine versus light therapy. Our meta-analysis of the results of the two trials 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), RR of remission 0.81 (95% CI 0.39 to 1.71). The number of adverse effects was similar in both groups.Two of the three randomised trials and three non-randomised studies contained adverse effect data on 225 participants who received fluoxetine, escitalopram, duloxetine, reboxetine, light therapy or placebo. We were only able to obtain crude rates of adverse effects, so any interpretation of this needs to be undertaken with caution. Between 22% and 100% of participants who received a SGA suffered an adverse effect and between 15% and 27% of participants withdrew from the studies because of adverse effects. AUTHORS' CONCLUSIONS: Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo, which shows a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy, which suggest equivalence between the two interventions. The lack of available evidence precludes the ability to draw 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. Therefore the data we obtained on adverse effects is not robust and our confidence in the data is limited. Overall, up to 27% of participants treated with SGAs for SAD withdrew from the studies early due to adverse effects. The overall quality of evidence in this review is very low.

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.

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.

Bach Flower Remedies for psychological problems and pain: a systematic review.

BACKGROUND: Bach Flower Remedies are thought to help balance emotional state and are commonly recommended by practitioners for psychological problems and pain. We assessed whether Bach Flower Remedies (BFRs) are safe and efficacious for these indications by performing a systematic review of the literature. METHODS: We searched MEDLINE, Embase, AMED, and the Cochrane Library from inception until June 2008 and performed a hand-search of references from relevant key articles. For efficacy, we included all prospective studies with a control group. For safety, we also included retrospective, observational studies with more than 30 subjects. Two authors abstracted data and determined risk of bias using a recognised rating system of trial quality. RESULTS: Four randomised controlled trials (RCTs) and two additional retrospective, observational studies were identified and included in the review. Three RCTs of BFRs for students with examination anxiety, and one RCT of BFRs for children with attention-deficit hyperactivity disorder (ADHD) showed no overall benefit in comparison to placebo. Due to the number and quality of the studies the strength of the evidence is low or very low. We did not find any controlled prospective studies regarding the efficacy of BFRs for pain. Only four of the six studies included for safety explicitly reported adverse events. CONCLUSION: Most of the available evidence regarding the efficacy and safety of BFRs has a high risk of bias. We conclude that, based on the reported adverse events in these six trials, BFRs are probably safe. Few controlled prospective trials of BFRs for psychological problems and pain exist. Our analysis of the four controlled trials of BFRs for examination anxiety and ADHD indicates that there is no evidence of benefit compared with a placebo intervention.

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.

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.

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.