DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models.

Down syndrome (DS) is caused by the trisomy of human chromosome 21 (HSA21). A major challenge in DS research is to identify the HSA21 genes that cause specific symptoms. Down syndrome cell adhesion molecule (DSCAM) is encoded by a HSA21 gene. Previous studies have shown that the protein level of the Drosophila homolog of DSCAM determines the size of presynaptic terminals. However, whether the triplication of DSCAM contributes to presynaptic development in DS remains unknown. Here, we show that DSCAM levels regulate GABAergic synapses formed on neocortical pyramidal neurons (PyNs). In the Ts65Dn mouse model for DS, where DSCAM is overexpressed due to DSCAM triplication, GABAergic innervation of PyNs by basket and chandelier interneurons is increased. Genetic normalization of DSCAM expression rescues the excessive GABAergic innervations and the increased inhibition of PyNs. Conversely, loss of DSCAM impairs GABAergic synapse development and function. These findings demonstrate excessive GABAergic innervation and synaptic transmission in the neocortex of DS mouse models and identify DSCAM overexpression as the cause. They also implicate dysregulated DSCAM levels as a potential pathogenic driver in related neurological disorders.

Mode of Onset Modifies the Effect of Time to Endovascular Reperfusion on Clinical Outcomes after Acute Ischemic Stroke: An Analysis of the DAWN Trial.

OBJECTIVE: We aimed to assess the impact of time to endovascular thrombectomy (EVT) on clinical outcomes in the DAWN trial, while also exploring the potential effect modification of mode of stroke onset on this relationship. METHODS: The association between every 1-h treatment delay with 90-day functional independence (modified Rankin Scale [mRS] score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs. witnessed vs. unwitnessed). RESULTS: Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6 to 12 hours and 12 to 24 hours time window, respectively. Considering all three modes of onset together, there was no statistically significant association between time last seen well to randomization with either functional independence or mortality at 90 days in either the endovascular thrombectomy (mRS 0-2 1-hour delay OR 1.07; 95% CI 0.93-1.24; mRS 6 OR 0.84; 95% CI 0.65-1.03) or medical management (mRS 0-2 1-hour delay OR 0.98; 95% CI 0.80-1.14; mRS 6 1-hour delay OR 0.94; 95% CI 0.79-1.09) groups. Moreover, there was no significant interaction between treatment effect and time (p = 0.439 and p = 0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between time last seen well to successful reperfusion (modified Treatment in Cerebral Infarction ≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p = 0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p = 0.018) negative slope in wake-up patients. There was no association between treatment times and symptomatic intracranial hemorrhage. INTERPRETATION: Mode of onset modifies the effect of time to reperfusion on thrombectomy outcomes, and should be considered when exploring different treatment paradigms in the extended window. ANN NEUROL 2024.

EWF: simulating exact paths of the Wright-Fisher diffusion.

MOTIVATION: The Wright-Fisher diffusion is important in population genetics in modelling the evolution of allele frequencies over time subject to the influence of biological phenomena such as selection, mutation and genetic drift. Simulating the paths of the process is challenging due to the form of the transition density. We present EWF, a robust and efficient sampler which returns exact draws for the diffusion and diffusion bridge processes, accounting for general models of selection including those with frequency dependence. RESULTS: Given a configuration of selection, mutation and endpoints, EWF returns draws at the requested sampling times from the law of the corresponding Wright-Fisher process. Output was validated by comparison to approximations of the transition density via the Kolmogorov-Smirnov test and QQ plots. AVAILABILITY AND IMPLEMENTATION: All softwares are available at https://github.com/JaroSant/EWF. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Therapeutic alliance in two forms of guided self-help for binge eating.

The role of therapeutic alliance within psychological treatments for eating disorders (EDs), including those delivered remotely, is well established. However, few studies have investigated alliance in guided self-help, a widely recommended first-line treatment for EDs characterised by regular binge eating. Using data from a randomised controlled trial, the current study examined both facilitator and patient assessments of alliance within e-mail-assisted and face-to-face guided self-help and looked at associations between alliance, ED symptoms and ED-related impairment. One hundred thirteen patients and 11 facilitators completed measures of alliance during and following a course of guided self-help. Whilst ratings were reliable across patients and facilitators, alliance scores were higher both in the patient sample and in the face-to-face condition. Ratings of alliance showed no correlations with ED symptoms at post-treatment, and early alliance was not significantly associated with outcome, which could inform how early symptom change is encouraged in guided self-help.

