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Introduction: Immune checkpoint inhibitors are the mainstay of treatment in patients with unresectable or metastatic melanoma. Combination immunotherapy with ipilimumab and nivolumab has shown to improve survival outcomes as compared to single agent immunotherapy in these patients. Neurological immune-related adverse effects (irAEs) are uncommon and cranial nerve palsies are seen even more infrequently., Case Presentation: A 66-year-old woman with a background of metastatic, unresectable melanoma with supraclavicular and axillary lymph nodal involvement presented with a headache, photophobia and diplopia 3 weeks after her first cycle of ipilimumab and nivolumab. She was subsequently diagnosed with a left-sided cranial nerve VI palsy and treated with high dose oral steroids and steroid eye drops, with complete resolution of symptoms. She also experienced Grade 3 dermatitis requiring topical steroids, Grade 2 hypothyroidism and vitiligo. She continues to have an excellent clinical and radiological response, despite further immunotherapy being suspended., Conclusion: This is the first reported UK case of immunotherapy-induced isolated cranial nerve VI palsy. Multiple irAEs are more common with combination immunotherapy and its occurrence is associated with more favourable outcomes in melanoma. Immunotherapy continues to revolutionise oncological care, but clinicians must be cognizant of unpredictable irAEs, which may require prompt assessment and intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Low, El-Shakankery, Brown, Christie, McCormack and Stares.)

Background: Physical activity plays an important role in the management of blood glucose levels. However, compelling evidence exists only for aerobic and resistance training. In this review, we aimed to identify the potential effects of stretching exercises on blood glucose levels., Methods: A systematic literature search was performed using the following databases: Scopus, NLM PubMed, and Web of Science. Studies regarding the effects of stretching exercise in humans on blood glucose or any related variable were included. Further inclusion criteria were: (1) original articles (published from database inception to October 2022), (2) applying stretching as a unique exercise modality, (3) having either longitudinal or acute interventions, (4) including healthy and pathological populations, and (5) having within each study a pre- and post-intervention measure. Quality assessment of the studies was conducted using the Downs and Black checklist., Results: A total of 13 articles were included. The quality assessment revealed an overall moderate quality of the included records. Ten articles included patients with type 2 diabetes (T2D), whereas the remaining three included at-risk populations. A total of 731 people with a mean age of 56.7 ± 6.1 years old were analysed. Fasting blood glucose, 2 h post-oral glucose uptake, post-stretching intervention blood glucose levels, and HbA1c were identified as variables related to blood glucose within the studies. After the stretching interventions, a significant reduction was observed in either blood glucose (ES = - 0.79; p = 0.0174) or HbA1c (ES = - 1.11; p =  < 0.0001). Meta-analytic results highlighted greater effects in T2D patients (ES = - 1.15; p = 0.02) and for studies applying stretching as an exercise intervention (ES = - 1.27; p = 0.006) rather than considering stretching as a control exercise modality., Conclusion: The results of this systematic review highlight the potential of stretching exercises to reduce blood glucose levels. In particular, if stretching is applied as a specific form of exercise intervention in patients with T2D greater effects are observed. However, further studies with more solid research designs are required, therefore, caution is needed before prescribing stretching as an exercise intervention for glycaemic management., (© 2024. The Author(s).)

Background: Chronic kidney disease (CKD) affects 10% of the global population costing over a hundred billion dollars per annum and leading to increased risk of cardiovascular disease. Many patients with CKD require regular haemodialyses. Synthetic arteriovenous grafts (AVG) are increasingly used to provide rapid vascular connection for dialysis. Initially, they have excellent patency rates but are critically limited by neointimal hyperplasia at the venous anastomosis, which drives subsequent thrombosis, graft failure and death., Methods: Here, we describe a system in which electrical impedance spectroscopy sensors are incorporated circumferentially into the wall of a synthetic arteriovenous graft. This is combined with an implantable radiotelemetry system for data transmission outside the patient. The system was tested using monolayers of endothelial and smooth muscle cells as well as swine blood and clots with explanted human carotid artery plaques. Sensor testing was then performed in vitro and the device was implanted in vivo in female swine., Results: The device can wirelessly report the accumulation of biological material, both cells and blood. Differences are also detected when comparing controls with pathological atheroma. In swine differences between blockage formation in a graft were remotely obtained and wireless reported., Conclusions: Combining electrical impedance spectroscopy and an implantable radiotelemetry system enables graft surveillance. This has the potential to be used for early detection of venous stenosis and blood clot formation in real-time in vivo. In principle, the concept could apply to other cardiovascular diseases and vascular implantable devices., (© 2024. The Author(s).)

Background: The aim of this manuscript is to investigate if stretching exercise administration order may influence outcomes pertinent to range of movement (ROM)., Methods: A total sample of 108 participants was randomized into five groups. Eight sets of unilateral static stretching (SS) of 30s duration each with a 30s rest were administered to the right leg. One group underwent SS of the knee extensors (KE), another to the knee flexors (KF), another first to the KE and then to the KF, another first to the KF and then to the KE while the last group was used as control (CG). Each group was assessed for ROM of both lower limbs for either the KE and KF motion (passive hip extention [PHE] and passive straight leg raise [PSLR], respectively). Measures were assessed before (T0), immediately after (T1), and 15 minutes after the intervention (T2)., Results: No differences were observed for time (T0 vs. T1 vs. T2) for all measures in the CG for both limbs. Time-x-group interactions were observed only in the intervention limb (P<0.0007 and 0.004, ES 0.73 and 0.55, for KE and KF, respectively). Within the intervention limb, a significant increase in the PHE was observed from T0 to T1 only in the KE and KF/KE groups. For measures of the PSLR, a significant increase was observed from T0 to T1 only in the KF and KE/KF groups. No differences neither for time or group were observed in the control limb., Conclusions: Our results highlight that exercise administration order has an effect on ROM outcomes. Measures of ROM significantly increase only for the last stretched muscle in each intervention group. No crossover effect was observed in the contralateral limb.

Background: Teenagers and young adults (TYAs; ages 16-24 in the United Kingdom) with cancer have specific needs and experience worse physiological and psychological outcomes compared with pediatric and adult cancer. In the United Kingdom, psychosocial screening is a mandatory part of TYA care. However, there is a lack of age-appropriate and acceptable psychosocial measures for this population. This review aimed to (1) identify the psychosocial measures utilized and available for TYA cancer and (2) describe their psychometric properties. Methods: We searched five databases for studies meeting the eligibility criteria. We extracted data relevant to the review and assessed study quality using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines and the Hughes Quality Assessment Tool developed by the research team. Results: We identified 40 studies that included 105 psychosocial measures. The main constructs measured were distress, depression, and anxiety. The TYA age range varied widely. Reporting of psychosocial measures and their psychometric properties was poor, and most measures were not validated or developed for TYA cancer populations. Discussion: There is an urgent need for psychosocial measures that are designed for and validated in TYA cancer populations. Appropriate measures would enable clinicians to reliably identify and effectively support the psychosocial challenges faced by TYAs. The use of validated psychosocial measures enables earlier detection of difficulties, fosters patient-centered care, and is cost-effective since resources can be allocated to those most in need.

