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A cardinal symptom of Parkinson's disease (PD) is motor dysfunction, including bradykinesia and tremors, which is quantified in the Unified PD Rating Scale (UPDRS). Although some medications provide palliative treatments for these motor deficits, their efficacy wanes and can produce unwanted side effects, such as dyskinesia. Deep-brain stimulation (DBS) has provided an alternative treatment strategy that can benefit many patients, but optimal target structures for DBS and its long-term efficacy are not fully understood. The present study represents a meta-analysis of the long-term (> 5 years) effects of DBS on the two most common targets, the subthalamic nucleus (STN) and the globus pallidus interna (GPi), on scores of motor performance using the UPDRS-III. The initial search of PubMed, Cochrane Library, and Clinical Trials resulted in 197 articles, of which 28 met the criteria for our analysis. Of the 1321 patients included, 1179 received STN DBS group and 142 received GPi DBS. UPDRS-III scores for both target groups were analyzed at baseline and at either 5-8 or 10-15 years later for both on- and off-medication phases. The results indicated that the STN stimulation is effective at reducing motor symptoms during off-medication treatment for up to 15 years and that the GPi stimulation can be effective for up to at least 8 years. Our findings further suggest that STN- and GPi-targeted DBS may wear off during the on-medication phase between 5 and 10 years of treatment. This study supports findings that both DBSs of either the STN or GPi have long-term efficacy, especially during off-medication periods., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Makenna Huhn et al.)

Fluorescence in marine animals has mainly been studied in Cnidaria but is found in many different phyla such as Annelida, Crustacea, Mollusca, and Chordata. While many fluorescent proteins and molecules have been identified, very little information is available about the biological functions of fluorescence. In this review, we focus on describing the occurrence of fluorescence in marine animals and the behavioural and physiological functions of fluorescent molecules based on experimental approaches. These biological functions of fluorescence range from prey and symbiont attraction, photoprotection, photoenhancement, stress mitigation, mimicry, and aposematism to inter- and intraspecific communication. We provide a comprehensive list of marine taxa that utilise fluorescence, including demonstrated effects on behavioural or physiological responses. We describe the numerous known functions of fluorescence in anthozoans and their underlying molecular mechanisms. We also highlight that other marine taxa should be studied regarding the functions of fluorescence. We suggest that an increase in research effort in this field could contribute to understanding the capacity of marine animals to respond to negative effects of climate change, such as rising sea temperatures and increasing intensities of solar irradiation., (© 2024 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Sleep disturbances are an important symptom dimension of post-traumatic-stress-disorder (PTSD). There is no meta-analytic evidence examining the effects of all types of pharmacotherapy on sleep outcomes among patients with PTSD., Methods: Medline/Embase/PsychInfo/CENTRAL/clinicaltrials.gov/ICTRP, reference lists of published reviews and all included studies were searched for Randomised Controlled Trials (RCTs) examining any pharmacotherapy vs. placebo or any other drug among patients with PTSD., Primary Outcomes: total sleep time, nightmares, sleep quality., Secondary Outcomes: sleep onset latency, number of nocturnal awakenings, time spent awake following sleep onset, dropouts due to sleep-related adverse-effects, insomnia/somnolence/vivid-dreams as adverse-effects. Pairwise and network meta-analyses were performed., Results: 99 RCTs with 10,481 participants were included. Prazosin may be the most effective treatment for insomnia (SMD = -0.88, 95%CI = [-1.22;-0.54], nightmares (SMD = -0.44, 95%CI = [-0.84;-0.04]) and poor sleep quality (SMD = -0.55, 95%CI = [-1.01;-0.10]). Evidence is scarce and indicates lack of efficacy for SSRIs, Mirtazapine, z-drugs and benzodiazepines, which are widely used in daily practice. Risperidone and Quetiapine carry a high risk of causing somnolence without having a clear therapeutic benefit. Hydroxyzine, Trazodone, Nabilone, Paroxetine and MDMA-assisted psychotherapy may be promising options, but more research is needed., Conclusions: Underpowered individual comparisons and very-low to moderate confidence in effect estimates hinder the generalisability of the results. More RCTs, specifically reporting on sleep-related outcomes, are urgently needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fluorescence is a widespread phenomenon found in animals, bacteria, fungi, and plants. In marine environments fluorescence has been proposed to play a role in physiological and behavioral responses. Many fluorescent proteins and other molecules have been described in jellyfish, corals, and fish. Here we describe fluorescence in marine species, which we observed and photographed during night dives in the Banda Sea, Indonesia, and in the Red Sea, Egypt. Among various phyla we found fluorescence in sponges, molluscs, tunicates, and fish. Our study extends the knowledge on how many different organisms fluoresce in marine environments. We describe the occurrence of fluorescence in 27 species, in which fluorescence has not been described yet in peer-reviewed literature. It especially extends the knowledge beyond Scleractinia, the so far best described taxon regarding diversity in fluorescent proteins., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Poding et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: In general, medical students perceive themselves as inadequately prepared to assist in disasters. This study evaluated the impact of a disaster preparedness curriculum and medical students' views toward required preparedness education for health care professionals., Methods: A comprehensive disaster preparedness curriculum was evaluated on its effect on medical students' views on preparedness education requirements, preparedness, and prior disaster training using self-report survey methodology., Results: Results provide evidence to support curricular effectiveness in significantly increasing initial participant views of health professionals' education requirements, perceived preparedness for integrating professional roles into the emergency response system, and confidence in exposure risk assessment and triage skills. Most participants possessed limited recent prior disaster training and drill experience. Most interestingly, the majority consistently believed throughout the study that disaster preparedness training should be a medical license mandate., Conclusions: For those instructing current medical students in disaster preparedness, it is suggested that a curriculum be chosen that can create participant initial anticipation, awareness, and belief in the importance of and need for disaster preparedness training. Further investigation is recommended into the relationship between students' perceived training importance and any future curriculum delivery efforts on behalf of required or mandatory preparedness offerings in continuing professional development.

