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Abstract Objectives To develop and evaluate a multi-task deep-learning (DL) model for automated segment-level coronary artery calcium (CAC) scoring on non-contrast computed tomography (CT) for precise localization and quantification of calcifications in the coronary artery tree. Methods This study included 1514 patients (mean age, 60.0 ± 10.2 years; 56.0% female) with stable chest pain from 26 centers participating in the multicenter DISCHARGE trial (NCT02400229). The patients were randomly assigned to a training/validation set (1059) and a test set (455). We developed a multi-task neural network for performing the segmentation of calcifications on the segment level as the main task and the segmentation of coronary artery segment regions with weak annotations as an auxiliary task. Model performance was evaluated using (micro-average) sensitivity, specificity, F1-score, and weighted Cohen’s κ for segment-level agreement based on the Agatston score and performing interobserver variability analysis. Results In the test set of 455 patients with 1797 calcifications, the model assigned 73.2% (1316/1797) to the correct coronary artery segment. The model achieved a micro-average sensitivity of 0.732 (95% CI: 0.710–0.754), a micro-average specificity of 0.978 (95% CI: 0.976–0.980), and a micro-average F1-score of 0.717 (95% CI: 0.695–0.739). The segment-level agreement was good with a weighted Cohen’s κ of 0.808 (95% CI: 0.790–0.824), which was only slightly lower than the agreement between the first and second observer (0.809 (95% CI: 0.798–0.845)). Conclusion Automated segment-level CAC scoring using a multi-task neural network approach showed good agreement on the segment level, indicating that DL has the potential for automated coronary artery calcification classification. Critical relevance statement Multi-task deep learning can perform automated coronary calcium scoring on the segment level with good agreement and may contribute to the development of new and improved calcium scoring methods. Key Points Segment-level coronary artery calcium scoring is a tedious and error-prone task. The proposed multi-task model achieved good agreement with a human observer on the segment level. Deep learning can contribute to the automation of segment-level coronary artery calcium scoring. Graphical Abstract

Abstract In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet treatable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of ‘improved’ OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edit human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplant them into rodent models of chronic lesions. Edited hOPCs display enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. We show that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS.

Abstract Under predicted future ocean conditions, corals will experience frequent and intense thermal stress events while simultaneously being exposed to chronic ocean acidification. Yet, some corals will likely be more resistant and/or resilient to these predicted conditions than others and may be critical to reef persistence in the future. Following natural thermal stress in two consecutive years (2014 and 2015), we evaluated the effects of feeding and simulated ocean acidification on the physiological recovery of Montipora capitata and Porites compressa sourced from Kāneʻohe Bay and Waimānalo Bay, Hawaiʻi. Following the 2014 thermal stress event, simulated ocean acidification did not slow recovery of the holobiont and feeding enhanced recovery. However, feeding did not decrease susceptibility to the 2015 thermal stress event, and simulated ocean acidification did not increase susceptibility. Recovery strategies employed between species and between sites clearly differed, highlighting that coral reef restoration and management should consider species-level and site-specific vulnerabilities. Overall, our findings call attention to the immediate threat which ocean warming presents, the lack of additional stress to the holobiont from ocean acidification, the importance of heterotrophy in coral resilience, and the potential significance of additional local biotic stressors (i.e., predator outbreaks) for coral resiliency under annual thermal stress.

Abstract Background Diagnosis of alcohol use disorder (AUD) in primary care is critical for increasing access to alcohol treatment. However, AUD is underdiagnosed and may be inequitably diagnosed due to societal structures that determine access to resources (e.g., structural racism that limits opportunities for some groups and influences interpersonal interactions in and beyond health care). This study described patterns of provider-documented AUD in primary care across intersections of race, ethnicity, sex, and community-level socioeconomic status (SES). Methods This cross-sectional study used EHR data from a regional healthcare system with 35 primary care clinics that included adult patients who completed alcohol screenings between 3/1/2015 and 9/30/2020. The prevalence of provider-documented AUD in primary care based on International Classification of Diseases-9 (ICD-9) and ICD-10 diagnoses was compared across intersections of race, ethnicity, sex, and community-level SES. Results Among 439,375 patients, 6.6% were Latine, 11.0% Asian, 5.4% Black, 1.3% Native Hawaiian/Pacific Islander (NH/PI), 1.5% American Indian/Alaska Native (AI/AN), and 74.2% White, and 58.3% women. The overall prevalence of provider-documented AUD was 1.0% and varied across intersecting identities. Among women, the prevalence was highest for AI/AN women with middle SES, 1.5% (95% CI 1.0–2.3), and lowest for Asian women with middle SES, 0.1% (95% CI 0.1–0.2). Among men, the prevalence was highest for AI/AN men with high and middle SES, 2.0% (95% CI 1.1–3.4) and 2.0% (95% CI 1.2–3.2), respectively, and lowest for Asian men with high SES, 0.5% (95% CI 0.3–0.7). Black and Latine patients tended to have a lower prevalence of AUD than White patients, across all intersections of sex and SES except for Black women with high SES. There were no consistent patterns of the prevalence of AUD diagnosis that emerged across SES. Conclusion The prevalence of provider-documented AUD in primary care was highest in AI/AN men and women and lowest in Asian men and women. Findings of lower prevalence of provider-documented AUD in Black and Hispanic than White patients across most intersections of sex and SES differed from prior studies. Findings may suggest that differences in access to resources, which vary in effects across these identity characteristics and lived experiences, influence the diagnosis of AUD in clinical care.

Abstract The Clostridia produce and secrete Large Clostridial Glucosylating Toxins (LCGTs) responsible for disease symptoms, but the secretion mechanism is largely unknown. Recently, a holin-like protein was shown to be essential for toxin secretion. Holins, typically bacteriophage-specific proteins, are part of the holin-endo(lysin) system that releases phage progeny. To determine if the clostridia also use a lysin, we investigated two conserved putative lysins, M7404_01910 and M7404_02200, in the release of the LCGTs TcdA and TcdB from a Clostridioides difficile ribotype 027 strain, M7404. Sequence analysis and structural modelling indicates that both proteins are related to N-acetylmuramoyl-l-alanine amidases, similar to CD27L, a lysin from the C. difficile phage ΦCD27. Disruption of these genes reveal that only M7404_02200 contributes to toxin secretion and does so in a non-lytic fashion. Peptidoglycan hydrolysis assays show that recombinant M7404_02200 is an active peptidoglycan amidase, confirming its role in TcdA and TcdB secretion in C. difficile M7404.

Abstract Background Lyme disease continues to expand in Canada and the USA and no single intervention is likely to curb the epidemic. Methods We propose a platform to quantitatively assess the effectiveness of a subset of Ixodes scapularis tick management approaches. The platform allows us to assess the impact of different control treatments, conducted either individually (single interventions) or in combination (combined efforts), with varying timings and durations. Interventions include three low environmental toxicity measures in differing combinations, namely reductions in white-tailed deer (Odocoileus virginianus) populations, broadcast area-application of the entomopathogenic fungus Metarhizium anisopliae, and fipronil-based rodent-targeted bait boxes. To assess the impact of these control efforts, we calibrated a process-based mathematical model to data collected from residential properties in the town of Redding, southwestern Connecticut, where an integrated tick management program to reduce I.xodes scapularis nymphs was conducted from 2013 through 2016. We estimated parameters mechanistically for each of the three treatments, simulated multiple combinations and timings of interventions, and computed the resulting percent reduction of the nymphal peak and of the area under the phenology curve. Results Simulation outputs suggest that the three-treatment combination and the bait boxes–deer reduction combination had the overall highest impacts on suppressing I. scapularis nymphs. All (single or combined) interventions were more efficacious when implemented for a higher number of years. When implemented for at least 4 years, most interventions (except the single application of the entomopathogenic fungus) were predicted to strongly reduce the nymphal peak compared with the no intervention scenario. Finally, we determined the optimal period to apply the entomopathogenic fungus in residential yards, depending on the number of applications. Conclusions Computer simulation is a powerful tool to identify the optimal deployment of individual and combined tick management approaches, which can synergistically contribute to short-to-long-term, costeffective, and sustainable control of tick-borne diseases in integrated tick management (ITM) interventions. Graphical Abstract

