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Abstract Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with “epidrugs” is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development.

Abstract Buruli ulcer (BU) is a necrotizing disease of skin and soft tissue caused by the bacterium Mycobacterium ulcerans (MU). In Australia, where the disease is emerging in new geographic areas and human case numbers are increasing, native possum species act as reservoir hosts. To better understand the life history of MU in one of its natural hosts, we conducted intra-dermal challenge of six wild caught, MU-naïve common ringtail possums (Pseudocheirus peregrinus). All six animals developed BU disease consistent with that observed in naturally infected ringtail possums. Time to ulceration varied between 49 and 77 days (mean = 61.8 days). Molecular evidence of systemic infection was detected in five animals and was supported by consistent histopathological findings in four animals. Pathological findings included random, multifocal, granulomatous hepatitis in four possums, one of which also had a mild, multifocal, interstitial granulomatous pneumonia. Acid-fast bacilli were only evident in inflammatory foci beyond the primary inoculation site in one possum. The ringtail possum model of MU infection is an important tool for the investigation of bacterial transmission dynamics, pathogenesis and immune response in a natural host. Data from this model may improve disease risk modelling and help identify intervention points to stop zoonotic transmission and disease spread.

Abstract Mozambique is making progress towards elimination of trachoma as a public health problem, but in some districts trachomatous inflammation—follicular (TF) prevalence remains above the 5% elimination threshold despite years of various interventions, including antibiotic mass drug administration. To characterize transmission in four districts, we incorporated testing of ocular infection and serology into routine trachoma impact surveys (TIS) in August 2022. We examined residents aged ≥ 1 year for trachoma and collected information on household water, sanitation, and hygiene. Among children aged 1–9 years, we tested conjunctival swabs for Chlamydia trachomatis nucleic acid and dried blood spots for C. trachomatis antibodies. We modeled age-dependent seroprevalence to estimate seroconversion rate (SCR). We examined 4841 children aged 1–9 years. TF prevalence ranged between 1.1 and 6.0% with three districts below the 5% threshold. PCR-confirmed infection prevalence ranged between 1.1 and 4.8%, and Pgp3 seroprevalence ranged between 8.8 and 24.3%. Pgp3 SCR was 1.9 per 100 children per year in the district with the lowest TF prevalence. Two other districts with TF

Abstract Background In Australia, diabetes is the fastest growing chronic condition, with prevalence trebling over the past three decades. Despite reported sex differences in diabetes outcomes, disparities in management and health targets remain unclear. This population-based retrospective study used MedicineInsight primary healthcare data to investigate sex differences in diabetes prevalence, incidence, management, and achievement of health targets. Methods Adults (aged ≥ 18 years) attending 39 general practices in Western Australia were included. Diabetes incidence and prevalence were estimated by age category. Health targets assessed included body mass index (BMI), blood pressure, blood lipids, and glycated haemoglobin (HbA1c) levels. Medical management of diabetes-associated conditions was also investigated. Time-to-incident diabetes was modelled using a Weibull regression. A multilevel mixed-effects logistic regression model investigated risk-adjusted sex differences in achieving the HbA1c health target (HbA1c ≤ 7.0% (≤ 53 mmol/mol)). Results Records of 668,891 individuals (53.4% women) were analysed. Diabetes prevalence ranged from 1.3% (95% confidence interval (CI) 1.2%-1.3%) in those aged

Abstract Carbon with depleted d13C (down to − 25.6‰ VPDB) found in > 3.7 billion year old metamorphic sediments from the Isua Supracrustal Belt, Southwestern Greenland, has been proposed to represent the oldest remains of life on Earth. Graphitic inclusions within garnet porphyroblasts from this locality have been shown to associate with elements consistent with biogenic remains. In this report, we focus on certain liquid inclusions found in the Isua garnets, characterizing their chemical composition using atomic force microscopy, AFM-based infrared spectroscopy, optical photothermal infrared spectroscopy, Raman spectroscopy, and time-of-flight secondary ion mass spectrometry. Our results show that the liquid inclusions contain functional groups consisting of carbon, nitrogen, and oxygen in a configuration similar to amide functional groups. We suspect that the amide groups formed from N, O and C-containing volatile components that were released from the original kerogenous material enclosed in the garnets, as this was graphitized during thermal maturation. This is consistent with the observed inclusion assemblage of solid graphitic and viscous fluid inclusions alike. Our observations are compatible with the inclusions forming from biogenic precursor material, and when considered alongside previous reports on the carbonaceous material in the Isua metamorphic sediments, these and our study collectively indicate that the carbonaceous material in the Isua metasediments represents the oldest traces of life on Earth.

To explore associations between histoplasmosis and race and ethnicity, socioeconomic status, and rurality, we conducted an in-depth analysis of social determinants of health and histoplasmosis in 8 US states. Using the Minority Health Social Vulnerability Index (MH SVI), we analyzed county-level histoplasmosis incidence (cases/100,000 population) from the 8 states by applying generalized linear mixed hurdle models. We found that histoplasmosis incidence was higher in counties with limited healthcare infrastructure and access as measured by the MH SVI and in more rural counties. Other social determinants of health measured by the MH SVI tool either were not significantly or were inconsistently associated with histoplasmosis incidence. Increased awareness of histoplasmosis, more accessible diagnostic tests, and investment in rural health services could address histoplasmosis-related health disparities.

Abstract Background When creating resources, such as psychoeducational materials, for children and families, it is essential to consult all stakeholders. By asking service users what they would find helpful, we can ensure that psychoeducational materials developed are directly addressing a need. This report summarises the process of co-developing a psychoeducational video with young people for the adults in their lives. Methods and results The idea for a psychoeducational video originated from discussions within a Youth Advisory Group in a South London Child and Adolescent Mental Health Service. The group shared that they wanted a way of letting the adults in their lives know what is and is not helpful to hear when they are experiencing mental health distress. A workshop was held with young people to gather ideas for the content and style of a psychoeducational video resource. Through co-design methods, themes were identified including prioritising the young person’s lived experience, the importance of listening, respecting and validating, adults not making assumptions about a diagnosis, and actively involving young people in care planning. A script and accompanying video were produced over several co-design sessions and shared via multiple online mass communication channels. Conclusions This project was co-produced at all stages by young people with lived experience of mental health difficulties to develop a digital resource that they considered necessary and meaningful. Centring the voices of young people when producing materials concerning their mental health results in valuable resources and can bring autonomy to those involved.

