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When studies use different scales to measure continuous outcomes, standardised mean differences (SMD) are required to meta-analyse the data. However, outcomes are often reported as endpoint or change from baseline scores. Combining corresponding SMDs can be problematic and available guidance advises against this practice. We aimed to examine the impact of combining the two types of SMD in meta-analyses of depression severity. We used individual participant data on pharmacological interventions (89 studies, 27,409 participants) and internet-delivered cognitive behavioural therapy (iCBT; 61 studies, 13,687 participants) for depression to compare endpoint and change from baseline SMDs at the study level. Next, we performed pairwise (PWMA) and network meta-analyses (NMA) using endpoint SMDs, change from baseline SMDs, or a mixture of the two. Study-specific SMDs calculated from endpoint and change from baseline data were largely similar, although for iCBT interventions 25% of the studies at 3 months were associated with important differences between study-specific SMDs (median 0.01, IQR -0.10, 0.13) especially in smaller trials with baseline imbalances. However, when pooled, the differences between endpoint and change SMDs were negligible. Pooling only the more favourable of the two SMDs did not materially affect meta-analyses, resulting in differences of pooled SMDs up to 0.05 and 0.13 in the pharmacological and iCBT datasets, respectively. Our findings have implications for meta-analyses in depression, where we showed that the choice between endpoint and change scores for estimating SMDs had immaterial impact on summary meta-analytic estimates. Future studies should replicate and extend our analyses to fields other than depression.

Some patients benefit from a treatment while others may do so less or do not benefit at all. We have previously developed a two-stage network meta-regression prediction model that synthesized randomized trials and evaluates how treatment effects vary across patient characteristics. In this article, we extended this model to combine different sources of types in different formats: aggregate data (AD) and individual participant data (IPD) from randomized and non-randomized evidence. In the first stage, a prognostic model is developed to predict the baseline risk of the outcome using a large cohort study. In the second stage, we recalibrated this prognostic model to improve our predictions for patients enrolled in randomized trials. In the third stage, we used the baseline risk as effect modifier in a network meta-regression model combining AD, IPD randomized clinical trial to estimate heterogeneous treatment effects. We illustrated the approach in the re-analysis of a network of studies comparing three drugs for relapsing--remitting multiple sclerosis. Several patient characteristics influence the baseline risk of relapse, which in turn modifies the effect of the drugs. The proposed model makes personalized predictions for health outcomes under several treatment options and encompasses all relevant randomized and non-randomized evidence.

Abstract Access to defined glycans and glycoconjugates is pivotal for discovery, dissection, and harnessing of a range of biological functions orchestrated by cellular glycosylation processes and the glycome. We previously employed genetic glycoengineering by nuclease-based gene editing to develop sustainable production of designer glycoprotein therapeutics and cell-based glycan arrays that display glycans in their natural context at the cell surface. However, access to human glycans in formats and quantities that allow structural studies of molecular interactions and use of glycans in biomedical applications currently rely on chemical and chemoenzymatic syntheses associated with considerable labor, waste, and costs. Here, we develop a sustainable and scalable method for production of glycans in glycoengineered mammalian cells by employing secreted Glycocarriers with repeat glycosylation acceptor sequence motifs for different glycans. The Glycocarrier technology provides a flexible production platform for glycans in different formats, including oligosaccharides, glycopeptides, and multimeric glycomodules, and offers wide opportunities for use in bioassays and biomedical applications.

Abstract The continuous emergence of SARS-CoV-2 variants of concern has rendered many therapeutic monoclonal antibodies (mAbs) ineffective. To date, there are no clinically authorized therapeutic antibodies effective against the recently circulating Omicron sub-lineages BA.2.86 and JN.1. Here, we report the isolation of broad and potent neutralizing human mAbs (HuMabs) from a healthcare worker infected with SARS-CoV-2 early in the pandemic. These include a genetically unique HuMab, named K501SP6, which can neutralize different Omicron sub-lineages, including BQ.1, XBB.1, BA.2.86 and JN.1, by targeting a highly conserved epitope on the N terminal domain, as well as an RBD-specific HuMab (K501SP3) with high potency towards earlier circulating variants that was escaped by the more recent Omicron sub-lineages through spike F486 and E484 substitutions. Characterizing SARS-CoV-2 spike-specific HuMabs, including broadly reactive non-RBD-specific HuMabs, can give insight into the immune mechanisms involved in neutralization and immune evasion, which can be a valuable addition to already existing SARS-CoV-2 therapies.