Background: Recent technological advancements offer new ways to monitor and manage epilepsy. The adoption of these devices in routine clinical practice will strongly depend on patient acceptability and usability, with their perspectives being crucial. Previous studies provided feedback from patients, but few explored the experience of them using independently multiple devices independently at home., Purpose: The study, assessed through a mixed methods design, the direct experiences of people with epilepsy independently using a non-invasive monitoring system (EEG@HOME) for an extended duration of 6 months, at home. We aimed to investigate factors affecting engagement, gather qualitative insights, and provide recommendations for future home epilepsy monitoring systems., Materials and Methods: Adults with epilepsy independently were trained to use a wearable dry EEG system, a wrist-worn device, and a smartphone app for seizure tracking and behaviour monitoring for 6 months at home. Monthly acceptability questionnaires (PSSUQ, SUS) and semi-structured interviews were conducted to explore participant experience. Adherence with the procedure, acceptability scores and systematic thematic analysis of the interviews, focusing on the experience with the procedure, motivation and benefits and opinion about the procedure were assessed., Results: Twelve people with epilepsy took part into the study for an average of 193.8 days (range 61 to 312) with a likelihood of using the system at six months of 83 %. The e-diary and the smartwatch were highly acceptable and preferred to a wearable EEG system (PSSUQ score of 1.9, 1.9, 2.4). Participants showed an acceptable level of adherence with all solutions (Average usage of 63 %, 66 %, 92 %) reporting more difficulties using the EEG twice a day and remembering to complete the daily behavioural questionnaires. Clear information and training, continuous remote support, perceived direct and indirect benefits and the possibility to have a flexible, tailored to daily routine monitoring were defined as key factors to ensure compliance with long-term monitoring systems., Conclusions: EEG@HOME study demonstrated people with epilepsy' interest and ability in active health monitoring using new technologies. Remote training and support enable independent home use of new non-invasive technologies, but to ensure long term acceptability and usability systems will require to be integrated into patients' routines, include healthcare providers, and offer continuous support and personalized feedback., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EN is an employee of Seer Medical and MS is the CEO of ANT Neuro GmbH and ANT Neuro UK Ltd. P.F.V. has received consultancy and travel fees from UNEEG Medical., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Building health services and workforce that are both well supported and fit for purpose is a key consideration for improving health outcomes in rural populations. Achieving this requires an understanding of the roles and practice characteristic of each professional group, including allied health professionals. This study explores what it means to be an allied health professional practicing in rural Aotearoa New Zealand., Design: A qualitative study design was used, involving individual semi-structured interviews with 13 rural allied health professionals in the Otago and Northland regions. The interviews explored participants journey into rural practice, their experiences working rurally, and their views on rural practice., Findings: Four main themes were derived: Identity; Connectedness; Expectations; and Providing Care., Discussion: Proud of being rural, these allied health professionals are immersed within their community, intertwining their professional and personal identities. The unique nature of this dual identity while empowering for some, can also isolate rural allied health professionals from their professional bodies and urban peers. This leads to a sense of vulnerability and feeling undervalued and invisible. In response, rural allied health professionals choose to form strong connections to their local interprofessional team and their community. The connections they forge, and the breadth of their skills cumulate to enable allied health professionals to provide dynamic and responsive health services for their rural communities., Conclusion: This study provides the first insight into experiences and perspectives of allied health professionals within rural Aotearoa New Zealand. Despite the challenges, a sense of pride is associated with practicing rurally for allied health professionals., (© 2023 The Authors. Australian Journal of Rural Health published by John Wiley & Sons Australia, Ltd on behalf of National Rural Health Alliance Ltd.)

Significance: Glioblastoma (GBM) is a rare but deadly form of brain tumor with a low median survival rate of 14.6 months, due to its resistance to treatment. An independent simulation of the INtraoperative photoDYnamic therapy for GliOblastoma (INDYGO) trial, a clinical trial aiming to treat the GBM resection cavity with photodynamic therapy (PDT) via a laser coupled balloon device, is demonstrated., Aim: To develop a framework providing increased understanding for the PDT treatment, its parameters, and their impact on the clinical outcome., Approach: We use Monte Carlo radiative transport techniques within a computational brain model containing a GBM to simulate light path and PDT effects. Treatment parameters (laser power, photosensitizer concentration, and irradiation time) are considered, as well as PDT's impact on brain tissue temperature., Results: The simulation suggests that 39% of post-resection GBM cells are killed at the end of treatment when using the standard INDYGO trial protocol (light fluence = 200    J / cm 2 at balloon wall) and assuming an initial photosensitizer concentration of 5    μ M . Increases in treatment time and light power (light fluence = 400    J / cm 2 at balloon wall) result in further cell kill but increase brain cell temperature, which potentially affects treatment safety. Increasing the p hotosensitizer concentration produces the most significant increase in cell kill, with 61% of GBM cells killed when doubling concentration to 10    μ M and keeping the treatment time and power the same. According to these simulations, the standard trial protocol is reasonably well optimized with improvements in cell kill difficult to achieve without potentially dangerous increases in temperature. To improve treatment outcome, focus should be placed on improving the photosensitizer., Conclusions: With further development and optimization, the simulation could have potential clinical benefit and be used to help plan and optimize intraoperative PDT treatment for GBM., (© 2024 The Authors.)

This study aimed to examine the association of prior mental health diagnoses with the onset of Post-COVID-19 condition (PCC). We conducted a retrospective comparative cohort study and secondary analysis of routinely collected claims data from participants in statutory health insurance in Bavaria, Germany, from January 2015 to June 2022. Study participants were 619,560 patients with confirmed COVID-19, 42,969 with other respiratory tract infection (ORI), and 438,023 controls. Using diagnoses coded according to the German modification of the ICD-10, the associations between prior mental health diagnoses and a PCC diagnosis (primary outcome) or associated symptoms (secondary outcomes) were estimated using multiple Cox proportional hazards regression models. Mental disorders (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.30-1.42), anxiety (HR 1.14, 95% CI 1.07-1.20), depression (HR 1.25, 95% CI 1.19-1.30) and somatoform disorders (HR 1.30, 95% CI 1.24-1.36) were associated with higher risks for PCC. Mental disorders were associated with the same or even greater risk for a diagnosis of malaise and fatigue in the control cohort (HR 1.71, 95% CI 1.52-1.93) and ORI cohort (HR 1.43, 95% CI 1.20-1.72), than in the COVID-19 cohort (HR 1.43, 95% CI 1.35-1.51). In summary, prior mental comorbidity was associated with an increased risk of PCC and its associated symptoms in all cohorts, not specifically in COVID-19 patients., (© 2024. The Author(s).)