Background: Side-effects of psychiatric medication impair quality of life and functioning. Furthermore, they contribute to morbidity, mortality, stigma, and poor treatment concordance resulting in relapse of psychiatric illness. Guidelines recommend discussing side-effects with patients when making treatment decisions, but a synthesis of antidepressant and antipsychotic side-effects to guide this process is missing, and considering all side-effects is a complex, multidimensional process. We aimed to create comprehensive databases of antipsychotic and antidepressant side-effects, and a digital tool to support database navigation., Methods: To create the databases, we did an umbrella review of Embase, PsycINFO, and MEDLINE from database inception to June 26, 2023. We included meta-analyses of randomised controlled trials examining antipsychotic monotherapy in the treatment of schizophrenia or antidepressant monotherapy in the treatment of major depressive disorder. We included meta-analyses in adults (aged ≥18 years) that assessed drugs with a common comparator. The search was complemented by a review of national and international guidelines and consensus statements for the treatment of major depressive disorder and schizophrenia in adults. Effect sizes for antipsychotic and antidepressant side-effects were extracted from meta-analyses examining the largest number of drugs. In cases of incomplete meta-analytic coverage, data were imputed on the basis of guideline-derived ordinal rankings or, if imputation was not possible, ordinal scores were extracted. Both meta-analytic and ordinal outcomes were normalised to provide values between 0 and 1. We then constructed a digital tool, the Psymatik Treatment Optimizer, to combine the side-effect databases with side-effect concerns of an individual user, to enable users to select side-effects of concern and the relative degree of concern for each side-effect. Concern weightings and the side-effect databases are synthesised via a multicriteria decision analysis method (technique for order of preference by similarity to ideal situation, or TOPSIS)., Findings: Of 3724 citations, 14 articles containing 68 meta-analyses of individual side-effects met inclusion criteria. After review of 19 guidelines, seven provided ordinal data. Antipsychotic data were extracted from five studies (11 meta-analyses, n=65 594 patients) and four guidelines, and antidepressant data were extracted from three guidelines. The resultant databases included data on 32 antipsychotics (14 side-effects) and 37 antidepressants (nine side-effects). The databases highlighted the clinical dilemma associated with balancing side-effects, with avoidance of one side-effect (eg, weight gain for antipsychotics) increasing the risk of others (eg, akathisia). To aid with this dilemma, the Psymatik Treatment Optimizer synthesises the side-effect databases with individual user-defined concern weights. After computing up to 5851 pairwise comparisons for antidepressants and 5142 pairwise comparisons for antipsychotics, Psymatik ranks treatments in order of preference for the individual user, with the output presented in a heatmap., Interpretation: By facilitating collaborative, personalised, and evidence-based prescribing decisions, the side-effect databases and digital application supports care delivery that is consistent with international regulatory guidance for the treatment of schizophrenia and depression, and it therefore has promise for informing psychiatric practice and improving outcomes., Funding: National Institute for Health and Care Research, Maudsley Charity, Wellcome Trust, Medical Research Council., Competing Interests: Declaration of interests TP has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Janssen, Schwabe Pharma, ROVI Biotech, and Recordati. RAMcC has participated in advisory or speaker meetings organised by Otsuka, Karuna, Boehringer Ingelheim, and Janssen. TP and RAMcC are directors of Pharmatik that funds website hosting for Psymatik. Neither TP nor RAMcC have holdings or financial stakes in any pharmaceutical company. MH has received honoraria for advisory boards and lectures from Recordati. SJ has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Janssen, and Boehringer Ingelheim. FG has received honoraria from Lundbeck, Otsuka, Sunovion, and Boehringer Ingelheim. ODH has received investigator-initiated research funding from or participated in advisory or speaker meetings organised by Angellini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche, Viatris (formerly Mylan), and ROVI Biotech. AHY has delivered paid lectures and advisory boards for the following companies: AstraZeneca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Pathways, Sage, Novartis, and Neurocentrx. CUC has been a consultant or advisor to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, COMPASS Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen, Johnson & Johnson, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris; has provided expert testimony for Janssen and Otsuka; has served on a data safety monitoring board for COMPASS Pathways, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; has received grant support from Janssen and Takeda; has received royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, MindPax, LB Pharma, and Quantic. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Develop a cancer-specific machine learning (ML) model that accurately predicts 30-day unplanned readmissions in patients with solid tumors., Methods: The initial cohort included patients 18 years or older diagnosed with a solid tumor. Two distinct cohorts were generated: one with and one without detailed social determinants of health (SDOHs) data. For each cohort, data were temporally partitioned in 70% (training), 20% (validation), and 10% (testing). Tree-based ML models were developed and validated on each cohort. The metrics used to evaluate the model's performance were receiver operating characteristic curve (ROC), area under the ROC curve, precision, recall (R), accuracy, and area under the precision-recall curve., Results: We included 13,717 patients in this study in two cohorts (5,059 without SDOH data and 8,658 with SDOH data). Unplanned 30-day readmission occurred in 21.3% of the cases overall. The five main non-SDOH factors most highly associated with an unplanned 30-day readmission (R, 0.74; IQR, 0.58-0.76) were: number of previous unplanned readmissions; higher Charlson comorbidity score; nonelective index admission; discharge to anywhere other than home, hospice, or nursing facility; and higher anion gap during the admission. Neighborhood crime index, neighborhood median home values, annual income, neighborhood median household income, and wealth index were the main five SDOH factors important for predicting a high risk for an unplanned hospital readmission (R, 0.66; IQR, 0.56-0.72). The models were not directly comparable., Conclusion: Key drivers of unplanned readmissions in patients with cancer are complex and involve both clinical factors and SDOH. We developed a cancer-specific ML model that with reasonable accuracy identified patients with cancer at high risk for an unplanned hospital readmission.

Most acute phase antipsychotic drug trials in schizophrenia last only a few weeks, but patients must usually take these drugs much longer. We examined the long-term efficacy of antipsychotic drugs in acutely ill patients using network meta-analysis. We searched the Cochrane Schizophrenia Group register up to March 6, 2022 for randomized, blinded trials of at least 6-month duration on all second-generation and 18 first-generation antipsychotics. The primary outcome was change in overall symptoms of schizophrenia; secondary outcomes were all-cause discontinuation; change in positive, negative and depressive symptoms; quality of life, social functioning, weight gain, antiparkinson medication use, akathisia, serum prolactin level, QTc prolongation, and sedation. Confidence in the results was assessed by the CINeMA (Confidence in Network Meta-Analysis) framework. We included 45 studies with 11,238 participants. In terms of overall symptoms, olanzapine was on average more efficacious than ziprasidone (standardized mean difference, SMD=0.37, 95% CI: 0.26-0.49), asenapine (SMD=0.33, 95% CI: 0.21-0.45), iloperidone (SMD=0.32, 95% CI: 0.15-0.49), paliperidone (SMD=0.28, 95% CI: 0.11-0.44), haloperidol (SMD=0.27, 95% CI: 0.14-0.39), quetiapine (SMD=0.25, 95% CI: 0.12-0.38), aripiprazole (SMD=0.16, 95% CI: 0.04-0.28) and risperidone (SMD=0.12, 95% CI: 0.03-0.21). The 95% CIs for olanzapine versus aripiprazole and risperidone included the possibility of trivial effects. The differences between olanzapine and lurasidone, amisulpride, perphenazine, clozapine and zotepine were either small or uncertain. These results were robust in sensitivity analyses and in line with other efficacy outcomes and all-cause discontinuation. Concerning weight gain, the impact of olanzapine was higher than all other antipsychotics, with a mean difference ranging from -4.58 kg (95% CI: -5.33 to -3.83) compared to ziprasidone to -2.30 kg (95% CI: -3.35 to -1.25) compared to amisulpride. Our data suggest that olanzapine is more efficacious than a number of other antipsychotic drugs in the longer term, but its efficacy must be weighed against its side effect profile., (© 2023 World Psychiatric Association.)

Background: As comparatively few trials in subgroups of patients with schizophrenia have been done, clinicians need to know whether they can rely on the results of randomised controlled trials (RCTs) in the general population of patients with schizophrenia. We aimed to compare the efficacy and side-effects of antipsychotic drugs in different subgroups., Methods: In this systematic review and meta-analysis, we searched reference lists of previous systematic reviews and meta-analyses, the Cochrane Schizophrenia Group's Study-Based Register (from database inception to April 27, 2020), and PubMed (from April 1, 2020 to June 14, 2021). We excluded studies in patients with stable schizophrenia (ie, relapse prevention studies), studies with a high risk of bias, and studies from mainland China due to quality concerns concerning allocation and masking methods. We included single-blind RCTs or better that assessed one or more of 16 second-generation and 18 first-generation antipsychotics in the general population of patients with schizophrenia or in one or more of the subgroups: children and adolescents (age range as defined in the original studies), patients with a first episode, patients with predominant or prominent negative symptoms, patients with comorbid substance use, patients with treatment-resistant schizophrenia, or older patients (age range as defined in the original studies). Two authors independently screened the results of the search, retrieved full-text articles, and checked the inclusion criteria. Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, all parameters were extracted in duplicate. The primary outcome was change in overall symptoms. We compared drug efficacy between subgroups, by sex, schizoaffective disorder versus schizophrenia, and study origin using random-effects, inverse variance meta-analyses and random-effects subgroup tests, and meta-regression., Findings: We included 537 RCTs with 76 382 participants, 26 627 (34·9%) women, 49 755 (65·1%) men, mean age 37·3 years (range of means 7·9-80·2; ethnicity data not available). 412 RCTs included patients in the general population of patients with schizophrenia, 42 included patients with treatment-resistant schizophrenia, 25 included children and adolescents, 20 included patients with their first episode, 20 included patients with predominant or prominent negative symptoms, 13 included patients with comorbid substance use, and 11 included older patients. Of 507 random-effects subgroup tests done, 46 (9%) showed a significant difference (p<0·05) between subgroups, but there was no clear indication as to which drug should be used in which subgroup., Interpretation: The effects of antipsychotics in various patient subgroups were usually similar to those in the general population of patients with schizophrenia, but comparably few studies contributed to the subgroups, in particular in terms of side-effects. If the evidence for treatment in a given subgroup is small, guideline makers and clinicians should consider using the results in the much better studied group of the general population of patients with schizophrenia., Funding: German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; FKZ 01KG1508)., Competing Interests: Declaration of interests In the past 3 years, SL has received honoraria as a consultant, adviser, or lecturer from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharpp and Dome, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitsubishi. JP has a leadership role at the German Association of Psychiatry, Psychotherapy and Psychosomatics (DGPPN), is a board member of SIAPPS2, and holds patent WO/2006/120030. MH has received honoraria as an adviser and lecturer from Recordati. The other authors have no conflict of interest to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Antipsychotics are the treatment of choice in the therapy of schizophrenia. These drugs can be associated with changes in heart rate, but this question has never been examined systematically., Objective: We aimed to analyse changes in heart rate during treatment with antipsychotics using the frequency of tachycardia and bradycardia events., Design: For this systematic review and meta-analysis, we included all randomized controlled trials for the acute treatment of schizophrenia comparing antipsychotics head-to-head or with placebo., Data Sources and Methods: We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform and ClinicalTrials.gov (last search June 2021). Two authors independently selected studies and extracted data. We conducted pairwise meta-analyses using a random-effects model. Outcomes were tachycardia and bradycardia events., Results: We found 469 trials meeting the inclusion criteria. Seventy-seven studies with 16,907 participants provided data on tachycardia or bradycardia events. We found no significant differences between antipsychotics and placebo or between antipsychotics for bradycardia events based on sparse data. Antipsychotics had a higher risk for tachycardia events compared with placebo [ N  = 37, n  = 7827, risk ratio (RR) = 1.83, 95% confidence interval (CI) = 1.40-2.41], with large differences between the individual substances (iloperidone RR = 14.05, chlorpromazine RR = 4.84, loxapine RR = 4.52, risperidone RR = 3.38, quetiapine RR = 2.64, paliperidone RR = 1.65). Some head-to-head comparisons were also significantly different: olanzapine versus haloperidol RR = 2.87, chlorpromazine versus thiothixene RR = 2.92, quetiapine versus lurasidone RR = 3.22, risperidone versus aripiprazole RR = 4.37, iloperidone versus ziprasidone RR = 4.65)., Conclusion: Many studies do not report data for cardiac outcomes, but the available evidence indicates that treatment with antipsychotics raises the risk for tachycardia. Therefore, especially patients with cardiac risk factors should be monitored closely during antipsychotic treatment., Registration: PROSPERO: CRD42014014919., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: MH has received honoraria as a consultant for Recordati. In the past 3 years, SL has received honoraria as a consultant/advisor and/or for lectures from Angelini, Boehringer Ingelheim, Gedeon Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, SanofiAventis, Sandoz, Sunovion, TEVA, Eisai, Rovi, Medichem and Mitsubishi. All other authors declare no competing interests., (© The Author(s), 2022.)