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) affects approximately 5% of children globally, with symptoms often persisting into adulthood. While pharmacological interventions are commonly employed for management, understanding the optimal dosing for efficacy and tolerability remains crucial. This study aims to conduct a dose–response network meta-analysis to estimate the efficacy of pharmacological treatments across different doses, aiming to inform clinical decision-making and improve treatment outcomes. Methods This updated systematic review will include randomized controlled trials evaluating ADHD medication efficacy in children, adolescents, and adults. An updated search from a 2018 NMA will be conducted across multiple electronic databases with no language restrictions, using specific eligibility criteria focused on randomized controlled trials. The primary outcome will assess the severity of ADHD core symptoms, while secondary outcomes will consider treatment tolerability. A dose–response Bayesian hierarchical model will be used to estimate dose–response curves for each medication, identifying optimal dosing strategies. Discussion With this dose–response network meta-analysis, we aim to better understand the dose–response relationship of pharmacological treatment in ADHD, which could help clinician to the identification of optimal doses. Systematic review registration OSF https://doi.org/10.17605/OSF.IO/3MY4A .

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Background Muscarinic receptor agonism and positive allosteric modulation is a promising mechanism of action for treating psychosis, not present in most D2R-blocking antipsychotics. Xanomeline, an M1/M4-preferring agonist, has shown efficacy in late-stage clinical trials, with more compounds being investigated. Therefore, we aim to synthesize evidence on the preclinical efficacy of muscarinic receptor agonists and positive allosteric modulators in animal models of psychosis to provide unique insights and evidence-based information to guide drug development. Methods We plan a systematic review and meta-analysis of in vivo animal studies comparing muscarinic receptor agonists or positive allosteric modulators with control conditions and existing D2R-blocking antipsychotics in animals subjected to any method that induces behavioural changes of relevance for psychosis. We will identify eligible studies by searching multiple electronic databases. At least two independent reviewers will conduct the study selection and data extraction using prespecified forms and assess the risk of bias with the SYRCLE’s tool. Our primary outcomes include locomotor activity and prepulse inhibition measured with standardized mean differences. We will examine other behavioural readouts of relevance for psychosis as secondary outcomes, such as social interaction and cognitive function. We will synthesize the data using multi-level meta-analysis with a predefined random-effects structure, considering the non-independence of the data. In meta-regressions we will explore potential sources of heterogeneity from a predefined list of characteristics of the animal population, model, and intervention. We will assess the confidence in the evidence considering a self-developed instrument thatconsiders the internal and external validity of the evidence. Protocol registration PROSPERO-ID: CRD42024520914

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

Background Muscarinic receptor agonism is a promising mechanism of action for treating psychosis, not present in most D 2R-blocking antipsychotics. Xanomeline, an M1/M4-preferring agonist, has shown efficacy in late-stage clinical trials, with more compounds being investigated. Therefore, we aim to synthesize evidence on the preclinical efficacy of muscarinic receptor agonists in animal models of psychosis to provide unique insights and evidence-based information to guide drug development. Methods We plan a systematic review and meta-analysis of in vivo animal studies comparing muscarinic receptor agonists or positive allosteric modulators with control conditions and existing D2R-blocking antipsychotics in animals subjected to any method that induces behavioural changes of relevance for psychosis. We will identify eligible studies by searching multiple electronic databases. At least two independent reviewers will conduct the study selection and data extraction using prespecified forms and assess the risk of bias with the SYRCLE’s tool. Our primary outcomes include locomotor activity and prepulse inhibition measured with standardized mean differences. We will examine other behavioural readouts of relevance for psychosis as secondary outcomes, such as social interaction and cognitive function. We will synthesize the data using multi-level meta-analysis with a predefined random-effects structure, considering the non-independence of the data. In meta-regressions we will explore potential sources of heterogeneity from a predefined list of characteristics of the animal population, model, and intervention. We will assess the confidence in the evidence considering a self-developed instrument thatconsiders the internal and external validity of the evidence. Protocol registration PROSPERO-ID: CRD42024520914