N6-methyladenosine (m6A) is the most abundant internal eukaryotic mRNA modification, and is involved in the regulation of various biological processes. Direct Nanopore sequencing of native RNA (dRNA-seq) emerged as a leading approach for its identification. Several software were published for m6A detection and there is a strong need for independent studies benchmarking their performance on data from different species, and against various reference datasets. Moreover, a computational workflow is needed to streamline the execution of tools whose installation and execution remains complicated. We developed NanOlympicsMod, a Nextflow pipeline exploiting containerized technology for comparing 14 tools for m6A detection on dRNA-seq data. NanOlympicsMod was tested on dRNA-seq data generated from in vitro (un)modified synthetic oligos. The m6A hits returned by each tool were compared to the m6A position known by design of the oligos. In addition, NanOlympicsMod was used on dRNA-seq datasets from wild-type and m6A-depleted yeast, mouse and human, and each tool's hits were compared to reference m6A sets generated by leading orthogonal methods. The performance of the tools markedly differed across datasets, and methods adopting different approaches showed different preferences in terms of precision and recall. Changing the stringency cut-offs allowed for tuning the precision-recall trade-off towards user preferences. Finally, we determined that precision and recall of tools are markedly influenced by sequencing depth, and that additional sequencing would likely reveal additional m6A sites. Thanks to the possibility of including novel tools, NanOlympicsMod will streamline the benchmarking of m6A detection tools on dRNA-seq data, improving future RNA modification characterization., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Multiparametric remote measurement technologies (RMTs), which comprise smartphones and wearable devices, have the potential to revolutionize understanding of the etiology and trajectory of major depressive disorder (MDD). Engagement with RMTs in MDD research is of the utmost importance for the validity of predictive analytical methods and long-term use and can be conceptualized as both objective engagement (data availability) and subjective engagement (system usability and experiential factors). Positioning the design of user interfaces within the theoretical framework of the Behavior Change Wheel can help maximize effectiveness. In-app components containing information from credible sources, visual feedback, and access to support provide an opportunity to promote engagement with RMTs while minimizing team resources. Randomized controlled trials are the gold standard in quantifying the effects of in-app components on engagement with RMTs in patients with MDD., Objective: This study aims to evaluate whether a multiparametric RMT system with theoretically informed notifications, visual progress tracking, and access to research team contact details could promote engagement with remote symptom tracking over and above the system as usual. We hypothesized that participants using the adapted app (intervention group) would have higher engagement in symptom monitoring, as measured by objective and subjective engagement., Methods: A 2-arm, parallel-group randomized controlled trial (participant-blinded) with 1:1 randomization was conducted with 100 participants with MDD over 12 weeks. Participants in both arms used the RADAR-base system, comprising a smartphone app for weekly symptom assessments and a wearable Fitbit device for continuous passive tracking. Participants in the intervention arm (n=50, 50%) also had access to additional in-app components. The primary outcome was objective engagement, measured as the percentage of weekly questionnaires completed during follow-up. The secondary outcomes measured subjective engagement (system engagement, system usability, and emotional self-awareness)., Results: The levels of completion of the Patient Health Questionnaire-8 (PHQ-8) were similar between the control (67/97, 69%) and intervention (66/97, 68%) arms (P value for the difference between the arms=.83, 95% CI -9.32 to 11.65). The intervention group participants reported slightly higher user engagement (1.93, 95% CI -1.91 to 5.78), emotional self-awareness (1.13, 95% CI -2.93 to 5.19), and system usability (2.29, 95% CI -5.93 to 10.52) scores than the control group participants at follow-up; however, all CIs were wide and included 0. Process evaluation suggested that participants saw the in-app components as helpful in increasing task completion., Conclusions: The adapted system did not increase objective or subjective engagement in remote symptom tracking in our research cohort. This study provides an important foundation for understanding engagement with RMTs for research and the methodologies by which this work can be replicated in both community and clinical settings., Trial Registration: ClinicalTrials.gov NCT04972474; https://clinicaltrials.gov/ct2/show/NCT04972474., International Registered Report Identifier (irrid): RR2-10.2196/32653., (©Katie M White, Ewan Carr, Daniel Leightley, Faith Matcham, Pauline Conde, Yatharth Ranjan, Sara Simblett, Erin Dawe-Lane, Laura Williams, Claire Henderson, Matthew Hotopf. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 19.01.2024.)

Competing Interests: TH and KAH are supported by a Wellcome Trust Fellowship (203919/Z/16/Z). MDP is supported by a UK FCDO grant, OJEU reference number: 2018/S 196-44348. ET is supported by an institutional grant from UK aid: LIGHT consortium. No authors have any other potential or actual competing interests, financial or otherwise.

Introduction: The objectives of the present study were twofold: first, to identify the specific relative load at which the concentric motion transforms into a purely propulsive action among women, and second, to compare the load-velocity relationships between men and women during the bench press throw. Methods: Fourteen men and fourteen women participated in a test where they progressively increased the load until reaching their one-repetition maximum (1RM) in the bench press exercise. Linear regression models were employed to elucidate the relationships between load and velocity, as well as load and the propulsive phase (% of total concentric time). Additionally, ANCOVA was utilized to compare the linear regression models between men and women. Results: The results revealed strong and linear associations between load and mean propulsive velocity (MPV) for both men and women, as well as between load and the propulsive phase. Notably, there were significant differences in MPV and the propulsive phase concerning load between men and women. Women transitioned into a fully propulsive concentric phase at approximately 80% of their 1RM, while men achieved this entirely propulsive phase at around 85% of their 1RM. Furthermore, women exhibited reduced velocities when handling lighter relative loads compared to men. Conversely, women demonstrated higher velocities when dealing with loads exceeding 85% of their 1RM in contrast to their male counterparts. Discussion: These findings hold notable implications for prescribing bench press throw loads for women, which should differ from those recommended for men. Further studies are necessary to validate the efficacy of the proposed load recommendations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Izadi, Pillitteri, Thomas, Battaglia, Bianco and Bellafiore.)

The AlphaFold Database Protein Structure Database (AlphaFold DB, https://alphafold.ebi.ac.uk) has significantly impacted structural biology by amassing over 214 million predicted protein structures, expanding from the initial 300k structures released in 2021. Enabled by the groundbreaking AlphaFold2 artificial intelligence (AI) system, the predictions archived in AlphaFold DB have been integrated into primary data resources such as PDB, UniProt, Ensembl, InterPro and MobiDB. Our manuscript details subsequent enhancements in data archiving, covering successive releases encompassing model organisms, global health proteomes, Swiss-Prot integration, and a host of curated protein datasets. We detail the data access mechanisms of AlphaFold DB, from direct file access via FTP to advanced queries using Google Cloud Public Datasets and the programmatic access endpoints of the database. We also discuss the improvements and services added since its initial release, including enhancements to the Predicted Aligned Error viewer, customisation options for the 3D viewer, and improvements in the search engine of AlphaFold DB., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The Spillover Interface Project aims at assessing the encounter of wildlife, domestic animals, and humans along a landscape gradient from a protected area to a residential community, through areas of reforestation and agricultural land. Here, we present the protocols of the project that combine virus screening in humans, bats, rodents and dogs with camera trapping, land-use characterization, and network analyses. The project is taking place in the sub-district of Saen Thong (Nan Province, Thailand) in collaboration with local communities, the District Public Health Office, and Nanthaburi National Park. To formulate a predictive hypothesis for the Spillover Interface Project, we assess the wildlife diversity and their viral diversity that could be observed in Saen Thong through a data science analysis approach. Potential mammalian species are estimated using data from the International Union for Conservation of Nature (IUCN) and their associated viral diversity from a published open database. A network analysis approach is used to represent and quantify the transmission of the potential viruses hosted by the mammals present in Saen Thong, according to the IUCN. A total of 57 viruses are expected to be found and shared between 43 host species, including the domestic dog and the human species. By following the protocols presented here, the Spillover Interface Project will collect the data and samples needed to test this data-driven prediction., Competing Interests: The authors declare no competing interest., (Copyright: © 2024 Thinphovong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Comprehensive health data interoperability is recognized as an essential element of high-functioning and accountable health service. Canada is lagging in health data interoperability compared to international comparators, and lacks a comprehensive approach to human factor interoperability, defined as system-level relationships that impact the capacity of health sector stakeholders to adopt harmonized health data standards and technology. Without addressing these system-level relationships, the adoption of harmonized health data standards and technology will be obstructed and Canadians will be underserved. The proposed health data interoperability framework articulates the factors that Canada needs to address to optimize health data design to support quality health programs and services., (Copyright © 2024 Longwoods Publishing.)

