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Background: Clinical guidelines remain unclear on which medications for gambling disorder are to be preferred in terms of efficacy and tolerability. We aimed to compare pharmacological treatments for gambling disorder in terms of efficacy and tolerability, using network meta-analysis (NMA). Methods: Based on our pre-registered protocol [CRD42022329520], a structured search was conducted across broad range of databases, for double-blind randomized controlled trials (RCTs) of medications for gambling disorder. Data were independently extracted by two researchers. We used standardized mean differences (SMD) using Hedges' g to measure the efficacy outcomes, and for the effect for tolerability we used dropout rate due to medication side effects, expressed as odds ratio (OR). Confidence in the network estimates was assessed using the CINeMA framework. We followed the PRISMA-NMA guidelines for this work. Outcomes were gambling symptom severity and quality of life (for efficacy), and tolerability. Findings: We included 22 RCTs in the systematic review and 16 RCTs (n = 977 participants) in the NMA. Compared with placebo, moderate confidence evidence indicated that nalmefene [Standardized Mean Difference (SMD): −0.86; 95 % confidence interval (CI: −1.32,-0.41)] reduced gambling severity, followed by naltrexone (SMD: -0.42; 95 %CI: (−0.85,0.01)). Naltrexone (SMD: -0.50; 95 %CI: (−0.85,-0.14)) and nalmefene (SMD: -0.36; 95 %CI: (−0.72,-0.01) were also more beneficial than placebo in terms of quality of life. Olanzapine and topiramate were not more efficacious than placebo. Nalmefene [Odds Ratio (OR): 7.55; 95 %CI: (2.24–25.41)] and naltrexone (OR: 7.82; 95 %CI: (1.26–48.70)) had significantly higher dropout due to side effects (lower tolerability) compared with placebo. Interpretation: Based on NMA, nalmefene and naltrexone currently have the most supportive evidence for the pharmacological treatment of gambling disorder. Further clinical trials of novel compounds, and analysis of individual participant data are needed, to strengthen the evidence base, and help tailor treatments at the individual patient level.

Objective: To assess how inadequate reporting of cointerventions influences estimated treatment effects in recent cardiovascular trials. Methods: Medline/Embase were systematically searched from January 1, 2011 to July 1, 2021 for trials evaluating pharmacologic interventions on clinical cardiovascular outcomes published in 5 high-impact journals. Information on adequate vs inadequate reporting of cointerventions, blinding, risk of bias due to deviations of intended interventions (low vs high/some concerns), funding (nonindustry vs industry), design (superiority vs noninferiority), and results were assessed by 2 reviewers. The association with effect sizes was assessed using meta-regression random-effect analysis, expressed as ratios of odds ratios (ROR). RORs of >1.0 indicated that trials with the methodological factor pointing to lower quality report larger treatment estimates. Results: In total, 164 trials were included. Of the 164 trials, 124 (74%) did not adequately report cointerventions; 89 of the 164 trials (54%) provided no information regarding cointerventions, and 70 of the 164 (43%) were at risk of bias due to inadequate blinding. Moreover, 86 of the 164 (53%) were at risk of bias due to deviation of intended interventions. Of the 164 trials, 144 (88%) were funded by the industries. Trials with inadequate reporting of cointerventions had larger treatment estimates for the primary end point (ROR, 1.08; 95% CI, 1.01-1.15; I2=0%). No significant association with results for blinding (ROR, 0.97; 95% CI, 0.91-1.03; I2=66%), deviation of intended interventions (ROR, 0.98; 95% CI, 0.92-1.04; I2=0%), or funding (ROR, 1.01; 95% CI, 0.93-1.09; I2=0%) was found. Conclusion: We conclude that trials with inadequate reporting of cointerventions showed larger treatment effect estimates, potentially indicating overestimation of therapeutic benefit. Trial Registration: Prospero Identifier: CRD42017072522

Background There is debate over whether statins increase risk of hemorrhagic stroke, so we assessed current evidence, including data from new statin trials and trials of nonstatin low‐density lipoprotein‐cholesterol (LDL‐C)– and triglyceride‐lowering therapies. Methods and Results We performed a systematic review of large randomized clinical trials (≥1000 patients with ≥2 years follow‐up) of LDL‐C–lowering therapy (statin, ezetimibe, and PCSK‐9 [proprotein convertase subtilisin/kexin type 9] inhibitor) and triglyceride‐lowering therapy (omega‐3 supplements and fibrate) that reported hemorrhagic stroke as an outcome. We searched MEDLINE, Embase, and Cochrane Library up to July 2, 2021 and updated a meta‐analysis of cardiovascular statin trials published in 2012. Among our several subgroup analyses, we looked at difference depending on stroke status and also depending on age. We identified 37 trials for LDL‐C lowering (284 301 participants) and 11 for triglyceride lowering (120 984 participants). Overall, we found a higher risk of hemorrhagic stroke for LDL‐C lowering, risk ratio (RR) 1.16 (95% CI, 1.01–1.32, P=0.03). For statins (33 trials, 216 258 participants), RR=1.17 (95% CI, 1.01–1.36); for PCSK‐9 inhibitors (2 trials, 46 488 participants), RR=0.86 (95% CI, 0.43–1.74); and for ezetimibe (2 trials, 21 555 participants), RR=1.14 (95% CI, 0.64–2.03). In statin trials of patients with previous stroke/transient ischemic attack, RR was 1.46 (95% CI, 1.05–2.04), and in trials with mean age ≥65 years old, RR=1.34 (95% CI, 1.04–1.73) (Pint=0.14 and Pint=0.23 respectively); for triglyceride lowering (11 trials, 120 984 participants), RR=1.05 (95% CI, 0.86–1.30). Conclusions We found evidence for a small increased risk of hemorrhagic stroke events with LDL‐C–lowering therapies but no clear evidence for triglyceride‐lowering therapies. Registration URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42021275363.

BackgroundLipid-lowering therapy (LLT) reduces cardiovascular (CV) events, but data are conflicting on all-cause mortality, especially among older adults. Though LLT does not induce cancer, some randomized clinical trials (RCTs) found a pattern of increased cancer death under LLT. Our objective was to assess a possible shift from CV to cancer death in LLT trials (i.e. an increase in cancer and decrease in CV death) and to investigate potential subgroups at risk.MethodsWe performed a systematic review and meta-analysis. We retrieved RCTs from MEDLINE, Embase, and Cochrane Central until 08/2023. We extracted the number of CV and cancer deaths in the treatment vs. in the control arm, calculated the relative risk (RR) by dividing the risk of death in the treatment over the risk of death in the control group and then pooled them using random-effect meta-analysis. We performed subgroup analyses on primary and secondary prevention, and according to different age cut-offs.ResultsWe included 27 trials with 188'259 participants (23 statin; 4 ezetimibe trials). The trials reported 4056 cancer deaths, 2061 under LLT and 1995 in control groups. Overall, there was no increased risk of cancer mortality (RR 1.03, 95% confidence interval 0.97-1.10), with no difference between primary and secondary prevention. In the subgroup analyses for RCTs with ≥15% of participants aged ≥75 years, the RR of cancer death was 1.11 (1.00-1.23), while the RR for CV death was 0.96 (0.91-1.01). For RCTs with a mean age ≥ 70 years, the RR for cancer death was 1.21 (0.99-1.47).ConclusionLLT does not lead to a shift from CV to cancer death. However, there might be a possible shift with a pattern of increased cancer deaths in trials with more older adults, particularly ≥75 years. Individual participant data from LLT trials should be made public to allow further investigations.Prospero registrationCRD42021271658.