Abstract Whilst. pharmacological therapies remain the cornerstone of pain management in chronic pain, factors including the current opioid epidemic have led to non-pharmacological techniques becoming a more attractive proposition. We explored the prevalence of medical device use and their treatment efficacy in non-cancer pain management. A systematic methodology was developed, peer reviewed and published in PROSPERO (CRD42021235384). Key words of medical device, pain management devices, chronic pain, lower back pain, back pain, leg pain and chronic pelvic pain using Science direct, PubMed, Web of Science, PROSPERO, MEDLINE, EMBASE, PorQuest and ClinicalTrials.gov. All clinical trials, epidemiology and mixed methods studies that reported the use of medical devices for non-cancer chronic pain management published between the 1st of January 1990 and the 30th of April 2022 were included. 13 studies were included in systematic review, of these 6 were used in the meta-analysis. Our meta-analysis for pain reduction showed that transcutaneous electrical nerve stimulation combined with instrument-assisted soft tissue mobilization treatment and pulsed electromagnetic therapy produced significant treatment on chronic lower back pain patients. Pooled evidence revealed the use of medical device related interventions resulted in 0.7 degree of pain reduction under a 0–10 scale. Significant improvement in disability scores, with a 7.44 degree reduction in disability level compared to a placebo using a 50 score range was also seen. Our analysis has shown that the optimal use of medical devices in a sustainable manner requires further research, needing larger cohort studies, greater gender parity, in a more diverse range of geographical locations.

Longitudinal population studies (LPS) have a long history of providing insights into how individual consumption patterns and other lifestyle choices affect health and socio-economic outcomes. LPS typically operate as research databanks, integrating rich and deep phenotypic data - covering diverse aspects of individual, family and household status - with genomic data and linked records on health and socio-economic outcomes. However, individual consumption and behavioural choices are traditionally studied solely using self-report methods which are prone to known biases. We propose to enrich LPS databanks with a new form of digital footprint data – individual shopping history records. These are collected by supermarkets through “loyalty” card schemes and can provide a new perspective on real world behaviours and history of consumption. However, as a novel class of data in the context of longitudinal research, our ability to assess the quality and completeness of the data is unknown, as is our ability to effectively triangulate between self-reported and linked data. This paper describes a protocol for linking individual level shopping history data into a LPS using Avon Longitudinal Study of Parents and Children (ALSPAC) as a testbed. The protocol covers the process of establishing participant fair processing, an ethical and legal basis for the linkage framework itself, and how these data will be integrated into the ALSPAC databank. It does not cover the subsequent research use of these data. The protocol was built on an extensive participant engagement and acceptability work and has been approved by the ALSPAC Law and Ethics committee.

Introduction We aimed to explore how digital technology is currently used, could be used and how services could be improved in order to optimise bronchiectasis physiotherapy care. Methods Online surveys were designed and distributed amongst people with bronchiectasis and physiotherapists in Northern Ireland. Responses to closed and open question formats were collected and analysed. Results The survey was completed by 48 out of 100 physiotherapists (48%) between January 2020 and January 2021 and by 205 out of 398 people with bronchiectasis (52%) between October 2020 and October 2021. 56% of physiotherapists (27 out of 48) reporting using some type of digital technology to facilitate services, whereas 44% (21 out of 48) reported that they had never used a digital technology in this patient group. When physiotherapists were asked whether they would be likely to use certain remote and/or digital options to deliver follow-up care for airway clearance techniques, most (31–38 out of 48; 65–79%) indicated that they would. Regarding patient responses, most reported that they would use telephone consultation (145 out of 199, 73%) and a smaller proportion were likely to use video consultation (64 out of 199, 32%). The most commonly mentioned theme for improvement amongst patients was follow-ups, while improved access, quality of services and treatments were the most commonly mentioned amongst physiotherapists. Conclusion Despite a large proportion of physiotherapists in this survey reporting no current use of digital technology in bronchiectasis physiotherapy care, there was significant interest and willingness to do so, amongst both physiotherapists and patients. This survey highlighted a range of care areas, specifically follow-up visits, where digital methods could be further explored.

Introduction The Road to Recovery (R2R) Initiative is an innovative model of substance use care that seeks to increase treatment capacity by creating approximately 100 new addiction treatment beds to provide on-demand addiction care in Vancouver, British Columbia, for patients with substance use disorders. The new model also coordinates the region’s existing clinical substance use services to support patients across a care continuum that includes traditional office-based addiction treatment and harm reduction services, early withdrawal management and more intensive abstinence-based treatment programming. To understand the impact of offering on-demand and coordinated substance use care, an observational cohort of individuals who access any R2R clinical service will be created to examine health and social outcomes over time.Methods and analysis This prospective mixed-methods study will invite individuals from Vancouver, Canada, who access substance use treatment through the R2R model of care to (1) complete a baseline and 12-month follow-up quantitative questionnaire that solicits sociodemographic, substance use and previous addiction treatment data and (2) provide consent to the use of participants’ personal identifiers to access health records for chart review and for annual linkage to select health and administrative databases to allow for ongoing (virtual) community follow-up over 5 years. Additionally, a purposive sample of cohort participants will be invited to participate in baseline and 12-month follow-up qualitative interviews to share their experiences accessing R2R and identify challenges and opportunities associated with the implementation of R2R.Ethics and dissemination The study was approved by the University of British Columbia Providence Health Care Research Ethics Board in September 2023. Results from the proposed study will be published in peer-reviewed journals, presented at national and international scientific conferences and disseminated through regular meetings with policymakers, individuals with lived and living experience, and other high-level stakeholders, academic presentations and lay media.

Objective To undertake a review of systematic reviews on the clinical outcomes of robotic-assisted surgery across a mix of intracavity procedures, using evidence mapping to inform the decision makers on the best utilisation of robotic-assisted surgery.Eligibility criteria We included systematic reviews with randomised controlled trials and non-randomised controlled trials describing any clinical outcomes.Data sources Ovid Medline, Embase and Cochrane Library from 2017 to 2023.Data extraction and synthesis We first presented the number of systematic reviews distributed in different specialties. We then mapped the body of evidence across selected procedures and synthesised major findings of clinical outcomes. We used a measurement tool to assess systematic reviews to evaluate the quality of systematic reviews. The overlap of primary studies was managed by the corrected covered area method.Results Our search identified 165 systematic reviews published addressing clinical evidence of robotic-assisted surgery. We found that for all outcomes except operative time, the evidence was largely positive or neutral for robotic-assisted surgery versus both open and laparoscopic alternatives. Evidence was more positive versus open. The evidence for the operative time was mostly negative. We found that most systematic reviews were of low quality due to a failure to deal with the inherent bias in observational evidence.Conclusion Robotic surgery has a strong clinical effectiveness evidence base to support the expanded use of robotic-assisted surgery in six common intracavity procedures, which may provide an opportunity to increase the proportion of minimally invasive surgeries. Given the high incremental cost of robotic-assisted surgery and longer operative time, future economic studies are required to determine the optimal use of robotic-assisted surgery capacity.

