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Histaminergic neurons are crucial to maintain wakefulness, but their role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients with narcolepsy. For this randomised, double-blind, placebo-controlled trial we recruited patients with narcolepsy from 16 sleep centres in nine countries (Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, and Ukraine). Patients were eligible if they were aged 18 years or older, diagnosed with narcolepsy with cataplexy according to version two of the International Classification of Sleep Disorders criteria, experienced at least three cataplexies per week, and had excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via an interactive web response system to randomly assign patients to receive either pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks of four. Participants and investigators were masked to treatment allocation. Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 mg). The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01800045. The trial was done between April 19, 2013, and Jan 28, 2015. We screened 117 patients, 106 of whom were randomly assigned to treatment (54 to pitolisant and 52 to placebo) and, after dropout, 54 patients from the pitolisant group and 51 from the placebo group were included in the intention-to-treat analysis. The WCR during the stable dosing period compared with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15; WCRfinal/baseline=0·25) in patients who received pitolisant and 38% (WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who received placebo (rate ratio 0·512; 95% CI 0·43–0·60, p<0·0001). Treatment-related adverse events were significantly more common in the pitolisant group than in the placebo group (15 [28%] of 54 vs 6 [12%] of 51; p=0·048). There were no serious adverse events, but one case of severe nausea in the pitolisant group. The most frequent adverse events in the pitolisant group (headache, irritability, anxiety, and nausea) were mild or moderate except one case of severe nausea. No withdrawal syndrome was detected following pitolisant treatment; one case was detected in the placebo group. Pitolisant was well tolerated and efficacious in reducing cataplexy. If confirmed in long-term studies, pitolisant might constitute a useful first-line therapy for cataplexy in patients with narcolepsy, for whom there are currently few therapeutic options. Bioprojet, France.

Most patients with amyotrophic lateral sclerosis (ALS) develop respiratory insufficiency in the advanced stage of their disease. Non-invasive ventilation (NIV) is commonly regarded to be a treatment that is effective in reducing these complaints. To assess whether the effect of NIV on gas exchange and quality of life (QOL) is different in patients with ALS versus without ALS. A post hoc analysis was done with data from a previously published trial, in which all patients were instituted on NIV. Arterial blood gasses were assessed next to QOL by generic as well as disease-specific questionnaires. 77 patients started NIV: 30 with ALS and 47 without. Both groups showed significant improvements in blood gasses after 2 and 6 months. Compared to the non-ALS group, the ALS group had significantly worse scores after 6 months in MRF-28, SRI, HADS and SF-36 than the non-ALS group. This study shows that NIV improves gas exchange, both in patients with and without ALS. QOL improves markedly more in patients without ALS than in those with ALS, in whom only some domains improve. Our observation of little or no effect in ALS patients warrants a large study limited to ALS patients only.

Background and objective Patients with focal seizures recruited into adjunctive antiepileptic drug (AED) trials have become more refractory and severe over time; concurrently, placebo responses have increased. To attempt to account for heterogeneity among trials, propensity-score weighted patient-level data were used to indirectly compare placebo responses reported in brivaracetam and levetiracetam trials. Methods Patient-level data from randomised, placebo-controlled brivaracetam (recruited 2007–2014) and levetiracetam (1993–1998) trials were pooled. Consistent inclusion/exclusion criteria were applied and outcomes were defined consistently. Potentially confounding baseline characteristics were adjusted for using propensity score weighting. Weighting success was assessed using placebo response. Results In total, 707 and 473 active drug and 399 and 253 placebo patients comprised the brivaracetam and levetiracetam groups, respectively. Before weighting, several baseline variables were significantly different between groups; after weighting, prior vagal nerve stimulation, co-morbid depression and co-morbid anxiety remained different. Before weighting, median seizure frequency reduction was 21.7 and 3.9% in the brivaracetam and levetiracetam placebo arms, respectively; after weighting, median reduction was 15.0 and 6.0%. The comparison of non-randomised groups could be biased by unobserved confounding factors and region of residence. Lifetime AED history was unavailable in the brivaracetam trials and excluded from analysis. Conclusions Placebo responses remained different between brivaracetam and levetiracetam trials after propensity score weighting, indicating the presence of residual confounding factors associated with placebo response in these trials. It therefore remains problematic to conduct reliable indirect comparisons of brivaracetam and levetiracetam given the current evidence base, which may apply to comparisons between other AED trials.