Abstract Introduction Fenfluramine (FFA) is an amphetamine derivative that promotes the release and blocks the neuronal reuptake of serotonin. Initially introduced as an appetite suppressant, FFA also showed antiseizure properties. This systematic review aimed to assess the efficacy and safety of FFA for the treatment of seizures in patients with epilepsy. Methods We systematically searched (in week 3 of June 2022) MEDLINE, the Cochrane Central Register of Controlled Trials, and the US National Institutes of Health Clinical Trials Registry. Randomized, double- or single-blinded, placebo-controlled studies of FFA in patients with epilepsy and uncontrolled seizures were identified. Efficacy outcomes included the proportions of patients with ≥ 50% and 100% reductions in baseline seizure frequency during the treatment period. Tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and suffered adverse events (AEs). The risk of bias in the included studies was assessed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. The risk ratio (RR) along with the 95% confidence interval (CI) were estimated for each outcome. Results Three trials were identified and a total of 469 Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) subjects were randomized. All three trials were judged to be at low risk of biases. In patients with DS, the RRs for ≥ 50% and 100% reductions in convulsive seizure frequency for the FFA group compared to placebo were 5.61 (95% CI 2.73–11.54) and 4.71 (95% CI 0.57–39.30), respectively. In patients with LGS, the corresponding RRs for ≥ 50% and 100% reductions in drop seizure frequency were 2.58 (95% CI 1.33–5.02) and 0.50 (95% CI 0.031–7.81), respectively. The drug was withdrawn for any reason in 10.1% and 5.8% of patients receiving FFA and placebo, respectively (RR 1.79, 95% CI 0.89–3.59). Treatment discontinuation due to AEs occurred in 5.4% and 1.2% of FFA- and placebo-treated patients, respectively (RR 3.63, 95% CI 0.93–14.16). Decreased appetite, diarrhoea, fatigue, and weight loss were AEs associated with FFA treatment. Conclusion Fenfluramine reduces the frequency of seizures in patients with DS and LGS. Decreased appetite, diarrhoea, fatigue, and weight loss are non-cardiovascular AEs associated with FFA.

Introduction Suicide is an important public health problem. Providing evidence-based psychosocial interventions to individuals presenting with self-harm is recognised as an important suicide prevention strategy. Therefore, it is crucial to understand which intervention is most effective in preventing self-harm repetition. We will evaluate the comparative efficacy of psychosocial interventions for the prevention of self-harm in adults.Methods and analysis We will perform a systematic review and network meta-analysis (NMA) of randomised controlled trials (RCTs) testing psychosocial interventions for the prevention of self-harm repetition. We will include RCTs in adults (mean age: 18 years or more) who presented with self-harm in the 6 months preceding enrolment in the trial. Interventions will be categorised according to their similarities and underpinning theoretical approaches (eg, cognitive behavioural therapy, case management). A health sciences librarian will update and adapt the search strategy from the most recent Cochrane pairwise systematic review on this topic. The searches will be performed in MEDLINE (Ovid), Embase (Ovid), PsycInfo (Ovid), CINAHL (EBSCO), Cochrane Central (Wiley), Cochrane Protocols (Wiley), LILACS and PSYNDEX from 1 July 2020 (Cochrane review last search date) to 1 September 2023. The primary efficacy outcome will be self-harm repetition. Secondary outcomes will include suicide mortality, suicidal ideation and depressive symptoms. Retention in treatment (ie, drop-outs rates) will be analysed as the main acceptability outcome. Two reviewers will independently assess the study eligibility and risk of bias (using RoB-2). An NMA will be performed to synthesise all direct and indirect comparisons. Ranked forest plots and Vitruvian plots will be used to represent graphically the results of the NMA. Credibility of network estimates will be evaluated using Confidence in NMA (CINeMA).Ethics and dissemination As this is the protocol for an aggregate-data level NMA, ethical approval will not be required. Results will be disseminated at national/international conferences and in peer-review journals.Trial registration number CRD42021273057.

Metformin is considered as first-line treatment for type 2 diabetes and an effective treatment for polycystic ovary syndrome (PCOS). However, evidence regarding its safety in pregnancy is limited. We conducted a systematic review and meta-analysis of major congenital malformations (MCMs) risk after first-trimester exposure to metformin in women with PCOS and pregestational diabetes mellitus (PGDM). Randomized controlled trials (RCTs) and observational cohort studies with a control group investigating risk of MCM after first-trimester pregnancy exposure to metformin were searched until December 2021. ORs and 95% CIs were calculated separately according to indications and study type using Mantel-Haenszel method; outcome data were combined using random-effects model. Eleven studies (two RCTs; nine observational cohorts) met the inclusion criteria: four included pregnant women with PCOS, four included those with PGDM and three evaluated both indications separately and were considered in both indication groups. In PCOS group, there were two RCTs (57 exposed, 52 control infants) and five observational studies (472 exposed, 1892 control infants); point estimates for MCM rates in RCTs and observational studies were OR 0.93 (95% CI 0.09 to 9.21) (I2=0%; Q test=0.31; p value=0.58) and OR 1.35 (95% CI 0.37 to 4.90) (I2=65%; Q test=9.43; p value=0.05), respectively. In PGDM group, all seven studies were observational (1122 exposed, 1851 control infants); the point estimate for MCM rates was OR 1.05 (95% CI 0.50 to 2.18) (I2=59%; Q test=16.34; p value=0.01). Metformin use in first-trimester pregnancy in women with PCOS or PGDM do not meaningfully increase the MCM risk overall. However, further studies are needed to characterize residual safety concerns.

Background Randomized clinical trials (RCTs) might not be representative of the real‐world population because of unreasonable exclusion criteria. We sought to determine which groups of patients are excluded from RCTs that included lipid‐lowering therapy. Methods and Results We retrieved all trials from the Cholesterol Treatment Trialists Collaboration and systematically searched for large (≥1000 participants) lipid‐lowering therapy RCTs, defined as statins, ezetimibe, and PCSK9 inhibitors. We predefined groups: older adults (>70 or >75 years), women, non‐Whites, chronic kidney failure, heart failure, immunosuppression, cancer, dementia, treated thyroid disease, chronic obstructive pulmonary disease, mental illness, atrial fibrillation, multimorbidity (≥2 chronic diseases), and polypharmacy. We counted the number of RCTs excluding patients of the predefined groups and meta‐analyzed the prevalence of included patients to obtain pooled estimates with a random‐effects model. We included 42 RCTs (298 605 patients). Eighty‐one percent of trials excluded patients with severe and 76% those with moderate kidney failure. Seventy‐one percent of trials excluded groups of women, 64% excluded patients with moderate to severe heart failure, 64% those with immunosuppressant conditions, 48% those with cancer, 29% those with dementia, and 29% of trials excluded older adults. The pooled prevalence for patients >70 years of age was 25% (95% CI, 0%–49%), 11% (3%–18%) for >75 years of age, and 51% (38%–63%) for multimorbidity. Conclusions The majority of lipid‐lowering therapy trials excluded patients with common diseases, such as moderate‐to‐severe kidney disease or heart failure or with immunosuppression. Underrepresenting certain populations, including women and older adults, might lead to limited transportability of study results and uncertainty on possible side‐effects and efficacy in these groups. Future trials should promote diversity in the recruitment strategies and improve equity in cardiovascular research. Registration URL: ClinicalTrials.gov; Unique Identifier: CRD42021253909.

