Are the results of open randomised controlled trials comparing antipsychotic drugs in schizophrenia biased?:Exploratory meta- and subgroup analysis

A recent meta-epidemiological study did not reveal major differences between the results of blinded and open randomised-controlled trials (RCTs). Fewer patients may consent to double-blind RCTs than to open RCTs, compromising generalisability, making this question very important. However, the issue has not been addressed in schizophrenia. We used a database of randomised, acute-phase antipsychotic drug trials. Whenever at least one open and one blinded RCT was available for a comparison of two drugs, we contrasted the results by random-effects meta-analysis with subgroup tests. The primary outcome was overall symptoms as measured by the Positive and Negative Syndrome Scale, supplemented by seven secondary efficacy and side-effect outcomes. We also examined whether open RCTs were biased in favour of more recently introduced antipsychotics, less efficacious or more prone to side-effects antipsychotics, and pharmaceutical sponsors. 183 RCTs (155 blinded and 28 open) with 34715 participants comparing two active drugs were available. The results did not suggest general differences between open and blinded RCTs, which examined two active drugs. Only 12 out of 122 subgroup tests had a p-value below 0.1, four below 0.05, and if a Bonferroni correction for multiple tests had been applied, only one would have been significant. There were some exceptions which, however, did not always confirm the originally hypothesized direction of bias. Due to the relatively small number of open RCTs, our analysis is exploratory, but this fundamental question should be given more scientific attention. Currently, open RCTs should be excluded from meta-analyses, at least in sensitivity analyses.</p

Dismantling cognitive-behaviour therapy for panic disorder: a systematic review and component network meta-analysis.

Cognitive-behaviour therapy (CBT) for panic disorder may consist of different combinations of several therapeutic components such as relaxation, breathing retraining, cognitive restructuring, interoceptive exposure and/or in vivo exposure. It is therefore important both theoretically and clinically to examine whether specific components of CBT or their combinations are superior to others in the treatment of panic disorder. Component network meta-analysis (NMA) is an extension of standard NMA that can be used to disentangle the treatment effects of different components included in composite interventions. We searched MEDLINE, EMBASE, PsycINFO and Cochrane Central, with supplementary searches of reference lists and clinical trial registries, for all randomized controlled trials comparing different CBT-based psychological therapies for panic disorder with each other or with control interventions. We applied component NMA to disentangle the treatment effects of different components included in these interventions. After reviewing 2526 references, we included 72 studies with 4064 participants. Interoceptive exposure and face-to-face setting were associated with better treatment efficacy and acceptability. Muscle relaxation and virtual-reality exposure were associated with significantly lower efficacy. Components such as breathing retraining and in vivo exposure appeared to improve treatment acceptability while having small effects on efficacy. The comparison of the most v. the least efficacious combination, both of which may be provided as 'evidence-based CBT,' yielded an odds ratio for the remission of 7.69 (95% credible interval: 1.75 to 33.33). Effective CBT packages for panic disorder would include face-to-face and interoceptive exposure components, while excluding muscle relaxation and virtual-reality exposure

Minimal important changes in standard deviation units are highly variable and no universally applicable value can be determined

[Objectives] This study aims to describe the distribution of anchor-based minimal important change (MIC) estimates in standard deviation (SD) units and examine if the robustness of such estimates depends on the specific SD used or on the methodological credibility of the anchor-based estimates. [Design and Setting] We included all anchor-based MIC estimates from studies published in MEDLINE and relevant literature databases upto October 2018. Each MIC was converted to SD units using baseline, endpoint, and change from baseline SDs. We performed a descriptive analysis of MICs in SD units and checked how the distribution would change if MICs with low methodological credibility were excluded from the analysis. [Results] We included 1, 009 MIC estimates from 182 studies. The medians and interquartile ranges of MICs in SD units were 0.43 (0.25 to 0.69), 0.42 (0.22 to 0.70), and 0.51 (0.28 to 0.78) for baseline, endpoint, and change SD units, respectively. Some MICs were extremely large or small. The distribution did not change significantly after excluding MICs estimated by less credible methods. [Conclusions] The size of the universally applicable MIC in SD units could not be determined. Anchor-based MICs in SD units were widely distributed, with more than half in the range of 0.2 to 0.8

Association between exposure to environmental tobacco smoke and biomarkers of oxidative stress among patients hospitalised with acute myocardial infarction

Objective To determine whether exposure to environmental tobacco smoke was associated with oxidative stress among patients hospitalised for acute myocardial infarction.&lt;p&gt;&lt;/p&gt; Design An existing cohort study of 1,261 patients hospitalised for acute myocardial infarction.&lt;p&gt;&lt;/p&gt; Setting Nine acute hospitals in Scotland.&lt;p&gt;&lt;/p&gt; Participants Sixty never smokers who had been exposed to environmental tobacco smoke (admission serum cotinine ≥3.0 ng/mL) were compared with 60 never smokers who had not (admission serum cotinine ≤0.1 ng/mL).&lt;p&gt;&lt;/p&gt; Intervention None.&lt;p&gt;&lt;/p&gt; Main outcome measures Three biomarkers of oxidative stress (protein carbonyl, malondialdehyde (MDA) and oxidised low-density lipoprotein (ox-LDL)) were measured on admission blood samples and adjusted for potential confounders.&lt;p&gt;&lt;/p&gt; Results After adjusting for baseline differences in age, sex and socioeconomic status, exposure to environmental tobacco smoke was associated with serum concentrations of both protein carbonyl (beta coefficient 7.96, 95% CI 0.76, 15.17, p = 0.031) and MDA (beta coefficient 10.57, 95% CI 4.32, 16.81, p = 0.001) but not ox-LDL (beta coefficient 2.14, 95% CI −8.94, 13.21, p = 0.703).&lt;p&gt;&lt;/p&gt; Conclusions Exposure to environmental tobacco smoke was associated with increased oxidative stress. Further studies are requires to explore the role of oxidative stress in the association between environmental tobacco smoke and myocardial infarction.&lt;p&gt;&lt;/p&gt