Inhibitory synaptic transmission is impaired in the Kölliker-Fuse of male, but not female, Rett syndrome mice.

Rett syndrome (RTT) is a severe neurodevelopmental disorder that mainly affects females due to silencing mutations in the X-linked MECP2 gene. One of the most troubling symptoms of RTT is breathing irregularity, including apneas, breath-holds, and hyperventilation. Mice with silencing mutations in Mecp2 exhibit breathing abnormalities similar to human patients and serve as useful models for studying mechanisms underlying breathing problems in RTT. Previous work implicated the pontine, respiratory-controlling Kölliker-Fuse (KF) in the breathing problems in RTT. The goal of this study was to test the hypothesis that inhibitory synaptic transmission is deficient in KF neurons from symptomatic male and female RTT mice. We performed whole cell voltage-clamp recordings from KF neurons in acute brain slices to examine spontaneous and electrically evoked inhibitory post-synaptic currents (IPSCs) in RTT mice and age- and sex-matched wild-type mice. The frequency of spontaneous IPSCs was reduced in KF neurons from male RTT mice but surprisingly not in female RTT mice. In addition, electrically evoked IPSCs were less reliable in KF neurons from male, but not female, RTT mice, which was positively correlated with paired-pulse facilitation, indicating decreased probability of release. KF neurons from male RTT mice were also more excitable and exhibited shorter-duration action potentials. Increased excitability of KF neurons from male mice was not explained by changes in axon initial segment length. These findings indicate impaired inhibitory neurotransmission and increased excitability of KF neurons in male but not female RTT mice and suggest that sex-dependent mechanisms contribute to breathing problems in RTT.NEW & NOTEWORTHY Kölliker-Fuse (KF) neurons in acute brain slices from male Rett syndrome (RTT) mice receive reduced inhibitory synaptic inputs compared with wild-type littermates. In female RTT mice, inhibitory transmission was not different in KF neurons compared with controls. The results from this study show that sex-specific alterations in synaptic transmission occur in the KF of RTT mice.

Ongoing Recombination in SARS-CoV-2 Revealed through Genealogical Reconstruction.

The evolutionary process of genetic recombination has the potential to rapidly change the properties of a viral pathogen, and its presence is a crucial factor to consider in the development of treatments and vaccines. It can also significantly affect the results of phylogenetic analyses and the inference of evolutionary rates. The detection of recombination from samples of sequencing data is a very challenging problem and is further complicated for SARS-CoV-2 by its relatively slow accumulation of genetic diversity. The extent to which recombination is ongoing for SARS-CoV-2 is not yet resolved. To address this, we use a parsimony-based method to reconstruct possible genealogical histories for samples of SARS-CoV-2 sequences, which enables us to pinpoint specific recombination events that could have generated the data. We propose a statistical framework for disentangling the effects of recurrent mutation from recombination in the history of a sample, and hence provide a way of estimating the probability that ongoing recombination is present. We apply this to samples of sequencing data collected in England and South Africa and find evidence of ongoing recombination.

Nationwide Outcomes following Percutaneous Cholecystostomy for Acute Calculous Cholecystitis and the Impact of Coronavirus Disease 2019: Results of the Multicentre Audit of Cholecystostomy and Further Interventions (MACAFI study).