Summary: Pancreatic ductal adenocarcinoma (PDAC) poses significant clinical challenges, often presenting as unresectable with limited biopsy options. Here, we show that circulating tumor cells (CTCs) offer a promising alternative, serving as a “liquid biopsy” that enables the generation of in vitro 3D models and highly aggressive in vivo models for functional and molecular studies in advanced PDAC. Within the retrieved CTC pool (median 65 CTCs/5 mL), we identify a subset (median content 8.9%) of CXCR4+ CTCs displaying heightened stemness and metabolic traits, reminiscent of circulating cancer stem cells. Through comprehensive analysis, we elucidate the importance of CTC-derived models for identifying potential targets and guiding treatment strategies. Screening of stemness-targeting compounds identified stearoyl-coenzyme A desaturase (SCD1) as a promising target for advanced PDAC. These results underscore the pivotal role of CTC-derived models in uncovering therapeutic avenues and ultimately advancing personalized care in PDAC.

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

Gunshot wound morphology and gunshot residues (GSRs) evaluation have been poorly investigated in veterinary forensic pathology. The aims of the present study were to assess the gunshot wound morphology in animals and evaluate the detectability of lead deriving from GSRs using colorimetric techniques. To these aims, cadavers were divided into four different groups. Group A comprised eight animals who died from firearm-related injuries, while groups B and C included dog limbs shot using different shooting ranges; group D comprised dog limbs stabbed with a screwdriver. Morphological analysis was performed on all entry gunshot wounds. Lead residues were investigated using a Bullet Hole Testing Kit (BTK) and Rhodizonate Sodium histochemical staining (NaR-s). Gunshot wounds in group A showed an abrasion ring associated with hemorrhages and tissue necrosis. Groups B and C showed injuries related to the shooting range. NaR-s showed positive results in both animals that died from gunshot wounds and experimentally shot limbs. However, the number of positive cases and the pattern of lead distribution varied with the shooting range. Positive results by BTK were limited to close-contact shots in group B limbs. Our results suggest that both pathological examination and NaR tests represent valid tools for investigating gunshot wounds in veterinary pathology.

Abstract Background Monitoring of HIV and sexually transmitted infection (STI) prevention is important for guiding national sexual health programmes for both the general population and key populations. The objectives of this study were to examine trends and patterns of condom use at last intercourse and lifetime HIV testing in 2007, 2012 and 2017 in Switzerland, and to explore factors associated with these behaviours in men and women with opposite-sex partners and with same sex partners. Methods We analysed data from the 2007, 2012 and 2017 Swiss Health Survey. For each time point, outcome and population group, we conducted a descriptive analysis of weighted data and conducted multivariable logistic regression to obtain adjusted odds ratios (aOR) with 95% confidence intervals (CI) and compared outcomes between the timepoints. Results In total, 46,320 people were interviewed: 21,847 men and 23,141 women, who reported having sex only with partners of the opposite sex, 633 men who reported sex with a male partner and 699 women who reported sex with a female partner. Among the three surveys the prevalence of condom did not change but varied from 22 to 26% of men and 15 to 21% in women with only opposite-sex partners (aOR men, 0.93, 95% CI 0.82, 1.06; women 0.98, 95% CI 0.86 to 1.11). In men with any same sex partner the prevalence of condom use was 40% in 2007, 33% in 2012 and 54% in 2017 (aOR 1.80, 95% CI 0.97, 3.34). In multivariable analysis, the factor most strongly associated with condom use was sex with an occasional partner at last intercourse. HIV testing ever increased across all three survey years in people with opposite sex partners: 2017 vs. 2007, aOR men with only opposite-sex partners 1.64 (95% CI 1.49, 1.82), women with only opposite-sex partners 1.67 (1.51, 1.85), men with any same sex partner 0.98 (0.49, 1.96), women with any same sex partner 1.31 (0.74, 2.30). Conclusions Monitoring of condom use, and HIV testing should continue and contribute to the development of the national sexual health programme. Stronger promotion of condoms for people with opposite-sex partners might be needed, since overall condom use at last intercourse has not changed since 2007.