Abstract Developmental assets are critical to the health and wellbeing of youth. The current study examines the influence of developmental assets on PrEP use and HIV testing among YBMSM ages 18–24. Using a cross-sectional survey of YBMSM (N = 225), this study explored the role of external (e.g., family support, other adult support) and internal (e.g., personal responsibility) assets in explaining HIV prevention behaviors. Participants were recruited from Mechanical Turk (M-Turk) internet-based platform, social media sites, and community-based organizations. A path analysis was conducted to investigate the direct/indirect effects of internal and external assets on PrEP use and HIV testing. Family support (β = 0.40, p

Abstract In the United States, Asian and Pacific Islander (A/PI) communities have faced significant discrimination and stigma during the COVID-19 pandemic. We assessed the association between discrimination and depression, anxiety, and loneliness symptoms among Asian or Pacific Islander adults (n = 543) using data from a 116-item nationally distributed online survey of adults (≥ 18 years old) in the United States conducted between 5/2021–1/2022. Discrimination was assessed using the 5-item Everyday Discrimination Scale. Anxiety, depression, and loneliness symptoms were assessed using the 2-item Generalized Anxiety Disorder, 2-item Patient Health Questionnaire, and UCLA Loneliness Scale—Short form, respectively. We used multivariable logistic regression to estimate the association between discrimination and mental health. Overall, 42.7% of participants reported experiencing discrimination once a month or more. Compared with no discrimination, experiencing discrimination once a month was associated with increased odds of anxiety (Adjusted Odds Ratio [aOR] = 2.60, 95% CI = 1.38–4.77), depression (aOR = 2.58, 95% CI = 1.46–4.56), and loneliness (aOR = 2.86, 95% CI = 1.75–4.67). Experiencing discrimination once a week or more was associated with even higher odds of anxiety (aOR = 6.90, 95% CI = 3.71–12.83), depression, (aOR = 6.96, 95% CI = 3.80–12.74), and loneliness (aOR = 6.91, 95% CI = 3.38–13.00). Discrimination is detrimental to mental health, even at relatively low frequencies; however, more frequent discrimination was associated with worse mental health symptoms. Public health interventions and programs targeting anti-A/PI hate and reducing A/PI mental health burden are urgently needed.

Abstract The fishing cat, Prionailurus viverrinus, faces a population decline, increasing the importance of maintaining healthy zoo populations. Unfortunately, zoo-managed individuals currently face a high prevalence of transitional cell carcinoma (TCC), a form of bladder cancer. To investigate the genetics of inherited diseases among captive fishing cats, we present a chromosome-scale assembly, generate the pedigree of the zoo-managed population, reaffirm the close genetic relationship with the Asian leopard cat (Prionailurus bengalensis), and identify 7.4 million single nucleotide variants (SNVs) and 23,432 structural variants (SVs) from whole genome sequencing (WGS) data of healthy and TCC cats. Only BRCA2 was found to have a high recurrent number of missense mutations in fishing cats diagnosed with TCC when compared to inherited human cancer risk variants. These new fishing cat genomic resources will aid conservation efforts to improve their genetic fitness and enhance the comparative study of feline genomes.

Abstract A real-world study was conducted with the aim to reduce people’s fresh fruit and vegetables waste within their homes. For 6 weeks participants measured their fresh produce waste. Half the participants were impelled to complete food waste logs whilst the other half was a control group. This was followed by a 6-month monitoring period to establish if changes would last. Fresh produce waste decreased with over a quarter of what the participants had wasted at the beginning of the 6 weeks, for all groups. Additionally, an attitude questionnaire distributed at the onset and at the end of the study showed a shift in pro-reduction of food waste. As this indicated that thinking about food waste prompts engagement, we tested this idea using a different sample group. A questionnaire measuring attitudes and cognition confirmed the importance of thinking and provided further insight into the findings from the first study.

Abstract Magnetic resonance imaging (MRI) has increasingly been used to characterize structure–function relationships during white matter neuroplasticity. Biological sex differences may be an important factor that affects patterns of neuroplasticity, and therefore impacts learning and rehabilitation. The current study examined a participant cohort before and after visuo-motor training to characterize sex differences in microstructural measures. The participants (N = 27) completed a 10-session (4 week) complex visuo-motor training task with their non-dominant hand. All participants significantly improved movement speed and their movement speed variability over the training period. White matter neuroplasticity in females and males was examined using fractional anisotropy (FA) and myelin water fraction (MWF) along the cortico-spinal tract (CST) and the corpus callosum (CC). FA values showed significant differences in the middle portion of the CST tract (nodes 38–51) across the training period. MWF showed a similar cluster in the inferior portion of the tract (nodes 18–29) but did not reach significance. Additionally, at baseline, males showed significantly higher levels of MWF measures in the middle body of the CC. Combining data from females and males would have resulted in reduced sensitivity, making it harder to detect differences in neuroplasticity. These findings offer initial insights into possible female versus male differences in white matter neuroplasticity during motor learning. This warrants investigations into specific patterns of white matter neuroplasticity for females versus males across the lifespan. Understanding biological sex-specific differences in white matter neuroplasticity may have significant implications for the interpretation of change associated with learning or rehabilitation.

BackgroundGay, bisexual, and other men who have sex with men living with HIV (GBMSM-LWH) in the United States bear a heavy burden of bacterial sexually transmitted infections (STIs). Timely diagnosis and treatment are key to prevention. Only a few studies have combined home specimen self-collection for bacterial STI screening with live audio and video (AV) conferencing. None have focused on GBMSM-LWH or incorporated motivational interviewing (MI), a client-centered, strengths-based counseling approach that seeks to support individuals to create positive behavioral change. ObjectiveOur study seeks to investigate the feasibility and acceptability of an MI-based telehealth intervention that integrates home specimen self-collection from different anatomical sites of possible exposure and MI delivered via live AV conferencing to engage sexually active GBMSM-LWH in bacterial STI screening. MethodsParticipants are being recruited from across the United States via advertising on mobile dating apps and social networking sites and via peer referral. Phase 1 involves piloting the delivery of an innovative telehealth intervention for bacterial STI screening to 75 GBMSM-LWH. Our intervention includes three components: (1) a pretest live AV conferencing session involving an MI-guided discussion to elicit awareness of bacterial STIs; fill any knowledge gaps; bolster the perceived importance of regularly testing for gonorrhea, chlamydia, and syphilis; and build self-efficacy for specimen self-collection; (2) home self-collection and return via mail of a urine sample (for gonorrhea and chlamydia testing), a throat swab (for gonorrhea and chlamydia testing), a rectal swab (for gonorrhea and chlamydia testing), and a finger-stick blood sample (for syphilis testing); and (3) a posttest live AV conferencing session involving an MI-guided discussion to prepare participants for receiving test results and formulate personalized action plans for seeking treatment (if warranted) and repeat testing. Descriptive statistics and progression ratios will be calculated, and potential variations in our intervention’s feasibility and acceptability will be numerically summarized and graphically visualized. Phase 2 involves elucidating attitudes, facilitators, and barriers related to engaging in each intervention component via semistructured in-depth interviews with a purposive subsample of 20 participants who complete progressively smaller subsets of the pretest session, specimen return for bacterial STI testing, and the posttest session. Thematic analysis will be used to identify, analyze, and report patterns in the data. Quantitative and qualitative data will be integrated at the design, methods, interpretation, and reporting levels. ResultsStudy procedures were approved by the Institutional Review Board at the University of Michigan in September 2023. Participant recruitment began in April 2024. ConclusionsOur study will advance multiple goals of the STI National Strategic Plan for the United States for 2021 to 2025, specifically those pertaining to preventing new STIs; accelerating progress in STI research, technology, and innovation; and reducing STI-related health disparities. Trial RegistrationClinicalTrials.gov NCT06100250; https://www.clinicaltrials.gov/study/NCT06100250 International Registered Report Identifier (IRRID)DERR1-10.2196/64433