Target prioritization is essential for drug discovery and repositioning. Applying computational methods to analyze and process multi-omics data to find new drug targets is a practical approach for achieving this. Despite an increasing number of methods for generating datasets such as genomics, phenomics, and proteomics, attempts to integrate and mine such datasets remain limited in scope. Developing hybrid intelligence solutions that combine human intelligence in the scientific domain and disease biology with the ability to mine multiple databases simultaneously may help augment drug target discovery and identify novel drug-indication associations. We believe that integrating different data sources using a singular numerical scoring system in a hybrid intelligent framework could help to bridge these different omics layers and facilitate rapid drug target prioritization for studies in drug discovery, development or repositioning. Herein, we describe our prototype of the StarGazer pipeline which combines multi-source, multi-omics data with a novel target prioritization scoring system in an interactive Python-based Streamlit dashboard. StarGazer displays target prioritization scores for genes associated with 1844 phenotypic traits, and is available via https://github.com/AstraZeneca/StarGazer., Competing Interests: Authors CL, AP, VG, RNH, EP, AF, SP, WY, MH, A-SS, KT, BS, TC, JM, FMK, and KS are or were employed by AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Lin, Prokop, Gopalakrishnan, Hanna, Papa, Freeman, Patel, Yu, Huhn, Sheikh, Tan, Sellman, Cohen, Mangion, Khan, Gusev and Shameer.)

Fast-track treatment pathways reduce the frequency of postoperative complications in elective colorectal resections by approximately 40% and due to the rapid recovery reduce the postoperative duration of hospitalization by approximately 50%. Specialized nursing personnel (enhanced recovery after surgery, ERAS, nurses) have already been appointed internationally to accompany and monitor the execution of multimodal perioperative treatment. In November 2018 a fast-track assistant was appointed in the Clinic for General and Visceral Surgery of the Municipal Clinic in Solingen for coordination of the fast-track treatment pathway. The results confirmed that a high adherence to perioperative fast-track treatment concepts can also be achieved in the German healthcare system by the assignment of specialized nursing personnel, with the known advantages for patients, nursing personnel, physicians and hospital sponsors., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose: Cancer and morbidity during a therapeutic regimen can result in somatic and psychiatric impairment. We have evaluated the need of appropriate psychological screening by analyzing a large collective of head and neck cancer (HNC) patients with particularly burdensome symptoms., Methods: HNC-aftercare patients were asked about somatic and psychological symptoms by means of standardized questionnaires of the European Organization for Research and Treatment of Cancer (EORTC Q30 and QLQ-H&N35). Patients with poor well-being values on the World Health Organization-5-Well-Being Index were screened for depression by using the Mini International Neuropsychiatric Interview, and adequate treatment was initiated, if necessary., Results: Our sample consisted of 453 HNC-aftercare patients (average age 64.5 years; 72.0% male; 28.0% female). 25.1% showed abnormalities based on their WHO-5 questionnaire. A current major depressive episode was observed in 8.5% of the total study group. Patients with lip and oral cavity tumors showed the highest depression prevalence (18.9%). Time since initial HNC diagnosis showed no clear trend with regard to the number of depression cases. 50.0% of patients with a current major depressive episode consented to receiving assistance and/or therapy. Within the total study population, the most burdensome symptoms were found to be "dry mouth" (48.3%), "trouble doing strenuous activities" (46.0%), "trouble taking a long walk" (38.5%), and "worry" (35.5%). Aftercare patients with a depression diagnosis tended to have heavier symptom burdens than people without major depression., Conclusions: Despite the various cancer-related burdensome factors, prevalence levels of depression among the HNC-aftercare patients and the general population were similar. Nevertheless, since the number of diagnosed depression cases is high, the need for psychological treatment should be considered within the tumor collective. Furthermore, screening for depression should be implemented in clinical routines by using the appropriate standardized questionnaires., (© 2021. The Author(s).)

Background: There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD., Methods: We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses., Results: We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles., Limitations: Most of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms., Conclusions: Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317., (© 2022. The Author(s).)