Abstract Cardiovascular imaging is exponentially increasing in the diagnosis, risk stratification, and therapeutic management of patients with cardiovascular disease. The European Society of Cardiovascular Radiology (ESCR) is a non-profit scientific medical society dedicated to promoting and coordinating activities in cardiovascular imaging. The purpose of this paper, written by ESCR committees and Executive board members and approved by the ESCR Executive Board and Guidelines committee, is to codify a standardized approach to creating ESCR scientific documents. Indeed, consensus development methods must be adopted to ensure transparent decision-making that optimizes national and global health and reaches a certain scientific credibility. ESCR consensus documents developed based on a rigorous methodology will improve their scientific impact on the management of patients with cardiac involvement. Critical relevance statement This document aims to codify the methodology for producing consensus documents of the ESCR. These ESCR indications will broaden the scientific quality and credibility of further publications and, consequently, the impact on the diagnostic management of patients with cardiac involvement. Key Points Cardiovascular imaging is exponentially increasing for diagnosis, risk stratification, and therapeutic management. The ESCR is committed to promoting cardiovascular imaging. A rigorous methodology for ESCR consensus documents will improve their scientific impact.

Abstract Background The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML. Methods Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples. Results IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002). Conclusions The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

Abstract Slow strain rate tensile testing was conducted on electrodeposited copper, which is a candidate coating material for used nuclear fuel containers. Embrittlement was observed in electrodeposited copper containing 26.4 ± 1.0 ppm hydrogen, with a strain rate sensitivity such that the embrittlement was exacerbated at lower strain rate (5 × 10−7 s−1). Tensile tests conducted at 100° and 200 °C also intensified embrittlement when compared with tests conducted at room temperature. In contrast, electrodeposited copper containing only 5.25 ± 0.97 ppm hydrogen exhibited ductile behavior at all tested strain rates and temperatures. These findings suggest that a previously unexplained slow strain rate hydrogen embrittlement can operate in electrodeposited copper provided that the hydrogen concentration is sufficiently high. Further analyses revealed that the deformation of embrittled copper is achieved by the formation of internal microcracks which coalesce at the point of failure.

Abstract Background Over two decades of research about traumatic brain injury (TBI) rehabilitation emphasized the persistence of racial health disparities in functional outcomes that disproportionately impact Black populations without naming or addressing racism as the root problem. Further, the experiences of Black people with TBI have yet to be documented and accounted for in scientific scholarship from the perspectives of Black persons in Canada. Purpose This study intended to examine the rehabilitation narratives of Black TBI survivors, family caregivers, and rehabilitation providers and use critical race theory as a conceptual framework to understand how anti-Black racism manifests in those experiences. Methods Through critical narrative inquiry informed by a critical constructivist paradigm and a critical race theory lens, in-depth narrative interviewing were conducted with seven survivors, three family caregivers, and four rehabilitation providers. Data were analyzed using reflexive thematic analysis within and across groups of participants to conceptualize themes and sub-themes. Findings Themes captured how racism becomes institutionalized in TBI rehabilitation: (1) the institutional construction of deficient Black bodies, (2) the institutional construction of rehabilitation access, (3) the institutional investment in resisting and approximating whiteness in rehabilitation practice, and (4) the institutional construction of deficient Black futures. Conclusion Study findings point to the dire need to ensure rehabilitation programs, services, and the delivery of care are not determined based on inequitable practices, racial biases and assumptions about Black people, which determine who deserves to get into rehabilitation and have opportunities to be supported in working towards living a full and meaningful life.

Introduction: Recent policy changes in Washington State presented a unique opportunity to pair evidence-based interventions with first responder services to combat increasing opioid overdoses. However, little is known about how these interventions should be implemented. In partnership with the Research with Expert Advisors on Drug Use team, a group of academically trained and community-trained researchers with lived and living experience of substance use, we examined facilitators and barriers to adopting leave-behind naloxone, field-based buprenorphine initiation, and HIV and hepatitis C virus (HCV) testing for first responder programs. Methods: Our team completed semi-structured, qualitative interviews with 32 first responders, mobile integrated health staff, and emergency medical services (EMS) leaders in King County, Washington, from February–May 2022. Semi-structured interviews were recorded, transcribed, and coded using an integrated deductive and inductive thematic analysis approach grounded in community-engaged research principles. We collected data until saturation was achieved. Data collection and analysis were informed by the Consolidated Framework for Implementation Research. Two investigators coded independently until 100% consensus was reached. Results: Our thematic analysis revealed several perceived facilitators (ie, tension for change, relative advantage, and compatibility) and barriers (ie, limited adaptability, lack of evidence strength and quality, and prohibitive cost) to the adoption of these evidence-based clinical interventions for first responder systems. There was widespread support for the distribution of leave-behind naloxone, although funding was identified as a barrier. Many believed field-based initiation of buprenorphine treatment could provide a more effective response to overdose management, but there were significant concerns that this intervention could run counter to the rapid care model. Lastly, participants worried that HIV and HCV testing was inappropriate for first responders to conduct but recommended that this service be provided by mobile integrated health staff. Conclusion: These results have informed local EMS strategic planning, which will inform roll out of process improvements in King County, Washington. Future work should evaluate the impact of these interventions on the health of overdose survivors.

Abstract Background Canada legalized recreational cannabis in 2018, and one of the primary objectives of the Cannabis Act was to protect youth by reducing their access to cannabis and providing public education. Canada has the highest prevalence of cannabis use worldwide, particularly among youth and young adults under the age of 25. Cannabis use is linked with many adverse effects for youth and young adults including psychosis, anxiety, depression, respiratory distress, cannabinoid hyperemesis syndrome, and impaired cognitive performance. Despite the high prevalence of cannabis use and the evolution of policies in Canada and globally, significant knowledge and research gaps remain regarding youth and young adult cannabis use. The aim of this scoping review is to map the extent, nature, and range of evidence available on youth and young adult cannabis use in Canada since its legalization, in order to strengthen policies, services, treatments, training, and public education strategies. Methods Using a scoping review framework developed by Arksey and O’Malley, along with the PRISMA-ScR guidelines, we conducted a rigorous search in five academic databases: MEDLINE, Embase, APA PsycINFO, CINAHL and Web of Science Core Collection. We included empirical studies that collected data in Canada after the legalization of recreational cannabis (October 2018) and focused on youth or young adults

Abstract Background Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel. Methods MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a “significant IrAE” (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs. Discussion The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment. Trial Registration The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

Abstract Henry’s law constant, which describes the proportionality of dissolved gas to partial pressure of free gas in liquid–gas equilibrium systems, can also be applied to mass transport applications. In this work, we investigated an approach for determining the solubility of noble gases in a molten salt liquid utilizing the equilibrium concept of Henry’s gas constant. Henry’s gas constant is described as a mathematical function dependent on the van der Waals radius of the noble gas and the temperature of the molten salt. The alteration in Gibbs free energy encompasses contributions from both surface and volume energies. Enthalpy and entropy are deduced from these surface and volume energies in the Gibbs free energy formulation. A comparative analysis was conducted between the conventional method and our proposed model. Moreover, useful chemical properties can be determined from examination of surface and volume energies. Our findings provide an accurate and general theory of Gibbs free energy that can be validated experimentally based on the model proposed herein. This work unifies the prediction of Henry gas constant and subsequently the entropy and enthalpy calculation for noble gases in a molten salt solution to a single functional form using van der Waals radius of the gas and temperature of the system. This functional form is then used to perform a multiple regression method to find two parameters corresponding to the surface energy and volume energy. These two parameters are consistent between all combinations of noble gas and molten salt.