Background: BRAF+MEK inhibitors extend life expectancy of patients with BRAF V600 mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen., Methods: Patients with BRAF V600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAF V600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection threshold., Results: 79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95 %CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95 %CI 0.87-3.28, p = 0.121), ORR 57 % vs 77 %. INT patients experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs (53 % vs 42 %). QoL favoured CONT. Detection of BRAF V600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95 %CI 1.25-5.21, p = 0.01) in both arms. A change to undetected during treatment did not significantly predict better OS., Conclusion: INTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Far-UVC, from filtered Krypton-Chloride lamps, is promising for reducing airborne transmission of disease. While significant research has been undertaken to investigate skin safety of these lamps, less work has been undertaken on eye safety. There is limited data on human eye safety or discomfort from the deployment of this germicidal technology. In this pilot study, immediate and delayed eye discomfort were assessed in a simulated office environment with deployment of Krypton-Chloride lamps, located on the ceiling and directed downwards into the occupied room. Discomfort was assessed immediately postexposure and several days after exposure using validated, Standard Patient Evaluation Eye Dryness (SPEED) and Ocular Surface Disease Index (OSDI) questionnaires. Our results show no significant eye discomfort or adverse effects from the deployment of Far-UVC in this simulated office environment, even when lamps were operated continuously with participants receiving head exposures of up to 50 mJ cm -2 . In addition, a statistically significant reduction in bacteria and fungi of 52% was observed. Far-UVC in this simulated office environment did not cause any clinically significant eye discomfort and was effective at reducing pathogens in the room. These results contribute an important step to further investigation of the interaction of Far-UVC with the human eye., (© 2023 The Authors. Photochemistry and Photobiology published by Wiley Periodicals LLC on behalf of American Society for Photobiology.)

Most mammalian cells have a single primary cilium that acts as a signalling hub in mediating cellular functions. However, little is known about the mechanisms that result in aberrant supernumerary primary cilia per cell. In this study, we re-analysed a previously published whole-genome siRNA-based reverse genetic screen for genes mediating ciliogenesis to identify knockdowns that permit multi-ciliation. We identified siRNA knockdowns that caused significant formation of supernumerary cilia, validated candidate hits in different cell-lines and confirmed that RACGAP1, a component of the centralspindlin complex, was the strongest candidate hit at the whole-genome level. Following loss of RACGAP1, mother centrioles were specified correctly prior to ciliogenesis and the cilia appeared normal. Live cell imaging revealed that increased cilia incidence was caused by cytokinesis failure which led to the formation of multinucleate cells with supernumerary cilia. This suggests that the signalling mechanisms for ciliogenesis are unable to identify supernumerary centrosomes and therefore allow ciliation of duplicated centrosomes as if they were in a new diploid daughter cell. These results, demonstrating that aberrant ciliogenesis is de-coupled from cell cycle regulation, have functional implications in diseases marked by centrosomal amplification., (© 2023 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.)

Cell invasion is a multi-step process, initiated by the acquisition of a migratory phenotype and the ability to move through complex 3D extracellular environments. We determine the composition of cell-matrix adhesion complexes of invasive breast cancer cells in 3D matrices and identify an interaction complex required for invasive migration. βPix and myosin18A (Myo18A) drive polarized recruitment of non-muscle myosin 2A (NM2A) to adhesion complexes at the tips of protrusions. Actomyosin force engagement then displaces the Git1-βPix complex from paxillin, establishing a feedback loop for adhesion maturation. We observe active force transmission to the nucleus during invasive migration that is needed to pull the nucleus forward. The recruitment of NM2A to adhesions creates a non-muscle myosin isoform gradient, which extends from the protrusion to the nucleus. We postulate that this gradient facilitates coupling of cell-matrix interactions at the protrusive cell front with nuclear movement, enabling effective invasive migration and front-rear cell polarity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Alcohol misuse is common in the United Kingdom Armed Forces (UKAF), with prevalence significantly higher than in the general population. To date, digital health initiatives to support alcohol misuse have focused on male individuals, who represent approximately 89% of the UKAF. However, female veterans drink disproportionally more than female members of the public., Objective: This 2-arm participant-blinded (single-blinded) confirmatory randomized controlled trial (RCT) aims to assess the efficacy of a brief alcohol intervention (DrinksRation) in reducing weekly self-reported alcohol consumption between baseline and a 3-month follow-up (day 84) among women who have served in the UKAF., Methods: In this 2-arm single-blinded RCT, a smartphone app that includes interactive user-focused features tailored toward the needs of female veterans and designed to enhance participants' motivations to reduce the amount of alcohol they consume is compared with the UK Chief Medical Officer guidance on alcohol consumption. The trial will be conducted among women who have served at least 1 day of paid service in the UKAF. Recruitment, consent, and data collection will be carried out automatically through the DrinksRation app or the BeAlcoholSmart platform. The primary outcome is change in self-reported weekly alcohol consumption between baseline (day 0) and the 3-month follow-up (day 84) measured using the Timeline Follow Back for alcohol consumption. The secondary outcome is the change in the Alcohol Use Disorders Identification Test score measured at baseline and 3-month follow-up between the control and intervention groups. The process evaluation measures include (1) app use and (2) usability ratings as measured by the mHealth App Usability Questionnaire., Results: RCT recruitment will begin in January 2024 and last for 5 months. We aim to complete all data collection, including interviews, by May 2024., Conclusions: This study will assess whether a smartphone app tailored to the needs of women who have served in the UKAF is efficacious in reducing self-reported alcohol consumption. If successful, the digital therapeutics platform could be used not only to support women who have served in the UKAF but also for other conditions and disorders., Trial Registration: ClinicalTrials.gov NCT05970484; https://www.clinicaltrials.gov/study/NCT05970484., International Registered Report Identifier (irrid): PRR1-10.2196/51531., (©Grace Williamson, Ewan Carr, Nicola T Fear, Simon Dymond, Kate King, Amos Simms, Laura Goodwin, Dominic Murphy, Daniel Leightley. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 19.12.2023.)