Background: Schizophrenia is a common, severe, and usually chronic disorder. Maintenance treatment with antipsychotic drugs can prevent relapse but also causes side-effects. We aimed to compare the efficacy and tolerability of antipsychotics as maintenance treatment for non-treatment resistant patients with schizophrenia., Methods: In this systematic review and network meta-analysis, we searched, without language restrictions, the Cochrane Schizophrenia Group's specialised register between database inception and April 27, 2020, PubMed from April 1, 2020, to Jan 15, 2021, and the lists of included studies from related systematic reviews. We included randomised controlled trials (RCTs; ≥12 weeks of follow-up) that recruited adult participants with schizophrenia or schizoaffective disorder with stable symptoms who were treated with antipsychotics (monotherapy; oral or long-acting injectable) or placebo. We excluded RCTs of participants with specific comorbidities or treatment resistance. In duplicate, two authors independently selected eligible RCTs and extracted aggregate data. The primary outcome was the number of participants who relapsed and was analysed by random-effects, Bayesian network meta-analyses. The study was registered on PROSPERO, CRD42016049022., Findings: We identified 4157 references through our search, from which 501 references on 127 RCTs of 32 antipsychotics (comprising 18 152 participants) were included. 100 studies including 16 812 participants and 30 antipsychotics contributed to our network meta-analysis of the primary outcome. All antipsychotics had risk ratios (RRs) less than 1·00 when compared with placebo for relapse prevention and almost all had 95% credible intervals (CrIs) excluding no effect. RRs ranged from 0·20 (95% CrI 0·05-0·41) for paliperidone oral to 0·65 (0·16-1·14) for cariprazine oral (moderate-to-low confidence in estimates). Generally, we interpret that there was no clear evidence for the superiority of specific antipsychotics in terms of relapse prevention because most comparisons between antipsychotics included a probability of no difference., Interpretation: As we found no clear differences between antipsychotics for relapse prevention, we conclude that the choice of antipsychotic for maintenance treatment should be guided mainly by their tolerability., Funding: The German Ministry of Education and Research and Oxford Health Biomedical Research Centre., Competing Interests: Declaration of interests In the past 3 years, SL has received honoraria as a consultant, adviser, or both, or for lectures, from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharp and Dohme, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitsubishi. TAF reports grants from Mitsubishi-Tanabe and Shionogi, outside the submitted work; personal fees from Mitsubishi-Tanabe, MSD, SONY, and Shionogi, outside the submitted work; a patent (2018–177688) concerning smartphone cognitive behavioural therapy apps pending; and intellectual properties for the Kokoro app licensed to Mitsubishi-Tanabe. ACi has received research and consultancy fees from the Italian Network for Paediatric Trials, the CARIPLO Foundation, and Angelini Pharma, outside the submitted work. MH has received honoraria as an adviser from Recordati. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: In many studies, clozapine has been reported to have superior effectiveness compared to other antipsychotics. So far there is little systematic data on the practice of clozapine prescription and characteristics of patients treated., Method: Retrospective evaluation of all 392 treatment courses of inpatients with schizophrenic psychoses during one year. Detailed analysis of the patients treated with clozapine including the dosages and additional psychotropic medication., Result: Patients treated with clozapine showed a higher disease severity than patients without clozapine. They received more frequently pharmacological combination therapies, which in some cases significantly contradicted the current guideline recommendations., Conclusion: The results underline the pronounced disease severity of patients receiving clozapine treatment and substantiate evidence from the literature on the limited implementation of guidelines in prescribing practice. The study carried out serves as a pilot survey of a multicenter research project on the practice of prescribing clozapine in psychiatric hospitals in different German regions., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Side effects of antipsychotic drugs play a key role in nonadherence of treatment in schizophrenia spectrum disorders (SSD). While clinical observations suggest that side effect variability between patients may be considerable, statistical evidence is required to confirm this. Here, we hypothesized to find larger side effect variability under treatment compared with control. We included double-blind, placebo-controlled, randomized controlled trials (RCTs) of adults with a diagnosis of SSD treated with 1 out of 14 antipsychotics. Standard deviations of the pre-post treatment differences of weight gain, prolactin levels, and corrected QT (QTc) times were extracted. The outcome measure was the variability ratio of treatment to control for individual antipsychotic drugs and the overall variability ratio of treatment to control across RCTs. Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model. We included N = 16 578 patients for weight gain, N = 16 633 patients for prolactin levels, and N = 10 384 patients for QTc time. Variability ratios (VR) were significantly increased for weight gain (VR = 1.08; 95% CI: 1.02-1.14; P = .004) and prolactin levels (VR = 1.38; 95% CI: 1.17-1.62; P < .001) but did not reach significance for QTc time (VR = 1.05; 95% CI: 0.98-1.12; P = 0.135). We found marked differences between individual antipsychotics and increased variability in side effects in patients under treatment with antipsychotics suggesting that subgroups of patients or individual patients may benefit from treatment allocation through stratified or personalized medicine., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A bicyclic peptide scaffold was chemically adapted to generate diarylethene-based photoswitchable inhibitors of serine protease Bos taurus trypsin 1 (T1). Starting from a prototype molecule-sunflower trypsin inhibitor-1 (SFTI-1)-we obtained light-controllable inhibitors of T1 with K i in the low nanomolar range, whose activity could be modulated over 20-fold by irradiation. The inhibitory potency as well as resistance to proteolytic degradation were systematically studied on a series of 17 SFTI-1 analogues. The hydrogen bond network that stabilizes the structure of inhibitors and possibly the enzyme-inhibitor binding dynamics were affected by isomerization of the photoswitch. The feasibility of manipulating enzyme activity in time and space was demonstrated by controlled digestion of gelatin-based hydrogel and an antimicrobial peptide BP100-RW. Finally, our design principles of diarylethene photoswitches are shown to apply also for the development of other serine protease inhibitors., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Although the human immune response to cancer is naturally potent, it can be severely disrupted as a result of an immunosuppressive tumor microenvironment. Infiltrating regulatory T lymphocytes contribute to this immunosuppression by inhibiting proliferation of cytotoxic CD8 + T lymphocytes, which are key to an effective anti-cancer immune response. Other important contributory factors are thought to include metabolic stress caused by the local nutrient deprivation common to many solid tumors. Interleukin-33 (IL-33), an alarmin released in reaction to cell damage, and sphingosine-1-phosphate (S1P) are known to control cell positioning and differentiation of T lymphocytes. In an in vitro model of nutrient deprivation, we investigated the influence of IL-33 and S1P receptor 4 (S1P 4 ) on the differentiation and migration of human CD8 + T lymphocytes. Serum starvation of CD8 + T lymphocytes induced a subset of CD8 Low and IL-33 receptor-positive (ST2L + ) cells characterized by enhanced expression of the regulatory T cell markers CD38 and CD39. Both S1P 1 and S1P 4 were transcriptionally regulated after stimulation with IL-33. Moreover, expression of the chemokine receptor CXCR4 was increased in CD8 + T lymphocytes treated with the selective S1P 4 receptor agonist CYM50308. We conclude that nutrient deprivation promotes CD8 Low T lymphocytes, contributing to an immunosuppressive microenvironment and a poor anti-cancer immune response by limiting cytotoxic effector functions. Our results suggest that S1P 4 signaling modulation may be a promising target for anti-CXCR4 cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Burkard, Dreis, Herrero San Juan, Huhn, Weigert, Pfeilschifter and Radeke.)

Fast-track or ERAS programs can give clinically relevant benefits for patients undergoing surgery. They also have financial advantages for the hospital. Despite these facts, fast-track has been implemented in only very few hospitals in Germany. Neither scientific evidence nor reimbursement regulations explain this lack of fast-track acceptance. It seems however that a structured process of change from traditional perioperative medicine to evidence based fast-track therapy is missing in Germany. In other countries, structured programs for fast-track or ERAS implementation have been successful in many hospitals. This article describes structured fast-track implementation divided into three consecutive steps: organisational preparation, clinical implementation and continuous examination of fast-track adherence, functional recovery, morbidity and postoperative length of hospital stay. Due to its complex nature, fast-track implementation should be guided by external fast-track experts., Competing Interests: W. S. hat in den letzten 5 Jahren von den Firmen B. Braun Aeskulap, Dr. Falk Pharma, Ethicon und Medtronic Honorare für eingeladene Vorträge erhalten und ist Berater der Firma Ethicon zu den Themen Fast-Track, ERAS und perioperative Medizin. I. L. hat gegen Honorar von der B. Braun Stiftung einen Vortrag zum Fast-Track und der Funktion der Fast-Track-Assistentin gehalten., (Thieme. All rights reserved.)

Objective and Method: A case series of three patients with Delusional Misidentification Syndroms (DMS) and violent behavior is presented with respect to the correlation between DMS and violence as well as to the management of such occurrences., Results and Conclusion: DMS could be one of the reasons for violent behavior of patients with psychiatric disorders. In such case violent behavior is not just restricted to intimates and relatives but also turns on non-familiar caregivers. DMS could be a risk factor for violent behavior and should therefore be registered with help of a nuanced psychopathological exploration at the time of clinical admission and in course of treatment. Moreover risk assessment tools and safety measures (e. g. medication, monitoring) could be considered for patients with DMS., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

As the course of schizophrenic disorders is often chronic, treatment guidelines recommend continuous maintenance treatment to prevent relapses, but antipsychotic drugs can cause many side effects. It, therefore, seems reasonable to try to reduce doses in stable phases of the illness or even try to stop medication. We conducted a 26 weeks, randomized, rater blind, feasibility study to examine individualized antipsychotic dose reduction versus continuous maintenance treatment (Register Number: NCT02307396). We included chronic, adult patients with schizophrenia or schizoaffective disorder, who were treated with any antipsychotic drug except clozapine, who had not been hospitalized in the last 3 years and who were in symptomatic remission at baseline. The primary outcome was relapse of positive symptoms. Symptom severity, social functioning and side effects were also examined as secondary outcomes. 20 patients were randomized. Relapse rates in the two groups were not significantly different. No patient had to be hospitalized. One patient in the control group dropped out. The mean reduction of antipsychotic dose in the individualized dose-reduction group was 42%, however only one patient discontinued drug completely. There were no significant differences in efficacy or safety outcomes. This randomized trial provides evidence, that reduction of antipsychotic medication in chronic stable schizophrenic patients may be feasible. The results need to be confirmed in a larger trial with a longer follow-up period.

(Reprinted with permission from the Lancet 2019; 394: 939-51)., (Copyright © 2020 by the American Psychiatric Association.)

Background: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms., Methods: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 ., Results: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = - 0.32, 95% CI [- 0.39, - 0.25], in repetitive behaviors - 0.23[- 0.32, - 0.15] and in scales measuring overall core symptoms - 0.36 [- 0.46, - 0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain., Limitations: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers., Conclusions: Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.