PURPOSE: To assess the mortality, readmission rates, and practice variation of percutaneous cholecystostomy (PC) in patients with acute calculous cholecystitis in the United Kingdom (UK). MATERIALS AND METHODS: A total of 1,186 consecutive patients (636 men [53.6%]; median age, 75 years; range, 24-102 years) who underwent PC for acute calculous cholecystitis between January 1, 2019, and December 31, 2020, were included from 36 UK hospitals. The exclusion criteria were diagnostic aspirations, absence of acute calculous cholecystitis, and age less than 16 years. The coronavirus disease 2019 (COVID-19) lockdown was declared on March 26, 2020, in the UK, which served to distinguish among groups. RESULTS: Most patients (66.3%) underwent PC as definitive treatment, whereas 31.3% underwent PC as a bridge to surgery. The overall 30-day readmission rate was 42.2% (500/1,186), and the 30-day mortality was 9.1% (108/1,186). Centers performing fewer than 30 PCs per year had higher 90-day mortality than those performing more than 60 (19.3% vs 11.0%, respectively; P = .006). A greater proportion of patients presented with complicated acute calculous cholecystitis during the COVID-19 pandemic compared to prior (49.9% vs 40.9%, respectively; P = .007), resulting in more PCs (61.3 vs 37.9 per month, respectively; P < .001). More PCs were performed in tertiary hospitals than in district general hospitals (9 vs 3 per 100 beds, respectively; P < .001), with a greater proportion performed as a bridge to surgery (50.5% vs 22.8%, respectively; P < .001). CONCLUSIONS: The practice of PC is highly variable throughout the UK. The readmission rates are high, and there is significant correlation between mortality and PC case volume.

An estimator for the recombination rate from a continuously observed diffusion of haplotype frequencies.

Recombination is a fundamental evolutionary force, but it is difficult to quantify because the effect of a recombination event on patterns of variation in a sample of genetic data can be hard to discern. Estimators for the recombination rate, which are usually based on the idea of integrating over the unobserved possible evolutionary histories of a sample, can therefore be noisy. Here we consider a related question: how would an estimator behave if the evolutionary history actually was observed? This would offer an upper bound on the performance of estimators used in practice. In this paper we derive an expression for the maximum likelihood estimator for the recombination rate based on a continuously observed, multi-locus, Wright-Fisher diffusion of haplotype frequencies, complementing existing work for an estimator of selection. We show that, contrary to selection, the estimator has unusual properties because the observed information matrix can explode in finite time whereupon the recombination parameter is learned without error. We also show that the recombination estimator is robust to the presence of selection in the sense that incorporating selection into the model leaves the estimator unchanged. We study the properties of the estimator by simulation and show that its distribution can be quite sensitive to the underlying mutation rates.

Factors associated with injury among Maine logging workers.

INTRODUCTION: Despite dramatic improvements in safety, logging remains one of the most dangerous industries in the United States. The purpose of this study was to explore longitudinal injury trends among Maine logging workers. METHODS: Loggers participated in seven quarterly surveys, over the course of 18 months. Categorical and free text data related to traumatic and acute injury, musculoskeletal disorders (MSD), and chronic pain were exported from REDCap into SAS 9.4, Excel, and NVivo, for quantitative and qualitative analysis, respectively. Time to injury was modeled using two different approaches: (1) time to the occurrence of first injury modeled by proportional hazard regression and (2) an intensity model for injury frequency. Two research team members also analyzed qualitative data using a content analysis approach. RESULTS: During the study, 204 injuries were reported. Of the 154 participants, 93 (60.4%) reported musculoskeletal pain on at least one survey. The majority of injuries were traumatic, including fractures, sprains, and strains. Lack of health insurance was found to be related to increased risk of first injury [HR = 1.41, 95% CI = 0.97-2.04, p = 0.069]. Variables found to be related to injury intensity at the univariate level were: (1) a lack of health insurance [HR = 1.51, 95% CI = 1.04-2.20, p = 0.030], (2) age [HR for 10-year age increase;= 1.12, 95% CI = 0.99-1.27, p = 0.082], and (3) years employed in logging industry [HR for 10-year increase = 1.12, 95% CI = 0.99-1.26, p = 0.052]. Seeking medical attention for injury was not a priority for this cohort, and narratives revealed a trend for self-assessment. A variety of barriers, including finances, prevented loggers from seeking medical attention. DISCUSSION: We found that loggers still experience serious, and sometimes disabling, injuries associated with their work. It was unsurprising that many injuries were due to slips, trips, and falls, along with contact with logging equipment and trees/logs. The narratives revealed various obstacles preventing loggers from achieving optimal health. Examples included geographic distance from healthcare, lack of time to access care, and entrenched values that prioritized independence and traditional masculinity. Financial considerations were also consistently cited as a primary barrier to adequate care. CONCLUSION: There is a continued need to emphasize occupational health and safety in the logging industry. Implementation of relevant safety programs is key, but it is likely that the benefits of these will not be fully realized until a cultural shift takes place within this industry.

