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Computational protein design is advancing rapidly. Here we describe efficient routes starting from validated parallel and antiparallel peptide assemblies to design two families of α-helical barrel proteins with central channels that bind small molecules. Computational designs are seeded by the sequences and structures of defined de novo oligomeric barrel-forming peptides, and adjacent helices are connected by loop building. For targets with antiparallel helices, short loops are sufficient. However, targets with parallel helices require longer connectors; namely, an outer layer of helix-turn-helix-turn-helix motifs that are packed onto the barrels. Throughout these computational pipelines, residues that define open states of the barrels are maintained. This minimizes sequence sampling, accelerating the design process. For each of six targets, just two to six synthetic genes are made for expression in Escherichia coli. On average, 70% of these genes express to give soluble monomeric proteins that are fully characterized, including high-resolution structures for most targets that match the design models with high accuracy.

Background: Hospital discharge summaries play an essential role in informing GPs of recent admissions to ensure excellent continuity of care and prevent adverse events; however, they are notoriously poorly written, time-consuming, and can result in delayed discharge. Aim: To evaluate the potential of artificial intelligence (AI) to produce high-quality discharge summaries equivalent to the level of a doctor who has completed the UK Foundation Programme. Design & setting: Feasibility study using 25 mock patient vignettes. Method: Twenty-five mock patient vignettes were written by the authors. Five junior doctors wrote discharge summaries from the case vignettes (five each). The same case vignettes were input into ChatGPT. In total, 50 discharge summaries were generated; 25 by Al and 25 by junior doctors. Quality and suitability were determined through both independent GP evaluators and adherence to a minimum dataset. Results: Of the 25 AI-written discharge summaries 100% were deemed by GPs to be of an acceptable quality compared with 92% of the junior doctor summaries. They both showed a mean compliance of 97% with the minimum dataset. In addition, the ability of GPs to determine if the summary was written by ChatGPT was poor, with only a 60% accuracy of detection. Similarly, when run through an AI-detection tool all were recognised as being very unlikely to be written by AI. Conclusion: AI has proven to produce discharge summaries of equivalent quality to a junior doctor who has completed the UK Foundation Programme; however, larger studies with real-world patient data with NHS-approved AI tools will need to be conducted.

The impact of hypersensitive narcissism and anxiety sensitivity on online compulsive buying were examined. These transdiagnostic personality factors have not previously received attention in virtual, as opposed to real-world, contexts, and the study explored their interaction with the use of visual and textual social media platforms for online buying. The present study sampled 440 participants (264 female; 174 male), aged 18 – 37 years. Participants completed an online survey comprising: Online Edwards Compulsive Buying Scale Revised, Hypersensitive Narcissism Scale, and the Anxiety Sensitivity Index-3. Visual social networking usage was a risk factor for online compulsive buying, and there were significant positive relationships between both hypersensitive narcissism, and anxiety sensitivity, with online compulsive buying. Anxiety sensitivity mediated the relationship between hypersensitive narcissism and compulsive online buying when the dominate form of social media use was textual, but not when it was visual.

Introduction: Internet-based self-help interventions have shown to be effective in the treatment of depression. Several meta-analyses indicated that human contact has a crucial impact on adherence and outcome. While most research focused on the role of guidance during interventions, a review by Andersson and Johansson (2012) suggested that contact before the intervention too may play an important role. Objective: We investigated the impact of the degree of contact in internet-based interventions (IBIs) for depression on outcome in adults suffering from elevated symptoms of depression. Methods: We conducted a preregistered meta-analysis (www.osf.io/4mzyd) and included trials comparing IBIs for depression against control conditions (treatment as usual [TAU] or waiting list [WL]) in patients with symptoms of unipolar depression searching the databases PsycINFO and Cochrane's Central Register of Controlled Trials (CENTRAL) limited to entries from EMBASE and PubMed. Following Andersson and Johansson (2012), contact before an intervention was defined as having had a diagnostic interview before the IBI, and contact during intervention was defined as having received guidance during the IBI. IBIs were grouped as providing (0) no contact, (1) contact before the IBI, (2) contact during the IBI, or (3) contact both before and during the IBI. The primary outcome was standardized mean difference (SMD) of the IBI and control in depressive symptoms at treatment termination. Secondary outcomes were study dropout and adherence to the IBI. Results: We included 56 eligible trials that randomized 13,335 patients to 75 internet-based intervention conditions and control groups (TAU in 23 trials, WL in 33 trials). In total, 44 trials (78.57 %) were judged to show some concerns or a high risk of bias. Overall heterogeneity was high regarding the primary outcome (I2s