Objectives: Symptoms of insomnia are highly prevalent in the elderly. A significant number of pharmacological and non-pharmacological interventions exist, but, up-to-date, their comparative efficacy and safety has not been sufficiently assessed., Methods: We integrated the randomized evidence from every available treatment for insomnia in the elderly (>65 years) by performing a network meta-analysis. Several electronic databases were searched up to May 25, 2019. The two primary outcomes were total sleep time and sleep quality. Data for other 6 efficacy and 8 safety outcomes were also analyzed., Results: Fifty-three RCTs with 6832 participants (75 years old on average) were included, 43 of which examined the efficacy of one or more drugs. Ten RCTs examined the efficacy of non-pharmacological interventions and were evaluated only with pairwise meta-analyses because they were disconnected from the network. The overall confidence in the evidence was very low primarily due to the small amount of data per comparison and their sparse connectedness. Several benzodiazepines, antidepressants, and z-drugs performed better in both primary outcomes, but few comparisons had data from more than one trial. The limited evidence on non-pharmacological interventions suggested that acupressure, auricular acupuncture, mindfulness-based stress reduction program, and tart cherry juice were better than their control interventions. Regarding safety, no clear differences were detected among interventions due to large uncertainty., Conclusions: Insufficient evidence exists on which intervention is more efficacious for elderly patients with insomnia. More RCTs, with longer duration, making more direct interventions among active treatments and presenting more outcomes are urgently needed., (© 2020 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise questions regarding the unclarified heterogeneity of pathological mechanisms promoting disease progression. While biomarkers for the differentiation of Crohn's disease (CD) versus ulcerative colitis (UC) have been suggested, specific markers for a CD subclassification in ileal CD versus colonic CD are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterize potential biomarkers by focusing on the downstream enzymes and metabolites of kynurenine metabolism. Using immunohistochemical stainings, we analyzed and compared the mucosal tryptophan immune metabolism in bioptic samples from patients with active inflammation due to UC or CD versus healthy controls. Localization-specific quantification of immune cell infiltration, tryptophan-metabolizing enzyme expression and mucosal tryptophan downstream metabolite levels was performed. We found generally increased immune cell infiltrates in the tissue of all patients with IBD. However, in patients with CD, significant differences were found between regulatory T cell and neutrophil granulocyte infiltration in the ileum compared with the colon. Furthermore, we observed decreased kynurenine levels as well as strong kynureninase (KYNU) expression specifically in patients with ileal CD. Correspondingly, significantly elevated levels of the kynurenine metabolite 3-hydroxyanthranilic acid were detected in the ileal CD samples. Highlighting the heterogeneity of the different phenotypes of CD, we identified KYNU as a potential mucosal biomarker allowing the localization-specific differentiation of ileal CD versus colonic CD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: We examined patient and study characteristics of pharmacotherapy and psychotherapy trials to establish whether the effects of these 2 treatment strategies can be compared meaningfully., Methods: We inspected all randomized controlled trials included in 2 recent meta-analyses on antipsychotics and psychotherapy in patients with positive symptoms of schizophrenia, searching EMBASE, MEDLINE, PsycINFO, Cochrane Library, and ClinicalTrials.gov. Differences between psychotherapy and pharmacotherapy trials were analyzed with Wilcoxon-Mann-Whitney and chi-square tests., Results: Eighty studies with 18 271 participants on antipsychotic drugs and 53 studies with 4068 participants on psychotherapy were included. Psychotherapy studies included less severely ill patients (P < .0001), with a shorter duration of illness (P = .021), lasted for a longer period (P < .0001), administered the intervention as add-on to antipsychotics (P < .0001), had higher risk of bias in some domains including blinding of outcome assessment (P < .0001), and were funded publicly more frequently (P < .0001). Antipsychotic trials had larger sample sizes (P < .0001) and more study centers (P < .0001), included more males (P = .0001), inpatients (P < .0001), and slightly older patients (P = .031), more often used diagnostic operationalized criteria (P = .006), and were sponsored by pharmaceutical companies. They did not differ in conflict of interest (P = .24)., Conclusions: We found key differences between the 2 groups of studies that encompass higher risk of bias in psychotherapy studies and the inclusion of more severe patients in drug trials. These differences imply that study and patient characteristics should be carefully taken into account before considering a network meta-analysis. In the interest of patients, psychopharmacologists and psychotherapists should optimize their treatments rather than seeing them in competition., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades. Previous studies have tried to identify potential explanatory factors focusing on response to placebo; however, it is still not clear which factors, if any, specifically moderate drug-response, as they may be different from those moderating placebo-response. Therefore, in this meta-regression analysis we explore whether there is an interaction between drug-response and placebo-response in terms of effect size. We systematically searched multiple electronic databases, ClinicalTrials.gov, and the US Food and Drug Administration website for randomized, placebo-controlled trials investigating the efficacy of antipsychotics in patients with acute schizophrenia (last update: October 2016). The main outcome was the change on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale score from baseline to endpoint after at least 3 weeks of treatment. Multiple patient-, design-, and drug-related potential predictors of response were analyzed by meta-regressions, as predefined in the study protocol. Overall, 167 trials with 28,102 participants were included. Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes. No other factors had a significant effect on either drug-response or placebo-response. In conclusion, as individual moderators may have different impact on placebo-response and drug-response, it is important to consider also the specific factors influencing drug-response in order to fully understand the difference between antipsychotics and placebo. These results shed further light on the phenomenon of decreasing effect size of antipsychotics for schizophrenia over time and should help design future randomized controlled trials in the field (Prospero registration number CRD42013003342).

Background: Schizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials., Methods: We did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919., Findings: We identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from -0·89 (95% CrI -1·08 to -0·71) for clozapine to -0·03 (-0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from -0·69 (95% CrI -0·86 to -0·52) for amisulpride to -0·17 (-0·31 to -0·04) for brexpiprazole, for negative symptoms (32 015 participants) from -0·62 (-0·84 to -0·39; clozapine) to -0·10 (-0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from -0·90 (-1·36 to -0·44; sulpiride) to 0·04 (-0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from -0·16 kg (-0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low., Interpretation: There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences., Funding: German Ministry of Education and Research and National Institute for Health Research., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Antipsychotic drugs might cause acutely occurring, serious side-effects and thus contribute to the increased physical morbidity and mortality observed in patients with severe mental health disorders. We examined this hypothesis by doing a meta-analysis of International Conference on Harmonisation-Good Clinical Practice-defined serious adverse events occurring in placebo-controlled trials of antipsychotics., Methods: For this systematic review and meta-analysis, we included randomised controlled trials (RCTs) comparing second-generation antipsychotics with placebo. We searched MEDLINE, Embase, Cochrane CENTRAL, BIOSIS, PsycINFO, PubMed, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for trials published in any language from database inception up until Jan 27, 2017. Trials were included without limitations in population (diagnostic category, age, sex, ethnicity), dosing regimen, blinding status, duration, or publication year. Only psychological studies lasting less than 1 day and trials done in mainland China were excluded. We contacted pharmaceutical companies, drug regulatory authorities, and study investigators for additional data. The primary outcome was the number of patients with at least one somatic serious adverse event. We estimated minimum and maximum numbers of patients with the outcome in each study group and synthesised the results with odds ratios (ORs) in a common-effects meta-analysis. This study is registered with PROSPERO, number CRD42016033930., Findings: We identified 597 RCTs, comprising 108 664 participants, that met the inclusion criteria. 314 trials (67 642 participants) with details on individual serious adverse events available constituted the main dataset for meta-analysis. 88% of these were 13 weeks (approximately 3 months) or shorter in duration (median 6 weeks, IQR 4-9). At least one somatic serious adverse event occurred in 698 (1·63%) to 862 (2·02%) of 42 600 patients on antipsychotics, and in 343 (1·37%) to 419 (1·67%) of 25 042 patients on placebo. The odds ratios (ORs) were 1·24 (95% CI 1·08-1·42) and 1·24 (1·10-1·41) based on the minimum and maximum estimate, respectively. In predefined subgroup analyses we found evidence suggesting a larger effect in older patients (>65 years; OR 1·56, 95% CI 1·22-1·98; 1·58, 1·25-1·99) as compared with adults (18-65 years; 1·09, 0·91-1·29; 1·10, 0·95-1·28); likewise in children or adolescents (<18 years) although the evidence was more uncertain (1·49, 0·81-2·75; 1·54, 0·85-2·77). Of 597 included RCTs, 30 (5%), 358 (60%), and 209 (35%) were rated at high, moderate, or low risk of bias, respectively. τ 2 was zero for both analyses of the primary outcome (minimum estimate, maximum estimate). A Bayesian sensitivity analysis using external information on heterogeneity gave similar results., Interpretation: We found evidence that antipsychotics cause short-term somatic serious adverse events on top of somatic serious adverse events occurring independent of treatment. This effect appears to be mainly driven by results in older patients. Hence, clinicians should be aware that antipsychotics are potentially toxic, particularly when treating patients sharing risk factors with the older population., Funding: German Ministry of Education and Research., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