Homologous recombination deficiency (HRD) is a predictive biomarker for poly(ADP-ribose) polymerase 1 inhibitor (PARPi) sensitivity. Routine HRD testing relies on identifying BRCA mutations, but additional HRD-positive patients can be identified by measuring genomic instability (GI), a consequence of HRD. However, the cost and complexity of available solutions hamper GI testing. We introduce a deep learning framework, GIInger, that identifies GI from HRD-induced scarring observed in low-pass whole-genome sequencing data. GIInger seamlessly integrates into standard BRCA testing workflows and yields reproducible results concordant with a reference method in a multisite study of 327 ovarian cancer samples. Applied to a BRCA wild-type enriched subgroup of 195 PAOLA-1 clinical trial patients, GIInger identified HRD-positive patients who experienced significantly extended progression-free survival when treated with PARPi. GIInger is, therefore, a cost-effective and easy-to-implement method for accurately stratifying patients with ovarian cancer for first-line PARPi treatment., Competing Interests: Declaration of interests G.A., T.C., C.P., J.B., R.K., L.F., A.S., F.C.B., L.R., A.A., R.M., M.F., A.C.M., E.S., A.W., and Z.X. are SOPHiA GENETICS employees. A.H. received consultant fees from SOPHiA GENETICS and honoraria from AstraZeneca, Janssen, and GSK. P.G. received honoraria from AstraZeneca. M.B. has received honoraria for consulting, advisory role, speakers’ bureau, travel, accommodation, and expenses from MSD Oncology, Roche/Genetech, AstraZeneca, Thermo Fisher Scientific, and Illumina. S.P. has received honoraria and research funding from AstraZeneca, MSD, GSK, and Roche and honoraria from Clovis. E.P.-L. served on a data safety monitoring board for Agenus Incyte, as a consultant for Roche, and as an advisory board member for AstraZeneca and GSK. I.V. as a consulting or advisory role at AstraZeneca. P.-A.J. has conducted teaching events for GSK, Roche, and EISAI. N.C. has reported fees for advisory board membership for AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, Pieris, and Roche; fees as an invited speaker for AstraZeneca, Novartis, Clovis Oncology, GSK, and MSD/Merck; and institutional research grants from AstraZeneca and Roche. She has also reported non-remunerated activities as a member of the ESMO Guidelines Steering Committee and chair of the Scientific Committee of ACTO (Alleanza contro il tumore ovarico). A.G.-M. has received fees for different educational or advisory-related activities from Alkermes, AstraZeneca, Clovis, Genmab, GSK, HederaDx, Immunogen, Illumina, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Roche, SOTIO, SUTRO, Seagen, and Takeda. P.H. has received honoraria from AstraZeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab, and MSD and has acted in advisory/consultancy for AstraZeneca, Roche, Tesaro, Lilly, Clovis, Immunogen, and MSD/Merck., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The prevalence, prediction and impact of acute kidney injury (AKI) in alcohol-related hepatitis (AH) is uncertain., Aims: We aimed to determine AKI incidence; association with mortality; evaluate serum biomarkers and the modifying effects of prednisolone and pentoxifylline in the largest AH cohort to date., Methods: Participants in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial with day zero (D0) creatinine available were included. AKI was defined by modified International Club of Ascites criteria; incident AKI as day 7 (D7) AKI without D0-AKI. Survival was compared by Kaplan-Meier; mortality associations by Cox regression; associations with AKI by binary logistic regression; biomarkers by AUROC analyses., Results: D0-AKI was present in 198/1051 (19%) participants; incident AKI developed in a further 119/571 (21%) with available data. Participants with D0-AKI had higher 90-day mortality than those without (32% vs. 25%, p = 0.008), as did participants with incident AKI compared to those without D0-AKI or incident AKI (47% vs. 25%, p < 0.001). Incident AKI was associated with D90 mortality adjusted for age and discriminant function (AHR 2.15, 1.56-2.97, p < 0.001); D0-AKI was not. Prednisolone therapy reduced incident AKI (AOR 0.55, 0.36-0.85, p = 0.007) but not mortality. D0 bilirubin and IL-8 combined, miR-6826-5p, and miR-6811-3p predicted incident AKI (AUROCs 0.726, 0.821, 0.770, p < 0.01)., Conclusions: Incident AKI is associated with 90-day mortality independent of liver function. Prednisolone therapy was associated with reduced incident AKI. IL-8 and several miRNAs are potential biomarkers to predict AKI. Novel therapies to prevent incident AKI should be evaluated in AH to reduce mortality., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: In some countries, enrolled nurses (also known as Licensed Practical Nurses) have become essential members of the healthcare team, supporting registered nurses to address patient care needs. Registered nurses' readiness to practice is well documented in the literature, however, less is known about the preparedness of enrolled nurses for practice., Objective: To explore and synthesize the available evidence on the graduate enrolled nurse practice readiness upon completion of their nursing qualification and at the time of entering the nursing workforce., Design: A scoping review was conducted., Data Sources: Databases such as CINAHL Complete, Directory of access journal, Cochrane Library, Medline, PubMed, Scopus, Web of Science, ProQuest and Google scholar were searched., Review Method: The review was conducted using The Joanna Briggs Institute Methodology for Scoping reviews., Results: Seven studies were identified for inclusion and two themes were constructed as 'ambiguous roles and expectations' and 'lack of educational preparation'. Findings from the selected studies showed a lack of clarity on the role of an enrolled nurse. In some healthcare settings, enrolled nurses were expected to undertake the same role as registered nurses. Furthermore, it was expected that enrolled nurses would be educationally prepared to work in specialty areas such as mental health, acute care and aged care upon completion of their studies. Though, none of these studies provided any conclusive evidence of whether enrolled nurses were ready to transition to practice., Conclusion: In line with the limited evidence, there is a need to undertake further studies to understand the graduate enrolled nurse practice readiness from graduates' and industry stakeholders' perspectives. The findings will assist the education providers to strengthen their curriculum and health industry to support enrolled nurse transition to practice., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that have relevance to the content of this article., (Copyright © 2023. Published by Elsevier Ltd.)

Significance: Rapid advances in medical imaging technology, particularly the development of optical systems with non-linear imaging modalities, are boosting deep tissue imaging. The development of reliable standards and phantoms is critical for validation and optimization of these cutting-edge imaging techniques., Aim: We aim to design and fabricate flexible, multi-layered hydrogel-based optical standards and evaluate advanced optical imaging techniques at depth., Approach: Standards were made using a robust double-network hydrogel matrix consisting of agarose and polyacrylamide. The materials generated ranged from single layers to more complex constructs consisting of up to seven layers, with modality-specific markers embedded between the layers., Results: These standards proved useful in the determination of the axial scaling factor for light microscopy and allowed for depth evaluation for different imaging modalities (conventional one-photon excitation fluorescence imaging, two-photon excitation fluorescence imaging, second harmonic generation imaging, and coherent anti-Stokes Raman scattering) achieving actual depths of 1550, 1550, 1240, and 1240    μ m , respectively. Once fabricated, the phantoms were found to be stable for many months., Conclusions: The ability to image at depth, the phantom's robustness and flexible layered structure, and the ready incorporation of "optical markers" make these ideal depth standards for the validation of a variety of imaging modalities., (© 2023 The Authors.)

Background: Padel is a racket sport similar to tennis, which since the COVID-19 pandemic has been gaining popularity among recreational players. Despite its popularity, epidemiological studies are still lacking. This study aimed to identify the prevalence of injuries among Italian recreational padel players and associated risk factors., Methods: A questionnaire was administered to 127 recreational padel players between January 2022 to March 2022. The questionnaire consisted of questions to collect information regarding intrinsic and extrinsic factors related to padel practice, injury location, and injury typology. Frequencies and proportions were calculated for variable description. Binomial logistic regression was adopted to identify potential risk factors., Results: Of the 127 participants, 100 (78.8%) reported having had an injury during the previous year. Such injury in most cases (37%) resulted in an absence from padel from 8 to 28 days. The most common injury locations were lower leg/Achilles tendon (17.1%) and elbow (13.8%), while the most common injury typologies were tendinopathies (33.6%) and contusions (14.9%). Among the identified risk factors the amount of time played padel (3.5-5 hours/week), racket type (round), and racket weight (either not knowing or 356-375 g) resulted in an increase in the probability of occurring an injury., Conclusions: Recreational padel results in a high percentage of injuries. These frequently result in tendinopathies of the Achilles tendon and elbow. Inadequate racket characteristics and the amount of time played could contribute to an increase in injury incidence.