Objective Pain in inflammatory bowel disease (IBD) is frequently neglected/overlooked, particularly in ulcerative colitis, and communication about pain can be suboptimal. The current study juxtaposes clinicians’ conceptualisations of patients’ pain with patient narratives. The aim was to inform the development of a pain reporting tool and provide guidance for better communication about IBD pain.Methods In-depth semistructured interviews with 13 IBD clinicians in the UK: gastroenterologists (n=5), colorectal surgeons (n=2), specialist nurses (n=4) and psychologists (n=2). Primary analysis of these data and secondary analysis of earlier interviews about pain in IBD with clinicians (n=12) and patients (n=71) followed principles of reflexive thematic analysis. Themes were compared across participant groups.Results Clinicians state that they regularly ask about pain in Crohn’s disease, but not ulcerative colitis. Patients, however, report inconsistent attention to pain in either condition, with power dynamics constraining their pain report. Some clinicians acknowledged that they assume that patients manage their pain independently, leading to insufficient follow-up (Theme 1: Contradictions and ambiguities when discussing pain in IBD). Inadequate acknowledgement of pain by clinicians was attributed to time constraints and systemic issues. Where inflammatory or structural causes were lacking, some clinicians default to attributing pain to irritable bowel syndrome, contributing to patients feeling uncared for (Theme 2: Consequences of limited tools and time for pain). Addressing pain was further complicated by the reluctance of some patients to express discomfort or pain and others who avoided activities that might lead to pain (Theme 3: Addressing pain in patients who do not complain).Conclusion The study emphasises the importance of consistent pain evaluation and management, advocating for more open dialogues between clinicians and patients.

ABSTRACT Early mortality syndrome (EMS) or acute hepatopancreatic necrosis syndrome (AHPND) is an epizootic bacterial infection of shrimp that has had significant negative impact on the global shrimp aquaculture industry. This disease is largely attributed to pathogenic Vibrio parahaemolyticus EMS strains (VP‐EMS). Application of probiotics was examined for control of pathogenic VP‐EMS infections in Pacific white shrimp (Litopenaeus vannamei) under laboratory‐scale conditions. Two probiotic products, a single strain (O14VRQ) of Bacillus subtilis and a blend (Plus10) of five strains of Bacillus from four different species (Bacillus amyloliquifaciens, Bacillus megaterium, Bacillus brevis, and two distinct strains of Bacillus subtilis), were evaluated at various concentrations as feed additives (applied as a top coat on commercial feed) or dosed directly into the culture water. Two trials were conducted in which shrimp were fed either a control feed (no probiotics) or probiotic‐coated feed for 7 days prior to be being challenged with VP‐EMS. Shrimp were observed for clinical signs of disease and mortalities during the disease challenge study. These experiments demonstrated that while both Bacillus probiotic products were shown to significantly (p < 0.05) improve shrimp survival, the O14VRQ strain provided the most consistent protection across the trials in top‐coated feed. Overall, better efficacy was observed with probiotic‐coated feeds. Findings were directly and positively correlated with concentration for top‐coated and even more so for direct in‐tank applications. Collectively, these findings contribute to our understanding about how probiotic strains could be applied to enhance shrimp health in aquaculture.

The professional identity of scientists has historically been cultivated to value research over teaching, which can undermine initiatives that aim to reform science education. Course-Based Research Experiences (CRE) and the inclusive Research and Education Communities (iREC) are two successful and impactful reform efforts that integrate research and teaching. The aim of this study is to explicate the professional identity of instructors who implement a CRE within an established iREC and to explore how this identity contributes to the success of these programs. 97 CRE instructors from the Science Education Alliance (SEA) iREC participated in a 2-year, multi-stage, qualitative research project that involved weekly reflective journaling, autoethnographic description, small group evaluation and writing, and large-scale community checking. The resulting description of professional identity consisted of shared values (inclusivity, student success, community membership, ownership/agency, science, overcoming failure, and persistence), specified roles (mentor, advocate, scientist, educator, motivator, collaborator, community builder, learner, evaluator and project manager) and a stated sense of self (dedicated, resilient, pride in students, multiskilled, valued, community member, responsible and overworked). Analysis of individual reflective diary entries revealed how a professional identity underpinned and facilitated the ways in which faculty addressed challenges that arose and worked toward the success of every student. It is the self-concept of the professional identity of the instructor in the context of the CRE classroom that directed the extended commitment and effort that these instructors evidently put into their work with students, which facilitated student engagement, student persistence, and their collective scientific output. The study concludes that a professional identity of STEM faculty in the context of a CRE and iREC combines being a researcher and educator, and that this integrated identity is central for current initiatives aimed at transforming undergraduate STEM education.

The taxonomy of king cobras (Ophiophagus) was reevaluated using qualitative, mensural and meristic characters, based on 148 entire and five skeletal specimens, and supported by a recent molecular phylogenetic analysis. We provide nomenclatural synopses of both the genus and species-series nomina. We restrict the concept of Ophiophagus hannah s. str. to populations from eastern Pakistan, northern and eastern India, the Andaman Islands, Indo-Burma and Indo-China, south to central Thailand. The nomen Ophiophagus bungarus (Schlegel, 1837) comb. nov. is revived for the populations inhabiting the Sunda Shelf area, including the Malay Peninsula, the Greater Sunda Islands and parts of the southern Philippines. We describe two new species, Ophiophagus kaalinga Gowri Shankar, Das & Ganesh sp. nov. endemic to the Western Ghats of south-western India and Ophiophagus salvatana Gowri Shankar, Das & Wüster sp. nov., inhabiting the island of Luzon in northern Philippines. For the purpose of nomenclatural stability, we designate a neotype for Hamadryas hannah Cantor, 1836. A dichotomous identification key to the four species recognized here is provided.

Background In 2021 we launched the BronchStart study, which collected information on 17,899 presentations in children with serious respiratory tract infections following the release of lockdown restrictions. Our study informed the Joint Committee on Vaccination and Immunisation’s decision to recommend the introduction maternal respiratory syncytial virus (RSV) vaccination, which was introduced in the United Kingdom in August/September 2024. Study question We modified our original protocol to conduct a United Kingdom-wide assessment of maternal vaccination against RSV. Methods and likely impact We will conduct a multi-centre study, utilising the PERUKI network used in the original BronchStart study, to assess the effectiveness of maternal vaccination using a test-negative study design. We will gather detailed clinical information on children admitted with bronchiolitis in the post-RSV vaccination era, and understand possible reasons for incomplete vaccine uptake.

Background Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. Methods and Results In a double‐blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F‐sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24‐month change in coronary calcium score, and 12‐month changes in thoracic aorta calcium score, coronary and aortic 18F‐sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [−64 to 148] Agatston units) and either denosumab (94 [0–212] Agatston units, P=0.24) or alendronic acid (34 [−62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22–512] Agatston units) and either denosumab (118 [11–340], P=0.75) or alendronic acid (116 [26–498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F‐sodium fluoride activity between treatment groups. Conclusions Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. registration https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer's disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Aβ) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in participants with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from 18 participants in an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau, and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812.

Habitat loss and fragmentation due to accelerated agriculture expansion is a major threat to existing wildlife populations across Asia. The human-wildlife interface mosaic across Asia is varied in terms of juxtaposition and structure, which can strongly influence biodiversity value and impacts on wildlife species. Here we analyzed habitat selection behavior of Asian elephant (Elephas maximus) across three study sites with different agriculture use patterns in Myanmar, a country recognized as a global biodiversity hotspot, including but not limited to, commercial palm oil and sugarcane plantations, and subsistence agriculture. These different agriculture use landscape capture landscape mosaic structure found across Asia. Given elephants exhibit heterogeneous spatial behavior, we fitted individual step selection and resource selection models to gain insight into the diversity of strategies employed at the local (step) and home range (third-order) scale. We used variance partitioning analysis to quantify the explanatory contribution of individual and study sites across both scales. We found that the variation in the resource selection behavior was mainly due to individual differences, and the configuration of agriculture present in an individual’s range was the most influential to its selection behavior. Enhancing understanding of how the level of fragmentation on the landscape relates to agricultural use can serve to help focus conservation efforts. Continued accelerated agriculture expansion is increasing the rate of contact between elephants and humans and, thereby escalating negative human-elephant interactions, often resulting in human and elephant deaths. Gaining a deeper understanding of habitat selection behavior by elephants across the changing landscapes of Asia can help inform management decisions and conservation actions.