Background Acne vulgaris (acne) is a common skin condition sometimes needing topical or oral antibiotic treatment. Pharmacists and pharmacy technicians (together known as pharmacy professionals) working in general practice are well placed to ensure their appropriate use.Objectives The objectives of this study are to pilot an evidence-based intervention (‘How to…’ tool) to review treatments in the management of acne and evaluate the capability, opportunity, motivation and behaviour (COM-B) of pharmacy professionals working in general practice before and after the use of this tool.Design, setting and participants A quantitative electronic survey was developed asking UK-based pharmacy professionals working in general practice to rate their agreement with 21 predefined statements related to the COM-B model.Intervention Participants were sent an initial survey, given time to access and use the ‘How to…’ acne resources and then sent a follow-up survey 2 weeks later.Outcome measures Primary outcome was change in 5-point Likert scale responses to statements on capability, opportunity and motivation in the management of acne. Secondary outcome was the perceived usefulness of the toolkit.Results 141 pharmacy professionals completed the initial survey; 19 completed the follow-up survey. Significant improvement in the 5-point Likert scale means that responses were observed after implementation of the acne ‘How to’ resource; capability 3.68 (SD 0.40) versus 4.11 (SD 0.29), t(189) =−5.10, p

Objectives Long-term sickness absence from employment has negative consequences for the economy and can lead to widened health inequalities. Sick notes (also called ‘fit notes’) are issued by general practitioners when a person cannot work for health reasons for more than 7 days. We quantified the sick note rate in people with evidence of COVID-19 in 2020, 2021 and 2022, as an indication of the burden for people recovering from COVID-19.Design Cohort study.Setting With National Health Service (NHS) England approval, we used routine clinical data (primary care, hospital and COVID-19 testing records) within the OpenSAFELY-TPP database.Participants People 18–64 years with a recorded positive test or diagnosis of COVID-19 in 2020 (n=365 421), 2021 (n=1 206 555) or 2022 (n=1 321 313); general population matched in age, sex and region in 2019 (n=3 140 326), 2020 (n=3 439 534), 2021 (n=4 571 469) and 2022 (n=4 818 870); people hospitalised with pneumonia in 2019 (n=29 673).Primary outcome measure Receipt of a sick note in primary care.Results Among people with a positive SARS-CoV-2 test or COVID-19 diagnosis, the sick note rate was 4.88 per 100 person-months (95% CI 4.83 to 4.93) in 2020, 2.66 (95% CI 2.64 to 2.67) in 2021 and 1.73 (95% CI 1.72 to 1.73) in 2022. Compared with the age, sex and region-matched general population, the adjusted HR for receipt of a sick note over the entire follow-up period (up to 10 months) was 4.07 (95% CI 4.02 to 4.12) in 2020 decreasing to 1.57 (95% CI 1.56 to 1.58) in 2022. The HR was highest in the first 30 days postdiagnosis in all years. Among people hospitalised with COVID-19, after adjustment, the sick note rate was lower than in people hospitalised with pneumonia.Conclusions Given the under-recording of postacute COVID-19-related symptoms, these findings contribute a valuable perspective on the long-term effects of COVID-19. Despite likely underestimation of the sick note rate, sick notes were issued more frequently to people with COVID-19 compared with those without, even in an era when most people are vaccinated. Most sick notes occurred in the first 30 days postdiagnosis, but the increased risk several months postdiagnosis may provide further evidence of the long-term impact.

Introduction Hepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications.Methods and analysis The HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age

Introduction Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk.Methods and analysis We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation.Ethics and dissemination We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309).Trial registration number NCT05148715.

Enterococcus faecium is a microbiota species in humans that can modulate host immunity (Griffin and Hang, 2022), but has also acquired antibiotic resistance and is a major cause of hospital-associated infections (Van Tyne and Gilmore, 2014). Notably, diverse strains of E. faecium produce SagA, a highly conserved peptidoglycan hydrolase that is sufficient to promote intestinal immunity (Rangan et al., 2016; Pedicord et al., 2016; Kim et al., 2019) and immune checkpoint inhibitor antitumor activity (Griffin et al., 2021). However, the functions of SagA in E. faecium were unknown. Here, we report that deletion of sagA impaired E. faecium growth and resulted in bulged and clustered enterococci due to defective peptidoglycan cleavage and cell separation. Moreover, ΔsagA showed increased antibiotic sensitivity, yielded lower levels of active muropeptides, displayed reduced activation of the peptidoglycan pattern-recognition receptor NOD2, and failed to promote cancer immunotherapy. Importantly, the plasmid-based expression of SagA, but not its catalytically inactive mutant, restored ΔsagA growth, production of active muropeptides, and NOD2 activation. SagA is, therefore, essential for E. faecium growth, stress resistance, and activation of host immunity.

BackgroundThousands of hospitals worldwide have adopted mobile artificial intelligence (AI)-based stroke care coordination platforms. Studies exploring the benefit of these platforms have been scrutinized due to small sample size, serial cohort design, and measurement of metrics with multiple determinants. In this large multi-center study, we evaluated the ability of an AI-based stroke care coordination platform to expedite contact with the interventionalist (NIR) for potential thrombectomy.MethodsAcute stroke consultations seen by TeleSpecialists, LLC physicians at 166 facilities (17 states) utilizing Viz.ai software (AI) vs. no AI software (non-AI) were extracted from the TeleCare by TeleSpecialists™ database from December 1, 2021, through March 31, 2022. The primary outcome was time from patient arrival to first contact with the interventionalist to discuss need for potential thrombectomy (Arrival-to-NIR notification).ResultsA total of 14,116 cases were analyzed. Compared to the non-AI cohort, Arrival-to-NIR notification in the AI cohort was: (1) 39.5 min faster (44.13% reduction, p < 0.001) in the overall analysis; (2) 33.0 min faster (34.0% reduction, p < 0.001) in the non-thrombectomy (non-TC) facility subgroup analysis; and (3) 34.0 min faster (43.59% reduction, p < 0.001) in the thrombectomy capable (TC) facility subgroup analysis. IQR range comparison demonstrated a significant improvement in uniformity of stroke workflow across all AI subgroups. Significant, albeit small, confounding biases were revealed in the data. The presence of AI within the non-TC subgroup correlated with a lower acceptance rate for thrombectomy by the NIR (delta = −10.79% absolute and 23.17% relative reduction, p < 0.0001).ConclusionsWhile this study was limited by our inability to capture detailed neuroimaging timelines and patient outcomes, it suggests a potential significant benefit of AI-based stroke care coordination platforms and underscores the critical need to development robust “big data” systems to study the effects of AI, and other emerging technologies, on stroke systems of care.