Abstract Background The relative treatment effects estimated from network meta-analysis can be employed to rank treatments from the most preferable to the least preferable option. These treatment hierarchies are typically based on ranking metrics calculated from a single outcome. Some approaches have been proposed in the literature to account for multiple outcomes and individual preferences, such as the coverage area inside a spie chart, that, however, does not account for a trade-off between efficacy and safety outcomes. We present the net-benefit standardised area within a spie chart, $$SAWIS$$ SAWIS to explore the changes in treatment performance with different trade-offs between benefits and harms, according to a particular set of preferences. Methods We combine the standardised areas within spie charts for efficacy and safety/acceptability outcomes with a value λ specifying the trade-off between benefits and harms. We derive absolute probabilities and convert outcomes on a scale between 0 and 1 for inclusion in the spie chart. Results We illustrate how the treatments in three published network meta-analyses perform as the trade-off λ varies. The decrease of the $$SAWIS$$ SAWIS quantity appears more pronounced for some drugs, e.g. haloperidol. Changes in treatment performance seem more frequent when SUCRA is employed as outcome measures in the spie charts. Conclusions $$SAWIS$$ SAWIS should not be interpreted as a ranking metric but it is a simple approach that could help identify which treatment is preferable when multiple outcomes are of interest and trading-off between benefits and harms is important.

Abstract Network meta-analysis compares multiple interventions and estimates the relative treatment effects between all interventions, combining both direct and indirect evidence. Recently, a framework was developed to assess the Risk Of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) which is part of the more comprehensive framework to evaluate the Confidence In the evidence for Network Meta-Analysis (CINeMA). To produce an overall risk of bias judgement for each network estimate, ROB-MEN: performs an assessment of the bias due to missing evidence in each possible pairwise comparison; combines the assessment with the contribution from the direct pairwise comparisons; considers the potential for small-study effects. To facilitate and semi-automate this process, ROB-MEN has been implemented in a user-friendly web-application ( https://cinema.ispm.unibe.ch/rob-men ). Here we provide a tutorial detailing the functionality and use of the application consisting of data upload, analysis configuration, output visualisation, and production of the tool’s output tables for recording the risk of bias assessment. We also illustrate an example application using the demo dataset available for download on the application’s homepage. The ROB-MEN web-application is open-source and freely available ( https://github.com/esm-ispm-unibe-ch/rob-men ).

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

Fire-related deaths are usually a consequence of carbon monoxide (CO) poisoning or shock from thermal injuries. In humans, high levels of carboxyhemoglobin (COHb) concentrations in the blood can support a diagnosis of CO poisoning. In veterinary medicine, few studies investigated the pathological changes and blood COHb% in fire victims, and no data are available on post-mortem changes in blood gas composition due to fire. This study aims to investigate the pathological changes and COHb levels in both animal victims of fire and cadavers experimentally exposed to fire. For this purpose, dogs were selected and subdivided into three groups. Group A comprised 9 adult dogs, and Group B comprised 7 puppies that died under fire-related conditions. Group C was represented by 4 dog cadavers experimentally exposed to heat and smoke. A complete macroscopic, histological, and COHb evaluation were performed on each animal. Animals in Groups A and B showed cherry-red discoloration, thermal-injuries and soot deposits along the respiratory tract. Animals in Group C showed thermal injuries and soot deposits limited to the upper respiratory tract. The mean COHb% values in cadavers in Group C were lower than those observed in the other groups but higher compared to the values detected before the heat and smoke treatment. These findings suggest that both pathological changes and COHb analysis are valid tools for investigating fire-related deaths in dogs. However, the increase of COHb levels in cadavers exposed post-mortem to heat and smoke highlights how the COHb analysis should always be evaluated together with macroscopical and microscopical findings to avoid significant misjudgments in investigating fire-related fatalities in veterinary forensic practice.

Background Approximately 30% of patients experience substantial improvement in depression after 2 months without treatment, and 45% with antidepressants. The smallest worthwhile difference (SWD) refers to an intervention’s smallest beneficial effect over a comparison patients deem worthwhile given treatment burdens (harms, expenses and inconveniences), but is undetermined for antidepressants.Objective Estimating the SWD of commonly prescribed antidepressants for depression compared to no treatment.Methods The SWD was estimated as a patient-required difference in response rates between antidepressants and no treatment after 2 months. An online cross-sectional survey using Prolific, MQ Mental Health and Amazon Mechanical Turk crowdsourcing services in the UK and USA between October 2022 and January 2023 garnered participants (N=935) that were a mean age of 44.1 (SD=13.9) and 66% women (n=617).Findings Of 935 participants, 124 reported moderate-to-severe depressive symptoms but were not in treatment, 390 were in treatment and 495 reported absent-to-mild symptoms with or without treatment experiences. The median SWD was a 20% (IQR=10–30%) difference in response rates for people with moderate-to-severe depressive symptoms, not in treatment, and willing to consider antidepressants, and 25% (IQR=10–35%) for the full sample.Conclusions Our observed SWDs mean that the current 15% antidepressant benefit over no treatment was sufficient for one in three people to accept antidepressants given the burdens, but two in three expected greater treatment benefits.Implications While a minority may be satisfied with the best currently available antidepressants, more effective and/or less burdensome medications are needed, with more attention given to patient perspectives.