IL-1 family member IL-33 exerts a variety of immune activating and regulating properties and has recently been proposed as a prognostic biomarker for cancer diseases, although its precise role in tumor immunity is unclear. Here we analyzed in vitro conditions influencing the function of IL-33 as an alarmin and a co-factor for the activity of cytotoxic CD8 + T cells in order to explain the widely discussed promiscuous behavior of IL-33 in vivo . Circulating IL-33 detected in the serum of healthy human volunteers was biologically inactive. Additionally, bioactivity of exogenous recombinant IL-33 was significantly reduced in plasma, suggesting local effects of IL-33, and inactivation in blood. Limited availability of nutrients in tissue causes necrosis and thus favors release of IL-33, which-as described before-leads to a locally high expression of the cytokine. The harsh conditions however influence T cell fitness and their responsiveness to stimuli. Nutrient deprivation and pharmacological inhibition of mTOR mediated a distinctive phenotype characterized by expression of IL-33 receptor ST2L on isolated CD8 + T cells, downregulation of CD8, a transitional CD45RA low RO low phenotype and high expression of secondary lymphoid organ chemokine receptor CCR7. Under nutrient deprivation, IL-33 inhibited an IL-12 induced increase in granzyme B protein expression and increased expression of GATA3 and FOXP3 mRNA. IL-33 enhanced the TCR-dependent activation of CD8 + T cells and co-stimulated the IL-12/TCR-dependent expression of IFNγ. Respectively, GATA3 and FOXP3 mRNA were not regulated during TCR-dependent activation. TCR-dependent stimulation of PBMC, but not LPS, initiated mRNA expression of soluble IL-33 decoy receptor sST2, a control mechanism limiting IL-33 bioactivity to avoid uncontrolled inflammation. Our findings contribute to the understanding of the compartment-specific activity of IL-33. Furthermore, we newly describe conditions, which promote an IL-33-dependent induction of pro- or anti-inflammatory activity in CD8 + T cells during nutrient deprivation.

Background: Tralokinumab is an anti-interleukin (IL)-13 monoclonal antibody investigated for the treatment of severe, uncontrolled asthma in two Phase III clinical trials, STRATOS 1 and 2. The STRATOS 1 biomarker analysis plan was developed to identify biomarker(s) indicative of IL-13 activation likely to predict tralokinumab efficacy and define a population in which there was an enhanced treatment effect; this defined population was then tested in STRATOS 2., Methods: The biomarkers considered were blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum dipeptidyl peptidase-4, serum periostin and total serum immunoglobulin E. Tralokinumab efficacy was measured as the reduction in annualised asthma exacerbation rate (AAER) compared with placebo (primary endpoint measure of STRATOS 1 and 2). The biomarker analysis plan included negative binomial and generalised additive models, and the Subgroup Identification based on Differential Effect Search (SIDES) algorithm, supported by robustness and sensitivity checks. Effects on the key secondary endpoints of STRATOS 1 and 2, which included changes from baseline in standard measures of asthma outcomes, were also investigated. Prior to the STRATOS 1 read-out, numerous simulations of the methodology were performed with hypothetical data., Results: FeNO and periostin were identified as the only biomarkers potentially predictive of treatment effect, with cut-offs chosen by the SIDES algorithm of > 32.3 ppb and > 27.4 ng/ml, respectively. The FeNO > 32.3 ppb subgroup was associated with greater AAER reductions and improvements in key secondary endpoints compared with the periostin > 27.4 ng/ml subgroup. Upon further evaluation of AAER reductions at different FeNO cut-offs, ≥37 ppb was chosen as the best cut-off for predicting tralokinumab efficacy., Discussion: A rigorous statistical approach incorporating multiple methods was used to investigate the predictive properties of five potential biomarkers and to identify a participant subgroup that demonstrated an enhanced tralokinumab treatment effect. Using STRATOS 1 data, our analyses identified FeNO at a cut-off of ≥37 ppb as the best assessed biomarker for predicting enhanced treatment effect to be tested in STRATOS 2. Our findings were inconclusive, which reflects the complexity of subgroup identification in the severe asthma population., Trial Registration: STRATOS 1 and 2 are registered on ClinicalTrials.gov ( NCT02161757 registered on June 12, 2014, and NCT02194699 registered on July 18, 2014).

Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine beta- and alpha-cell function in the Cftrtm1EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild-type mice aged 7-10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in 1) reduced number of docked insulin granules and reduced exocytosis, and 2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.

Patients with schizophrenia and substance related comorbidity or substance induced psychotic disorder are difficult to treat. Although the prevalence of a comorbid substance use is approximately 40% in schizophrenia, such patients are usually excluded from clinical trials. We therefore performed a random-effects meta-analysis of all randomized controlled antipsychotic drug trials in this patient subgroup. We searched multiple databases up to May, 2018. The primary outcome was the reduction of substance user; secondary outcomes were craving, mean reduction of substance use, overall change in schizophrenia symptoms, positive and negative symptoms, response, dropouts, quality of life, social functioning, weight gain, sedation, prolactin, extrapyramidal side effects and use of antiparkinsonian medication. We identified 27 references from 19 RCTs published from 1999 to March 2017 including 1742 participants. The most frequent types of substance abuse were cannabis (8 studies) and cocaine (6 studies) use/dependence. Clozapine was superior to other antipsychotics for reduction of substance use and risperidone to olanzapine for craving. Olanzapine, clozapine and risperidone showed superiority for symptom reduction compared to some other drugs. When reported, results of side-effects followed known patterns. The evidence-base is considerable (19 RCTs), however, firm conclusions cannot be drawn due to small sample sizes of individual studies and insufficient reporting., (Copyright © 2018. Published by Elsevier B.V.)

Background: Cognitive behavioural therapy has been used for schizophrenia, but to which extent it is effective is still controversial. Results of existing meta-analyses are of difficult interpretation, because they mainly present effect sizes in the form of standardized mean differences between intervention and control groups based on rating scales, which are of unclear clinical meaning. No meta-analysis has considered the number of patients responding to treatment yet. Based on this ground, we present the first meta-analysis examining the response rates of patients with schizophrenia and positive symptoms to cognitive behavioural therapy., Methods: We searched multiple databases for randomized controlled trials on psychological interventions of schizophrenia including patients with positive symptoms, and included for this analysis the studies on cognitive behavioural therapy (last search: January 2018). We applied a validated imputation method to calculate the number of responders from rating scales for the outcomes overall symptoms and positive symptoms, based on two criteria, at least 20% and at least 50% reduction from baseline on PANSS or BPRS total scores. Data were pooled in a single-group summary meta-analysis using R software. Additionally, several potential moderators of response to cognitive behavioural therapy were examined by subgroup and meta-regression analyses. The protocol has been registered in PROSPERO (CRD42017067795)., Results: We included 33 studies with a total of 1142 participants receiving cognitive behavioural therapy. On average, 44.5 and 13.2% of the patients reached a 20% (minimally improved) and 50% (much improved) reduction of overall symptoms. Similarly, 52.9 and 24.8% of the patients reached a 20%/50% reduction of positive symptoms. Subgroup and meta-regression analyses revealed a better treatment response in overall symptoms for patients that were not treatment resistant and in studies with researchers' allegiance. Of borderline significance was the better response in studies employing expert therapists and in patients that were more severely ill at baseline. Blinding of outcome assessor, number of sessions, treatment duration, age and gender were not significant moderators of response., Conclusions: Our findings suggest that adding cognitive behavioural therapy to pharmacotherapy brings about a minimal improvement in overall symptoms among 44.5% of its recipients. Several study and patients characteristics can moderate response rates.