Background Systematic literature searching is recognised as a critical component of the systematic review process. It involves a systematic search for studies and aims for a transparent report of study identification, leaving readers clear about what was done to identify studies, and how the findings of the review are situated in the relevant evidence. Information specialists and review teams appear to work from a shared and tacit model of the literature search process. How this tacit model has developed and evolved is unclear, and it has not been explicitly examined before. The purpose of this review is to determine if a shared model of the literature searching process can be detected across systematic review guidance documents and, if so, how this process is reported in the guidance and supported by published studies. Method A literature review. Two types of literature were reviewed: guidance and published studies. Nine guidance documents were identified, including: The Cochrane and Campbell Handbooks. Published studies were identified through ‘pearl growing’, citation chasing, a search of PubMed using the systematic review methods filter, and the authors’ topic knowledge. The relevant sections within each guidance document were then read and re-read, with the aim of determining key methodological stages. Methodological stages were identified and defined. This data was reviewed to identify agreements and areas of unique guidance between guidance documents. Consensus across multiple guidance documents was used to inform selection of ‘key stages’ in the process of literature searching. Results Eight key stages were determined relating specifically to literature searching in systematic reviews. They were: who should literature search, aims and purpose of literature searching, preparation, the search strategy, searching databases, supplementary searching, managing references and reporting the search process. Conclusions Eight key stages to the process of literature searching in systematic reviews were identified. These key stages are consistently reported in the nine guidance documents, suggesting consensus on the key stages of literature searching, and therefore the process of literature searching as a whole, in systematic reviews. Further research to determine the suitability of using the same process of literature searching for all types of systematic review is indicated.

The purpose of this analysis was to explore the potential role of anxious MDD as a treatment predictor and moderator in major depressive disorder (MDD) using a large escitalopram clinical trial dataset. Individual patient-level data from 13 double-blinded, randomized, controlled trials in patients with MDD were pooled. Both univariate, last observation carried forward (LOCF) analyses and repeated measurements analyses without imputation (MMRM) were carried out for change in symptom scores, response and remission rates. Of 3,919 patients, 48.0% were classified as having anxious MDD depression (HAMD) somatization/anxiety subscale score ≥7 at baseline. Patients with anxious MDD were less likely to report symptom improvement on some outcome measures than patients without anxious MDD (predictor analysis). Specifically, the difference in response rates for patients with vs. patients without anxious MDD according to the MADRS (55.6% vs. 57.7%, respectively) was not statistically different. However, the difference in remission rates for patients with versus without anxious MDD according to the MADRS (37.6% vs. 44.1%, respectively) was statistically significant. Escitalopram was more effective than placebo, and as effective as the SSRIs and SNRIs, in the treatment of anxious MDD. The present analysis provides some evidence that the presence of an anxious MDD subtype is a predictor of poor response. There was no difference in the response to treatment of patients with or without anxious MDD to escitalopram, SSRIs, or SNRIs. The present analysis did not support the notion that SNRIs are more effective than escitalopram in the treatment of anxious MDD, nor was there evidence to support treatment moderating effects for anxious MDD.