Aim To describe the pattern of the prevalence of mental health problems during the first year of the COVID-19 pandemic and examine the impact of containment measures on these trends.Methods We identified articles published until 30 August 2021 that reported the prevalence of mental health problems in the general population at two or more time points. A crowd of 114 reviewers extracted data on prevalence, study and participant characteristics. We collected information on the number of days since the first SARS-CoV-2 infection in the study country, the stringency of containment measures and the number of cases and deaths. We synthesised changes in prevalence during the pandemic using a random-effects model. We used dose-response meta-analysis to evaluate the trajectory of the changes in mental health problems.Results We included 41 studies for 7 mental health conditions. The average odds of symptoms increased during the pandemic (mean OR ranging from 1.23 to 2.08). Heterogeneity was very large and could not be explained by differences in participants or study characteristics. Average odds of psychological distress, depression and anxiety increased during the first 2 months of the pandemic, with increased stringency of the measures, reported infections and deaths. The confidence in the evidence was low to very low.Conclusions We observed an initial increase in the average risk of psychological distress, depression-related and anxiety-related problems during the first 2 months of the pandemic. However, large heterogeneity suggests that different populations had different responses to the challenges imposed by the pandemic.

Background Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions TAAR1 agonists may be less efficacious than dopamine D2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration PROSPERO-ID:CRD42023451628.

Abstract Background The covid-19 pandemic has highlighted the role of living systematic reviews. The speed of evidence generated during the covid-19 pandemic accentuated the challenges of managing high volumes of research literature. Methods In this article, we summarise the characteristics of ongoing living systematic reviews on covid-19, and we follow a life cycle approach to describe key steps in a living systematic review. Results We identified 97 living systematic reviews on covid-19, published up to 7th November 2022, which focused mostly on the effects of pharmacological interventions (n = 46, 47%) or the prevalence of associated conditions or risk factors (n = 30, 31%). The scopes of several reviews overlapped considerably. Most living systematic reviews included both observational and randomised study designs (n = 45, 46%). Only one-third of the reviews has been updated at least once (n = 34, 35%). We address practical aspects of living systematic reviews including how to judge whether to start a living systematic review, methods for study identification and selection, data extraction and evaluation, and give recommendations at each step, drawing from our own experience. We also discuss when it is time to stop and how to publish updates. Conclusions Methods to improve the efficiency of searching, study selection, and data extraction using machine learning technologies are being developed, their performance and applicability, particularly for reviews based on observational study designs should improve, and ways of publishing living systematic reviews and their updates will continue to evolve. Finally, knowing when to end a living systematic review is as important as knowing when to start.

Family is one of the closest people in helping individuals solve problems and serve as the foundation for developing coping strategies. Several factors influence coping strategies, including problem-solving skills and family support. This study aimed to explore the correlation between family support and coping strategies among female prisoners. The research employed a quantitative correlation design using a cross-sectional approach and a total sampling technique, with a sample of 33 female prisoners. The study included two variables: family support as the dependent variable and coping strategy as the independent variable. The chi-square test was used for data analysis. The results revealed that a majority of female prisoners received good family support (51.5%), and most of them used emotion-focused coping strategies (63.6%). The results indicate a significant correlation between family support and coping strategies for female prisoners, with a p-value of 0.004. It highlights the importance of family support for prisoners in developing effective coping strategies. The findings emphasize that family support plays a crucial role in enhancing coping strategies for inmates, ultimately contributing to an improved quality of life.