Introduction Self-harm and suicide are major public health concerns among children and adolescents. Many risk and protective factors for suicide and self-harm have been identified and reported in the literature. However, the capacity of these identified risk and protective factors to guide assessment and management is limited due to their great number. This protocol describes an ongoing systematic review and meta-analysis which aims to examine longitudinal studies of risk factors for self-harm and suicide in children and adolescents, to provide a comparison of the strengths of association of the various risk factors for self-harm and suicide and to shed light on those that require further investigation.Methods and analysis We perform a systematic search of the literature using the databases EMBASE, PsycINFO, Medline, CINAHL and HMIC from inception up to 28 October 2020, and the search will be updated before the systematic review publication. Additionally, we will contact experts in the field, including principal investigators whose peer-reviewed publications are included in our systematic review as well as investigators from our extensive research network, and we will search the reference lists of relevant reviews to retrieve any articles that were not identified in our search. We will extract relevant data and present a narrative synthesis and combine the results in meta-analyses where there are sufficient data. We will assess the risk of bias for each study using the Newcastle–Ottawa Scale and present a summary of the quantity and the quality of the evidence for each risk or protective factor.Ethics and dissemination Ethical approval will not be sought as this is a systematic review of the literature. Results will be published in mental health journals and presented at conferences focused on suicide prevention.PROSPERO registration number CRD42021228212.

Abstract Background Antiplatelet drugs may prevent recurrent ischemic events after ischemic stroke but their relative effectiveness and harms still need to be clarified. Within this network meta-analysis we aimed to summarize the current evidence for using antiplatelet drugs for secondary stroke prevention. Methods We searched MEDLINE, EMBASE and CENTRAL up to September 2020. Randomized controlled trials (RCTs) assessing antiplatelet drugs for secondary stroke prevention were included. We did pairwise meta-analyses and network meta-analyses using random-effects models. Primary outcomes were all strokes (ischemic or hemorrhagic) and all-cause mortality. Results The review included 57 RCTs, 50 (n = 165,533 participants) provided data for the meta-analyses. Compared to placebo/no treatment, moderate to high-confidence evidence indicated that cilostazol, clopidogrel, dipyridamole + aspirin, ticagrelor, ticlopidine, and aspirin ≤ 150 mg/day significantly reduced the risk of all strokes (odds ratios, ORs and absolute risk difference, ARD): cilostazol 0.51 (95 % confidence interval, CI, 0.37 to 0.71; 3.6 % fewer), clopidogrel 0.63 (95 % CI, 0.49 to 0.79; 2.7 % fewer), dipyridamole + aspirin 0.65 (95 % CI, 0.55 to 0.78; 2.5 % fewer), ticagrelor 0.68 (95 % CI, 0.50 to 0.93; 2.3 % fewer), ticlopidine 0.74 (95 % CI 0.59 to 0.93; 1.9 % fewer), aspirin ≤ 150 mg/day 0.79 (95 % CI, 0.66 to 0.95; 1.5 % fewer). Aspirin > 150 mg/day and the combinations clopidogrel/aspirin, ticagrelor/aspirin, also decrease all strokes but increase the risk of hemorrhagic events. Only aspirin > 150 mg/day significantly reduced all-cause mortality (OR 0.86, 95 % CI 0.76 to 0.97; ARD 0.9 %, 95 %CI 1.5–0.2 % fewer, moderate confidence). Compared to aspirin ≤ 150 mg/day, clopidogrel significantly reduced the risk of all strokes, cardiovascular events, and intracranial hemorrhage outcomes. Cilostazol also appeared to provide advantages but data are limited to the Asian population. Conclusions Considering the benefits and harms ratio, cilostazol, clopidogrel, dipyridamole + aspirin, ticagrelor, ticlopidine, and aspirin ≤ 150 mg/day appear to be the best choices as antiplatelet drugs for secondary prevention of patients with ischemic stroke or TIA. Systematic review registration PROSPERO CRD42020159896 .

Introduction Pharmacotherapy is an important component of the multimodal treatment of attention-deficit/hyperactivity disorder (ADHD). Cardiovascular safety of medications for ADHD is of concern from a clinical and public health standpoint. We aim to conduct a network meta-analysis (NMA) comparing the effects of available medications for ADHD on blood pressure (diastolic and systolic), heart rate and ECG parameters over the short-term and long-term treatment.Methods and analysis Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines for protocols and NMAs will be followed. We will include parallel group or cross-over randomised controlled trials (RCTs) conducted in patients with a primary diagnosis of ADHD (no age limits). We will search an extensive number of electronic databases (including MEDLINE, CINAHL, CENTRAL, EMBASE, ERIC, PsycINFO, OpenGrey, Web of Science) from their inception and contact study authors/drug manufacturers to gather relevant unpublished information. No language restrictions will be applied. The main outcomes (assessed at 12 weeks, 26 weeks and 52 weeks) will be: (1) change in diastolic and systolic blood pressure (mm Hg); (2) change in heart rate, measured in beats/min; (3) change in any available ECG parameters. We will conduct random effects of NMA using standardised mean differences with 95% CIs for continuous outcomes and ORs with 95% CIs for dichotomous outcomes. We will use the Cochrane risk of bias tool-version 2 to assess the risk of bias of included RCTs and the Confidence In Network Meta-Analysis tool to evaluate the confidence of evidence contributing to each network estimate. Sensitivity analyses will investigate effects at different dose regimens.Ethics and dissemination No institutional review board approval will be necessary. The results of this systematic review and meta-analysis will be presented at national and international conferences and published in peer-reviewed journals.PROSPERO registration number CRD42021295352.

The first canton in Switzerland to implement an organized colorectal cancer screening program (OSP) was Uri. Starting in 2013, it offered 50–69-year-olds free testing with colonoscopy every 10 years or fecal occult blood test (FOBT) every 2 years. We tested the association between the OSP and testing rates over time.We analyzed claims data of 50–69-year-olds from Uri and neighboring cantons (NB) provided by a large health insurance and complemented it with data from the OSP. We fitted multivariate adjusted logistic regression models to compare overall testing rates and by method (colonoscopy or FOBT/both) We computed the 2018 rate of the population up-to-date with testing (colonoscopy within 9 years/FOBT within 2 years).Yearly overall testing rates in Uri increased from 8.7% in 2010 to 10.8% in 2018 and from 6.5% to 7.9% in NB. In Uri, the proportion tested with FOBT/both increased from 4.7% to 6.0% but decreased from 2.8% to 1.1% in NB. Testing by FOBT/both increased more between 2015 and 2018 than 2010–2012 in Uri than in NB (OR:2.1[95%CI:1.8–2.4]), it increased less for colonoscopy (OR:0.60[95%CI:0.51–0.70]), with no change in overall CRC testing (OR:0.91[95%CI:0.81–1.02]). In 2018 in Uri, 42.5% were up-to-date with testing (FOBT/both:9.2%, colonoscopy:35.7%); in NBs, 40.7% (FOBT/both:2.7%, colonoscopy:39%).Yearly FOBT rates in Uri were always higher than in NB. Though the OSP in Uri was not associated with a greater increase in overall testing rates, the OSP was associated with increased FOBT.

