Davide Papola

Corticosteroids for treatment of sore throat: systematic review and meta-analysis of randomised trials

Objective To estimate the benefits and harms of using corticosteroids as an adjunct treatment for sore throat. Design Systematic review and meta-analysis of randomised control trials. Data sources Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), trial registries up to May 2017, reference lists of eligible trials, related reviews. Study selection Randomised controlled trials of the addition of corticosteroids to standard clinical care for patients aged 5 or older in emergency department and primary care settings with clinical signs of acute tonsillitis, pharyngitis, or the clinical syndrome of sore throat. Trials were included irrespective of language or publication status. Review methods Reviewers identified studies, extracted data, and assessed the quality of the evidence, independently and in duplicate. A parallel guideline committee (BMJ Rapid Recommendation) provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. Random effects model was used for meta-analyses. Quality of evidence was assessed with the GRADE approach. Results 10 eligible trials enrolled 1426 individuals. Patients who received single low dose corticosteroids (the most common intervention was oral dexamethasone with a maximum dose of 10 mg) were twice as likely to experience pain relief after 24 hours (relative risk 2.2, 95% confidence interval 1.2 to 4.3; risk difference 12.4%; moderate quality evidence) and 1.5 times more likely to have no pain at 48 hours (1.5, 1.3 to 1.8; risk difference 18.3%; high quality). The mean time to onset of pain relief in patients treated with corticosteroids was 4.8 hours earlier (95% confidence interval −1.9 to −7.8; moderate quality) and the mean time to complete resolution of pain was 11.1 hours earlier (−0.4 to −21.8; low quality) than in those treated with placebo. The absolute pain reduction at 24 hours (visual analogue scale 0-10) was greater in patients treated with corticosteroids (mean difference 1.3, 95% confidence interval 0.7 to 1.9; moderate quality). Nine of the 10 trials sought information regarding adverse events. Six studies reported no adverse effects, and three studies reported few adverse events, which were mostly complications related to disease, with a similar incidence in both groups. Conclusion Single low dose corticosteroids can provide pain relief in patients with sore throat, with no increase in serious adverse effects. Included trials did not assess the potential risks of larger cumulative doses in patients with recurrent episodes of acute sore throat. Systematic review registration PROSPERO CRD42017067808.

New EMA report on paliperidone 3-month injections: taking clinical and policy decisions without an adequate evidence base

Three-month long-acting paliperidone is a new, recently marketed, formulation of paliperidone, characterised by the longest available dosing interval among long-acting antipsychotics. The clinical profile of 3-month long-acting paliperidone was recently summarised by the European Medicines Agency (EMA) in a public assessment report, released in April 2016. In this commentary, the main strengths and limitations of the EMA assessment report were appraised and discussed, in order to highlight possible implications for clinical practice, future research and regulatory practices for drug approval.

Focused psychosocial interventions for children in low-resource humanitarian settings : a systematic review and individual participant data meta-analysis

BACKGROUND Results from studies evaluating the effectiveness of focused psychosocial support interventions in children exposed to traumatic events in humanitarian settings in low-income and middle-income countries have been inconsistent, showing varying results by setting and subgroup (eg, age or gender). We aimed to assess the effectiveness of these interventions, and to explore which children are likely to benefit most. METHODS We did a systematic review and meta-analysis of individual participant data (IPD) from 3143 children recruited to 11 randomised controlled trials of focused psychosocial support interventions versus waiting list. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, PsycArticles, Web of Science, and the main local low-income and middle-income countries (LMICs) databases according to the list of databases relevant to LMIC developed collaboratively by Cochrane and WHO Library, up to November, 2016. We included randomised controlled trials that assessed the effectiveness of focused psychosocial support interventions in children exposed to traumatic events in LMICs, compared with waiting lists (eg, inactive controls). We excluded quasi-randomised trials, studies that did not focus on psychosocial support interventions, and studies that compared two active interventions without control conditions. We requested anonymised data from each trial for each of the prespecified variables for each child who was randomly assigned. The main outcomes considered were continuous scores in post-traumatic stress disorder (PTSD) symptoms, depressive symptoms, and anxiety symptoms assessed with rating scales administered immediately (0-4 weeks) after the intervention. We harmonised all individual items from rating scales using item response theory methods. This study is registered with PROSPERO, number CRD42013006960. FINDINGS We identified a beneficial effect of focused psychosocial support interventions on PTSD symptoms (standardised mean difference [SMD] -0·33, 95% CI -0·52 to -0·14) that was maintained at follow-up (-0·21, -0·42 to -0·01). We also identified benefits at the endpoint for functional impairment (-0·29, -0·43 to -0·15) and for strengths: coping (-0·22, -0·43 to -0·02), hope (-0·29, -0·48 to -0·09), and social support (-0·27, -0·52 to -0·02). In IPD meta-analyses focused on age, gender, displacement status, region, and household size we found a stronger improvement in PTSD symptoms in children aged 15-18 years (-0·43, -0·63 to -0·23), in non-displaced children (-0·40, -0·52 to -0·27), and in children living in smaller households (<6 members; -0·27, -0·42 to -0·11). INTERPRETATION Overall, focused psychosocial interventions are effective in reducing PTSD and functional impairment, and in increasing hope, coping, and social support. Future studies should focus on strengthening interventions for younger children, displaced children, and children living in larger households. FUNDING European Commission FP7th Framework Programme for Research (Marie Curie International Outgoing Fellowship) and the National Institute on Aging.