Elderly patients with schizophrenia are a particularly vulnerable group often excluded from clinical trials. Currently there is no evidence-synthesis about the efficacy and safety of antipsychotics in this subgroup. We reviewed all randomized-controlled-trials, about antipsychotics in elderly schizophrenics (last search Dec 12, 2017). Pairwise meta-analyses were conducted. The primary outcome was overall symptoms. Secondary outcomes included positive symptoms, negative symptoms, response, dropouts, quality of life, social functioning and side-effects. We included 29 references from 18 unique randomized-controlled-trials with 1225 participants published from 1958 to 2009. The definition of "elderly" was very heterogeneous across the studies (minimum age 46-65, mean age 57-73). There were evidence gaps for most drugs in many outcomes. In terms of efficacy paliperidone was associated with fewer dropouts due to inefficacy than placebo in the only placebo-controlled-trial. Olanzapine was superior to haloperidol in overall symptoms, negative symptoms and response, and it was associated with fewer dropouts than risperidone. Risperidone and haloperidol produced more prolactin increase than olanzapine, and olanzapine was associated with less use of antiparkinson medication than haloperidol. Although we found no marked differences of the effects of these drugs in the elderly, the evidence presented was based on very few usually small studies. To examine specifically whether there are differences in efficacy and side-effects in elderly, which differs in meaningful ways from the general population, studies in patients who are defined by critiera as truly geriatric, which incorporates older age together with multimorbidity and fraility dimensions, may be more informative., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

Objective: A recent meta-regression had shown that the degree of placebo response, which has increased over the decades, is the major predictor of drug-placebo differences in antipsychotic drug trials in acutely ill patients with schizophrenia. Drug response, however, had remained stable. In the current meta-regression we explored the factors that are associated with placebo-response., Method: We searched multiple electronic databases, ClinicalTrials.gov and the FDA website for randomized, placebo-controlled, antipsychotic drug trials in patients with acute exacerbations of schizophrenia. The outcome was the degree of placebo response measured by the BPRS or PANSS change from baseline to endpoint. 26 patient-, design-, and drug-related potential predictors of placebo response were analyzed by univariable and multivariable meta-regressions., Results: 167 double-blind randomized controlled trials with 28,102 participants were included. The mean PANSS change from baseline was 6.25 (95% CI 4.64,7.85). More recent publication year, larger study sample size, more study sites, use of the PANSS rather than the BPRS scale to measure response, shorter wash-out phases, shorter study duration, lower mean age and shorter duration of illness were associated with larger placebo response in univariable analyses. In a multivariable analysis only the number of study participants and mean participant age had an impact on placebo response., Conclusions: The degree of placebo response is moderated by a number of design and patient-related factors. These explanatory variables of placebo response are only in part identical with those that moderated drug-placebo differences., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Psychological treatments are increasingly regarded as useful interventions for schizophrenia. However, a comprehensive evaluation of the available evidence is lacking and the benefit of psychological interventions for patients with current positive symptoms is still debated. The present study aimed to evaluate the efficacy, acceptability and tolerability of psychological treatments for positive symptoms of schizophrenia by applying a network meta-analysis approach, that can integrate direct and indirect comparisons. We searched EMBASE, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Library, World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov for randomized controlled trials of psychological treatments for positive symptoms of schizophrenia, published up to January 10, 2018. We included studies on adults with a diagnosis of schizophrenia or a related disorder presenting positive symptoms. The primary outcome was change in positive symptoms measured with validated rating scales. We included 53 randomized controlled trials of seven psychological interventions, for a total of 4,068 participants receiving the psychological treatment as add-on to antipsychotics. On average, patients were moderately ill at baseline. The network meta-analysis showed that cognitive behavioural therapy (40 studies) reduced positive symptoms more than inactive control (standardized mean difference, SMD=-0.29; 95% CI: -0.55 to -0.03), treatment as usual (SMD=-0.30; 95% CI: -0.45 to -0.14) and supportive therapy (SMD=-0.47; 95% CI: -0.91 to -0.03). Cognitive behavioural therapy was associated with a higher dropout rate compared with treatment as usual (risk ratio, RR=0.74; 95% CI: 0.58 to 0.95). Confidence in the estimates ranged from moderate to very low. The other treatments contributed to the network with a lower number of studies. Results were overall consistent in sensitivity analyses controlling for several factors, including the role of researchers' allegiance and blinding of outcome assessor. Cognitive behavior therapy seems to be effective on positive symptoms in moderately ill patients with schizophrenia, with effect sizes in the lower to medium range, depending on the control condition., (© 2018 World Psychiatric Association.)

Background: Negative symptoms are the core of schizophrenia, but whether antipsychotics are efficacious for their treatment is unclear. Moreover, there is debate whether patients in relevant trials should have predominant negative symptoms or whether prominent negative symptoms are also acceptable., Methods: We systematically reviewed randomised, blinded antipsychotic drug trials in patients with schizophrenia and either predominant or prominent negative symptoms (last search Dec 12, 2017). Separate pairwise meta-analyses were conducted in these two populations. The primary outcome was negative symptoms. Depressive, symptoms, positive symptoms, and extrapyramidal side-effects were analysed as causes of secondary negative symptoms., Findings: We included 21 randomized-controlled trials with 3451 participants which revealed the following significant differences in the primary outcome: in patients with predominant negative symptoms amisulpride was superior to placebo (N = 4; n = 590, SMD 0.47, CI 0.23, 0.71), olanzapine was superior to haloperidol in a small trial (n = 35) and cariprazine outperformed risperidone (N = 1, n = 456, SMD - 0.29, CI - 0.48, - 0.11). In patients with prominent negative symptoms, olanzapine and quetiapine were superior to risperidone in single trials. Overall, studies in prominent negative symptoms were potentially more confounded by improvements of secondary negative symptoms., Interpretation: Amisulpride is the only antipsychotic that outperformed placebo in the treatment of predominant negative symptoms, but there was a parallel reduction of depression. Cariprazine was better than risperidone in a large trial that was well-controlled for secondary negative symptoms, but the trial was sponsored by its manufacturer. Future trials should apply scientifically developed definitions such as the deficit syndrome and the persistent negative symptoms concept.

Background: Acutely occurring, life-threatening side-effects of antipsychotic drugs might contribute to the reduced life expectancy observed in patients with severe mental disorders. We aimed to assess this hypothesis by doing a systematic review and meta-analysis of deaths occurring in placebo-controlled trials of antipsychotic drugs., Methods: For this systematic review and meta-analysis, we included randomised controlled trials comparing second-generation antipsychotics with placebo across several diagnostic categories. We searched MEDLINE, EMBASE, Cochrane CENTRAL, BIOSIS, PsycINFO, PubMed, ClinicalTrials.gov, and WHO ICTRP from inception (the last search was done on Jan 21, 2017), and contacted pharmaceutical companies and regulatory authorities for further eligible trials. We examined mortality from any cause (the primary outcome) and mortality from natural causes, suicide, and other non-natural causes. We synthesised the results with odds ratios (ORs) in a common-effects meta-analysis. We investigated the effects of age, diagnostic category, sex, study duration, antipsychotic drug used, drug dose, and polypharmacy in subgroup and meta-regression analyses. This study is registered with PROSPERO, number CRD42016033930., Findings: We identified 596 randomised controlled trials published between 1978 and 2017, comprising 108 747 participants. 352 studies (comprising 84 988 participants) with mortality data available constituted the main dataset for our meta-analysis. 207 (0·4%) deaths were reported in 53 804 patients on an antipsychotic drug and 99 (0·3%) deaths in 31 184 patients on placebo. 300 (85%) of 352 trials were 13 weeks (3 months) or shorter in duration (median 6 weeks; IQR 4-10). We found no evidence of a difference between antipsychotic drugs and placebo in mortality by any cause (OR 1·19; 95% CI 0·93-1·53), from natural causes (1·29; 0·85-1·94), from suicide (1·15; 0·47-2·81), and from other non-natural causes (1·55; 0·66-3·63). Most subgroup and meta-regression analyses did not indicate any important effect moderators. The exceptions were increased mortality in patients with dementia (OR 1·56; 95% CI 1·10-2·21), in elderly patients (1·38; 1·01-1·89), in aripiprazole-treated patients (2·20; 1·00-4·86), and in studies with a higher proportion of women (regression coefficient 0·025; 95% credible interval 0·010-0·040). However, the effects in elderly patients, aripiprazole-treated patients, and women were mainly based on the included dementia trials. For patients with schizophrenia there was no evidence of an increased mortality risk (OR 0·69; 95% CI 0·35-1·35)., Interpretation: Overall, and for the main indication of schizophrenia, there is no evidence from randomised trials that antipsychotic drugs increase mortality. However, vulnerable populations (particularly patients with dementia) might be at increased risk. This meta-analysis could only address acute treatment effects leading to death in the short-term, and not long-term effects of antipsychotic drugs on mortality., Funding: German Ministry of Education and Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Children and adolescents with schizophrenia are a particularly vulnerable group. Thus, we integrated all the randomized evidence from the available antipsychotics used for this subgroup by performing a network-meta-analysis and pairwise meta-analysis using a random-effects model. We searched multiple databases up to Nov 17, 2016 (final update search in PubMed: Dec 12, 2017). The primary outcome was efficacy as measured by overall change/endpoint in symptoms of schizophrenia. Secondary outcomes included positive and negative symptoms, response, dropouts, quality of life, social functioning, weight gain, sedation, prolactin, extrapyramidal side effects (EPS) and antiparkinsonian medication. Twenty-eight randomized controlled trials (RCTs) with 3003 unique participants (58% males; mean age 14.41 years) published from 1967 to 2017 were identified. Clozapine was significantly more effective than all other analyzed antipsychotics. Nearly all antipsychotics were more efficacious compared to placebo, but ziprasidone showed no efficacy. In terms of preventing weight gain, molindone, lurasidone and ziprasidone were benign. The highest weight gain was found for clozapine, quetiapine and olanzapine. Most antipsychotics had some sedating effects. Risperidone, haloperidol, paliperidone and olanzapine were associated with prolactin increase. There were evidence gaps for some drugs and many outcomes, especially safety outcomes. Most of the comparisons are based only on one study or just on indirect evidence. Nevertheless, the available direct and indirect evidence showed that the treatment effects were similar compared to findings in adult patients with schizophrenia., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