Recent recommendations for colorectal cancer (CRC) screening suggest fecal occult blood test (FOBT) or colonoscopy. Since 2013, mandatory health insurance in Switzerland reimburse CRC screening. We set out to determine if CRC testing rate and type of CRC screening changed in Switzerland from 2007 to 2017 and between the three main language regions. We extracted data on 50–75-year-olds from the Swiss Health Interview Survey (SHIS) 2007, 2012 and 2017 to determine rates of self-reported testing with FOBT within last 2 years and colonoscopy within last 10 years. We estimated prevalence ratio (PR) in multivariate-adjusted logistic regression models and compared rates in German-, French- and Italian-speaking regions, adjusting for sociodemographic, self-rated health and insurance variables. Overall testing rates (FOBT or colonoscopy) increased in all regions from 2007 to 2017 (German-speaking 33.6% to 48.3%; French-speaking 30.8% to 48.8%; Italian-speaking 37.9% to 46.8%), mainly because of an increase in colonoscopy rate for screening reasons (p

Introduction Hypertension management remains a major public health challenge in primary care. Innovative interventions to improve blood pressure (BP) control are needed. One approach is through community-based models of care with the involvement of pharmacists and other non-physician healthcare professionals. Our objective is to systematically review the evidence of the impact of pharmacist care alone or in collaboration with other healthcare professionals on BP among hypertensive outpatients compared with usual care. Because these interventions can be complex, with various components, the effect size may differ between the type of interventions. One major focus of our study will be to assess carefully the heterogeneity in the effects of these interventions to identify which ones work best in a given healthcare setting.Methods and analysis Systematic searches of the Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica (Embase) and Central Register of Controlled Trials (CENTRAL) databases will be conducted. Randomised controlled trials assessing the effect of pharmacist interventions on BP among outpatients will be included. Examples for pharmacist interventions are patient education, feedback to physician and medication management. The outcome will be the change in BP or BP at follow-up or BP control. Results will be synthesised descriptively and, if appropriate, will be pooled across studies to perform meta-analyses. If feasible, we will also perform a network meta-analysis to compare interventions that have not been compared directly head-to-head by using indirect evidence. Heterogeneity in the effect will be evaluated through prespecified subgroup and stratified analyses, accounting notably for the type and intensity of interventions, patients’ characteristics and healthcare setting.Ethics and dissemination Ethical approval is not required as the results will be drawn from currently available published literature. Outcomes of the review will be shared through peer-reviewed journal and used for implementation policy.PROSPERO registration number CRD42021279751.

Introduction It is unclear how pharmacological and non-pharmacological interventions compare with each other in terms of efficacy and tolerability for core symptoms and additional problems in adults with attention-deficit/hyperactivity disorder (ADHD). We aim to conduct the first network meta-analysis (NMA) comparing pharmacological and non-pharmacological interventions (or their combinations) in adults with ADHD.Methods and analysis We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for NMAs. We will search a broad set of electronic databases/registries and contact drug companies and experts in the field to retrieve published and unpublished randomised controlled trials (RCTs) (parallel or cross-over) of medications (either licensed or unlicensed) and any non-pharmacological intervention in adults (≥18 years) with ADHD. Primary outcomes will be: (1) change in severity of ADHD core symptoms, and (2) acceptability (all-cause discontinuation). Secondary outcomes will include tolerability (drop-out due to side effects) and change in the severity of emotional dysregulation, executive dysfunctions and quality of life. The risk of bias in each individual RCT included in the NMA will be assessed using the Cochrane Risk of Bias tool-version 2. We will evaluate the transitivity assumption comparing the distribution of possible effect modifiers across treatment comparisons. We will perform Bayesian NMA for each outcome with random-effects model in OpenBUGS. Pooled estimates of NMA will be obtained using the Markov Chains Monte Carlo method. We will judge the credibility in the evidence derived from the NMA using the CINeMA tool (which includes assessment of publication bias). We will conduct a series of sensitivity analyses to assess the robustness of the findings.Ethics and dissemination As this is the protocol for an aggregate-data level NMA, ethical approval will not be required. Results will be disseminated at national/international conferences and in peer-reviewed journals.PROSPERO registration number CRD42021265576.

BackgroundIn non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC).MethodsFor the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA.ResultsTen of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score.ConclusionANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.

ContextMultimorbidity is highly prevalent among older adults and associated with a high mortality. Prediction of mortality in multimorbid people would be clinically useful but there is no mortality risk index designed for this population. Our objective was therefore to develop and internally validate a 1-year mortality prognostic index for older multimorbid adults.MethodsWe analysed data of the OPERAM cohort study in Bern, Switzerland, including 822 adults aged 70 years or more with multimorbidity (3 or more chronic medical conditions) and polypharmacy (use of 5 drugs or more for >30 days). Time to all-cause mortality was assessed up to 1 year of follow-up. We performed a parametric Weibull regression model with backward stepwise selection to identify mortality risk predictors. The model was internally validated and optimism corrected using bootstrapping techniques. We derived a point-based risk score from the regression coefficients. Calibration and discrimination were assessed by the calibration slope and C statistic.Results805 participants were included in the analysis. During 1-year of follow-up, 158 participants (20%) had died. Age, Charlson-Comorbidity-Index, number of drugs, body mass index, number of hospitalizations, Barthel-Index (functional impairment), and nursing home residency were predictors of 1-year mortality in a multivariable model. Using these variables, the 1-year probability of dying could be predicted with an optimism-corrected C statistic of 0.70. The optimism-corrected calibration slope was 0.93. Based on the derived point-based risk score to predict mortality risk, 7% of the patients classified at low-risk of mortality, 19% at moderate-risk, and 37% at high-risk died after one year of follow-up. A simpler mortality score, without the Charlson-Comorbidity-Index and Barthel-Index, showed reduced discriminative power (optimism-corrected C statistic: 0.59) compared to the full score.ConclusionWe developed and internally validated a mortality risk index including for the first-time specific predictors for multimorbid adults. This new 1-year mortality prediction point-based score allowed to classify multimorbid older patients into three categories of increasing risk of mortality. Further validation of the score among various populations of multimorbid patients is needed before its implementation into practice.

Introduction Statin-associated muscle symptoms (SAMSs) are a major clinical issue in the primary and secondary prevention of cardiovascular events. Current guidelines advise various approaches mainly based on expert opinion. We will lead a systematic review and meta-analysis to explore the tolerability and acceptability and effectiveness of statin-based therapy management of patients with a history of SAMS. We aim to provide evidence on the tolerability and different strategies of statin-based management of patients with a history of SAMS.Methods and analysis We will conduct a systematic review of randomised controlled trials (RCTs) and non-randomised studies with a control group. We will search in Data sources MEDLINE, EMBASE, Cochrane Central Register of Controlled Clinical Trials, Scopus, Clinicaltrials.gov and Proquest from inception until April 2021. Two independent reviewers will carry out the study selection based on eligibility criteria. We will extract data following a standard data collection form. The reviewers will use the Cochrane Collaboration’s tools and Newcastle-Ottawa Scale to appraise the study risk of bias. Our primary outcome will be tolerability and our secondary outcomes will be acceptability and effectiveness. We will conduct a qualitative analysis of all included studies. In addition, if sufficient and homogeneous data are available, we will conduct quantitative analysis. We will synthesise dichotomous data using OR with 95% CI and continuous outcomes by using mean difference or standardised mean difference (with 95% CI). We will determine heterogeneity visually with forest plots and quantitatively with I2 and Q-test. We will summarise the confidence in the quantitative estimate by using Grading of Recommendations Assessment, Development and Evaluation approach.Ethics and dissemination As a systematic review of literature without collection of new clinical data, there will be no requirement for ethical approval. We will disseminate findings through peer-reviewed publications.PROSPERO registration number CRD42020202619.

