Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock-in mice.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.

An Analysis of Healthcare Usage & Place of Death in England for All Adults Who Died in 2021/22.

OBJECTIVE: We wanted to examine the healthcare use and non-elective activity in the UK population of expected deaths over an 1-year period to highlight and examine the reasons for variation. We did this to identify areas to focus interventions or resources on to reduce unnecessary emergency care use at the end of life. METHODS AND ANALYSIS: We assembled a data set of approximately 400 000 adults who died in England in the financial year 2021/22 (April 2021-March 2022). Any adults classified as a 'sudden death' were excluded. We used available data to ensure outcome measures were relevant used expert consensus to agree what to examine. We recorded place of death and examined urgent care in terms of admissions in the last year and 90 days of life. We also used recorded hospital care days as elective and non-elective usage. RESULTS: There were over 400 000 decedents included in our regression models. Close to half died in hospital (44%). Three-quarters (77%) had at least one day of unplanned hospital care in the 90 days before they died, and half (56%) had at least one day of planned hospital care. CONCLUSION: Reliance on urgent care for those approaching end-of-life may indicate poor care planning and integration of services. A relatively modest increase in the amount of community care a person receives at end-of-life can substantially reduce the likelihood of dying in hospital. Those with a cancer cause of death are far less likely to die in hospital.

Advancing Point-of-Care Applications with Droplet Microfluidics: From Single-Cell to Multicellular Analysis.

Recent advances in single-cell and multicellular microfluidics technology have provided powerful tools for studying cancer biology and immunology. The ability to create controlled microenvironments, perform high-throughput screenings, and monitor cellular interactions at the single-cell level has significantly advanced our understanding of tumor biology and immune responses. We discuss cutting-edge multicellular and single-cell microfluidic technologies and methodologies utilized to investigate cancer-immune cell interactions and assess the effectiveness of immunotherapies. We explore the advantages and limitations of the wide range of 3D spheroid and single-cell microfluidic models recently developed, highlighting the various approaches in device generation and applications in immunotherapy screening for potential opportunities for point-of-care approaches.

Characterizing influence of rCHOP treatment on diffuse large B-cell lymphoma microenvironment through in vitro microfluidic spheroid model.

For over two decades, Rituximab and CHOP combination treatment (rCHOP) has remained the standard treatment approach for diffuse large B-cell lymphoma (DLBCL). Despite numerous clinical trials exploring treatment alternatives, few options have shown any promise at further improving patient survival and recovery rates. A wave of new therapeutic approaches have recently been in development with the rise of immunotherapy for cancer, however, the cost of clinical trials is prohibitive of testing all promising approaches. Improved methods of early drug screening are essential for expediting the development of the therapeutic approaches most likely to help patients. Microfluidic devices provide a powerful tool for drug testing with enhanced biological relevance, along with multi-parameter data outputs. Here, we describe a hydrogel spheroid-based microfluidic model for screening lymphoma treatments. We utilized primary patient DLBCL cells in combination with NK cells and rCHOP treatment to determine the biological relevance of this approach. We observed cellular viability in response to treatment, rheological properties, and cell surface marker expression levels correlated well with expected in vivo characteristics. In addition, we explored secretory and transcriptomic changes in response to treatment. Our results showed complex changes in phenotype and transcriptomic response to treatment stimuli, including numerous metabolic and immunogenic changes. These findings support this model as an optimal platform for the comparative screening of novel treatments.

Research Gaps in Pediatric Heart Failure: Defining the Gaps and Then Closing Them Over the Next Decade.

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.

Salmonella Vaccine Study in Oxford (SALVO) trial: protocol for an observer-participant blind randomised placebo-controlled trial of the iNTS-GMMA vaccine within a European cohort.

INTRODUCTION: Invasive non-typhoidal Salmonellosis (iNTS) is mainly caused by Salmonella enterica serovars Typhimurium and Enteritidis and is estimated to result in 77 500 deaths per year, disproportionately affecting children under 5 years of age in sub-Saharan Africa. Invasive non-typhoidal Salmonellae serovars are increasingly acquiring resistance to first-line antibiotics, thus an effective vaccine would be a valuable tool in reducing morbidity and mortality from infection. While NTS livestock vaccines are in wide use, no licensed vaccines exist for use in humans. Here, a first-in-human study of a novel vaccine (iNTS-GMMA) containing S. Typhimurium and S. Enteritidis Generalised Modules for Membrane Antigens (GMMA) outer membrane vesicles is presented. METHOD AND ANALYSIS: The Salmonella Vaccine Study in Oxford is a randomised placebo-controlled participant-observer blind phase I study of the iNTS-GMMA vaccine. Healthy adult volunteers will be randomised to receive three intramuscular injections of the iNTS-GMMA vaccine, containing equal quantities of S. Typhimurium and S. Enteritidis GMMA particles adsorbed on Alhydrogel, or an Alhydrogel placebo at 0, 2 and 6 months. Participants will be sequentially enrolled into three groups: group 1, 1:1 randomisation to low dose iNTS-GMMA vaccine or placebo; group 2, 1:1 randomisation to full dose iNTS-GMMA vaccine or placebo; group 3, 2:1 randomisation to full dose or lower dose (dependant on DSMC reviews of groups 1 and 2) iNTS-GMMA vaccine or placebo.The primary objective is safety and tolerability of the vaccine. The secondary objective is immunogenicity as measured by O-antigen based ELISA. Further exploratory objectives will characterise the expanded human immune profile. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the South Central-Oxford A Research Ethics Committee (Ethics REF:22/SC/0059). Appropriate documentation and regulatory approvals have been acquired. Results will be disseminated via peer-reviewed articles and conferences. TRIAL REGISTRATION NUMBER: EudraCT Number: 2020-000510-14.