Objective There is no standard tool for assessing risk of bias (RoB) in prevalence studies. For the purposes of a living systematic review during the COVID-19 pandemic, we developed a tool to evaluate RoB in studies measuring the prevalence of mental health disorders (RoB-PrevMH) and tested inter-rater reliability.Methods We decided on items and signalling questions to include in RoB-PrevMH through iterative discussions. We tested the reliability of assessments by different users with two sets of prevalence studies. The first set included a random sample of 50 studies from our living systematic review. The second set included 33 studies from a systematic review of the prevalence of post-traumatic stress disorders, major depression and generalised anxiety disorder. We assessed the inter-rater agreement by calculating the proportion of agreement and Kappa statistic for each item.Results RoB-PrevMH consists of three items that address selection bias and information bias. Introductory and signalling questions guide the application of the tool to the review question. The inter-rater agreement for the three items was 83%, 90% and 93%. The weighted kappa scores were 0.63 (95% CI 0.54 to 0.73), 0.71 (95% CI 0.67 to 0.85) and 0.32 (95% CI −0.04 to 0.63), respectively.Conclusions RoB-PrevMH is a brief, user-friendly and adaptable tool for assessing RoB in studies on prevalence of mental health disorders. Initial results for inter-rater agreement were fair to substantial. The tool’s validity, reliability and applicability should be assessed in future projects.

In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends. Living systematic reviews produce rigorous, up-to-date and informative evidence summaries that are particularly important where research is emerging rapidly, current evidence is uncertain and new findings might change policy or practice. Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis (GALENOS) aims to tackle the challenges of mental health science research by cataloguing and evaluating the full spectrum of relevant scientific research including both human and preclinical studies. GALENOS will also allow the mental health community—including patients, carers, clinicians, researchers and funders—to better identify the research questions that most urgently need to be answered. By creating open-access datasets and outputs in a state-of-the-art online resource, GALENOS will help identify promising signals early in the research process. This will accelerate translation from discovery science into effective new interventions for anxiety, depression and psychosis, ready to be translated in clinical practice across the world.

Background: Anhedonia is a key symptom of depression, and it has been suggested as a potential target for future individualised treatments. However, much is unknown about how interventions enhancing dopaminergic pathways may affect anhedonia symptoms in the context of depression. Methods: We will perform independent searches in multiple electronic databases to identify clinical and animal experimental studies on pro-dopaminergic interventions in individuals with depression or animal models for depression. The primary outcomes will be overall anhedonia symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. At least two independent reviewers will conduct the study selection, data extraction, and risk of bias assessments using pre-defined tools according to each record’s study design. We will develop ontologies to facilitate study identification and data extraction. We will synthesise data from clinical and animal studies separately. If appropriate, we will use random-effects meta-analyses, or synthesis without meta-analyses. We will investigate study characteristics as potential sources of heterogeneity. We will evaluate the confidence in the evidence for each outcome and source of evidence, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, we will draw an overall conclusion in a triangulation meeting involving a multidisciplinary team of experts. We plan updates of the review every 6 months, and any future modifications to the protocol will be documented. We will co-produce this review with multiple stakeholders. PROSPERO registration: CRD42023451821

Abstract Development of B-cell-based hepatitis C virus (HCV) vaccines that induce broadly neutralizing antibodies (bNAbs) is hindered by extensive sequence diversity and low immunogenicity of envelope glycoprotein vaccine candidates, most notably soluble E2 (sE2). To overcome this, we employed two-component approaches using self-assembling virus-like particles (cVLPs; component 1), displaying monomeric or oligomeric forms of HCV sE2 (sE2mono or sE2oligo; component 2). Immunization studies were performed in BALB/c mice and the neutralizing capacity of vaccine-induced antibodies was tested in cultured-virus-neutralizations, using HCV of genotypes 1–6. sE2-cVLP vaccines induced significantly higher levels of NAbs (p = 0.0065) compared to corresponding sE2 vaccines. Additionally, sE2oligo-cVLP was superior to sE2mono-cVLP in inducing bNAbs. Interestingly, human monoclonal antibody AR2A had reduced binding in ELISA to sE2oligo-cVLP compared with sE2mono-cVLP and competition ELISA using mouse sera from vaccinated animals indicated that sE2oligo-cVLP induced significantly less non-bNAbs AR2A (p = 0.0043) and AR1B (p = 0.017). Thus, cVLP-displayed oligomeric sE2 shows promise as an HCV vaccine candidate.

Background: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. Methods: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis.