Factor structure and measurement invariance of the Mood and Feelings Questionnaire: a cross-cultural study among Thai and British adolescents.

The Mood and Feelings Questionnaire-child self-report (MFQ-C) is a widely used measure of child and adolescent depression. This study evaluated possible factor solutions and examined the measurement invariance of the MFQ-C as a prerequisite for its use in cross-cultural comparisons between Thai (N = 1272) and British samples (N = 1817) by using multigroup confirmatory factor analysis (MGCFA). The latent means of Thai and British samples were also examined. A five-factor structure of the MFQ-C was confirmed through confirmatory factor analysis. A partial scalar invariant model was supported, and thus latent means were compared, with British adolescents reporting significantly higher mean MFQ-C scores than Thai adolescents on four of the five factors (Vegetative Symptoms, Suicidality, Cognitive Symptoms, Agitated Distress). There was no difference for the Core Symptoms factor. The findings also suggest that the MFQ-C is a valid measure to assess depression in Thai and British adolescents and maybe useful in cross-cultural comparisons of adolescent depression.

KwARG: parsimonious reconstruction of ancestral recombination graphs with recurrent mutation.

MOTIVATION: The reconstruction of possible histories given a sample of genetic data in the presence of recombination and recurrent mutation is a challenging problem, but can provide key insights into the evolution of a population. We present KwARG, which implements a parsimony-based greedy heuristic algorithm for finding plausible genealogical histories (ancestral recombination graphs) that are minimal or near-minimal in the number of posited recombination and mutation events. RESULTS: Given an input dataset of aligned sequences, KwARG outputs a list of possible candidate solutions, each comprising a list of mutation and recombination events that could have generated the dataset; the relative proportion of recombinations and recurrent mutations in a solution can be controlled via specifying a set of 'cost' parameters. We demonstrate that the algorithm performs well when compared against existing methods. AVAILABILITY AND IMPLEMENTATION: The software is available at https://github.com/a-ignatieva/kwarg. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Structural validity of the Eating Disorder Examination-Questionnaire: A systematic review.

OBJECTIVE: The main aim was to perform a systematic literature review of studies investigating the factor structure of the Eating Disorder Examination-Questionnaire (EDE-Q), a widely used measure of eating pathology. Secondary aims were to summarize the quality of reporting of latent variable (factor) analyses in these studies and review support for different factor solutions. METHOD: Literature was identified through Scopus, Medline, PsycInfo, and ProQuest databases published up to February 23, 2022 and outreach via an international listserv. All studies published in English reporting factor analysis of the EDE-Q were included with few restrictions. Sixty studies including 63,389 participants met inclusion criteria. RESULTS: The originally proposed four-factor solution received little empirical support, although few alternative models have been robustly evaluated. Items assessing shape and weight concerns frequently coalesce in factor solutions, suggesting that these constructs are closely related. Investigations of brief versions of the EDE-Q have produced more consistent findings, suggesting that these measures, particularly a seven-item version, might be useful alternatives to the full version. Quality of studies was reasonable, with important methodological elements of factor analysis often reported. DISCUSSION: The findings are of relevance to practitioners and researchers, suggesting that the "original" factor structure of the EDE-Q should be reconsidered and that use of a seven-item version is to be encouraged. PUBLIC SIGNIFICANCE: Self-report questionnaires are widely used in the assessment of disordered eating. The current study found that there is little consensus about the structure of a common measure of eating psychopathology. There is more consistent support for a brief, seven-item, version assessing dietary restraint, body dissatisfaction, and overvaluation of weight and shape.