Strategic use of new generation antidepressants for depression: SUN(^_^) D protocol update and statistical analysis plan

Background: SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan. Results: We implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken. Conclusion: This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results. Trial registration: ClinicalTrials.gov: NCT01109693(registered on 21 April 2010)

Localization and trafficking of aquaporin 2 in the kidney

Aquaporins (AQPs) are membrane proteins serving in the transfer of water and small solutes across cellular membranes. AQPs play a variety of roles in the body such as urine formation, prevention from dehydration in covering epithelia, water handling in the blood–brain barrier, secretion, conditioning of the sensory system, cell motility and metastasis, formation of cell junctions, and fat metabolism. The kidney plays a central role in water homeostasis in the body. At least seven isoforms, namely AQP1, AQP2, AQP3, AQP4, AQP6, AQP7, and AQP11, are expressed. Among them, AQP2, the anti-diuretic hormone (ADH)-regulated water channel, plays a critical role in water reabsorption. AQP2 is expressed in principal cells of connecting tubules and collecting ducts, where it is stored in Rab11-positive storage vesicles in the basal state. Upon ADH stimulation, AQP2 is translocated to the apical plasma membrane, where it serves in the influx of water. The translocation process is regulated through the phosphorylation of AQP2 by protein kinase A. As soon as the stimulation is terminated, AQP2 is retrieved to early endosomes, and then transferred back to the Rab 11-positive storage compartment. Some AQP2 is secreted via multivesicular bodies into the urine as exosomes. Actin plays an important role in the intracellular trafficking of AQP2. Recent findings have shed light on the molecular basis that controls the trafficking of AQP2

Deese-roediger-McDermott paradigm: Effect of previous recall and type of memory task

Pretendeu-se averiguar se a activação dos itens críticos no paradigma de Deese-Roediger-McDermott também ocorreria numa tarefa de completamento. Para analisar a contaminação explícita explorámos a existência de resultados dissociados em função da manipulação do nível de processamento. Na tarefa de completamento, a primação semântica foi estatisticamente superior à primação directa. A ausência do efeito do nível de processamento demonstra que o teste foi de memória implícita. Também avaliámos o impacto de uma tarefa de evocação numa tarefa de memória posterior. Verificámos que a evocação prévia anulou o efeito do nível de processamento na tarefa de reconhecimento. Na tarefa de completamento de inícios de palavras, o incremento de inícios de palavras completados com associados só foi expressivo quando as palavras foram codificadas superficialmente.This study aimed to verifj whether lhe activation ofcritical items in the Deese-Roediger-McDermott paradigm ofproducing false memories could also occur in the word stem completion task. The finding that lhe levei ofprocessing did not seem to have any effect on the word stem completion task supported lhe conclusion that the stem completion task was in fact an irnplicit memory test. The impact of a previous recali in a followng memory task was also evaluated. The results indicated that lhe previous recall inhibited the effect ofthe processing levei in lhe recognition task. In the word stem completion task lhe increase ofstems completed with associates was only relevam when words were encoded superficialiy.(undefined

Prognostic factors and effect modifiers for personalisation of internet-based cognitive behavioural therapy among university students with subthreshold depression: A secondary analysis of a factorial trial

BACKGROUND: Internet-cognitive behavioural therapy (iCBT) for depression can include multiple components. This study explored depressive symptom improvement prognostic factors (PFs) and effect modifiers (EMs) for five common iCBT components including behavioural activation, cognitive restructuring, problem solving, self-monitoring, and assertion training. METHODS: We used data from a factorial trial of iCBT for subthreshold depression among Japanese university students (N = 1093). The primary outcome was the change in PHQ-9 scores at 8 weeks from baseline. Interactions between each component and various baseline characteristics were estimated using a mixed-effects model for repeated measures. We calculated multiplicity-adjusted p-values at 5 % false discovery rate using the Benjamini-Hochberg procedure. RESULTS: After multiplicity adjustment, the baseline PHQ-9 total score emerged as a PF and exercise habits as an EM for self-monitoring (adjusted p-values <0.05). The higher the PHQ-9 total score at baseline (range: 5-14), the greater the decrease after 8 weeks. For each 5-point increase at baseline, the change from baseline to 8 weeks was bigger by 2.8 points. The more frequent the exercise habits (range: 0-2 points), the less effective the self-monitoring component. The difference in PHQ-9 change scores between presence or absence of self-monitoring was smaller by 0.94 points when the participant exercised one level more frequently. Additionally, the study suggested seven out of 36 PFs and 14 out of 160 EMs examined were candidates for future research. LIMITATIONS: Generalizability is limited to university students with subthreshold depression. CONCLUSIONS: These results provide some helpful information for the future development of individualized iCBT algorithms for depression