Background Older multimorbid adults have a high risk of mortality and a short life expectancy (LE). Providing high-value care and avoiding care overuse, including of preventive care, is a serious challenge among multimorbid patients. While guidelines recommend to tailor preventive care according to the estimated LE, there is no tool to estimate LE in this specific population. Our objective is therefore to develop an LE estimator for older multimorbid adults by transforming a mortality prognostic index, which will be developed and internally validated in a prospective cohort.Methods and analysis We will analyse data of the Optimising Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older People cohort study in Bern, Switzerland. 822 participants were included at hospitalisation with age of 70 years or older, multimorbidity (three or more chronic medical conditions) and polypharmacy (use of five drugs or more for >30 days). All-cause mortality will be assessed during 3 years of follow-up. We will apply a flexible parametric survival model with backward stepwise selection to identify the mortality risk predictors. The model will be internally validated using bootstrapping techniques. We will derive a point-based risk score from the regression coefficients. We will transform the 3-year mortality prognostic index into an LE estimator using the Gompertz survival function. We will perform a qualitative assessment of the clinical usability of the LE estimator and its application. We will conduct the development and validation of the mortality prognostic index following the Prognosis Research Strategy (PROGRESS) framework and report it following the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement.Ethics and dissemination Written informed consent by patients themselves or, in the case of cognitive impairment, by a legal representative, was required before enrolment. The local ethics committee (Kantonale Ethikkommission Bern) has approved the study. We plan to publish the results in peer-reviewed journals and present them at national and international conferences.

Abstract Background Statins may prevent recurrent ischemic events after ischemic stroke. Determining which statin to use remains controversial. We aimed to summarize the evidence for the use of statins in secondary prevention for patients with ischemic stroke by comparing benefits and harms of various statins. Methods We searched for randomized controlled trials (RCTs) assessing statins in patients with ischemic stroke or transient ischemic attack (TIA) in MEDLINE, EMBASE, and CENTRAL up to July 2017. Two authors extracted data and appraised risks of bias. We performed pairwise meta-analyses and trial sequential analyses (TSA) to compare statins versus placebo/no statin, and network meta-analyses using frequentist random-effects models to compare statins through indirect evidence. We used GRADE to rate the overall certainty of evidence. Primary outcomes were all-cause mortality and all strokes. Secondary outcomes were different types of strokes, cardiovascular events, and adverse events. Results We identified nine trials (10,741 patients). No head-to-head RCTs were found. The median follow-up period was 2.5 years. Statins did not seem to modify all stroke and all-cause mortality outcomes; they were associated with a decreased risk of ischemic stroke (odds ratio, OR, 0.81 [95% CI, 0.70 to 0.93]; absolute risk difference, ARD, − 1.6% [95% CI, − 2.6 to − 0.6%]), ischemic stroke or TIA (OR, 0.75 [95% CI, 0.64 to 0.87]; ARD, − 4.2% [95% CI, − 6.2 to − 2.1%]), and cardiovascular event (OR, 0.75 [95% CI, 0.69 to 0.83]; ARD, − 5.4% [95% CI, − 6.8 to − 3.6%]), and did not seem to modify rhabdomyolysis, myalgia, or rise in creatine kinase. In the comparison of different statins, moderate- to high-quality evidence indicated that differences between pharmaceutical products seemed modest, with high doses (e.g., atorvastatin 80 mg/day and simvastatin 40 mg/day) associated with the greatest benefits. TSA excluded random error as a cause of the findings for ischemic stroke and cardiovascular event outcomes. Evidence for increased risk of hemorrhagic stroke was sensitive to the exclusion of the SPARCL trial. Conclusions Evidence strongly suggests that statins are associated with a reduction in the absolute risk of ischemic strokes and cardiovascular events. Differences in effects among statins were modest, signaling potential therapeutic equivalence. Trial registration PROSPERO CRD42018079112

Introduction Refugees and asylum seekers are vulnerable to common mental disorders, including post-traumatic stress disorder (PTSD). Using a network meta-analysis (NMA) approach, the present systematic review compared and ranked psychosocial interventions for the treatment of PTSD in adult refugees and asylum seekers.Methods Randomised studies of psychosocial interventions for adult refugees and asylum seekers with PTSD were systematically identified. PTSD symptoms at postintervention was the primary outcome. Standardised mean differences (SMDs) and ORs were pooled using pairwise and NMA. Study quality was assessed with the Cochrane Risk of Bias (RoB) tool, and certainty of evidence was assessed through the Confidence in Network Meta-Analysis application.Results A total of 23 studies with 2308 participants were included. Sixteen studies were conducted in high-income countries, and seven in low-income or middle-income countries. Most studies were at low risk of bias according to the Cochrane RoB tool. NMA on PTSD symptoms showed that cognitive behavioural therapy (CBT) (SMD=−1.41; 95% CI −2.43 to −0.38) and eye movement desensitisation and reprocessing (EMDR) (SMD=−1.30; 95% CI −2.40 to −0.20) were significantly more effective than waitlist (WL). CBT was also associated with a higher decrease in PTSD symptoms than treatment as usual (TAU) (SMD −1.51; 95% CI −2.67 to −0.36). For all other interventions, the difference with WL and TAU was not significant. CBT and EMDR ranked best according to the mean surface under the cumulative ranking. Regarding acceptability, no intervention had less dropouts than inactive interventions.Conclusion CBT and EMDR appeared to have the greatest effects in reducing PTSD symptoms in asylum seekers and refugees. This evidence should be considered in guidelines and implementation packages to facilitate dissemination and uptake in refugee settings.

Many healthcare interventions are complex, consisting of multiple, possibly interacting, components. Several methodological articles addressing complex interventions in the meta-analytical context have been published. We hereby provide an overview of methods used to evaluate the effects of complex interventions with meta-analytical models. We summarized the methodology, highlighted new developments, and described the benefits, drawbacks, and potential challenges of each identified method. We expect meta-analytical methods focusing on components of several multicomponent interventions to become increasingly popular due to recently developed, easy-to-use, software tools that can be used to conduct the relevant analyses. The different meta-analytical methods are illustrated through two examples comparing psychotherapies for panic disorder.

Background Older adults with chronic conditions are at high risk of complications from influenza and pneumococcal infections. Evidence about factors associated with influenza and pneumococcal vaccination among older multimorbid persons in Europe is limited. The aim of this study was to investigate the prevalence and determinants of these vaccinations in this population. Methods Multimorbid patients aged ≥70 years with polypharmacy were enrolled in 4 European centers in Switzerland, Belgium, the Netherlands, and Ireland. Data on vaccinations, demographics, health care contacts, and comorbidities were obtained from self-report, general practitioners and medical records. The association of comorbidities or medical contacts with vaccination status was assessed using multivariable adjusted log-binomial regression models. Results Among 1956 participants with available influenza vaccination data (median age 79 years, 45% women), 1314 (67%) received an influenza vaccination within the last year. Of 1400 patients with available pneumococcal vaccination data (median age 79 years, 46% women), prevalence of pneumococcal vaccination was 21% (n = 291). The prevalence of vaccination remained low in high-risk populations with chronic respiratory disease (34%) or diabetes (24%), but increased with an increasing number of outpatient medical contacts. Chronic respiratory disease was independently associated with the receipt of both influenza and pneumococcal vaccinations (prevalence ratio [PR] 1.09, 95% confidence interval [CI] 1.03–1.16; and PR 2.03, 95%CI 1.22–3.40, respectively), as was diabetes (PR 1.06, 95%CI 1.03–1.08; PR 1.24, 95%CI 1.16–1.34, respectively). An independent association was found between number of general practitioner visits and higher prevalence of pneumococcal vaccination (p for linear trend Conclusion Uptake of influenza and particularly of pneumococcal vaccination in this population of European multimorbid older inpatients remains insufficient and is determined by comorbidities and number and type of health care contacts, especially outpatient medical visits. Hospitalization may be an opportunity to promote vaccination, particularly targeting patients with few outpatient physician contacts.