Guided web-based self-help programs for individuals with depressive symptoms have shown to be more efficacious than unguided programs. However, research has paid little attention to why guided interventions are superior. The present study investigated whether working alliance and adherence to the program mediated the effect of guidance on depressive symptom outcome.The study is a secondary analysis of a randomized factorial trial. In the trial, 302 adults with mild to moderate depressive symptoms (Patient Health Questionnaire–9 score: 5–14) were randomized to either a guided or an unguided group. All participants received access to a web-based self-help program based on problem-solving therapy. Working alliance with the treatment providers was assessed using an adapted version of the Working Alliance Inventory for Guided Internet Interventions two weeks (early-treatment) and eight weeks (post-treatment) after pre-treatment. The primary outcome was depressive symptoms at post-treatment.The total working alliance score was significantly higher for guided participants compared to unguided participants (at early-treatment: t248.6 = −3.36, p

Introduction: The combination of internet-based intervention and psychotherapy, commonly termed blended therapy (BT), has gained popularity in recent years. While advantages and disadvantages of BT have been identified from the patient and therapist perspective, the two perspectives have rarely been examined within the same treatment. Moreover, almost all available research on patient and therapist experiences with BT is disorder-specific. This study aimed to investigate patient and therapist experiences within the same transdiagnostic BT. Methods: A qualitative analysis of semi-structured interviews with eight patients and eight therapists taking part in a transdiagnostic blended intervention focusing on the topic of emotion regulation was conducted. A qualitative content analysis approach was used. Category frequencies were calculated and similarities and differences between the patient and therapist experience were explored. Results: Ten main themes and 59 subthemes were identified in the category system for patient interviews and ten main themes and 50 subthemes were identified in the category system for therapist interviews. Similarities and differences between the two perspectives were reported with regard to 1) expectations toward the intervention, 2) the internet-based intervention, 3) symptomatology and emotion regulation, 4) the therapeutic relationship and 5) the blended format. Conclusion: This study provides first insights on the experiences with transdiagnostic BT focusing on emotion regulation. Based on the results, different recommendations for the improvement of transdiagnostic BT are made. Future research on patient and therapist experiences with transdiagnostic BT is necessary, in order to further improve the experience of those involved.

Over the course of an individual's lifetime, normal human cells accumulate mutations.sup.1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage.sup.2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma. The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues., Author(s): Luiza Moore [sup.1] [sup.2] , Alex Cagan [sup.1] , Tim H. H. Coorens [sup.1] , Matthew D. C. Neville [sup.1] , Rashesh Sanghvi [sup.1] , Mathijs A. Sanders [sup.1] [...]

Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing.sup.1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals. Somatic mutations obtained from laser microdissected biopsies of human tissues are used to reconstruct the developmental phylogenies of these tissues back to the zygote., Author(s): Tim H. H. Coorens [sup.1] , Luiza Moore [sup.1] [sup.2] , Philip S. Robinson [sup.1] [sup.3] , Rashesh Sanghvi [sup.1] , Joseph Christopher [sup.1] [sup.3] [sup.4] , James Hewinson [...]

Global concern over widely documented declines in pollinators.sup.1-3 has led to the identification of anthropogenic stressors that, individually, are detrimental to bee populations.sup.4-7. Synergistic interactions between these stressors could substantially amplify the environmental effect of these stressors and could therefore have important implications for policy decisions that aim to improve the health of pollinators.sup.3,8,9. Here, to quantitatively assess the scale of this threat, we conducted a meta-analysis of 356 interaction effect sizes from 90 studies in which bees were exposed to combinations of agrochemicals, nutritional stressors and/or parasites. We found an overall synergistic effect between multiple stressors on bee mortality. Subgroup analysis of bee mortality revealed strong evidence for synergy when bees were exposed to multiple agrochemicals at field-realistic levels, but interactions were not greater than additive expectations when bees were exposed to parasites and/or nutritional stressors. All interactive effects on proxies of fitness, behaviour, parasite load and immune responses were either additive or antagonistic; therefore, the potential mechanisms that drive the observed synergistic interactions for bee mortality remain unclear. Environmental risk assessment schemes that assume additive effects of the risk of agrochemical exposure may underestimate the interactive effect of anthropogenic stressors on bee mortality and will fail to protect the pollinators that provide a key ecosystem service that underpins sustainable agriculture. A meta-analysis of studies in which bees were exposed to combinations of agrochemicals, nutritional stressors and/or parasites revealed evidence for synergistic effects on mortality when bees were exposed to multiple agrochemicals at field-realistic levels., Author(s): Harry Siviter [sup.1] [sup.2] , Emily J. Bailes [sup.1] [sup.3] [sup.4] , Callum D. Martin [sup.1] , Thomas R. Oliver [sup.1] [sup.4] [sup.5] , Julia Koricheva [sup.1] , Ellouise [...]