OBJETIVO: El objetivo principal fue realizar una revisión sistemática de la literatura de los estudios que investigan la estructura factorial del Cuestionario de Eating Disorders Examination (EDE-Q), una medida ampliamente utilizada en la patología alimentaria. Los objetivos secundarios fueron resumir la calidad del informe de los análisis de variables latentes (factores) en estos estudios y revisar el apoyo a diferentes soluciones factoriales. MÉTODO: La literatura se identificó a través de las bases de datos Scopus, Medline, PsycInfo y ProQuest publicadas hasta el 23 de febrero de 2022 y de divulgación a través de un servidor de listas internacional. Todos los estudios publicados en inglés que reportaron el análisis factorial de la EDE-Q se incluyeron con pocas restricciones. Sesenta estudios con 63,389 participantes cumplieron los criterios de inclusión. RESULTADOS: La solución de cuatro factores propuesta originalmente recibió poco apoyo empírico, aunque pocos modelos alternativos han sido evaluados sólidamente. Los elementos que evalúan las preocupaciones de peso y figura corporal con frecuencia se unen en soluciones factoriales, lo que sugiere que estos constructos están estrechamente relacionados. Las investigaciones de versiones breves del EDE-Q han producido conclusiones más consistentes, lo que sugiere que estas mediciones, en particular una versión de siete ítems, podrían ser alternativas útiles a la versión completa. La calidad de los estudios fue razonable, y a menudo se reportaron elementos metodológicos importantes del análisis factorial. DISCUSIÓN: Los hallazgos son relevantes para los clínicos e investigadores, lo que sugiere que la estructura factorial "original" del EDE-Q debe reconsiderarse y que se debe alentar el uso de una versión de siete ítems.

Impact of pet dog or cat exposure during childhood on mental illness during adolescence: a cohort study.

BACKGROUND: In our prior study of 643 children, ages 4-11 years, children with pet dogs had lower anxiety scores than children without pet dogs. This follow-up study examines whether exposure to pet dogs or cats during childhood reduces the risk of adolescent mental health (MH) disorders. METHODS: Using a retrospective cohort study design, we merged our prior study database with electronic medical record (EMR) data to create an analytic database. Common MH diagnoses (anxiety, depression, ADHD) occurring from the time of prior study enrollment to 10/27/21 were identified using ICD-9 and ICD-10 codes. We used proportional hazards regression to compare time to MH diagnoses, between youths with and without pets. From 4/1/20 to 10/27/21, parents and youth in the prior study were interviewed about the amount of time the youth was exposed to a pet and how attached s/he was to the pet. Exposure included having a pet dog at baseline, cumulative exposure to a pet dog or cat during follow-up, and level of pet attachment. The main outcomes were anxiety diagnosis, any MH diagnosis, and MH diagnosis associated with a psychotropic prescription. RESULTS: EMR review identified 571 youths with mean age of 14 years (range 11-19), 53% were male, 58% had a pet dog at baseline. During follow-up (mean of 7.8 years), 191 children received a MH diagnosis: 99 were diagnosed with anxiety (52%), 61 with ADHD (32%), 21 with depression (11%), 10 with combined MH diagnoses (5%). After adjusting for significant confounders, having a pet dog at baseline was associated with lower risk of any MH diagnosis (HR = 0.74, p = .04) but not for anxiety or MH diagnosis with a psychotropic prescription. Among the 241 (42%) youths contacted for follow-up, parent-reported cumulative exposure to pet dogs was borderline negatively associated with occurrence of any MH diagnosis (HR = 0.74, p = .06). Cumulative exposure to the most attached pet (dog or cat) was negatively associated with anxiety diagnosis (HR = 0.57, p = .006) and any MH diagnosis (HR = 0.64, p = .013). CONCLUSION: Cumulative exposure to a highly attached pet dog or cat is associated with reduced risk of adolescent MH disorders.

Percutaneous transcystic removal of gallbladder and common bile duct stones: a narrative review.