Abstract Reproductive success requires the development of viable oocytes and the accurate segregation of chromosomes during meiosis. Failure to segregate chromosomes properly can lead to infertility, miscarriages, or developmental disorders. A variety of factors contribute to accurate chromosome segregation and oocyte development, such as spindle assembly and sister chromatid cohesion. However, many proteins required for meiosis remain unknown. In this study, we aimed to develop a screening pipeline for identifying novel meiotic and fertility genes using the genome of Drosophila melanogaster. To accomplish this goal, genes upregulated within meiotically active tissues were identified. More than 240 genes with no known function were silenced using RNA interference (RNAi) and the effects on meiosis and fertility were assessed. We identified 94 genes that when silenced caused infertility and/or high levels of chromosomal nondisjunction. The vast majority of these genes have human and mouse homologs that are also poorly studied. Through this screening process, we identified novel genes that are crucial for meiosis and oocyte development but have not been extensively studied in human or model organisms. Understanding the function of these genes will be an important step towards the understanding of their biological significance during reproduction.

Abstract It is estimated 1.5 billion of the global population suffer from chronic pain with prevalence increasing with demographics including age. It is suggested long-term exposure to chronic could cause further health challenges reducing people’s quality of life. Therefore, it is imperative to use effective treatment options. We explored the current pharmaceutical treatments available for chronic pain management to better understand drug efficacy and pain reduction. A systematic methodology was developed and published in PROSPERO (CRD42021235384). Keywords of opioids, acute pain, pain management, chronic pain, opiods, NSAIDs, and analgesics were used across PubMed, Science direct, ProQuest, Web of science, Ovid Psych INFO, PROSPERO, EBSCOhost, MEDLINE, ClinicalTrials.gov and EMBASE. All randomised controlled clinical trials (RCTs), epidemiology and mixed-methods studies published in English between the 1st of January 1990 and 30th of April 2022 were included. A total of 119 studies were included. The data was synthesised using a tri-partied statistical methodology of a meta-analysis (24), pairwise meta-analysis (24) and network meta-analysis (34). Mean, median, standard deviation and confidence intervals for various pain assessments were used as the main outcomes for pre-treatment pain scores at baseline, post-treatment pain scores and pain score changes of each group. Our meta-analysis revealed the significant reduction in chronic pain scores of patients taking NSAID versus non-steroidal opioid drugs was comparative to patients given placebo under a random effects model. Pooled evidence also indicated significant drug efficiency with Botulinum Toxin Type-A (BTX-A) and Ketamine. Chronic pain is a public health problem that requires far more effective pharmaceutical interventions with minimal better side-effect profiles which will aid to develop better clinical guidelines. The importance of understanding ubiquity of pain by clinicians, policy makers, researchers and academic scholars is vital to prevent social determinant which aggravates issue.

Abstract The COVID-19 pandemic posed a global threat to nearly every society around the world. Individuals turned to their political leaders to safely guide them through this crisis. The most direct way political leaders communicated with their citizens was through official speeches and press conferences. In this report, we compare psychological language markers of four different heads of state during the early stage of the pandemic. Specifically, we collected all pandemic-related speeches and press conferences delivered by political leaders in the USA (Trump), UK (Johnson), Germany (Merkel), and Switzerland (Swiss Federal Council) between February 27th and August 31st, 2020. We used natural language analysis to examine language markers of expressed positive and negative emotions, references to the community (we-talk), analytical thinking, and authenticity and compare these language markers across the four nations. Level differences in the language markers between the leaders can be detected: Trump’s language was characterized by a high expression of positive emotion, Merkel’s by a strong communal focus, and Johnson’s and the Swiss Federal Council by a high level of analytical thinking. Overall, these findings mirror different strategies used by political leaders to deal with the COVID-19 pandemic.

Abstract Background Maternal obesity and advanced age have been associated with an increased risk of structural congenital heart defects in the offspring. Whether these factors may also cause abnormalities in infant cardiac dimension and function is unknown. This study investigates whether maternal body mass index (BMI) and maternal age are associated with changes in left ventricular (LV) dimensions and function in the newborn. Methods Infants enrolled in the Copenhagen Baby Heart Study (CBHS), who were born at term, and contributed with a transthoracic echocardiography (TTE) within 60 days of birth were included. The exposure variables were prepregnancy maternal BMI (kg/m2)

Background Critically ill patients are at high risk of acquiring ventilator-associated pneumonia (VAP), which occurs in approximately 20% of mechanically ventilated patients. VAP results either from aspiration of pathogen-contaminated oropharyngeal secretions or contaminated biofilms that form on endotracheal tubes (ETTs) after intubation. VAP results in increased duration of mechanical ventilation, increased intensive care unit and hospital length of stay, increased risk of death and increased healthcare costs. Because of its impact on patient outcomes and the healthcare system, VAP is regarded as an important patient safety issue and there is an urgent need for better evidence on the efficacy of prevention strategies. Modified ETTs that reduce aspiration of oropharyngeal secretions with subglottic secretion drainage or reduce the occurrence of biofilm with a coating of ceragenins (CSAs) are available for clinical use in Canada. In this implementation study, we will evaluate the efficacy of these two types of Health Canada-licensed ETTs on the occurrence of VAP, and impact on patient-centred outcomes.Methods In this ongoing, pragmatic, prospective, longitudinal, interrupted time, cross-over implementation study, we will compare the efficacy of a CSA-coated ETT (CeraShield N8 Pharma) with an ETT with subglottic secretion drainage (Taper Guard, Covidien). The study periods consist of four alternating time periods of 11 or 12 weeks or a total of 23 weeks for each ETT. All patients intubated with the study ETT in each time period will be included in an intention-to-treat analysis. Outcomes will include VAP incidence, mortality and health services utilisation including antibiotic use and length of stay.Ethics and dissemination This study has been approved by the Health Sciences Research Ethics Board at Queen’s University. The results of this study will be actively disseminated through manuscript publication and conference presentations.Trial registration number NCT05761613.

Objective European Alliance of Associations for Rheumatology (EULAR) task forces (TF) requires participation of ≥2 junior members, a health professional in rheumatology (HPR) and two patient research partners for the development of recommendations or points to consider. In this study, participation of these junior and representative members was compared with the one of traditional TF members (convenor, methodologist, fellow and expert TF members).Methods An online survey was developed and emailed to previous EULAR TF members. The survey comprised multiple-choice, open-ended and 0–100 rating scale (fully disagree to fully agree) questions.Results In total, 77 responded, 48 (62%) women. In total, 46 (60%) had participated as a junior or representative TF member. Most junior/representative members reported they felt unprepared for their first TF (10/14, 71%). Compared with traditional members, junior/representative members expressed a significantly higher level of uncertainty about their roles within the TF (median score 23 (IQR 7.0–52.0) vs 7 (IQR 0.0–21.0)), and junior/representative members felt less engaged by the convenor (54% vs 71%). Primary factors that facilitated interaction within a TF were experience, expertise and preparation (54%), a supportive atmosphere (42%) and a clear role (12%).Conclusion Juniors, patients and HPR experience various challenges when participating in a EULAR TF. These challenges differ from and are generally less pronounced than those experienced by traditional TF members. The convenor should introduce the participants to the tasks, emphasise the value of their contributions and how to prepare accordingly for the TF meeting.