Chondroitin sulfate (CS) is one of the most abundant glycosaminoglycans in prostate cancers. Here the authors show that inhibition of the androgen receptor pathway leads to the upregulation of CS, which promotes prostate cancer growth and metastasis.

Funding agencies rely on peer review and expert panels to select the research deserving funding. Peer review has limitations, including bias against risky proposals or interdisciplinary research. The inter-rater reliability between reviewers and panels is low, particularly for proposals near the funding line. Funding agencies are also increasingly acknowledging the role of chance. The Swiss National Science Foundation (SNSF) introduced a lottery for proposals in the middle group of good but not excellent proposals. In this article, we introduce a Bayesian hierarchical model for the evaluation process. To rank the proposals, we estimate their expected ranks (ER), which incorporates both the magnitude and uncertainty of the estimated differences between proposals. A provisional funding line is defined based on ER and budget. The ER and its credible interval are used to identify proposals with similar quality and credible intervals that overlap with the provisional funding line. These proposals are entered into a lottery. We illustrate the approach for two SNSF grant schemes in career and project funding. We argue that the method could reduce bias in the evaluation process. R code, data and other materials for this article are available online.

Key Points: Question: Which antipsychotics are associated with the most beneficial outcomes regarding cognitive function and, secondarily, quality of life and social functioning? Findings: This systematic review and network meta-analysis including 68 studies involving 9525 participants found no clear differences in outcomes between antipsychotics; however, first-generation dopamine antagonists, such as haloperidol and fluphenazine, and clozapine with its anticholinergic properties, ranked low. Moreover, no specific antipsychotic could be connected with a clearly more favorable outcome than placebo, and the measurement of cognitive performance was highly heterogeneous and often not comprehensive. Meaning: Drugs with novel mechanisms of action need to be developed to adequately address the cognitive symptoms of schizophrenia spectrum disorders, and a common standard for cognitive assessment would be beneficial in clinical trials. This systematic review and network meta-analysis evaluates associations between antipsychotic drugs and cognitive function, quality of life, and social functioning. Importance: Cognitive deficits are a substantial part of the symptoms of schizophrenia spectrum disorders (SSDs) and contribute heavily to the burden of disease. Antipsychotic drugs are not cognitive enhancers, but due to their different receptor-binding profiles, they could differ in their effects on cognition. No previous network meta-analysis compared antipsychotics to placebo, which is important to determine whether use of these drugs is associated with cognitive performance in SSDs at all. Objective: To determine the association of treatment with various antipsychotics and cognition in patients with SSDs. Data Sources: Cochrane Schizophrenia Trials Register through June 25, 2023. Study Selection: Randomized clinical trials examining the effects on cognition of antipsychotic drugs or placebo in participants with SSD. Data Extraction and Synthesis: A systematic review and random-effects frequentist network meta-analysis was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses–Network Meta-analysis reporting guideline. Main Outcomes and Measures: The primary outcome was change in overall cognition score calculated for each study. Secondary outcomes included cognitive domains, quality of life, and functioning. Results: This study included 68 studies involving 9525 participants (mean [SD] age, 35.1 [8.9] years; 5878 male [70%] and 2890 [30%] female; some studies did not provide this information). There were few clear differences between antipsychotics, but first-generation dopamine antagonists haloperidol (standardized mean difference [SMD], 0.04; 95% CI, −0.25 to 0.33) and fluphenazine (SMD, 0.15; 95% CI, −0.39 to 0.69) as well as clozapine (SMD, 0.12; 95% CI, −0.23 to 0.48) ranked low. No individual antipsychotic was associated with a clearly better outcome than placebo, but antipsychotics as a group were, with small effect sizes (mean SMDs: adrenergic/low dopamine, −0.21; serotonergic/dopaminergic, −0.26; muscarinic, −0.28; dopaminergic, −0.40). Conclusion and Relevance: Although data are relatively sparse, those reviewed in this study suggest that first-generation dopamine antagonists and clozapine should be avoided when cognitive deficits are a concern. Antipsychotics are not procognitive drugs. The overall small superior outcomes compared to placebo may be explained by less disordered thought patterns associated with fewer positive symptoms rather than cognitive deficits in the proper sense. The findings also suggest that harmonizing measurement of cognitive function in randomized clinical trials would be beneficial. [ABSTRACT FROM AUTHOR]