The incidence of gallstone-related complications is rising, thus leading to increases in waiting list times for elective laparoscopic cholecystectomy (LC). Percutaneous cholecystostomy (PC) provides immediate biliary drainage and may be used as an emergency option in a critically unwell patient as a bridge to surgery, or as the management option of a patient who is not fit for surgery. However, a significant number of these patients may be readmitted after PC with recurrent acute cholecystitis or pancreatitis, leading to significant morbidity and mortality. The aim of the present review was to analyze the available literature surrounding the use of the transcystic approach, including the extraction and balloon expulsion method, in the management of patients with gallbladder stones and/or common bile duct (CBD) stones. The full text of 18 articles were reviewed, of which four were included in this review. Results showed an overall success rate of CBD stone extraction in 118 of 139 patients (84.9%), gallbladder stone extraction in 97 of 114 (85.0%), and CBD stone expulsion in 27 of 29 (93.1%). Percutaneous CBD and gallbladder stone extraction may be a safe management option for elderly or co-morbid patients who are not appropriate for surgical intervention. However, the evidence base surrounding this is very limited; therefore, further research is required in order to evaluate this in more detail.

Full agonist opioid prescribing by primary care clinicians after buprenorphine training.

BACKGROUND: While primary care clinicians are being trained to use buprenorphine for the treatment of Opioid Use Disorder (OUD) in order to increase access to addiction treatment, it is not known what impact such training and subsequent experience treating patients with OUD has on full agonist opioid prescribing.Methods: This retrospective cohort study compares the full agonist opioid prescribing patterns of Drug Addiction Treatment Act (DATA)-waivered ("X-waivered") primary care clinicians to non-trained, non-waivered clinicians in a rural health network. X-waivered clinicians also received Project ECHO training and telementoring support for one year. Using prescriber data generated by an electronic medical record system, opioid prescribing and morphine milligram equivalents (MME) per day per patient were calculated. A between-group analysis was used to compare the study groups six months pre-versus post-training.Results: Although the mean number of full agonist opioid prescriptions per clinician and per 100 patient encounters decreased among all clinicians, there was no change in full agonist opioid prescribing MME. As expected, buprenorphine prescribing by X-waivered, trained clinicians increased significantly post-training.Conclusions: X-waivers plus Project ECHO support for the treatment of OUD using buprenorphine had no effect on full agonist opioid prescribing by primary care clinicians.

Project ECHO and primary care buprenorphine treatment for opioid use disorder: Implementation and clinical outcomes.

Background: Our rural health system sought to (1) increase the number of primary care clinicians waivered to prescribe buprenorphine for treatment of opioid use disorder (OUD) and (2) consequently increase the number of our patients receiving this treatment. Methods: We used the Project for Extension for Community Health Outcomes (ECHO) tele-education model as an implementation strategy. We examined the number of clinicians newly waivered, the number of patients treated with buprenorphine, the relationship between clinician engagement with ECHO training and rates of buprenorphine prescribing, and treatment retention at 180 days. Results: The number of clinicians with a waiver and number of patients treated increased during and after ECHO training. There was a moderate correlation between the number of ECHO sessions attended by a clinician and number of their buprenorphine prescriptions (r = 0.50, p = 0.01). The 180-day retention rate was 80.7%. Conclusions: Project ECHO was highly effective for increasing access to this evidence-based treatment. The high retention rate in this rural context indicates that most patients are increasing their likelihood of favorable outcomes.

Cost-of-illness for non-underweight binge-eating disorders.

PURPOSE: This study examined economic costs associated with untreated eating disorders (EDs) characterised by regular binge eating in the absence of low weight. Both direct and indirect costs were assessed, reporting a limited societal perspective of economic impact as some costs were not included. METHODS: One hundred and twenty six adults seeking treatment for recurrent binge eating were asked to report impairment associated with an ED. Costs were calculated using 2017 prices, including an examination of variables associated with costs. RESULTS: Estimated societal costs for the year preceding assessment were £3268.47 (€3758.54) per person. In multivariate analyses, no reliable baseline associates of cost were identified. CONCLUSION: The economic burden of EDs characterised by regular binge eating is significant, and underscores the need for efficacious and cost-effective treatments. Individuals with binge-eating disorders report work impairment and healthcare use that may cost the United Kingdom economy upwards of £3.5 billion (€4bn) per annum. Further studies should consider academic impairment and the economic impact of EDs on families. LEVEL OF EVIDENCE: III: evidence obtained from well-designed cohort or case-control analytic studies.

Sodium channel ß1 subunits are post-translationally modified by tyrosine phosphorylation, S-palmitoylation, and regulated intramembrane proteolysis.