BackgroundAn increasing number of countries are currently implementing or scaling-up HIV pre-exposure prophylaxis (PrEP) care. With the introduction of PrEP, there was apprehension that condom use would decline and sexually transmitted infections (STIs) would increase. To inform sexual health counselling and STI screening programmes, we aimed to study sexual behaviour and STI incidence among men who have sex with men (MSM) and transgender women who use long-term daily or event-driven PrEP.Methods and findingsThe Amsterdam PrEP demonstration project (AMPrEP) was a prospective, closed cohort study, providing oral daily PrEP and event-driven PrEP to MSM and transgender women from 2015 to 2020. Participants could choose their PrEP regimen and could switch at each three-monthly visit. STI testing occurred at and, upon request, in-between 3-monthly study visits. We assessed changes in numbers of sex partners and condomless anal sex (CAS) acts with casual partners over time using negative binomial regression, adjusted for age. We assessed HIV incidence and changes in incidence rates (IRs) of any STI (i.e., chlamydia, gonorrhoea, or infectious syphilis) and individual STIs over time using Poisson regression, adjusted for age and testing frequency. A total of 367 participants (365 MSM) commenced PrEP and were followed for a median 3.9 years (interquartile range [IQR] = 3.4-4.0). Median age was 40 years (IQR = 32-48), 315 participants (85.8%) self-declared ethnicity as white and 280 (76.3%) had a university or university of applied sciences degree. Overall median number of sex partners (past 3 months) was 13 (IQR = 6-26) and decreased per additional year on PrEP (adjusted rate ratio [aRR] = 0.86/year, 95% confidence interval [CI] = 0.83-0.88). Overall median number of CAS acts with casual partners (past 3 months) was 10 (IQR = 3-20.5) and also decreased (aRR = 0.92/year, 95% CI = 0.88-0.97). We diagnosed any STI in 1,092 consultations during 1,258 person years, resulting in an IR of 87/100 person years (95% CI = 82-92). IRs of any STI did not increase over time for daily PrEP or event-driven PrEP users. Two daily PrEP users, and no event-driven PrEP users, were diagnosed with HIV during their first year on PrEP. Study limitations include censoring follow-up due to COVID-19 measures and an underrepresentation of younger, non-white, practically educated, and transgender individuals.ConclusionsIn this prospective cohort with a comparatively long follow-up period of 4 years, we observed very low HIV incidence and decreases in the numbers of casual sex partners and CAS acts over time. Although the STI incidence was high, it did not increase over time.Trial registrationThe study was registered at the Netherlands Trial Register (NL5413) https://www.onderzoekmetmensen.nl/en/trial/22706.

Objectives Researchers face numerous challenges when recruiting participants for health and social care research. This study reports on the challenges faced recruiting older adults for Being Your Best, a co-designed holistic intervention to manage and reduce frailty, and highlights lessons learnt amidst the COVID-19 pandemic.Design A qualitative study design was used. Referrer interviews were conducted to explore the recruitment challenges faced by the frontline workers. An audit of the research participant (aged ≥65) database was also undertaken to evaluate the reasons for refusal to participate and withdrawal from the study.Setting Hospital emergency departments (EDs) and a home care provider in Melbourne, Australia.Participants Frontline workers and older adults.Results From May 2022 to June 2023, 71 referrals were received. Of those referrals, only 13 (18.3%) agreed to participate. Three participants withdrew immediately after baseline data collection, and the remaining 10 continued to participate in the programme. Reasons for older adult non-participation were (1) health issues (25.3%), (2) ineligibility (18.3%), (3) lack of interest (15.5%), (4) perceptions of being ‘too old’ (11.2%) and (5) perceptions of being too busy (5.6%). Of those participating, five were female and five were male. Eleven referrer interviews were conducted to explore challenges with recruitment, and three themes were generated after thematic analysis: (1) challenges arising from the COVID-19 pandemic, (2) characteristics of the programme and (3) health of older adults.Conclusion Despite using multiple strategies, recruitment was much lower than anticipated. The ED staff were at capacity associated with pandemic-related activities. While EDs are important sources of participants for research, they were not suitable recruitment sites at the time of this study, due to COVID-19-related challenges. Programme screening characteristics and researchers’ inability to develop rapport with potential participants also contributed to low recruitment numbers.Trial registration number ACTRN12620000533998; Pre-results.

Introduction Telehealth service provision and uptake has rapidly increased since the COVID-19 pandemic, allowing healthcare to be delivered safely and reducing non-essential face-to-face (F2F) contact. In Australia, the expansion of subsidisation of telehealth during COVID has led to its permanent installation within Australian primary care in 2022. However, little is known about consumer preferences and experiences with these services, particularly in relation to allied health practice (AHP). Previous studies on telehealth services have focused on general practice rather than allied health (AH) and broader primary care. Given that AH professionals make up a large proportion of the Australian healthcare workforce, the purpose of this study is to explore consumer preferences and experiences with telehealth AHP healthcare.Methods and analysis This study uses a mixed methods research design that incorporates three independent but interrelated phases. Phase 2 of the study will use a focus group methodology to discuss consumer attitudes and experiences via a semistructured interview format. Phase 3 involves a discrete choice experiment (DCE) involving a large online survey conducted across the general population. The DCE will be informed by the qualitative findings from phases 1 and 2. The experiment aims to elicit consumer preferences in relation to AH services delivered through telehealth or F2F consultations, based on several hypothetical scenarios and preferences over several different dimensions.Ethics and dissemination Ethics approval has been obtained from La Trobe University (approval number HEC23404). Findings will be disseminated as reports, presentations and peer-reviewed journal articles.