Over the last two decades, there have been numerous initiatives to improve undergraduate student outcomes in STEM. One model for scalable reform is the inclusive Research Education Community (iREC). In an iREC, STEM faculty from colleges and universities across the nation are supported to adopt and sustainably implement course-based research – a form of science pedagogy that enhances student learning and persistence in science. In this study, we used pathway modeling to develop a qualitative description that explicates the HHMI Science Education Alliance (SEA) iREC as a model for facilitating the successful adoption and continued advancement of new curricular content and pedagogy. In particular, outcomes that faculty realize through their participation in the SEA iREC were identified, organized by time, and functionally linked. The resulting pathway model was then revised and refined based on several rounds of feedback from over 100 faculty members in the SEA iREC who participated in the study. Our results show that in an iREC, STEM faculty organized as a long-standing community of practice leverage one another, outside expertise, and data to adopt, implement, and iteratively advance their pedagogy. The opportunity to collaborate in this manner and, additionally, to be recognized for pedagogical contributions sustainably engages STEM faculty in the advancement of their pedagogy. Here, we present a detailed pathway model of SEA that, together with underpinning features of an iREC identified in this study, offers a framework to facilitate transformations in undergraduate science education.

Abstract Background The finger lime (Citrus australasica), one of six Australian endemic citrus species shows a high natural phenotypic diversity and novel characteristics. The wide variation and unique horticultural features have made this lime an attractive candidate for domestication. Currently no haplotype resolved genome is available for this species. Here we present a high quality, haplotype-resolved reference genome for this species using PacBio HiFi and Hi-C sequencing. Results Hifiasm assembly and SALSA scaffolding resulted in a collapsed genome size of 344.2 Mb and 321.1 Mb and 323.2 Mb size for the two haplotypes. The nine pseudochromosomes of the collapsed genome had an N50 of 35.2 Mb, 99.1% genome assembly completeness and 98.9% gene annotation completeness (BUSCO). A total of 41,304 genes were predicted in the nuclear genome. Comparison with C. australis revealed that 13,661 genes in pseudochromosomes were unique in C. australasica. These were mainly involved in plant-pathogen interactions, stress response, cellular metabolic and developmental processes, and signal transduction. The two genomes showed a syntenic arrangement at the chromosome level with large structural rearrangements in some chromosomes. Genetic variation among five C. australasica cultivars was analysed. Genes related to defense, synthesis of volatile compounds and red/yellow coloration were identified in the genome. A major expansion of genes encoding thylakoid curvature proteins was found in the C. australasica genome. Conclusions The genome of C. australasica present in this study is of high quality and contiguity. This genome helps deepen our understanding of citrus evolution and reveals disease resistance and quality related genes with potential to accelerate the genetic improvement of citrus.

Abstract Surfaces on transit vehicles are frequently touched and could potentially act as reservoirs for micro-organism transmission. Regular cleaning and disinfection to minimize the spread of micro-organisms is operationally challenging due to the need to keep vehicles in circulation. The application of copper (Cu) alloys to high- touch surfaces could help reduce the risk of cross-contamination, however, little is known about the durability and efficacy of engineered copper surfaces after prolonged use. Three Cu products (decal, thermal fabrication, and alloy covers) were assessed over a 12-month period. These Cu products were randomly installed on 110 stanchions on three buses and four train (SkyTrain) cars in Vancouver and three buses, two subway cars, and two streetcars in Toronto with mirrored control surfaces directly opposite. Bacterial counts (Colony forming units, CFU) and ATP bioluminescence (ATPB) were measured every two months after peak morning routes. Durability of the Cu products were assessed monthly through visual inspection and colorimetry assays or by ex-situ microscopy. Cu products on stanchions reduced the mean colony forming units (CFU) of all vehicles by 42.7% in the mean CFU (0.573 (CI 95% 0.453–0.726), p-value

Objective Holographic Memory Resolution® (HMR®), a mind‐based therapy, has been used for decades as a nonpharmacologic intervention for trauma imprinting to alleviate depression, anxiety, pain, and post‐traumatic stress disorder (PTSD). No clinical studies were found examining the use of HMR®. This study examined the feasibility and preliminary efficacy of administering HMR® to individuals experiencing chronic pain and related biopsychosocial symptoms. Methods A feasibility, mixed‐methods study was conducted between October 2021 and July 2022 and included four HMR® sessions over 1–12 weeks. A convenience sample was comprised of 60 adults suffering from chronic physical or emotional pain of 4+ (0–10 scale) over 6+ months at two clinics in the U.S. Baseline and subsequent surveys after sessions 2, 3, and 4 assessed symptom response. Symptoms were longitudinally measured via self‐report of depression, anxiety, somatic symptom burden, PTSD, and vitality. Results 73% completed all four sessions, demonstrating feasibility. Ages ranged from 19 to 80 years, 85% were female, and 87% were Caucasian. 52% reported high risk for toxic stress. Four symptoms decreased significantly: depression (p = 0.05), anxiety (p = 0.03), symptom burden (p

Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system – comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.

ABSTRACTHigh levels of COVID-19 vaccine hesitancy have been reported among Black and Latinx populations, with lower vaccination coverage among racialized versus White sexual and gender minorities. We examined multilevel contexts that influence COVID-19 vaccine uptake, barriers to vaccination, and vaccine hesitancy among predominantly racialized sexual and gender minority individuals. Semi-structured online interviews explored perspectives and experiences around COVID-19 vaccination. Interviews were recorded, transcribed, uploaded into ATLAS.ti, and reviewed using thematic analysis. Among 40 participants (mean age, 29.0 years [SD, 9.6]), all identified as sexual and/or gender minority, 82.5% of whom were racialized. COVID-19 vaccination experiences were dominated by structural barriers: systemic racism, transphobia and homophobia in healthcare and government/public health institutions; limited availability of vaccination/appointments in vulnerable neighborhoods; absence of culturally-tailored and multi-language information; lack of digital/internet access; and prohibitive indirect costs of vaccination. Vaccine hesitancy reflected in uncertainties about a novel vaccine amid conflicting information and institutional mistrust was integrally linked to structural factors. Findings suggest that the uncritical application of “vaccine hesitancy” to unilaterally explain undervaccination among marginalized populations risks conflating structural and institutional barriers with individual-level psychological factors, in effect placing the onus on those most disenfranchised to overcome societal and institutional processes of marginalization. Rather, disaggregating structural determinants of vaccination availability, access, and institutional stigma and mistrust from individual attitudes and decision-making that reflect vaccine hesitancy, may support 1) evidence-informed interventions to mitigate structural barriers in access to vaccination, and 2) culturally-informed approaches to address decisional ambivalence in the context of structural homophobia, transphobia, and racism.

Abstract Impedance aggregometry is an alternative to light transmission aggregometry that allows analysis of platelet function in whole blood samples. We hypothesized (1) impedance aggregometry would produce repeatable results, (2) inhibition of cyclooxygenase with aspirin would attenuate aggregation responses to collagen and abolish the aggregation response to arachidonic acid (AA), and (3) thromboxane receptor antagonism (terutroban) would attenuate the aggregation response to AA. Venous blood was obtained from 11 participants three times separated by at least 2 weeks. One sample followed 7‐day‐aspirin intervention (81 mg once daily; ASA), the others no intervention (control). Aggregation was induced using 1 μg/mL collagen ([col 1]), 5 μg/mL collagen ([col 5]), and 50 mM AA via impedance aggregometry to determine total aggregation (AUC) analyzed for intra‐test repeatability, inter‐test repeatability, intervention (ASA or control), and incubation (saline or terutroban). [col 1] showed high intra‐test (p ≤ 0.03 visit 1 and 2) and inter‐test repeatability (p

Background There is a growing interest in practice-based implementation research, yet too often research prioritizes and is most successful in academic settings. During a national implementation trial to evaluate the effectiveness of Collaborative Care for co-occurring opioid use and mental health disorders, we lost three of our 11 participating implementation sites, all representing community sites. Method To better understand needed supports for implementation trial participation, we conducted exit interviews ( n = 5) with key staff at these community sites. Interview transcripts were double-coded and analyzed using Rapid Assessment Process. Qualitative themes were iteratively reviewed by the study team. Results Three themes emerged characterizing challenges for community sites, including that: (1) research threatens sites’ most precious resource—staff; (2) staff lack comfort with and skills for research; and (3) research participation in its current form does not offer a clear return on investment. Conclusions Learnings from this work illuminate some of the barriers community sites face when trying to participate in multisite implementation research. An undercurrent of participant perspectives was the belief that community sites like theirs are just not set up to successfully participate in clinical trial research, including population-based implementation trials. Future implementation trials should consider strategies that disrupt traditional approaches, increasing the equitable inclusion of diverse practice settings in implementation research.