Voltage-gated sodium channel (VGSC) ß1 subunits are multifunctional proteins that modulate the biophysical properties and cell-surface localization of VGSC α subunits and participate in cell-cell and cell-matrix adhesion, all with important implications for intracellular signal transduction, cell migration, and differentiation. Human loss-of-function variants in SCN1B, the gene encoding the VGSC ß1 subunits, are linked to severe diseases with high risk for sudden death, including epileptic encephalopathy and cardiac arrhythmia. We showed previously that ß1 subunits are post-translationally modified by tyrosine phosphorylation. We also showed that ß1 subunits undergo regulated intramembrane proteolysis via the activity of ß-secretase 1 and γ-secretase, resulting in the generation of a soluble intracellular domain, ß1-ICD, which modulates transcription. Here, we report that ß1 subunits are phosphorylated by FYN kinase. Moreover, we show that ß1 subunits are S-palmitoylated. Substitution of a single residue in ß1, Cys-162, to alanine prevented palmitoylation, reduced the level of ß1 polypeptides at the plasma membrane, and reduced the extent of ß1-regulated intramembrane proteolysis, suggesting that the plasma membrane is the site of ß1 proteolytic processing. Treatment with the clathrin-mediated endocytosis inhibitor, Dyngo-4a, re-stored the plasma membrane association of ß1-p.C162A to WT levels. Despite these observations, palmitoylation-null ß1-p.C162A modulated sodium current and sorted to detergent-resistant membrane fractions normally. This is the first demonstration of S-palmitoylation of a VGSC ß subunit, establishing precedence for this post-translational modification as a regulatory mechanism in this protein family.

Clinical and cost-effectiveness of two ways of delivering guided self-help for people with an eating disorder: A multi-arm randomized controlled trial.

OBJECTIVE: Increasing the availability and accessibility of evidence-based treatments for eating disorders is an important goal. This study investigated the effectiveness and cost-effectiveness of guided self-help via face-to-face meetings (fGSH) and a more scalable method, providing support via email (eGSH). METHOD: A pragmatic, randomized controlled trial was conducted at three sites. Adults with binge-eating disorders were randomized to fGSH, eGSH, or a waiting list condition, each lasting 12 weeks. The primary outcome variable for clinical effectiveness was overall severity of eating psychopathology and, for cost-effectiveness, binge-free days, with explorative analyses using symptom abstinence. Costs were estimated from both a partial societal and healthcare provider perspective. RESULTS: Sixty participants were included in each condition. Both forms of GSH were superior to the control condition in reducing eating psychopathology (IRR = -1.32 [95% CI -1.77, -0.87], p < .0001; IRR = -1.62 [95% CI -2.25, -1.00], p < .0001) and binge eating. Attrition was higher in eGSH. Probabilities that fGSH and eGSH were cost-effective compared with WL were 93% (99%) and 51% (79%), respectively, for a willingness to pay of £100 (£150) per additional binge-free day. DISCUSSION: Both forms of GSH were associated with clinical improvement and were likely to be cost-effective compared with a waiting list condition. Provision of support via email is likely to be more convenient for many patients although the risk of non-completion is greater.

The challenge of environmental sustainability in radiology training and potential solutions.

The environmental impact of training has been poorly recognised for many years. With the emergence of high-profile climate activists and a wider appreciation of the need for sustainable healthcare, training within radiology can no longer be excused from its responsibility to consider the environment in its actions. In this paper, we aim to evaluate the environmental impact of the travel undertaken by trainees within the Peninsula training programme, with the aim of developing practices and providing suggestions (evidence-based where possible) on how to improve the impact on the environment of trainee travel. We envisage that many of the lessons and suggestions may be transferrable to other training schemes in the UK and further afield. During the early months of 2020, in addition to the environmental crisis, COVID-19 escalated to a pandemic resulting in the alteration of working practices across the UK (and the rest of the world). This led to many environmentally beneficial working practices being adopted in Radiology in the South West Peninsula Deanery, and throughout this paper we have evaluated these changes and used our collective experience of these to inform our suggestions on how to improve the environmental sustainability of Medical and Radiological training.