Introduction Prenatal and postnatal exposure to environmental tobacco smoke (ETS) has been linked with early childhood caries (ECC), but the specific molecular mechanisms and pathways remain largely unknown. The Caries Risk from exposure to Environmental tobacco Smoke (CARES) within the Household Air Pollution Intervention Network (HAPIN) study aims to establish the association between ETS and ECC by employing epidemiological and novel biomarker-based approaches. Here, we outline the overall design and rationale of the project.Methods and analysis We will leverage the infrastructure and data from the HAPIN trial (India) to mount the CARES study. In this ambidirectional cohort study, children (n=735, aged: 3–5 years) will undergo ECC examination by a trained dentist using standard criteria and calibrated methods. Structured questionnaires will be used to gather information on sociodemographic variables, dietary habits, oral hygiene, oral health-related quality of life and current exposure to ETS. We will collect non-invasive or minimally invasive biospecimens (i.e., saliva, buccal cells, dried blood spots and urine) from a subset of HAPIN children (n=120) to assess a battery of biomarkers indicative of exposure to ETS, early biological effect and epigenetic modifications. Both self-reported and objective measures of ETS exposure collected longitudinally during in utero and early postnatal periods will be accessed from the HAPIN database. We will apply current science data techniques to assess the association and interrelationships between ETS, ECC, and multiple biomarkers.Ethics and dissemination Information gathered in this research will be published in peer-reviewed journals and summaries will be shared with the key stakeholders as well as patients and their parents/guardians involved in this study. Sri Ramachandra Institute of Higher Education and Research Ethics Board has approved the study protocol (IEC-NI22/JUL/83/82).Trial registration number NCT02944682.

BackgroundSexual minority cisgender men and transgender (SMMT) individuals, particularly emerging adults (aged 18-34 years), often report hazardous drinking. Given that alcohol use increases the likelihood of HIV risk behaviors, and HIV disproportionately affects SMMT individuals, there is a need to test interventions that reduce hazardous alcohol use and subsequent HIV risk behaviors among this population. Ecological momentary interventions (EMIs), which use mobile phones to deliver risk reduction messages based on current location and behaviors, can help to address triggers that lead to drinking in real time. ObjectiveThis study will test an EMI that uses motivational interviewing (MI), smartphone surveys, mobile breathalyzers, and location tracking to provide real-time messaging that addresses triggers for drinking when SMMT individuals visit locations associated with hazardous alcohol use. In addition, the intervention will deliver harm reduction messaging if individuals report engaging in alcohol use. MethodsWe will conduct a 3-arm randomized controlled trial (N=405 HIV-negative SMMT individuals; n=135, 33% per arm) comparing the following conditions: (1) Tracking and Reducing Alcohol Consumption (a smartphone-delivered 4-session MI intervention), (2) Tracking and Reducing Alcohol Consumption and Environmental Risk (an EMI combining MI with real-time messaging based on geographic locations that are triggers to drinking), and (3) a smartphone-based alcohol monitoring–only control group. Breathalyzer results and daily self-reports will be used to assess the primary and secondary outcomes of drinking days, drinks per drinking day, binge drinking episodes, and HIV risk behaviors. Additional assessments at baseline, 3 months, 6 months, and 9 months will evaluate exploratory long-term outcomes. ResultsThe study is part of a 5-year research project funded in August 2022 by the National Institute on Alcohol Abuse and Alcoholism. The first 1.5 years of the study will be dedicated to planning and development activities, including formative research, app design and testing, and message design and testing. The subsequent 3.5 years will see the study complete participant recruitment, data collection, analyses, report writing, and dissemination. We expect to complete all study data collection in or before January 2027. ConclusionsThis study will provide novel evidence about the relative efficacy of using a smartphone-delivered MI intervention and real-time messaging to address triggers for hazardous alcohol use and sexual risk behaviors. The EMI approach, which incorporates location-based preventive messaging and behavior surveys, may help to better understand the complexity of daily stressors among SMMT individuals and their impact on hazardous alcohol use and HIV risk behaviors. The tailoring of this intervention toward SMMT individuals helps to address their underrepresentation in existing alcohol use research and will be promising for informing where structural alcohol use prevention and treatment interventions are needed to support SMMT individuals. Trial RegistrationClinicalTrials.gov NCT05576350; https://www.clinicaltrials.gov/study/NCT05576350 International Registered Report Identifier (IRRID)PRR1-10.2196/55166

Background When the Avon Longitudinal Study of Parents and Children (ALSPAC) was planned, it was assumed that the clinical obstetric data would be easily accessible from the newly developed National Health Service computerised ‘STORK’ system. Pilot studies, however, showed that, although fairly accurate in regard to aspects of labour and delivery, it was, at the time (1990-2), inadequate for identifying the full antenatal and postnatal details of clinical complications and treatments of the women in the Study. Methods A scheme was therefore developed to train research staff to find and abstract relevant details from clinical records onto proformas designed for the purpose. Extracting such data proved very time consuming (up to six hours for complicated pregnancies) and consequently expensive. Funding for the enterprise was obtained piecemeal using specific focussed grants to extract data for subsamples of the Study, including a random sample to serve as controls. Results To date, detailed records have been completed for 8369 pregnancies, and a further 5336 (13,705 in total) have complete details on specific prenatal areas, including serial measures of maternal blood pressure, proteinuria and weight. In this Data Note we describe the information abstracted from the obstetric medical records concerning the mother during pregnancy, labour, delivery and the first two weeks of the puerperium. Information abstracted relating to the fetus (including fetal monitoring, presentation, method of delivery) and neonate (signs of asphyxia, resuscitation, treatment and well-being) have been described in a further Data Note. Conclusions These data add depth to ALSPAC concerning ways in which the signs and symptoms, procedures and treatments of the mother prenatally, intrapartum and postnatally, may impact on the long-term health and development of both mother and child. They augment the data collected from the mothers’ questionnaires (described elsewhere) and the ‘STORK’ digital hospital data.

The number of overdose-related fatalities continues to reach historic levels across Canada, despite ongoing efforts by authorities. To reduce mortality, a clinical trajectory ranging from preventative measures to crisis intervention, skill training to treatment, and risk assessment to risk management needs to be supported. The web-based Risk Assessment and Management Platform (RAMP) was developed to realize this concept and to empower people who use drugs through an integrated tool that allows them to better understand and manage their risk of overdose. This paper outlines the architecture and development of RAMP, which is built on the WordPress platform. WordPress components are mapped onto a 3-tier architecture that consists of presentation, application, and database layers. The architecture facilitates the development of a modular software that includes several features that are independent in functionality but interact with each other in an integrated platform. The relatively low coupling and high coherence of the features may reduce the cost of maintenance and increase flexibility of future developments. RAMP’s architecture comprises a user interface, conceptual framework, and backend layers. The RAMP front end effectively uses some of the WordPress’ features such as HTML5, CSS, and JavaScript to create a mobile, friendly, and scalable user interface. The RAMP backend uses several standard and custom WordPress plug-ins to support risk assessment and monitoring, with the goal of mitigating the impacts and eliminating risks together. A rule-based decision support system has been hard-coded to suggest relevant modules and goals to complement each user’s lifestyle and goals based on their risk assessment. Finally, the backend uses the MySQL database management system and communicates with the RAMP framework layer via the data access layer to facilitate a timely and secure handling of information. Overall, RAMP is a modular system developed to identify and manage the risk of opioid overdose in the population of people who use drugs. Its modular design uses the WordPress architecture to efficiently communicate between layers and provide a base for external plug-ins. There is potential for the current system to adopt and address other related fields such as suicide, anxiety, and trauma. Broader implementation will support this concept and lead to the next level of functionality.