Community residents have repeatedly organized and identified policy solutions to address rapidly increasing housing pressures within the greater Boston area. However, resident expertise is often dismissed as anecdotal. Since 2015, The Healthy Neighborhoods Research Consortium (HNRC) has used a participatory action research (PAR) approach to articulate research questions, design mixed methods instruments, collect and analyze data, and share findings to meet community-identified research priorities. We argue in favor of research processes that enable resident experiences and expertise to be used in conjunction with quantitative data analysis, and that support real-time action to address the harms of gentrification in their communities. The goals of this brief are to describe the HNRC’s process for developing a “PAR Analytic Network” — a program focused on building community residents’ power to create new academic partnerships for the purpose of answering their broader systems-level questions. Based on our experience we offer four recommendations: 1) Apply a PAR approach to identify research question(s) of mutual interest; 2) Community control over the academic partner selection process; 3) Academic Partners: Trust the PAR process; and 4) Community Residents: Identify the Silver Linings.

Background Atopic eczema is a common childhood skin problem linked with asthma, food allergy and allergic rhinitis that impairs quality of life. Objectives To determine whether advising parents to apply daily emollients in the first year can prevent eczema and/or other atopic diseases in high-risk children. Design A United Kingdom, multicentre, pragmatic, two-arm, parallel-group randomised controlled prevention trial with follow-up to 5 years. Setting Twelve secondary and four primary care centres. Participants Healthy infants (at least 37 weeks’ gestation) at high risk of developing eczema, screened and consented during the third trimester or post delivery. Interventions Infants were randomised (1 : 1) within 21 days of birth to apply emollient (Doublebase Gel®; Dermal Laboratories Ltd, Hitchin, UK or Diprobase Cream®) daily to the whole body (excluding scalp) for the first year, plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). Families were not blinded to allocation. Main outcome measures Primary outcome was eczema diagnosis in the last year at age 2 years, as defined by the UK Working Party refinement of the Hanifin and Rajka diagnostic criteria, assessed by research nurses blinded to allocation. Secondary outcomes up to age 2 years included other eczema definitions, time to onset and severity of eczema, allergic rhinitis, wheezing, allergic sensitisation, food allergy, safety (skin infections and slippages) and cost-effectiveness. Results One thousand three hundred and ninety-four newborns were randomised between November 2014 and November 2016; 693 emollient and 701 control. Adherence in the emollient group was 88% (466/532), 82% (427/519) and 74% (375/506) at 3, 6 and 12 months. At 2 years, eczema was present in 139/598 (23%) in the emollient group and 150/612 (25%) in controls (adjusted relative risk 0.95, 95% confidence interval 0.78 to 1.16; p = 0.61 and adjusted risk difference −1.2%, 95% confidence interval −5.9% to 3.6%). Other eczema definitions supported the primary analysis. Food allergy (milk, egg, peanut) was present in 41/547 (7.5%) in the emollient group versus 29/568 (5.1%) in controls (adjusted relative risk 1.47, 95% confidence interval 0.93 to 2.33). Mean number of skin infections per child in the first year was 0.23 (standard deviation 0.68) in the emollient group versus 0.15 (standard deviation 0.46) in controls; adjusted incidence rate ratio 1.55, 95% confidence interval 1.15 to 2.09. The adjusted incremental cost per percentage decrease in risk of eczema at 2 years was £5337 (£7281 unadjusted). No difference between the groups in eczema or other atopic diseases was observed during follow-up to age 5 years via parental questionnaires. Limitations Two emollient types were used which could have had different effects. The median time for starting emollients was 11 days after birth. Some contamination occurred in the control group (< 20%). Participating families were unblinded and reported on some outcomes. Conclusions We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children. Emollient use was associated with a higher risk of skin infections and a possible increase in food allergy. Emollient use is unlikely to be considered cost-effective in this context. Future research To pool similar studies in an individual patient data meta-analysis. Trial registration This trial is registered as ISRCTN21528841. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information. Plain language summary Eczema is a troublesome itchy skin condition affecting 1 in 5 children and 1 in 10 UK adults. There is no cure and affected children are more likely to develop food allergies. We wanted to see if we could prevent eczema by protecting the skin of babies at higher risk of developing eczema (with an immediate relative with eczema, asthma or hay fever) with moisturisers used to treat dry skin. Previous research suggested that protecting the skin barrier might also prevent food allergy. One thousand three hundred and ninety-four families took part in a study; half of them were asked to apply moisturiser every day to their newborn baby for the first year and half to look after their baby’s skin in the normal way. At the age of 2 years, we did not see any difference in how common eczema was between the two groups: 23% had eczema in the moisturiser group and 25% in the normal care group. It did not matter how we defined eczema – whether examined by a researcher or parent report. We did not find any differences in related conditions like asthma or hay fever either. We found that children using moisturisers had seen their doctor slightly more often for mild skin infections. There was a hint that food allergy might have been increased in the moisturiser group, but there was not enough data to be sure. We followed up the children to age 5 years, but we still did not find any benefits from using moisturisers in early life. Since this study, other similar research has been done using newer types of moisturisers, but their results are the same. This study shows that using daily moisturisers on healthy babies with a high risk of eczema does not prevent eczema. It is one less thing for busy families to worry about. Scientific summary Background Eczema, also known as atopic eczema (AE) or atopic dermatitis, is a common inflammatory skin disease that typically starts in early life. Eczema affects around 20% of children and 10% of adults in developed countries. Although most cases are mild, moderate to severe disease can have a major impact on the quality of life of an affected child and their family. The main symptom of this systemic inflammatory disease is itching which leads to scratching, bleeding, secondary infection as well as sleep loss and the social stigma of a visible skin disease. Genetic factors such as mutations in the gene encoding filaggrin (FLG) – a protein that is important for maintaining skin barrier function – have been shown to be important in increasing eczema risk, severity and persistence. Epidemiological studies showing that eczema is more common in smaller families, migrant populations and in higher socioeconomic status also suggest that the environment is critically important in determining disease expression. Eczema is closely related to other ‘atopic’ conditions including asthma, hay fever and food allergy. Some evidence suggests that the impaired skin barrier caused by eczema in early life is an important route for the development of food allergy as a result of sensitisation through the skin. Treatment of eczema depends on severity: mild eczema can be treated with emollients (moisturisers) and weak topical corticosteroids. Moderate eczema usually needs potent topical corticosteroids and other anti-inflammatory treatments such as topical tacrolimus, whereas severe eczema is treated by ultraviolet light or systemic treatments including ciclosporin, methotrexate, dupilumab and an emerging pipeline of new biologics. While good progress has been made with treatment, prevention of eczema remains challenging. Strategies include avoidance of allergens (foods and house dust mite) during pregnancy and early life, exclusive breastfeeding, or different timing of introducing solids, but these have not shown convincing preventative effects. Probiotics and prebiotics have shown some benefit, but the exact strain or combination and timing of intervention remain unclear. One previously unexplored eczema prevention strategy is enhancement of the skin barrier in early life. The hypothesis is that enhancing the skin barrier could interrupt an early cascade of inflammatory events that can lead to chronic auto-immune eczema and potentially prevent skin sensitisation to common allergens that can lead to food allergy. Two small pilot studies suggested that protecting the skin of babies who had a first-degree relative with eczema, asthma or hay fever with emollients could prevent the development of eczema in the first year of life. We wanted to see whether daily emollient application for the first year of life in such high-risk babies can prevent eczema and other allergic diseases in a sustained and convincing way by means of a definitive pragmatic randomised controlled trial. Objectives The primary objective was to determine whether advising parents to apply emollient daily for the first year of life could prevent eczema at 2 years of age when compared with standard skin-care advice alone in children at high risk of developing eczema. Secondary objectives included evaluating whether prophylactic use of emollients would delay the onset of eczema or reduce eczema severity when compared to standard skin-care advice, whether any preventive effect at age 2 years was sustained up to age 5 years and to determine the safety and cost-effectiveness of such a strategy. We also sought to determine whether emollients could prevent the development of other associated allergic conditions including food allergy, asthma and hay fever up to the age of 5 years. Methods We conducted a multicentre, pragmatic, two-arm parallel group randomised controlled prevention trial which recruited participants from 12 hospitals and 4 general practices in the UK. Participants were infants of at least 37 weeks’ gestation at high risk of developing eczema defined by having at least one first-degree relative with a parental report of doctor-diagnosed eczema, allergic rhinitis or asthma. Mothers had to be 16 years or older, and the consenting adult had to understand English. We excluded babies with a severe widespread skin condition that would make eczema assessment difficult; a serious health issue that would make it difficult for