Background Scoping reviews are used to identify knowledge gaps, set research agendas, and identify implications for decision-making. The conduct and reporting of scoping reviews is inconsistent in the literature. We conducted a scoping review to identify: papers that utilized and/or described scoping review methods; guidelines for reporting scoping reviews; and studies that assessed the quality of reporting of scoping reviews. Methods We searched nine electronic databases for published and unpublished literature scoping review papers, scoping review methodology, and reporting guidance for scoping reviews. Two independent reviewers screened citations for inclusion. Data abstraction was performed by one reviewer and verified by a second reviewer. Quantitative (e.g. frequencies of methods) and qualitative (i.e. content analysis of the methods) syntheses were conducted. Results After searching 1525 citations and 874 full-text papers, 516 articles were included, of which 494 were scoping reviews. The 494 scoping reviews were disseminated between 1999 and 2014, with 45 % published after 2012. Most of the scoping reviews were conducted in North America (53 %) or Europe (38 %), and reported a public source of funding (64 %). The number of studies included in the scoping reviews ranged from 1 to 2600 (mean of 118). Using the Joanna Briggs Institute methodology guidance for scoping reviews, only 13 % of the scoping reviews reported the use of a protocol, 36 % used two reviewers for selecting citations for inclusion, 29 % used two reviewers for full-text screening, 30 % used two reviewers for data charting, and 43 % used a pre-defined charting form. In most cases, the results of the scoping review were used to identify evidence gaps (85 %), provide recommendations for future research (84 %), or identify strengths and limitations (69 %). We did not identify any guidelines for reporting scoping reviews or studies that assessed the quality of scoping review reporting. Conclusion The number of scoping reviews conducted per year has steadily increased since 2012. Scoping reviews are used to inform research agendas and identify implications for policy or practice. As such, improvements in reporting and conduct are imperative. Further research on scoping review methodology is warranted, and in particular, there is need for a guideline to standardize reporting.

Background An increasing number of qualitative evidence syntheses papers are found in health care literature. Many of these syntheses use a strictly exhaustive search strategy to collect articles, mirroring the standard template developed by major review organizations such as the Cochrane and Campbell Collaboration. The hegemonic idea behind it is that non-comprehensive samples in systematic reviews may introduce selection bias. However, exhaustive sampling in a qualitative evidence synthesis has been questioned, and a more purposeful way of sampling papers has been proposed as an alternative, although there is a lack of transparency on how these purposeful sampling strategies might be applied to a qualitative evidence synthesis. We discuss in our paper why and how we used purposeful sampling in a qualitative evidence synthesis about ‘sexual adjustment to a cancer trajectory’, by giving a worked example. Methods We have chosen a mixed purposeful sampling, combining three different strategies that we considered the most consistent with our research purpose: intensity sampling, maximum variation sampling and confirming/disconfirming case sampling. Results The concept of purposeful sampling on the meta-level could not readily been borrowed from the logic applied in basic research projects. It also demands a considerable amount of flexibility, and is labour-intensive, which goes against the argument of many authors that using purposeful sampling provides a pragmatic solution or a short cut for researchers, compared with exhaustive sampling. Opportunities of purposeful sampling were the possible inclusion of new perspectives to the line-of-argument and the enhancement of the theoretical diversity of the papers being included, which could make the results more conceptually aligned with the synthesis purpose. Conclusions This paper helps researchers to make decisions related to purposeful sampling in a more systematic and transparent way. Future research could confirm or disconfirm the hypothesis of conceptual enhancement by comparing the findings of a purposefully sampled qualitative evidence synthesis with those drawing on an exhaustive sample of the literature.