MutLα, a heterodimer consisting of MLH1 and PMS2, plays an important role in DNA mismatch repair and has been shown to be additionally involved in several other important cellular mechanisms. Previous work indicated that AKT could modulate PMS2 stability by phosphorylation. Still, the mechanisms of regulation of MutLα remain unclear. The stability of MutLα subunits was investigated by transiently overexpression of wild type and mutant forms of MLH1 and PMS2 using immunoblotting for measuring the protein levels after treatment. We found that treatment with the cell-permeable serine/threonine phosphatase inhibitor, Calyculin, leads to degradation of PMS2 when MLH1 or its C-terminal domain is missing or if amino acids of MLH1 essential for PMS2 interaction are mutated. In addition, we discovered that the C-terminal tail of PMS2 is relevant for this Calyculin-dependent degradation. A direct involvement of AKT, which was previously described to be responsible for PMS2 degradation, could not be detected. The multi-kinase inhibitor Sorafenib, in contrast, was able to avoid the degradation of PMS2 which postulates that cellular phosphorylation is involved in this process. Together, we show that pharmacologically induced phosphorylation by Calyculin can induce the selective proteasome-dependent degradation of PMS2 but not of MLH1 and that the PMS2 degradation could be blocked by Sorafenib treatment. Curiously, the C-terminal Lynch Syndrome-variants MLH1 L749P and MLH1 Y750X make PMS2 prone to Calyculin induced degradation. Therefore, we conclude that the specific degradation of PMS2 may represent a new mechanism to regulate MutLα., (© 2017 Wiley Periodicals, Inc.)

Objective: Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences., Method: The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression., Results: The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time., Conclusions: Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients.

Background: The first episode of schizophrenia is a pivotal phase of this debilitating illness. Which drug to use remains controversial without a summary of all direct or indirect comparisons of drugs. We did a systematic review with pairwise and network meta-analyses of efficacy and tolerability., Methods: We searched MEDLINE, Embase, PsycINFO, Cochrane Library, PubMed, Biosis, and ClinicalTrials.gov for randomised controlled trials of antipsychotics for the acute treatment of first-episode schizophrenia, published up to Nov 17, 2016. Our primary outcome was overall change in symptoms. Secondary outcomes were change in positive and negative symptoms, categorical response to treatment, study dropout for any reason and for inefficacy of treatment, use of drugs to treat parkinsonian symptoms, weight gain, sedation, increase in prolactin release, overall functioning, and quality of life. We did the meta-analyses with a random-effects model to calculate standardised mean differences (SMDs) or odds ratios (ORs) with 95% CIs., Findings: We identified 19 relevant randomised controlled trials of 12 antipsychotic drugs that involved 2669 participants. 13 of the studies presented data on the primary outcome. For overall reduction of symptoms, amisulpride (SMD -0·37, 95% CI -0·61 to -0·14), olanzapine (-0·25, -0·39 to -0·12), ziprasidone (-0·25, -0·48 to -0·01), and risperidone (-0·14, -0·27 to -0·01) were significantly more efficacious than haloperidol, but the evidence was very low to moderate quality. Amisulpride was superior for reduction of symptoms to quetiapine (SMD -0·25, 95% CI -0·50 to -0·01). Olanzapine was superior to haloperidol and risperidone for reduction of negative symptoms. Several second-generation antipsychotics were superior to haloperidol in terms of all-cause discontinuation. Olanzapine was associated with at least one use of drugs to treat parkinsonian symptoms and quetiapine with less akathisia than haloperidol, aripiprazole, risperidone, and olanzapine, but, again, evidence was very low to low quality. Molindone was superior to risperidone, haloperidol, and olanzapine in terms of weight gain, and superior to risperidone in terms of increase in prolactin release., Interpreation: Haloperidol seems to be a suboptimum treatment option for acute treatment of first-episode schizophrenia, but we found little difference between second-generation antipsychotics. The evidence was generally of low quality and the numbers of patients for each drug were small. Thus, the choice of treatment should be guided primarily by side-effects., Funding: German Federal Ministry of Education and Research., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

It is often stated that first-episode patients tend to respond better to antipsychotics than chronic patients, but the exact numbers and moderators of response in this population are unclear. We, therefore, present the first systematic review on response rates of first episode patients with schizophrenia in randomized trials. We searched multiple databases for randomized-controlled trials of antipsychotics in acutely ill patients with a first episode of schizophrenia (last search: November 17, 2016). The outcomes were response rate based on two criteria, at least 50% PANSS or BPRS total score reduction from baseline and at least 20% reduction. Data were pooled in a single-group summary meta-analysis using Comprehensive Meta-Analysis software. Moreover, several potential moderators of response to antipsychotics were examined by meta-regression. We included 17 studies with a total of 3156 participants. On the average, 81.3%/51.9% of the first-episode patients reached an at least 20%/50% PANSS or BPRS reduction from baseline, respectively. Meta-regressions revealed a better treatment response in female patients, in more severely ill patients at baseline, in antipsychotic naïve patients, in patients with a shorter illness duration and in open studies. Study duration and dosage were no significant moderators of response. Our finding suggest that more than 80% of first-episode patients achieved 20% PANSS/BPRS reduction from baseline and around 50% achieved a 50% PANSS/BPRS reduction. Several patient characteristics moderated response rates., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Marine bivalves are known to ingest microplastics, but information on the consequences for their physiological performance is limited. To investigate a potential exposure pathway that has not yet been addressed, we mimicked the resuspension of microplastics from the sediment in a laboratory exposure experiment. For this, we exposed the Asian green mussel Perna viridis to 4 concentrations (0mg/l, 21.6mg/l, 216mg/l, 2160mg/l) of suspended polyvinylchloride (PVC) particles (1-50μm) for two 2-hour-time-periods per day. After 44days, mussel filtration and respiration rates as well as byssus production were found to be a negative function of particle concentration. Furthermore, within 91days of exposure, mussel survival declined with increasing PVC abundance. These negative effects presumably go back to prolonged periods of valve closure as a reaction to particle presence. We suggest that microplastics constitute a new seston component that exerts a stress comparable to natural suspended solids., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

It is an open question whether adverse habitat conditions, characteristic for many anthropogenically impacted coastal habitats, can determine resistance to abiotic stress in populations of residing invertebrates. We tested experimentally for differences in stress tolerance between individuals of the Asian green mussel Perna viridis stemming from the heavily impacted Jakarta Bay and from two natural sites, Lada Bay and Pelabuhan Ratu, West Java. Mussel performance under hyposalinity and hypoxia was assessed in laboratory assays by measuring fitness-related response variables, e.g. body condition index, relative shell weight, byssus production, respiration rates and survival. We found stress-specific and population-specific differences in mussel resistance to adverse conditions: Individuals from the impacted Jakarta Bay performed better under hypoxia than their conspecifics from the natural sites, whereas the latter were more resistant to hyposalinity. We explain these differences by differential acclimation to environmental conditions in the respective habitats and by diverging degrees of food supply., (Copyright © 2016 Elsevier Ltd. All rights reserved.)