the family to take part in the trial; or a condition that would make the use of emollient inadvisable. Informed consent was obtained from mothers during pregnancy, or mother, father or guardian post delivery. The intervention group was advised to use one of two study emollients (Doublebase Gel® or Diprobase Cream®) at least once daily to the whole body (excluding the scalp) until the child reached 1 year, plus standard skin-care advice (designated the ‘emollient group’). The control group was advised to use standard skin-care advice only. Standard skin-care guidance, in booklet and video format at the time of randomisation, provided advice to use mild cleansers and shampoos specifically formulated for infants, and to avoid soap, bubble bath and baby wipes, and was given to both groups. Intervention adherence was measured at 3, 6 and 12 months and defined as satisfactory if emollients were applied at least three to four times per week to most of the child’s body. A similar definition was used to define contamination in the control group. The primary outcome was presence of eczema in the last year when the baby was aged 2 years, defined as meeting the United Kingdom Working Party (UKWP) Diagnostic Criteria for AE for children under 4 years. Secondary outcomes encompassed other ways of defining eczema including any parental report of a clinical diagnosis of eczema up to 2 years, parent completion of UKWP criteria at 1 and 2 years, and presence of visible eczema at 2 years recorded by a nurse masked to treatment allocation. Other eczema secondary outcomes included time to onset of eczema (based on first parent report of clinician diagnosis and first topical corticosteroid or immunosuppressant prescription); severity of eczema measured by trained nurses using the Eczema Area and Severity Index at 2 years and parent-reported Patient-Oriented Eczema Measure at 1 and 2 years. Other secondary outcomes included parent-reported wheezing and allergic rhinitis between 1 and 2 years; allergic sensitisation (masked skin prick tests) to milk, egg, peanut, cat dander, grass pollen or dust mite at 2 years; parent-reported food allergy; parental report of clinical diagnosis of food allergy at 1 and 2 years; and allergy to milk, egg or peanut at 2 years confirmed either by oral food challenge or for cases in which no oral food challenge was done, an expert panel of experienced paediatric allergists masked to treatment allocation. The panel decisions were made using an algorithm, validated using data from a previous trial, which incorporates all available data including skin prick test results, previous reaction history, frequency of food ingestion and allergy tests done outside the trial. The main economic outcome measure was incremental cost per percentage decrease in risk of eczema at 2 years in a cost-effectiveness analysis (CEA). Cost–utility analyses using quality-adjusted life-years (QALYs) derived from the proxy Child Health Utility instrument-9 domains (CHU-9D) for the child was also conducted as a secondary analysis. Safety outcomes were parent-reported skin infections (parents were asked what the doctor called the infection) and emollient-related infant slippages during the intervention period (year 1). Tertiary outcomes at 3, 4 and 5 years were to evaluate if emollients in early life could also prevent later-onset allergic diseases including asthma, hay fever and food allergy, and to see whether any early possible benefits of eczema prevention were sustained. Outcomes included parental-reported presence of eczema; severity of eczema; wheezing; allergic rhinitis; food allergy symptoms and clinical diagnoses of asthma, allergic rhinitis and food allergy. Randomisation (1 : 1) within 21 days of birth was performed using computer-generated pseudo-random code with permuted blocks of randomly varying size and concealed from the trial investigators via a web-based randomisation system. Randomisation was stratified by recruiting centre and number of first-degree relatives with eczema, asthma or hay fever (1, 2 or > 2). Research nurses conducting outcome assessments were masked to participant treatment allocation. Families were not masked to the allocated interventions and were reminded not to reveal allocation to research nurses. The trial was powered to detect a relative reduction of 30% in the primary outcome at the 5% significance level (two-sided) with 90% power assuming that 30% of children in the control group would have eczema and 20% attrition, resulting in a sample size of 1282. The target sample size was reached faster than anticipated at which point the Trial Steering Committee permitted that all pregnant mothers who had already consented to the trial could be randomised on the birth of the baby giving a maximum possible sample size of 1400. We analysed participants as randomised regardless of adherence with allocation using available data (i.e. without imputation for missing data) with sensitivity analyses for missing data. The adjusted relative risk (RR) and risk difference for the primary outcome were estimated using generalised estimating equations with the binomial family and log/identity link respectively, with an exchangeable correlation matrix to account for randomisation stratification by centre and number of immediate family members with atopic disease (one, two, or more than two) included as a covariate. A number of planned subgroup analyses for the primary outcome were conducted including according to FLG genotype, to test the hypothesis that FLG null genotype affects response to intensive emollient use from birth. Results One thousand three hundred and ninety-four newborns were randomised between 19 November 2014 and 18 November 2016; 693 to the emollient group and 701 to the control group. Primary outcome data at 2 years were collected for 1210 infants (87%). Unblinding of research nurses prior to skin examination occurred for 12 infants in the intervention group and 6 in the control group. Adherence in the emollient group was 88% (466/532) at 3 months, 82% (427/519) at 6 months and 74% (375/506) at 12 months. In the control group, contamination due to self-directed use of emollients was reported for 18% (82/457), 17% (62/372) and 15% (49/324) at 3, 6 and 12 months, respectively, for infants who did not have a parental report of a doctor diagnosis of eczema. At age 2 years, eczema was present in 139 (23%) of 598 infants in the emollient group and in 150 (25%) of 612 infants in the control group [adjusted RR 0.95, 95% confidence interval (CI) 0.78 to 1.16; p = 0.61; adjusted risk difference −1.2%, 95% CI −5.9% to 3.6%]. All sensitivity analyses conducted, including using multiple imputation for missing primary outcome data, were consistent with the primary analysis. There was no evidence of an interaction effect with allocated group for the primary eczema outcome in any of the subgroup analyses (including FLG genotype). Other eczema definitions supported the results of the primary analysis. Eczema severity and time to onset of eczema were also similar in the two groups. Mean number of skin infections per child in year 1 was 0.23 [standard deviation (SD) 0.68] in the emollient group versus 0.15 (SD 0.46) in the control group; adjusted incidence rate ratio 1.55 (95% CI 1.15 to 2.09). Infant slippage incidents were reported for 15/584 (2.6%) in the emollient group and 11/584 (1.9%) in the control group. Food allergies to milk, egg or peanut at 2 years were confirmed in 41/547 (7.5%) infants in the emollient group and 29/568 (5.1%) in the control group (adjusted RR 1.47, 95% CI 0.93 to 2.33). The largest difference was in the proportion of infants with confirmed food allergy to egg, with an adjusted RR of 1.56 (95% CI 0.92 to 2.65). Results of other measures of food allergy and food sensitisation were similar. The proportion of infants with allergic rhinitis, wheezing and allergic sensitisation to cat dander, grass pollen and dust mite was similar between groups at 2 years. The differences in quality of life (using CHU-9D for the child and EuroQol-5 Dimensions, five-level version for the main carer) between the two groups were very small. Although the emollient intervention period was the first year of life, parents in the emollient group continued to report more frequent moisturiser application through to 5 years than in the control group. By 5 years, 188/608 (31%) parents in the emollient group had reported a clinical diagnosis of eczema in their child since 12 months, compared with 178/631 (28%) in the control group (adjusted RR 1.10, 95% CI 0.93 to 1.30). A diagnosis of food allergy by 5 years was reported for 92/609 (15%) allocated to emollients and 87/632 (14%) allocated to control (adjusted RR 1.11, 95% CI 0.84 to 1.45). Similarly, the percentage of parents reporting that their child had a clinical diagnosis of asthma or allergic rhinitis by 5 years were similar in the two groups. In the complete-case CEA mean cost was £398.23 (SD 1408.39) per child in the emollient group (n = 598) and £312.16 (SD 1105.04) in the control group (n = 610). When intervention use was combined with other health resource use, the adjusted incremental cost was £87.45 (95% CI −54.31 to 229.27). The adjusted difference in the proportion of children without eczema at 2 years was 0.0164 (95% CI −0.0329 to 0.0656) higher in the emollient group compared to the control group. The adjusted incremental cost per percentage decrease in risk of eczema was £5337 at 2 years. Adjusted QALYs for children were very slightly improved (i.e. higher) in the emollient group at 2 years. Conclusions We found no evidence of a useful preventive effect of emollients for eczema at our primary outcome time of 2 years. The failure to show a reduction in eczema was consistent regardless of how eczema was assessed. Some evidence of an increase in skin infections during the intervention period and a possible increase in food allergy at age 2 years was observed. No benefit was observed for time to onset of eczema or eczema severity, and no benefits were observed for eczema, asthma, hay fever or food allergy in longer-term follow-up to 5 years. Emollient use is unlikely to be considered cost effective in this context. Inclusion of individual patient data from all similar eczema prevention studies in further meta-analysis may provide a clearer assessment of whether emollients can prevent eczema and related diseases and provide more certainty about potential harms. Implications for health care The study does not support the use of emollients to prevent eczema and has found a small signal of possible harms, so this intervention cannot be recommended for health care or public health use. As the study relates to prevention of eczema, emollients should continue to be used as part of standard treatment for eczema. Trial registration This trial is registered as ISRCTN21528841. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information.