Background: Infections are discussed as risk factor for multiple sclerosis (MS) development and relapses. This may lead to decreased vaccination frequency in newly diagnosed patients., Objective: The aim of this study was to evaluate the relation of MS diagnosis to subsequent vaccination frequency., Methods: Based on German ambulatory claims data from 2005 to 2019, regression models were used to assess the relation of MS diagnosis ( n = 12,270) to vaccination. A cohort of patients with MS was compared to control cohorts with Crohn's disease, psoriasis, and without these autoimmune diseases (total n = 198,126) in the 5 years after and before diagnosis., Results: Patients with MS were less likely to be vaccinated compared to persons without the autoimmune diseases 5 years after diagnosis (odds ratio = 0.91, p < 0.001). Exceptions were vaccinations against influenza (1.29, p < 0.001) and pneumococci (1.41, p < 0.001). Differences were strong but less pronounced after than before diagnosis ( p < 0.001). The likelihood of vaccination was also lower compared to patients with Crohn's disease or psoriasis., Conclusions: Patients with MS were not adequately vaccinated despite guideline recommendations. Increasing awareness about the importance of vaccination is warranted to reduce the risk of infection, in particular, in patients with MS receiving immunotherapies., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.H. has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon, and TG therapeutics; he or his institution has received speaker honoraria from Desitin; his institution received research grants from Regeneron and Roche for MS research. He holds part of two patents: one for the detection of antibodies against KIR4.1 in a subpopulation of patients with MS and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. Other authors declare they have no conflict of interest.

The usefulness of Foam Roller (FR) even without a rolling stimulus (e.g., static compression with or without dynamic joint movements) has been recently demonstrated; however, the different effects of these methods remain unclear. Thus, this study aimed to compare and investigate the effects of such FR intervention methods on knee extensors. The dominant knee extensors of 20 male university students were investigated using the following four conditions: control (CON), FR with rolling (FR&#95;rolling), FR with static compression (FR&#95;SC), and FR with static compression + dynamic movement of the knee joint (FR&#95;DM). FR&#95;SC was intervened to compress the muscle belly of the knee extensors. FR&#95;DM involved knee flexion and extension while maintaining the FR&#95;SC condition. Knee flexion ROM, pain pressure threshold (PPT), tissue hardness, and countermovement jump (CMJ) height were outcome variables; they were compared before and immediately after the intervention. The results of this study showed that knee flexion ROM was significantly (p < 0.01) increased in FR&#95;rolling (d = 0.38), FR&#95;SC (d = 0.28), and FR&#95;DM (d = 0.64). Tissue hardness was significantly (p < 0.01) decreased in FR&#95;rolling (d = -0.55), FR&#95;SC (d = -0.28), and FR&#95;DM (d = -0.42). A main effect of time ( p < 0.01) was observed in knee flexion ROM, PPT, and tissue hardness, but no change in CMJ was observed. The results of this study suggested that clinicians and athletes could choose any method they like as a warm-up routine., (© Journal of Sports Science and Medicine.)

Background: Cervical spine mobilizations may differentially modulate both components of the stress response, consisting of the autonomic nervous system and hypothalamic pituitary adrenal-axis, depending on whether the target location is the upper or lower cervical spine. To date, no study has investigated this., Methods: A randomized, crossover trial investigated the effects of upper versus lower cervical mobilization on both components of the stress response simultaneously. The primary outcome was salivary cortisol (sCOR) concentration. The secondary outcome was heart rate variability measured with a smartphone application. Twenty healthy males, aged 21-35, were included. Participants were randomly assigned to block-AB (upper then lower cervical mobilization, n  = 10) or block-BA (lower than upper cervical mobilization, n  = 10), separated by a one-week washout period. All interventions were performed in the same room (University clinic) under controlled conditions. Statistical analyses were performed with a Friedman's Two-Way ANOVA and Wilcoxon Signed Rank Test., Results: Within groups, sCOR concentration reduced thirty-minutes following lower cervical mobilization ( p  = 0.049). Between groups, sCOR concentration was different at thirty-minutes following the intervention ( p  = 0.018)., Conclusion: There was a statistically significant reduction in sCOR concentration following lower cervical spine mobilization, and between-group difference, 30 min following the intervention. This indicates that mobilizations applied to separate target locations within the cervical spine can differentially modulate the stress response.

Albinism is a clinically and genetically heterogeneous group of conditions characterised by visual abnormalities and variable degrees of hypopigmentation. Multiple studies have demonstrated the clinical utility of genetic investigations in individuals with suspected albinism. Despite this, the variation in the provision of genetic testing for albinism remains significant. One key issue is the lack of a standardised approach to the analysis of genomic data from affected individuals. For example, there is variation in how different clinical genetic laboratories approach genotypes that involve incompletely penetrant alleles, including the common, 'hypomorphic' TYR c.1205G>A (p.Arg402Gln) [rs1126809] variant. Here, we discuss the value of genetic testing as a frontline diagnostic tool in individuals with features of albinism and propose a practice pattern for the analysis of genomic data from affected families., Competing Interests: Competing interests: EB is a paid consultant and equity holder of Oxford Nanopore, a paid consultant to Dovetail, and a non-executive director of Genomics England, a limited company wholly owned by the UK Department of Health and Social Care. All other authors declare no competing interests. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

We investigate the full counting statistics of charge transport in U(1)-symmetric random unitary circuits. We consider an initial mixed state prepared with a chemical potential imbalance between the left and right halves of the system and study the fluctuations of the charge transferred across the central bond in typical circuits. Using an effective replica statistical mechanics model and a mapping onto an emergent classical stochastic process valid at large on-site Hilbert space dimension, we show that charge transfer fluctuations approach those of the symmetric exclusion process at long times, with subleading t^{-1/2} quantum corrections. We discuss our results in the context of fluctuating hydrodynamics and macroscopic fluctuation theory of classical nonequilibrium systems and check our predictions against direct matrix-product state calculations.

Background: Speech contains neuromuscular, physiological and cognitive components, and so is a potential biomarker of mental disorders. Previous studies indicate that speaking rate and pausing are associated with major depressive disorder (MDD). However, results are inconclusive as many studies are small and underpowered and do not include clinical samples. These studies have also been unilingual and use speech collected in controlled settings. If speech markers are to help understand the onset and progress of MDD, we need to uncover markers that are robust to language and establish the strength of associations in real-world data., Methods: We collected speech data in 585 participants with a history of MDD in the United Kingdom, Spain, and Netherlands as part of the RADAR-MDD study. Participants recorded their speech via smartphones every two weeks for 18 months. Linear mixed models were used to estimate the strength of specific markers of depression from a set of 28 speech features., Results: Increased depressive symptoms were associated with speech rate, articulation rate and intensity of speech elicited from a scripted task. These features had consistently stronger effect sizes than pauses., Limitations: Our findings are derived at the cohort level so may have limited impact on identifying intra-individual speech changes associated with changes in symptom severity. The analysis of features averaged over the entire recording may have underestimated the importance of some features., Conclusions: Participants with more severe depressive symptoms spoke more slowly and quietly. Our findings are from a real-world, multilingual, clinical dataset so represent a step-change in the usefulness of speech as a digital phenotype of MDD., Competing Interests: Declaration of competing interest The Authors declare no Competing Financial or Non-Financial Interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Few studies have investigated the effects of adopting a specific and prolonged posture on cyclists. This study aimed to evaluate the upright spine in a sample of recreational cyclists and compare it with a sample of non-cyclists, though still athletes, through a 3D scanning method., Methods: Forty-eight participants were enrolled in this observational study. The sample consisted of 25 cyclists for the cycling group and 23 non-cyclist athletes for the control group. The Spine3D device (Sensor Medica, Guidonia Montecelio, Rome, Italy) was used to evaluate the spine of the participants in both groups., Results: The results showed significantly greater spine inclination in the cycling group compared to the control group ( p < 0.01). Furthermore, there was a significant decrease in lumbar lordosis in the cycling group compared to the control group ( p < 0.01)., Conclusions: This case-control study raises the possibility that the onset of lower back pain in cyclists may be due to a reduction in lumbar lordosis. Furthermore, this study demonstrated that the Spine3D device can be used in sports to monitor the spine of athletes to prevent and reduce musculoskeletal deficits.