Evaluation of an experiment to increase availability of healthier snack foods in vending machines situated within English sports facilities.

OBJECTIVE: To evaluate the impact of increased availability of healthier options on purchasing of different types of vending snack products sold in English leisure (sports) centres. DESIGN: An evaluation of an intervention using pre-post methods and interrupted time series analysis. Products within the vending machines were altered over three phases to increase the availability of healthier options, using agreed nutrition criteria - Government Buying Standards for Food and Catering Services (GBSF) for England - as a guide, as well as product availability. The primary outcome was the change in mean weekly purchased energy between the first and third phase. Secondary outcomes included changes by phase and by week in weekly number of purchases, fats, sugars and salt for all products combined and by individual product categories. SETTING: Fifteen sports centres in the city of Leeds, West Yorkshire, UK. PARTICIPANTS: Snack products sold in eighteen vending machines. RESULTS: Energy purchased reduced from baseline to phase 2, for all product categories combined, by 47·25 MJ (95 % CI (-61·22, -33·27)) per machine and by 279 kJ, (95 % CI (-325, -266)) per product unit. There were reductions in most nutrients purchased in all individual product categories except chocolate confectionery. Nutrients per product unit decreased for all product categories except saturated fat in chocolate confectionery. Minimal underlying trends in the baseline phase were identified, indicating changes in outcomes were likely to be due to the intervention. CONCLUSIONS: Introducing standards to increase availability of healthier snack products in vending machines is feasible without substantially affecting sales.

Optimizing educational methods for the low FODMAP diet in disorders of gut-brain interaction: A feasibility randomized controlled trial.

BACKGROUND: A diet low in fermentable oligo-saccharides, di-saccharides, mono-saccharides and polyols (low FODMAP diet) is complex and clinical effectiveness is achieved with dietitian-led education, although dietitian availability in clinical practice varies. This study aimed to assess the feasibility of undertaking a trial to investigate the clinical and cost-effectiveness of different education delivery methods of the low FODMAP diet in patients with disorders of gut-brain interaction (DGBI). METHODS: In this feasibility randomized controlled trial, patients with DGBI requiring the low FODMAP diet were randomized to receive one of the following education delivery methods: booklet, app, or dietitian. Recruitment and retention rates, acceptability, symptoms, stool output, quality of life, and dietary intake were assessed. KEY RESULTS: Fifty-one patients were randomized with a recruitment rate of 2.4 patients/month and retention of 48 of 51 (94%). Nobody in the booklet group strongly agreed that this education delivery method enabled them to self-manage symptoms without further support, compared to 7 of 14 (50%) in the dietitian group (p = 0.013). More patients reported adequate relief of symptoms in the dietitian group (12, 80%) compared with the booklet group (7, 39%; p = 0.026), but not when compared to the app group (10, 63%, p > 0.05). There was a greater decrease in the IBS-SSS score in the dietitian group (mean -153, SD 90) compared with the booklet group (mean -90, SD 56; p = 0.043), but not when compared with the app group (mean -120, SD 62; p = 0.595). CONCLUSIONS & INFERENCES: Booklets were the least acceptable education delivery methods. Dietitian-led consultations led to high levels of clinical effectiveness, followed by the app, while the dietitian was superior to booklets alone. However, an adequately powered clinical trial is needed to confirm clinical effectiveness of these education delivery methods.

The manifold costs of being a non-native English speaker in science.

The use of English as the common language of science represents a major impediment to maximising the contribution of non-native English speakers to science. Yet few studies have quantified the consequences of language barriers on the career development of researchers who are non-native English speakers. By surveying 908 researchers in environmental sciences, this study estimates and compares the amount of effort required to conduct scientific activities in English between researchers from different countries and, thus, different linguistic and economic backgrounds. Our survey demonstrates that non-native English speakers, especially early in their careers, spend more effort than native English speakers in conducting scientific activities, from reading and writing papers and preparing presentations in English, to disseminating research in multiple languages. Language barriers can also cause them not to attend, or give oral presentations at, international conferences conducted in English. We urge scientific communities to recognise and tackle these disadvantages to release the untapped potential of non-native English speakers in science. This study also proposes potential solutions that can be implemented today by individuals, institutions, journals, funders, and conferences. Please see the Supporting information files (S2-S6 Text) for Alternative Language Abstracts and Figs 5 and 6.