Background Most pretest probability (PTP) tools for obstructive coronary artery disease (CAD) were Western ‐developed. The most appropriate PTP models and the contribution of coronary artery calcium score (CACS) in Asian populations remain unknown. In a mixed Asian cohort, we compare 5 PTP models: local assessment of the heart (LAH), CAD Consortium (CAD2), risk factor‐weighted clinical likelihood, the American Heart Association/American College of Cardiology and the European Society of Cardiology PTP and 3 extended versions of these models that incorporated CACS: LAH(CACS), CAD2(CACS), and the CACS‐clinical likelihood. Methods and Results The study cohort included 771 patients referred for stable chest pain. Obstructive CAD prevalence was 27.5%. Calibration, area under the receiver‐operating characteristic curves (AUC) and net reclassification index were evaluated. LAH clinical had the best calibration (χ2 5.8; P=0.12). For CACS models, LAH(CACS) showed least deviation between observed and expected cases (χ2 37.5; P

Vascular smooth muscle cells (VSMCs), known for their remarkable lifelong phenotypic plasticity, play a pivotal role in vascular pathologies through their ability to transition between different phenotypes. Our group discovered that the deficiency of the mitochondrial protein Poldip2 induces VSMC differentiation both in vivo and in vitro. Further comprehensive biochemical investigations revealed Poldip2's specific interaction with the mitochondrial ATPase caseinolytic protease chaperone subunit X (CLPX), which is the regulatory subunit for the caseinolytic protease proteolytic subunit (ClpP) that forms part of the ClpXP complex – a proteasome-like protease evolutionarily conserved from bacteria to humans. This interaction limits the protease's activity, and reduced Poldip2 levels lead to ClpXP complex activation. This finding prompted the hypothesis that ClpXP complex activity within the mitochondria may regulate the VSMC phenotype.Employing gain-of-function and loss-of-function strategies, we demonstrated that ClpXP activity significantly influences the VSMC phenotype. Notably, both genetic and pharmacological activation of ClpXP inhibits VSMC plasticity and fosters a quiescent, differentiated, and anti-inflammatory VSMC phenotype. The pharmacological activation of ClpP using TIC10, currently in phase III clinical trials for cancer, successfully replicates this phenotype both in vitro and in vivo and markedly reduces aneurysm development in a mouse model of elastase-induced aortic aneurysms. Our mechanistic exploration indicates that ClpP activation regulates the VSMC phenotype by modifying the cellular NAD+/NADH ratio and activating Sirtuin 1. Our findings reveal the crucial role of mitochondrial proteostasis in the regulation of the VSMC phenotype and propose the ClpP protease as a novel, actionable target for manipulating the VSMC phenotype.

Objectives Synthesis of the experience of women with pain from pelvic or vaginal mesh or its removal, to identify pain-related problems and to formulate psychological aspects of pain.Design Systematic review and thematic analysis of qualitative studies of pain from pelvic or vaginal mesh, or mesh removal, in women over 18 years, using individual interviews, focus groups, free text, or written or oral contributions to formal enquiries.Data sources Medline, Embase and PsycINFO, from inception to 26 April 2023.Eligibility criteria Qualitative studies of pain and other symptoms from pelvic or vaginal mesh or its removal; adults; no language restriction.Data extraction and synthesis Line-by-line coding of participant quotations and study author statements by one author to provide codes that were applied to half the studies by another author and differences resolved by discussion. Codes were grouped into subthemes and themes by both authors, then scrutinised and discussed by a focus group of mesh-injured women for omissions, emphasis and coherence. Studies were appraised using an amalgamation of the CASP and COREQ tools.Results 2292 search results produced 9 eligible studies, with 7–752 participants, a total of around 2000. Four recruited patients, four totally or partially from mesh advocacy groups, and two were national enquiries (UK and Australia). Four major themes were as follows: broken body, broken mind; distrust of doctors and the medical industry; broken life and keeping going—a changed future. Psychological content mainly concerned the loss of trust in medical care, leaving women unsupported in facing an uncertain future. Mesh-injured women strongly endorsed the findings.Conclusions Pain and other problems associated with pelvic mesh are profound and far-reaching for women affected. Worse, they feel subject to continued gaslighting, including denial of their mesh-related problems and dismissal of their concerns about continued mesh insertion.PROSPERO registration number CRD42022330527.

The future of successful public health practice requires public health students to be educated within a decolonised curriculum that challenges the historical biases and inequalities that are deeply embedded within global public health and society. In this commentary, we reflect on what it can mean and why it's important to decolonise and diversify a public health curriculum. We describe how we used a student-led approach to begin this process, and share recommendations that are applicable to national and international curricula.

Background: The COVID-19 pandemic disproportionately impacted Latin America (LATAM), significantly disrupting cardiovascular testing. This study evaluated cardiac procedure recovery in LATAM one year after the outbreak. Methods: The International Atomic Energy Agency (IAEA) surveyed 669 centers in 107 countries worldwide, including 135 facilities in 19 LATAM countries, to assess cardiovascular procedure volumes in March 2019, April 2020, and April 2021, and changes in center practices and staffing conditions one year into the COVID-19 pandemic. Findings: LATAM centers reported a 21 % decrease in procedure volumes in April 2021 from pre-pandemic-baseline, vs. a 0 % change in the rest of the world (RoW), and greater volume reductions for almost all procedure types. Centers in Central America and Mexico reported the largest procedure reductions (47 % reduction) compared to the Caribbean (15 %), and South America (14 %, p = 0.01), and this LATAM region was a significant predictor of lower procedure recovery in multivariable regression. More LATAM centers reported reduced salaries and increased layoffs of clinical staff compared to RoW, and LATAM respondents estimated that half of physician and non-physician staff experienced excess psychological stress related to the pandemic, compared to 25 % and 30 % in RoW (p

Abstract Background Late-stage human immunodeficiency virus (HIV) infection is typically characterized by low CD4 + T-cell count. We previously showed that profound changes in the monocyte turnover (MTO) rate in rhesus macaques infected by the simian immunodeficiency virus (SIV) outperforms declining CD4 + T-cell counts in predicting rapid health decline associated with progression to terminal disease. High MTO is associated with increased tissue macrophage death. However, MTO analysis is complex and not directly applicable to humans. Methods We explored blood-available biomarkers associated with MTO using comprehensive immune cell profiling via flow cytometry, blood cell count and chemistry, and ELISA. Results Plasma galectin-9 was identified as the most highly correlated marker with MTO. This correlation remained statistically significant during acute, chronic, and late-stage infections caused by three different SIV strains tested. In addition, the galectin-9 level also predicted decline in animal health, requiring medical cull. The correlation between MTO and galectin-9 was maintained even in uninfected animals showing variable MTO. Conclusions These findings support the exploration of galectin-9 as a surrogate biomarker of MTO for non-invasive monitoring of disease progression (e.g. HIV) that may also be applicable in humans and as a potential indicator of tissue macrophages apoptosis.