Drug dose as mediator of treatment effect in antidepressant drug trials: the case of fluoxetine

This study aimed at investigating whether dose is a mediator of treatment effect in fluoxetine‐randomized trials. Specifically, we investigated whether dose was higher in trials in which the aim was to demonstrate fluoxetine efficacy in comparison with older antidepressants and lower in trials in which the aim was to demonstrate a new drugs efficacy against fluoxetine.

Antipsychotic drug exposure and risk of myocardial infarction.

Patients experiencing psychoses and in need of antipsychotic agents may be exposed to a higher risk of myocardial infarction (MI) than the general population. As there have been no randomised studies investigating this association, a recent systematic review and meta-analysis included all observational studies that compared the incidence of MI among patients receiving antipsychotics v. no treatment. It found nine studies and calculated that the odds (risk) for developing MI were 1.88-fold higher in antipsychotic users compared with individuals who had not taken antipsychotic drugs. In this commentary, the results of this systematic review are discussed in view of their clinical implications for everyday clinical practice.

Factors associated with first- versus second-generation long-acting antipsychotics prescribed under ordinary clinical practice in Italy

Background For many years, long-acting intramuscular (LAI) antipsychotics have been prescribed predominantly to chronic and severe patients, as a last resort when other treatments failed. Recently, a broader and earlier use of LAIs, particularly second-generation LAIs, has been emphasized. To date, few studies attempted to frame how this change in prescribing took place in real-world practice. Therefore, this study aimed to describe the clinical features of patients prescribed with LAIs, and to explore possible prescribing differences between first- and second-generations LAIs under ordinary clinical practice in Italy. Methods The STAR Network “Depot” Study is an observational, longitudinal, multicenter study involving 35 centers in Italy. In the cross-sectional phase, patients prescribed with LAIs were consecutively recruited and assessed over a period of 12 months. Descriptive statistics and multivariable logistic regression analyses were employed. Results Of the 451 recruited patients, 61% were males. The level of social and working functioning was heterogeneous, as was the severity of disease. Seventy-two per cent of the patients had a diagnosis of the schizophrenia spectrum. Seventy per cent were prescribed with second-generation antipsychotic (SGA) LAIs (mostly paliperidone, aripiprazole and risperidone). Compared to first-generation antipsychotic (FGA) LAIs, patients prescribed with SGA LAIs were more often younger; employed; with a diagnosis of the schizophrenia spectrum or bipolar disorder; with higher levels of affective symptoms; with fewer LAI prescriptions in the past. Discussion LAIs’ prescribing practices appear to be more flexible as compared to the past, although this change is mostly restricted to SGA LAIs.

Antipsychotic combinations in schizophrenia

In the treatment of resistant schizophrenia, a number of meta-analyses attempted to quantify the efficacy and tolerability of antipsychotic (AP) polypharmacy v. monotherapy with contradictory results. Recently, a systematic review and meta-analysis of randomised controlled trials investigated the efficacy and tolerability of AP combination v. monotherapy in schizophrenia. It included 31 studies: 21 double-blind (considered high-quality studies) and 10 open-label (considered low-quality studies). The meta-analysis showed that, overall, the combination of two APs was more effective than monotherapy in terms of symptom reduction (standardised mean difference (SMD) = -0.53, 95% confidence interval (CI) -0.87 to -0.19); however, this result was confirmed only in the subgroup of low-quality studies. Negative symptoms improved when combining a D2 antagonist with a D2 partial agonist (SMD = -0.41, 95% CI -0.79 to -0.03) both in double-blind and open-label studies. In the present commentary, the results of this systematic review are critically discussed in terms of their clinical and research implications.

Association between statistical significance and time to publication among systematic reviews: a study protocol for a meta-epidemiological investigation

Introduction Many studies have indicated the impact of bias in dissemination and publication in medical research. Existence of such bias among clinical trials has been repeatedly pointed out, but it has not been well studied in the field of systematic reviews (SRs). We therefore aim to investigate whether or not time lag bias and publication bias in SRs based on statistical significance in results exist. In addition, we will examine at what stage of paper publication process such bias, if any, creeps in. Method and analysis The present study is a meta-epidemiological study. We will include all SRs of interventions registered in the international prospective register of SRs (PROSPERO) before December 2014 if the SR has completed its analysis irrespective of its publication status. All contact authors of eligible SRs will be asked to participate in a survey administered through the Internet. Our primary outcome is time from protocol registration to full publication of SR as a journal article, defined as time from the registration date to the acceptance date among all the relevant SRs. We will examine the impact of statistically significant findings on the primary outcomes through time to event analyses. Ethics and dissemination Ethics approval will be obtained from the Ethical Committee of the Kyoto University Graduate School of Medicine. This protocol has been registered in the University Hospital Medical Information Network Clinical Trials Registry. We will publish our findings in a peer-reviewed journal and also may present them at conferences. Trial registration number: UMIN000028325