Multivariate pattern recognition approaches have recently facilitated the search for reliable neuroimaging-based biomarkers in psychiatric disorders such as schizophrenia. By taking into account the multivariate nature of brain functional and structural changes as well as their distributed localization across the whole brain, they overcome drawbacks of traditional univariate approaches. To evaluate the overall reliability of neuroimaging-based biomarkers, we conducted a comprehensive literature search to identify all studies that used multivariate pattern recognition to identify patterns of brain alterations that differentiate patients with schizophrenia from healthy controls. A bivariate random-effects meta-analytic model was implemented to investigate the sensitivity and specificity across studies as well as to assess the robustness to potentially confounding variables. In the total sample of n=38 studies (1602 patients and 1637 healthy controls), patients were differentiated from controls with a sensitivity of 80.3% (95% CI: 76.7-83.5%) and a specificity of 80.3% (95% CI: 76.9-83.3%). Analysis of neuroimaging modality indicated higher sensitivity (84.46%, 95% CI: 79.9-88.2%) and similar specificity (76.9%, 95% CI: 71.3-81.6%) of rsfMRI studies as compared with structural MRI studies (sensitivity: 76.4%, 95% CI: 71.9-80.4%, specificity of 79.0%, 95% CI: 74.6-82.8%). Moderator analysis identified significant effects of age (p=0.029), imaging modality (p=0.019), and disease stage (p=0.025) on sensitivity as well as of positive-to-negative symptom ratio (p=0.022) and antipsychotic medication (p=0.016) on specificity. Our results underline the utility of multivariate pattern recognition approaches for the identification of reliable neuroimaging-based biomarkers. Despite the clinical heterogeneity of the schizophrenia phenotype, brain functional and structural alterations differentiate schizophrenic patients from healthy controls with 80% sensitivity and specificity.

The Cochrane Central Register of Controlled Trials (CENTRAL) is compiled from a number of sources, including PubMed and Embase. Since 2017, we have increased the number of sources feeding into CENTRAL and improved the efficiency of our processes through the use of application programming interfaces, machine learning, and crowdsourcing.Our objectives were twofold: (1) Assess the effectiveness of Cochrane's centralized search and screening processes to correctly identify references to published reports which are eligible for inclusion in Cochrane systematic reviews of randomized controlled trials (RCTs). (2) Identify opportunities to improve the performance of Cochrane's centralized search and screening processes to identify references to eligible trials. We identified all references to RCTs (either published journal articles or trial registration records) with a publication or registration date between 1st January 2017 and 31st December 2018 that had been included in a Cochrane intervention review. We then viewed an audit trail for each included reference to determine if it had been identified by our centralized search process and subsequently added to CENTRAL. We identified 650 references to included studies with a publication year of 2017 or 2018. Of those, 634 (97.5%) had been captured by Cochrane's Centralised Search Service. Sixteen references had been missed by the Cochrane's Centralised Search Service: six had PubMed-not-MEDLINE status, four were missed by the centralized Embase search, three had been misclassified by Cochrane Crowd, one was from a journal not indexed in MEDLINE or Embase, one had only been added to Embase in 2019, and one reference had been rejected by the automated RCT machine learning classifier. Of the sixteen missed references, eight were the main or only publication to the trial in the review in which it had been included. This analysis has shown that Cochrane's centralized search and screening processes are highly sensitive. It has also helped us to understand better why some references to eligible RCTs have been missed. The CSS is playing a critical role in helping to populate CENTRAL and is moving us toward making CENTRAL a comprehensive repository of RCTs. •Cochrane's Centralized Search Service is performing well with a recall of 97.5%.•The service uses machine learning and crowdsourcing for the identification of randomized trials.•Restricting searches to Cochrane Central Register of Controlled Trials might be adequate in certain contexts.

PubMed is one of the most commonly used search tools in biomedical and life sciences. Existing studies of database coverage generally conclude that searching PubMed may not be sufficient although some find that the contributions from other databases are modest at best. However, generalizability of the studies of the coverage of PubMed is typically restricted. The objective of this study is to analyze the coverage of PubMed across specialties and over time. We use the more than 50,000 included studies in all Cochrane reviews published from 2012 to 2016 as our population and examine if the studies and resulting publications can be identified in PubMed. The results show that PubMed has a coverage of 70.9, 95% confidence interval (CI) (68.40, 73.30) of all the included publications and 82.8%, 95% CI (80.9, 84.7) of the included studies. There are huge differences in coverage across and within specialties. In addition, coverage varies within groups over time. Databases used for searching topics within the groups with highly varying or low coverage should be chosen with care as PubMed may have a relatively low coverage. •This study presents the results of an analysis of more than 85,000 publications from the 53 Cochrane groups.•PubMed covers more than 80 percent of all studies and 71 percent of publications included in Cochrane reviews.•Coverage varies across specialties and within specialties over time.