ImportanceLevothyroxine prescriptions are rising worldwide. However, there are few data on factors associated with chronic use.ObjectiveTo assess the prevalence of chronic levothyroxine use, its rank among other chronic drugs and factors associated with chronic use. To assess the proportion of users outside the therapeutic range of thyroid-stimulating hormone (TSH).DesignCohort study (CoLaus|PsyCoLaus) with recruitment from 2003 to 2006. Follow-ups occurred 5 and 10 years after baseline.ParticipantsA random sample of Lausanne (Switzerland) inhabitants aged 35-75 years.Main outcomesWe evaluated the prevalence of chronic levothyroxine use and we then ranked it among the other most used chronic drugs. The ranking was compared to data from health insurance across the country. We assessed the association between each factor and chronic levothyroxine use in multivariable logistic regression models. The proportion of chronic levothyroxine users outside the usual TSH therapeutic range was assessed.Results4,334 participants were included in the analysis (mean±SD age 62.8±10.4 years, 54.9% women). 166 (3.8%) participants were chronic levothyroxine users. Levothyroxine was the second most prescribed chronic drug after aspirin in the cohort (8.2%) and the third most prescribed when using Swiss-wide insurance data. In multivariable analysis, chronic levothyroxine use was associated with increasing age [odds ratio 1.03, 95% confidence interval 1.01-1.05 per 1-year increase]; female sex [11.87 (5.24-26.89)]; BMI [1.06 (1.02-1.09) per 1-kg/m2 increase]; number of concomitant drugs [1.22 (1.16-1.29) per 1-drug increase]; and family history of thyroid pathologies [2.18 (1.37-3.48)]. Among chronic levothyroxine users with thyroid hormones assessment (n = 157), 42 (27%) were outside the TSH therapeutic range (17% overtreated and 10% undertreated).ConclusionsIn this population-based study, levothyroxine ranked second among chronic drugs. Age, female sex, BMI, number of drugs and family history of thyroid pathologies were associated with chronic levothyroxine use. More than one in four chronic users were over- or undertreated.

(1) Background: Tinnitus is the awareness of a sound in the absence of an external source. It affects around 10–15% of people, a significant proportion of whom also experience symptoms such as depression or anxiety that negatively affect their quality of life. Transcranial direct current stimulation (tDCS) is a technique involving constant low-intensity direct current delivered via scalp electrodes. It is a potential treatment option for tinnitus, as well as tinnitus-related conditions such as depression and anxiety. This systematic review estimates the effects of tDCS on outcomes relevant to tinnitus. In addition, it sheds light on the relationship between stimulation parameters and the effect of tDCS on these outcomes; (2) Methods: Exhaustive searches of electronic databases were conducted. Randomised controlled trials were included if they reported at least one of the following outcomes: tinnitus symptom severity, anxiety, or depression. Where available, data on quality of life, adverse effects, and neurophysiological changes were also reviewed. GRADE was used to assess the certainty in the estimate; (3) Results: Meta-analyses revealed a statistically significant reduction in tinnitus (moderate certainty) and depression (low certainty)-but not anxiety-following active tDCS compared to sham control. Network meta-analyses revealed potential optimal stimulation parameters; (4) Conclusions: The evidence synthesised in this review suggests tDCS has the potential to reduce symptom severity in tinnitus and depression. It further narrows down the number of potentially optimal stimulation parameters.

Introduction Panic disorder is among the most prevalent anxiety diseases. Although psychotherapy is recommended as first-line treatment for panic disorder, little is known about the relative efficacy of different types of psychotherapies. Moreover, there is little evidence concerning the effectiveness of different formats of major psychotherapeutic types, such as cognitive–behavioural therapy (CBT). In this protocol, we present an overarching project consisting of two systematic reviews and network meta-analyses (NMA) to shed light on which psychotherapy (NMA-1), and specifically, which CBT delivery format (NMA-2) should be considered most effective for adults suffering from panic disorder with or without agoraphobia.Methods and analyses Starting from a common pool of data, we will conduct two systematic reviews and NMA of randomised controlled trials examining panic disorder. A comprehensive search will be performed in electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Register of Controlled Trials—CENTRAL from database inception to 1 January 2021 to identify relevant studies. A systematic approach to searching, screening, reviewing and data extraction will be applied. Titles, abstract and—whenever necessary—full texts will be examined independently by at least two reviewers. The quality of the included studies will be assessed using the revised Cochrane risk of bias tool V.2. The primary efficacy outcome will be anxiety symptoms at study endpoint. The primary acceptability outcome will be all-cause discontinuation, as measured by the proportion of patients who had discontinued treatment for any reason at endpoint. Data will be pooled using a random-effects model. Pairwise and NMA will be conducted.Ethics and dissemination No ethical approval is necessary for these two studies, as there will be no collection of primary data. The results will be disseminated through peer-reviewed publications and presentations at national and international conferences and meetings.

Both colonoscopy and fecal occult blood test (FOBT) are commonly used for colorectal cancer (CRC) screening, but colonoscopy costs much more than FOBT. Swiss insurance offers high or low deductibles and choice of basic or private insurance. We hypothesized that high deductibles and basic insurance discourage colonoscopy, but do not change FOBT rates.We determined the proportion of patients tested for CRC in Switzerland (colonoscopy within 10 years, FOBT within 2 years), and determined associations with health insurance type.We extracted data on 50–75-year-olds from the Swiss Health Interview Surveys of 2012 to determine colonoscopy and FOBT testing rates (n = 7335). Multivariate logistic regression models estimated prevalence ratios (PRs) of CRC testing associated with health insurance type (deductible and private insurance), adjusted for socio-demographic factors (age, gender, education, income) and self-rated health.The weighted proportion of individuals tested for CRC within recommended intervals was 39.5%. Testing with colonoscopy was significantly associated with private insurance (PR 1.85, 95% CI: 1.46–2.35) and low deductible (PR 2.00, 95% CI: 1.56–2.57). Testing with FOBT was significantly associated with deductible (PR 1.71, 95%CI:1.09–2.68) but not with private insurance.About 60% of the Swiss population was not current with CRC testing. After adjusting for covariates, private insurance and low deductible was significantly associated with higher prevalence of CRC testing, indicating that waiving the deductible could increase CRC screening uptake and reduce health inequality.