The polygenic contribution to heart development and function along the health-disease continuum remains unresolved. To gain insight into the genetic basis of quantitative cardiac phenotypes, we utilize highly inbred Japanese rice fish models, Oryzias latipes , and Oryzias sakaizumii . Employing automated quantification of embryonic heart rates as core metric, we profiled phenotype variability across five inbred strains. We observed maximal phenotypic contrast between individuals of the HO5 and the HdrR strain. HO5 showed elevated heart rates associated with embryonic ventricular hypoplasia and impaired adult cardiac function. This contrast served as the basis for genome-wide mapping. In a segregation population of 1192 HO5 x HdrR F2 embryos, we mapped 59 loci (173 genes) associated with heart rate. Experimental validation of the top 12 candidate genes in loss-of-function models revealed their causal and distinct impact on heart rate, development, ventricle size, and arrhythmia. Our study uncovers new diagnostic and therapeutic targets for developmental and electrophysiological cardiac diseases and provides a novel scalable approach to investigate the intricate genetic architecture of the vertebrate heart., Competing Interests: Competing interests: Authors declare that they have no competing interests.

Objective: To determine the incidence and incidence trends over 2001-2022 of childhood-onset type 1 diabetes (T1D) in Western Australia and assess the impact of the COVID-19 pandemic., Methods: Children newly diagnosed with T1D aged 0-14 years in Western Australia from 1 January 2001 to 31 December 2022 were identified from the population-based Western Australian Children's Diabetes Database. Annual age- and sex-specific incidence was calculated, and Poisson regression was used to analyse trends by calendar year, month, sex and age group at diagnosis. Pandemic era impacts were also examined using the regression model adjusted for sex and age group., Results: Between 2001 and 2022, 2311 children (1214 boys, 1097 girls) were newly diagnosed with T1D aged 0-14 years, giving an overall mean annual incidence of 22.9 per 100,000 person-years (95% CI: 22.0, 23.9), with no significant difference observed between boys and girls. A significant linear increasing trend was only observed in 10-14 year olds with boys and girls combined (1.2% per year [IRR 1.012 (95% CI: 1.002, 1.022)]). No significant difference in the incidence was observed between the pre- and post-pandemic period., Conclusions: The incidence of type 1 diabetes in 0-14 year old Western Australian children continues to increase in the oldest age group. Longer term monitoring of the incidence during the COVID-19 pandemic is needed to determine its impact on this globally unique population which experienced a delayed start to the pandemic with severe containment measures remaining in place until January 2022., (© 2023 Diabetes UK.)

The success of mRNA-based vaccines during the Covid-19 pandemic has highlighted the value of this new platform for vaccine development against infectious disease. However, the CD8 + T cell response remains modest with mRNA vaccines, and these do not induce mucosal immunity, which would be needed to prevent viral spread in the healthy population. To address this drawback, we developed a dendritic cell targeting mucosal vaccination vector, the homopentameric STxB. Here, we describe the highly efficient chemical synthesis of the protein, and its in vitro folding. This straightforward preparation led to a synthetic delivery tool whose biophysical and intracellular trafficking characteristics were largely indistinguishable from recombinant STxB. The chemical approach allowed for the generation of new variants with bioorthogonal handles. Selected variants were chemically coupled to several types of antigens derived from the mucosal viruses SARS-CoV-2 and type 16 human papillomavirus. Upon intranasal administration in mice, mucosal immunity, including resident memory CD8 + T cells and IgA antibodies was induced against these antigens. Our study thereby identifies a novel synthetic antigen delivery tool for mucosal vaccination with an unmatched potential to respond to an urgent medical need., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Kinases are important therapeutic targets, and their inhibitors are classified according to their mechanism of action, which range from blocking ATP binding to covalent inhibition. Here, a mechanism of inhibition is highlighted by capturing p21-activated kinase 5 (PAK5) in an intermediate state of activation using an Affimer reagent that binds in the P+1 pocket. PAK5 was identified from a non-hypothesis-driven high-content imaging RNAi screen in urothelial cancer cells. Silencing of PAK5 resulted in reduced cell number, G1/S arrest, and enlargement of cells, suggesting it to be important in urothelial cancer cell line survival and proliferation. Affimer reagents were isolated to identify mechanisms of inhibition. The Affimer PAK5-Af17 recapitulated the phenotype seen with siRNA. Co-crystallization revealed that PAK5-Af17 bound in the P+1 pocket of PAK5, locking the kinase into a partial activation state. This mechanism of inhibition indicates that another class of kinase inhibitors is possible., Competing Interests: Declaration of interests A.L.T. owns personal shares in Avacta Life Sciences. D.C.T. is a named inventor on the “artificial binding protein” patent, which is held be the University of Leeds and covers the Affimer reagents used in the study., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Radiofrequency filings warn of more congestion in space, but also offer possible remedies.

Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM 4 -GlyR is a modular system based on the human α7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical ligands and the clinically approved drug varenicline. Here, we demonstrated the efficacy of this channel in silencing both mouse and human sensory neurons by the activation of large shunting conductances after agonist administration. Virally mediated expression of PSAM 4 -GlyR in mouse sensory neurons produced behavioral hyposensitivity upon agonist administration, which was recovered upon agonist washout. Stable expression of the channel led to similar reversible suppression of pain-related behavior even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM 4 -GlyR activation in acute and joint pain inflammation mouse models. Furthermore, suppression of mechanical hypersensitivity generated by a spared nerve injury model of neuropathic pain was also observed upon activation of the channel. Effective silencing of behavioral hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM 4 -GlyR activation decreased the excitability of human-induced pluripotent stem cell-derived sensory neurons and spontaneous activity due to a gain-of-function Na V 1.7 mutation causing inherited erythromelalgia. Our results demonstrate the contribution of sensory neuron hyperexcitability to neuropathic pain and the translational potential of an effective, stable, and reversible humanized chemogenetic system for the treatment of pain.