Abstract Background Endometriosis is a widespread problem in women of reproductive age, causing cyclical and non-cyclical pain in the pelvis and elsewhere, and associated with fatigue, fertility problems, and other symptoms. As a chronic pain problem, psychological variables are important in adjustment and quality of life, but have not been systematically studied. Methods A systematic search of multiple databases was conducted to obtain surveys and qualitative studies of women’s experience of pain from endometriosis. Surveys were combined narratively; qualitative studies were combined by thematic synthesis, and the latter rated for methodological quality. Results Over 2000 records were screened on title and abstract, and provided 22 surveys and 33 qualitative studies from which accounts could be extracted of the psychological components of pain in endometriosis. Surveys mostly addressed quality of life in endometriosis, with poorer quality of life associated with higher levels of pain and of distress, but few referred to coherent psychological models. Qualitative studies focused rather on women’s experience of living with endometriosis, including trajectories of diagnosis and treatment, with a few addressing meaning and identity. Thematic synthesis provided 10 themes, under the groupings of internal experience of endometriosis (impact on body, emotions, and life); interface with the external world (through self-regulation and social regulation); effects on interpersonal and social life, and encounters with medical care. Conclusions The psychological components of pain from endometriosis only partly corresponded with standard psychological models of pain, derived from musculoskeletal pain studies, with fewer fears about physical integrity and more about difficulties of managing pain and other symptoms in social settings, including work. Better understanding of the particular psychological threats of endometriosis, and integration of this understanding into medical care with opportunities for psychologically-based pain management, would substantially improve the experience and quality of life of women with painful endometriosis.

Abstract Background Unhealthy alcohol use (UAU) is particularly dangerous for people with chronic liver disease. Liver clinics may be an important setting in which to provide effective alcohol-related care by integrating evidence-based strategies, such as brief intervention and medications for alcohol use disorder. We conducted qualitative interviews with clinical stakeholders and patients at liver clinics in four Veterans Health Administration (VA) medical centers to understand barriers and facilitators of integrating alcohol-related care and to support tailoring of a practice facilitation implementation intervention. Methods Data collection and analysis were guided by the Consolidated Framework for Implementation Research (CFIR). Interviews were transcribed and qualitatively analyzed using a Rapid Assessment Process (RAP) guided by the CFIR. Results We interviewed 46 clinical stakeholders and 41 patient participants and analyzed findings based on the CFIR. Clinical stakeholders described barriers and facilitators that ranged from operations/clinic resource-based (e.g., time and capacity, desire for additional provider types, referral processes) to individual perspective and preference-based (e.g., supportiveness of leadership, individual experiences/beliefs). Patient participants shared barriers and facilitators that ranged from relationship-based (e.g., trusting the provider and feeling judged) to resource and education-based (e.g., connection to a range of treatment options, education about impact of alcohol). Many barriers and facilitators to integrating alcohol-related care in liver clinics were similar to those identified in other clinical settings (e.g., time, resources, role clarity, stigmatizing beliefs). However, some barriers (e.g., fellow-led care and lack of integration of liver clinics with addictions specialists) and facilitators (e.g., presence of quality improvement staff in clinics and integrated pharmacists and behavioral health specialists) were more unique to liver clinics. Conclusions These findings support the possibility of integrating alcohol-related care into liver clinics but highlight the importance of tailoring efforts to account for variation in provider beliefs and experiences and clinic resources. The barriers and facilitators identified in these interviews were used to tailor a practice facilitation implementation intervention in each clinic setting.

We explore properties of matter and characteristics of Rayleigh–Taylor mixing by analyzing data gathered in the state-of-the-art fine-resolution experiments in high-energy density plasmas. The eminent quality data represent fluctuations spectra of the X-ray imagery intensity versus spatial frequency. We find, by using the rigorous statistical method, that the fluctuations spectra are accurately captured by a compound function, being a product of a power law and an exponential and describing, respectively, self-similar and scale-dependent spectral parts. From the self-similar part, we find that Rayleigh–Taylor mixing has steep spectra and strong correlations. From the scale-dependent part, we derive the first data-based value of the kinematic viscosity in high-energy density plasmas. Our results explain the experiments, agree with the group theory and other experiments, and carve the path for better understanding Rayleigh–Taylor mixing in nature and technology.

Objectives: This study examined the effect of a 4-week unsweetened cranberry beverage (CRAN) (317 mg polyphenols) versus placebo beverage (PLAC) ingestion (240 mL/day) on moderating exercise-induced changes in innate immunity. Methods: Participants included 25 male and female non-elite cyclists. A randomized, placebo-controlled, double-blind crossover design was used with two 4-week supplementation periods and a 2-week washout period. Supplementation periods were followed by an intensive 2.25 h cycling bout. Six blood samples were collected before and after supplementation (in an overnight fasted state) and at 0 h, 1.5 h, 3 h, and 24 h post-exercise. Stool and urine samples were collected pre- and post-supplementation. Outcome measures included serum creatine kinase, myoglobin, and cortisol, complete blood counts, plasma untargeted proteomics, plasma-targeted oxylipins, untargeted urine metabolomics, and stool microbiome composition via whole genome shotgun (WGS) sequencing. Results: Urine CRAN-linked metabolites increased significantly after supplementation, but no trial differences in alpha or beta microbiota diversity were found in the stool samples. The 2.25 h cycling bout caused significant increases in plasma arachidonic acid (ARA) and 53 oxylipins (FDR q-value < 0.05). The patterns of increase for ARA, four oxylipins generated from ARA-cytochrome P-450 (CYP) (5,6-, 8,9-, 11,12-, and 14,15-diHETrEs), two oxylipins from linoleic acid (LA) and CYP (9,10-DiHOME, 12,13-DiHOME), and two oxylipins generated from LA and lipoxygenase (LOX) (9-HODE, 13-HODE) were slightly but significantly higher for the CRAN versus PLAC trial (all interaction effects, p < 0.05). The untargeted proteomics analysis showed that two protein clusters differed significantly between the CRAN and PLAC trials, with CRAN-related elevations in proteins related to innate immune activation and reduced levels of proteins related to the regulation of the complement cascade, platelet activation, and binding and uptake of ligands by scavenger receptors. No trial differences were found for cortisol and muscle damage biomarkers. Conclusions: CRAN versus PLAC juice resulted in a significant increase in CRAN-related metabolites but no differences in the gut microbiome. CRAN supplementation was associated with a transient and modest but significant post-exercise elevation in selected oxylipins and proteins associated with the innate immune system.

During the COVID-19 pandemic, parents quickly assumed the role of teachers to support their children's learning at home. Deaf and hard of hearing (DHH) students often rely on additional accommodations to access their education. The authors investigated the perspectives of 40 parents of K--12 DHH students on the use of virtual learning during the pandemic. An electronic survey was distributed through Qualtrics to gain an understanding of the new learning environment of remote instruction. The participants' responses revealed that they felt that challenges occurred in the areas of time management, language access, technology, motivation, and children's ability to function independently. The respondents were almost evenly split between satisfaction and dissatisfaction with their child's overall educational experience during the pandemic. The results indicated that degree of access significantly influenced the children's experiences of education in virtual learning settings.