Background A cointervention in a randomized clinical trial (RCT) is medical care given in addition to the tested intervention. If cointerventions are unbalanced between trial arms, the results may be biased. We hypothesized that cointerventions would be more adequately reported in RCTs without full blinding or at risk of bias. Methods and Results To describe the reporting of cointerventions and to evaluate the factors associated with their reporting, we did a systematic search of all RCTs evaluating pharmacological interventions on cardiovascular outcomes published in 5 high‐impact journals. The reporting of cointerventions, blinding, and risk of bias were extracted and evaluated independently by 2 reviewers (E.M., L.A.). Cointerventions were inadequately reported in 87 of 123 RCTs (70.7%), with 56 (45.5%) providing no information on cointerventions and 31 (25.2%) providing only partial information. Of the RCTs, 52 (42.3%) had inadequate blinding of participants and/or personnel and 63 (51.2%) of the RCTs were judged at risk of bias. In univariable analysis, the reporting of cointerventions was not associated with blinding of participants and/or personnel (odds ratio [OR], 1.04; 95% CI, 0.47–2.27 for adequately versus inadequately blinded trials) or with risk of bias (OR, 1.47; 95% CI, 0.67–3.21 for at low risk of bias versus trials at risk of bias). In multivariable analysis, only a follow‐up of

BACKGROUND:The evaluation of the credibility of results from a meta-analysis has become an important part of the evidence synthesis process. We present a methodological framework to evaluate confidence in the results from network meta-analyses, Confidence in Network Meta-Analysis (CINeMA), when multiple interventions are compared. METHODOLOGY:CINeMA considers 6 domains: (i) within-study bias, (ii) reporting bias, (iii) indirectness, (iv) imprecision, (v) heterogeneity, and (vi) incoherence. Key to judgments about within-study bias and indirectness is the percentage contribution matrix, which shows how much information each study contributes to the results from network meta-analysis. The contribution matrix can easily be computed using a freely available web application. In evaluating imprecision, heterogeneity, and incoherence, we consider the impact of these components of variability in forming clinical decisions. CONCLUSIONS:Via 3 examples, we show that CINeMA improves transparency and avoids the selective use of evidence when forming judgments, thus limiting subjectivity in the process. CINeMA is easy to apply even in large and complicated networks.

Abstract Screening and treatment of hypertension is a cornerstone of cardiovascular disease (CVD) prevention. Hypertension causes a large proportion of cases of stroke, coronary heart disease, heart failure, and associated disability and is highly prevalent especially among older adults. On the one hand, there is robust evidence that screening and treatment of hypertension prevents CVD and decreases mortality in the middle-aged population. On the other hand, among older adults, observational studies have shown either positive, negative, or no correlation between blood pressure (BP) and cardiovascular outcomes. Furthermore, there is a lack of high quality evidence for a favorable harm-benefit balance of antihypertensive treatment among older adults, especially among the oldest-old (i.e., above the age of 80 years), because very few trials have been conducted in this population. The optimal target BP may be higher among older treated hypertensive patients than among middle-aged. In addition, among frail or multimorbid older individuals, a relatively low BP may be associated with worse outcomes, and antihypertensive treatment may cause more harm than benefit. To guide hypertension screening and treatment recommendations among older patients, additional studies are needed to determine the most efficient screening strategies, to evaluate the effect of lowering BP on CVD risk and on mortality, to determine the optimal target BP, and to better understand the relationship between BP, frailty, multimorbidity, and health outcomes.

Abstract Background There are limited data on the characterization of medication-related visits (MRVs) to the emergency department (ED) in pediatric patients in Italy. We have estimated the frequency, severity, and classification of MRVs to the ED in pediatric patients. Methods We retrospectively analyzed data for children seeking medical evaluation for a MRV over an 8 years period. A medication-related ED visit was identified by using a random pharmacist assessment, emergency physician assessment, and in case of conflicting events, by a third investigators random assessment. Results In this study, regarding a single tertiary center in Italy, on a total of 147,643 patients from 0 to 14 years old, 497 medication-related visits were found, 54% of which occurred in children from 0 to 2 years of age. Severity was classified as mild in 21.6% of cases, moderate in 67.2% of cases, and severe in 11.2% of cases. The most common events were related to drug use without indication (51%), adverse drug reactions (30.3%), supratherapeutic dosage (13.2%) and improper drug selection (4.5%). The medication classes most frequently implicated in an ADE were anti-infective drugs for systemic use (28.9%), central nervous system agents (22.3%) and respiratory system drugs (10.8%). The most common symptom manifestations were dermatologic conditions (46.1%), general disorder and administration site conditions (29.7%) and gastrointestinal symptoms (16.0%). Conclusions To our knowledge, this is the first study in Italy evaluating the epidemiologic characteristics of MRVs confirming a significant cause of healthcare contact resulting in ED visits and hospital admissions with associated resource utilization. Our results suggests further future prospective, large-sample sized, and multicenter research is necessary to better understand the impact of MRVs and to develop strategies to provide care plans and monitor patients to prevent medication-related visits. Trial registration Not applicable.

Introduction Prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms have yielded conflicting findings, possibly because of differences in age, sex, thyroid-stimulating hormone cut-off levels or degree of baseline depressive symptoms. Analysis of individual participant data (IPD) may help clarify this association.Methods and analysis We will conduct a systematic review and IPD meta-analysis of prospective studies on the association between subclinical thyroid dysfunction and depressive symptoms. We will identify studies through a systematic search of the literature in the Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases from inception to April 2019 and from the Thyroid Studies Collaboration. We will ask corresponding authors of studies that meet our inclusion criteria to collaborate by providing IPD. Our primary outcome will be depressive symptoms at the first available individual follow-up, measured on a validated scale. We will convert all the scores to the Beck Depression Inventory scale. For each cohort, we will estimate the mean difference of depressive symptoms between participants with subclinical hypothyroidism or hyperthyroidism and control adjusted for depressive symptoms at baseline. Furthermore, we will adjust our multivariable linear regression analyses for age, sex, education and income. We will pool the effect estimates of all studies in a random-effects meta-analysis. Heterogeneity will be assessed by I2. Our secondary outcomes will be depressive symptoms at a specific follow-up time, at the last available individual follow-up and incidence of depression at the first, last and at a specific follow-up time. For the binary outcome of incident depression, we will use a logistic regression model.Ethics and dissemination Formal ethical approval is not required as primary data will not be collected. Our findings will have considerable implications for patient care. We will seek to publish this systematic review and IPD meta-analysis in a high-impact clinical journal.PROSPERO registration number CRD42018091627.