Objective: Alcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The management of ALD requires treatment of both liver disease and alcohol use; this necessitates effective and constructive multidisciplinary working. To support this, we have developed quality standard recommendations for the management of ALD, based on evidence and consensus expert opinion, with the aim of improving patient care., Design: A multidisciplinary group of experts from the British Association for the Study of the Liver and British Society of Gastroenterology ALD Special Interest Group developed the quality standards, with input from the British Liver Trust and patient representatives., Results: The standards cover three broad themes: the recognition and diagnosis of people with ALD in primary care and the liver outpatient clinic; the management of acutely decompensated ALD including acute alcohol-related hepatitis and the posthospital care of people with advanced liver disease due to ALD. Draft quality standards were initially developed by smaller working groups and then an anonymous modified Delphi voting process was conducted by the entire group to assess the level of agreement with each statement. Statements were included when agreement was 85% or greater. Twenty-four quality standards were produced from this process which support best practice. From the final list of statements, a smaller number of auditable key performance indicators were selected to allow services to benchmark their practice and an audit tool provided., Conclusion: It is hoped that services will review their practice against these recommendations and key performance indicators and institute service development where needed to improve the care of patients with ALD., Competing Interests: Competing interests: RP: research support from NIHR and LEeds Hospital Charity. Consulting fees from Durect. Fees for speaking from Norgine Pharmaceuticals. Advisory board fees from Novo Nordisk. LC: consulting fees from Novo Nordisk relating to non-alcohol-related fatty liver disease. TP: research grant support from NIHR, Society for the Study of Addiction, Office of Police and Crime Commissioner. SMorgan: research support from NIHR. Consulting fees from Norgine Pharmaceuticals, Payment or honoraria from Sandoz UK and Dr Falk. LEadership roles with BRitish Society of Gastroenterology, Alcohol HEalth Alliance, Medical Council on Alcohol.These authors declare no conflicts of interest: SA, MA, RA, SB, VB, RB, ID, AD, PD, RGailer, EForrest, EForster, RGoldin, VH, AJ, VL, DL, JMcDonagh, JMaurice, SMasson, TN, EO, GP, NRajoriya, NRainford, PR, JR, JS, MS, AS, ES, JT, RV, IW and AW., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is substantial variation in patient symptoms following psychological therapy for depression and anxiety. However, reliance on endpoint outcomes ignores additional interindividual variation during therapy. Knowing a patient's likely symptom trajectories could guide clinical decisions. We aimed to identify latent classes of patients with similar symptom trajectories over the course of psychological therapy and explore associations between baseline variables and trajectory class., Methods: Patients received high-intensity psychological treatment for common mental health problems at National Health Service Improving Access to Psychological Therapies services in South London ( N = 16 258). To identify trajectories, we performed growth mixture modelling of depression and anxiety symptoms over 11 sessions. We then ran multinomial regressions to identify baseline variables associated with trajectory class membership., Results: Trajectories of depression and anxiety symptoms were highly similar and best modelled by four classes. Three classes started with moderate-severe symptoms and showed (1) no change, (2) gradual improvement, and (3) fast improvement. A final class (4) showed initially mild symptoms and minimal improvement. Within the moderate-severe baseline symptom classes, patients in the two showing improvement as opposed to no change tended not to be prescribed psychotropic medication or report a disability and were in employment. Patients showing fast improvement additionally reported lower baseline functional impairment on average., Conclusions: Multiple trajectory classes of depression and anxiety symptoms were associated with baseline characteristics. Identifying the most likely trajectory for a patient at the start of treatment could inform decisions about the suitability and continuation of therapy, ultimately improving patient outcomes.

Gaussian boson sampling (GBS) has the potential to solve complex graph problems, such as clique finding, which is relevant to drug discovery tasks. However, realizing the full benefits of quantum enhancements requires large-scale quantum hardware with universal programmability. Here we have developed a time-bin-encoded GBS photonic quantum processor that is universal, programmable and software-scalable. Our processor features freely adjustable squeezing parameters and can implement arbitrary unitary operations with a programmable interferometer. Leveraging our processor, we successfully executed clique finding on a 32-node graph, achieving approximately twice the success probability compared to classical sampling. As proof of concept, we implemented a versatile quantum drug discovery platform using this GBS processor, enabling molecular docking and RNA-folding prediction tasks. Our work achieves GBS circuitry with its universal and programmable architecture, advancing GBS toward use in real-world applications., (© 2023. The Author(s).)

Should indication for transfusion in paediatric palliative care be based on the child's perspective rather than the biological results? An 8-year-old boy presenting a relapse of a stage IV neuroblastoma received regular blood transfusions. A severe exophtalmia led the doctors to question the transfusion strategy. Over 7.5 months, the child received 56 red blood cell units and 31 platelet units. He was hospitalised 50 times. Indication for blood test and transfusion may be regularly and collegially reassessed. Transfusion needs in a palliative strategy can be as high as in a curative strategy. Practices, benefits but also ethical and public health dimensions should be more studied., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Underlying classes capture differences between patient symptom trajectories during psychological therapy. This has not been explored for one-to-one internet-delivered therapy or functional impairment trajectories. Patients experiencing depression or anxiety received cognitive-behavioural therapy with a therapist using an online chat platform (N = 52,029). Trajectory classes of depression symptoms (PHQ9), anxiety symptoms (GAD7) and functional impairment (WSAS) were investigated using growth mixture modelling. Multinomial regressions tested associations between baseline variables and trajectory class. A four-class trajectory model was selected for each outcome, and these were highly similar. Each outcome showed three classes with initially moderate-severe symptoms or impairment: one demonstrated no change, one gradual improvement and one fast improvement. A fourth class had mild baseline scores and minimal improvement. In the moderate-severe classes, patients in the two with improvement were more likely to be employed and not to have obsessive-compulsive disorder. Fast improvement was likelier than gradual improvement or no change for patients with older age, no disability (e.g., physical, learning), or lower comorbid symptom or impairment scores. Associations with functional impairment classes were more similar to associations with depression classes than anxiety classes. Results were largely consistent with findings from face-to-face therapy. This study is an important step towards personalising therapy in terms of suitability and continuation., Competing Interests: Declaration of competing interest Ana Catarino and Stephanie Brown are employees of ieso, the company who provided the therapy for NHS patients and shared the anonymised patient data for analysis. All other authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: There is clinical equipoise as to whether hyperoxia is injurious to the myocardium, both in the setting of acute ischaemic insults and on the stable myocardium. This study examined the effect of extreme hyperoxia - in the form of hyperbaric oxygen treatment - on the myocardium through measurement of high-sensitivity cardiac troponin., Methods: Forty-eight individuals were enrolled to undergo a series of 30 exposures to hyperbaric oxygen for treatment of non-cardiac pathologies. High-sensitivity troponin T was measured before and after each session., Results: There was no clinically significant difference in troponin measurements following acute or recurrent sequential exposures to extreme hyperoxia, despite the studied patient population having a high rate of previous ischaemic heart disease or cardiovascular risk factors., Conclusions: This study demonstrates that profound hyperoxaemia does not induce any measurable cardiac injury at a biochemical level. Neither is there a reduction in cardiac troponin to suggest a cardioprotective effect of hyperbaric hyperoxia. This provides some reassurance as to the cardiac safety of the routine use of hyperbaric oxygen treatment in management of non-cardiac pathology., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Ongoing pain is driven by the activation and modulation of pain-sensing neurons, affecting physiology, motor function, and motivation to engage in certain behaviors. The complexity of the pain state has evaded a comprehensive definition, especially in non-verbal animals. Here, in mice, we used site-specific electrophysiology to define key time points corresponding to peripheral sensitivity in acute paw inflammation and chronic knee pain models. Using supervised and unsupervised machine learning tools, we uncovered sensory-evoked coping postures unique to each model. Through 3D pose analytics, we identified movement sequences that robustly represent different pain states and found that commonly used analgesics do not return an animal's behavior to a pre-injury state. Instead, these analgesics induce a novel set of spontaneous behaviors that are maintained even after resolution of evoked pain behaviors. Together, these findings reveal previously unidentified neuroethological signatures of pain and analgesia at heightened pain states and during recovery., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We report two new series of compounds that show the ferroelectric nematic, N F , phase in which the terminal chain length is varied. The longer the terminal chain, the weaker the dipole-dipole interactions of the molecules are along the director and thus the lower the temperature at which the axially polar N F phase is formed. For homologues of intermediate chain lengths, between the non-polar and ferroelectric nematic phases, a wide temperature range nematic phase emerges with antiferroelectric character. The size of the antiparallel ferroelectric domains critically increases upon transition to the N F phase. In dielectric studies, both collective ("ferroelectric") and non-collective fluctuations are present, and the "ferroelectric" mode softens weakly at the N-N X phase transition because the polar order in this phase is weak. The transition to the N F phase is characterized by a much stronger lowering of the mode relaxation frequency and an increase in its strength, and a typical critical behavior is observed., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)