BackgroundClinical guidelines recommend psychosocial interventions for cocaine and/or amphetamine addiction as first-line treatment, but it is still unclear which intervention, if any, should be offered first. We aimed to estimate the comparative effectiveness of all available psychosocial interventions (alone or in combination) for the short- and long-term treatment of people with cocaine and/or amphetamine addiction.Methods and findingsWe searched published and unpublished randomised controlled trials (RCTs) comparing any structured psychosocial intervention against an active control or treatment as usual (TAU) for the treatment of cocaine and/or amphetamine addiction in adults. Primary outcome measures were efficacy (proportion of patients in abstinence, assessed by urinalysis) and acceptability (proportion of patients who dropped out due to any cause) at the end of treatment, but we also measured the acute (12 weeks) and long-term (longest duration of study follow-up) effects of the interventions and the longest duration of abstinence. Odds ratios (ORs) and standardised mean differences were estimated using pairwise and network meta-analysis with random effects. The risk of bias of the included studies was assessed with the Cochrane tool, and the strength of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We followed the PRISMA for Network Meta-Analyses (PRISMA-NMA) guidelines, and the protocol was registered in PROSPERO (CRD 42017042900). We included 50 RCTs evaluating 12 psychosocial interventions or TAU in 6,942 participants. The strength of evidence ranged from high to very low. Compared to TAU, contingency management (CM) plus community reinforcement approach was the only intervention that increased the number of abstinent patients at the end of treatment (OR 2.84, 95% CI 1.24-6.51, P = 0.013), and also at 12 weeks (OR 7.60, 95% CI 2.03-28.37, P = 0.002) and at longest follow-up (OR 3.08, 95% CI 1.33-7.17, P = 0.008). At the end of treatment, CM plus community reinforcement approach had the highest number of statistically significant results in head-to-head comparisons, being more efficacious than cognitive behavioural therapy (CBT) (OR 2.44, 95% CI 1.02-5.88, P = 0.045), non-contingent rewards (OR 3.31, 95% CI 1.32-8.28, P = 0.010), and 12-step programme plus non-contingent rewards (OR 4.07, 95% CI 1.13-14.69, P = 0.031). CM plus community reinforcement approach was also associated with fewer dropouts than TAU, both at 12 weeks and the end of treatment (OR 3.92, P < 0.001, and 3.63, P < 0.001, respectively). At the longest follow-up, community reinforcement approach was more effective than non-contingent rewards, supportive-expressive psychodynamic therapy, TAU, and 12-step programme (OR ranging between 2.71, P = 0.026, and 4.58, P = 0.001), but the combination of community reinforcement approach with CM was superior also to CBT alone, CM alone, CM plus CBT, and 12-step programme plus non-contingent rewards (ORs between 2.50, P = 0.039, and 5.22, P < 0.001). The main limitations of our study were the quality of included studies and the lack of blinding, which may have increased the risk of performance bias. However, our analyses were based on objective outcomes, which are less likely to be biased.ConclusionsTo our knowledge, this network meta-analysis is the most comprehensive synthesis of data for psychosocial interventions in individuals with cocaine and/or amphetamine addiction. Our findings provide the best evidence base currently available to guide decision-making about psychosocial interventions for individuals with cocaine and/or amphetamine addiction and should inform patients, clinicians, and policy-makers.

Background. Multiple Sclerosis (MS), an autoimmune disease with neurodegeneration and inflammation, is characterized by several alterations of different T cell subsets. However, few data exist on the role of iNKT lymphocytes. Objective. To identify possible changes in the phenotype of iNKT cells in patients with different clinical forms of MS, and find alterations in their polyfunctionality (i.e., ability to produce simultaneously up to 4 cytokines such as IL-17, TNF-α, IFN-γ, IL-4).Methods. We studied a total of 165 patients, 91 with a Relapsing Remitting form RR; 31 were treated with interferon (IFN)1-β, 25 with natalizumab (Nat), 29 with glatiramer acetate (Gla); 17 were newly-diagnosed RR without treatment, 19 not active RR without treatment. Forty-four patients had a Progressive MS: 20 Primary Progressive (PP), 24 Secondary Progressive (SP). A total of 55 age- and sex-matched subjects represented healthy controls (CTR). Among fresh peripheral blood mononuclear cells (PBMC) iNKT cells were identified by flow cytometry. Moreover, the capability of iNKT cells to produce different cytokines (IL-17, TNF-α, IFN-γ, and IL-4) after in vitro stimulation were evaluated in 18 RR (11 treated with Nat and 7 with IFN), 4 PP, 6 SP and 16 CTR.Results. No main differences were found in iNKT cell phenotype among MS patients with different MS forms, or during different treatments. However, the polyfunctional response of iNKT cells showed Th1 and Th17 profiles. This was well evident in patients with secondary progressive form, who are characterized by high levels of inflammation and neurodegeneration, and exhibited a sustained increase in the production of Th17 cytokines. Patients treated with natalizumab displayed lower levels of iNKT cells producing IL-17, TNF-α and IFN-γ.Conclusion. Our data suggest that the progressive phase of the disease is characterized by permanent iNKT activation and a skewing towards an inflammatory phenotype. Compared to other treatments, natalizumab was able to modulate iNKT cell function.

BACKGROUND:Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients. METHODS AND FINDINGS:By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during high-dose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD): 2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD. CONCLUSIONS:Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM.

INTRODUCTION: Information on benefits and risks of drugs is a key element affecting doctors' prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. OBJECTIVES: Testing the short and long-term effectiveness on general practitioners' prescribing of small groups meetings led by pharmacists. METHODS: Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach--TEA, with information materials on osteoporosis or prostatic hyperplasia--and a single drug oriented approach--SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. RESULTS: In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio -8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (-7.6%, p = 0.02; and -9,8%, p = 0.03), but not at six months (-5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine -9.8%, p = 0.02; prescription of prulifloxacin -11.1%, p = 0.04), which persisted or increased over time. INTERPRETATION: These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially relevant long-term impact on prescribing habits, in particular when focusing on a single drug. National Health systems should invest in independent drug information programs. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN05866587.

Systematic reviews that collate data about the relative effects of multiple interventions via network meta-analysis are highly informative for decision-making purposes. A network meta-analysis provides two types of findings for a specific outcome: the relative treatment effect for all pairwise comparisons, and a ranking of the treatments. It is important to consider the confidence with which these two types of results can enable clinicians, policy makers and patients to make informed decisions. We propose an approach to determining confidence in the output of a network meta-analysis. Our proposed approach is based on methodology developed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group for pairwise meta-analyses. The suggested framework for evaluating a network meta-analysis acknowledges (i) the key role of indirect comparisons (ii) the contributions of each piece of direct evidence to the network meta-analysis estimates of effect size; (iii) the importance of the transitivity assumption to the validity of network meta-analysis; and (iv) the possibility of disagreement between direct evidence and indirect evidence. We apply our proposed strategy to a systematic review comparing topical antibiotics without steroids for chronically discharging ears with underlying eardrum perforations. The proposed framework can be used to determine confidence in the results from a network meta-analysis. Judgements about evidence from a network meta-analysis can be different from those made about evidence from pairwise meta-analyses.

Several studies in mouse model of invasive aspergillosis (IA) and in healthy donors have shown that different Aspergillus antigens may stimulate different adaptive immune responses. However, the occurrence of Aspergillus-specific T cells have not yet been reported in patients with the disease. In patients with IA, we have investigated during the infection: a) whether and how specific T-cell responses to different Aspergillus antigens occur and develop; b) which antigens elicit the highest frequencies of protective immune responses and, c) whether such protective T cells could be expanded ex-vivo. Forty hematologic patients have been studied, including 22 patients with IA and 18 controls. Specific T cells producing IL-10, IFN-γ, IL-4 and IL-17A have been characterized through enzyme linked immunospot and cytokine secretion assays on 88 peripheral blood (PB) samples, by using the following recombinant antigens: GEL1p, CRF1p, PEP1p, SOD1p, α1-3glucan, β1-3glucan, galactomannan. Specific T cells were expanded through short term culture. Aspergillus-specific T cells producing non-protective interleukin-10 (IL-10) and protective interferon-gamma (IFN-γ) have been detected to all the antigens only in IA patients. Lower numbers of specific T cells producing IL-4 and IL-17A have also been shown. Protective T cells targeted predominantly Aspergillus cell wall antigens, tended to increase during the IA course and to be associated with a better clinical outcome. Aspergillus-specific T cells could be successfully generated from the PB of 8 out of 8 patients with IA and included cytotoxic subsets able to lyse Aspergillus hyphae. Aspergillus specific T-cell responses contribute to the clearance of the pathogen in immunosuppressed patients with IA and Aspergillus cell wall antigens are those mainly targeted by protective immune responses. Cytotoxic specific T cells can be expanded from immunosuppressed patients even during the infection by using the above mentioned antigens. These findings may be exploited for immunotherapeutic purposes in patients with IA.