Abstract Evidence on the harms and benefits of social media use is mixed, in part because the effects of social media on well-being depend on a variety of individual difference moderators. Here, we explored potential neural moderators of the link between time spent on social media and subsequent negative affect. We specifically focused on the strength of correlation among brain regions within the frontoparietal system, previously associated with the top-down cognitive control of attention and emotion. Participants (N = 54) underwent a resting state functional magnetic resonance imaging scan. Participants then completed 28 days of ecological momentary assessment and answered questions about social media use and negative affect, twice a day. Participants who spent more than their typical amount of time on social media since the previous time point reported feeling more negative at the present moment. This within-person temporal association between social media use and negative affect was mainly driven by individuals with lower resting state functional connectivity within the frontoparietal system. By contrast, time spent on social media did not predict subsequent affect for individuals with higher frontoparietal functional connectivity. Our results highlight the moderating role of individual functional neural connectivity in the relationship between social media and affect.

Human conflict, such as the ongoing conflict in Ukraine, is an important driver of antimicrobial resistance. Here, we describe the challenges when addressing this problem during an ongoing conflict and the opportunities available to reduce the spread of antimicrobial resistance.

Abstract Past work has shown that brain structure and function differ between females and males. Males have larger cortical and sub-cortical volume and surface area (both total and subregional), while females have greater cortical thickness in most brain regions. Functional differences are also reported in the literature, yet to date little work has systematically considered whether patterns of brain activity indexed with functional magnetic resonance imaging (fMRI) differ between females and males. The current study sought to remediate this issue by employing task-based whole brain motor mapping analyses using an openly available dataset. We tested differences in patterns of functional brain activity associated with 12 voluntary movement patterns in females versus males. Results suggest that females exhibited smaller volumes of brain activation across all 12 movement tasks, and lower patterns of variability in 10 of the 12 movements. We also observed that females had greater cortical thickness, which is in alignment with previous analyses of structural differences. Overall, these findings provide a basis for considering biological sex in future fMRI research and provide a foundation of understanding differences in how neurological pathologies present in females vs males.

Abstract Background Physician decision-making skills training is a priority to improve adoption of the cerebral palsy (CP) clinical guideline and, through this, lower the age of CP diagnosis. Clinical guideline implementation aims to improve physician practice, but evaluating meaningful change is complex. Limitations in the validity evidence of evaluation instruments impact the evidence base. Validity frameworks, such as Kane’s, enable a targeted process to gather evidence for instrument scores, congruent to context and purpose. Yet, application of argument-based methodology to implementation validation is rare. Key-features examination methodology has established validity evidence supporting its use to measure decision-making skills, with potential to predict performance. We aimed to apply Kane’s framework to evaluate a pilot key-features examination on physician decision-making in early CP diagnosis. Methods Following Kane’s framework, we evaluated evidence across inferences of scoring, generalisation, extrapolation and implications in a study design describing the development and pilot of a CP diagnosis key-features examination for practising physicians. If found to be valid, we proposed to use the key-feature scores as an outcome measure of decision-making post education intervention to expedite CP diagnosis and to correlate with real-world performance data to predict physician practice. Results Supporting evidence for acceptance of scoring inferences was achieved through examination development with an expert group (n = 10) and pilot results (n = 10): (1) high internal consistency (0.82); (2) acceptable mean item-discrimination (0.34); and (3) acceptable reliability of examination scorers (95.2% congruence). Decreased physician acceptance of examination time (70%) was identified as a threat and prioritised in case reduction processes. Partial acceptance of generalisation, extrapolation and implications inferences were defensible with: (1) accumulated development evidence following established key-features methodology; (2) high pilot acceptance for authenticity (90%); and (3) plausibility of assumptions of score correlation with population register data. Conclusions Kane’s approach is beneficial for prioritising sources of validity evidence alongside the iterative development of a key-features examination in the CP field. The validity argument supports scoring assumptions and use of scores as an outcome measure of physician decision-making for CP guideline education implementation interventions. Scoring evidence provides the foundation to direct future studies exploring association of key-feature scores with real-world performance.

Fentanyl overdose is a survivable condition that commonly resolves without chronic overt changes in phenotype. While the acute physiological effects of fentanyl overdose, such as opioid-induced respiratory depression (OIRD) and Wooden Chest Syndrome, represent immediate risks of lethality, little is known about longer-term systemic or organ-level impacts for survivors. In this study, we investigated the effects of a single, bolus fentanyl overdose on components of the cardiopulmonary system up to one week post. SKH1 mice were administered subcutaneous fentanyl at the highest non-lethal dose (62 mg/kg), LD10 (110 mg/kg), or LD50 (135 mg/kg), before euthanasia at 40 min, 6 h, 24 h, or 7 d post-exposure. The cerebral cortex, heart, lungs, and plasma were assayed using an immune monitoring 48-plex panel. The results showed significantly dysregulated cytokine, chemokine, and growth factor concentrations compared to time-matched controls, principally in hearts, then lungs and plasma to a lesser extent, for the length of the study, with the cortex largely unaffected. Major significant analytes contributing to variance included eotaxin-1, IL-33, and betacellulin, which were generally downregulated across time. The results of this study suggest that cardiopulmonary toxicity may persist from a single fentanyl overdose and have wide implications for the endurance of the expanding population of survivors.

OBJECTIVES/GOALS: Specialty care for asthmatic children should prevent adverse asthma outcomes. This study of children receiving care in the Arkansas Medicaid program used a comparative effectiveness research design to test whether allergy specialty care was associated with reduced adverse asthma outcomes. METHODS/STUDY POPULATION: Using the Arkansas All Payer Claims Database we studied Medicaid-enrolled children with asthma using a propensity score greedy nearest neighbor one-to-one matching algorithm. We matched children with (treatment) and without (comparison) an allergy specialist visit in 2018. The propensity score model included 26 covariates (demographic, clinical, and social determinants of health). Multivariable adjusted logistic regression was used to estimate adverse asthma events (AAE: emergency department visit or inpatient hospitalization with a primary or secondary diagnosis of asthma in 2019). RESULTS/ANTICIPATED RESULTS: We identified 3,031 children with an allergy specialist visit in 2018, and successfully propensity-score matched 2,910 of the treatment group with a non-allergy specialist visit comparison group. The rate of AAEs in 2019 was 9.5% for individuals with an allergy specialist visit versus 10.1% among those without a specialist visit (p=0.450). The adjusted regression analysis showed 20.3% lower rates of AAEs (aOR: 0.797; 95% Confidence Interval: 0.650, 0.977; p=0.029) in 2019 for children with an allergy specialist visit in 2018 compared to those that did not. DISCUSSION/SIGNIFICANCE: Utilizing allergy specialist care was associated with better asthma outcomes in our statewide study of Arkansas Medicaid-enrolled children with asthma. Asthma quality metrics based on guideline-based recommendations for allergy specialist care should be considered in population health management programs.

Abstract After stroke, impaired motor performance is linked to an increased demand for cognitive resources. Aerobic exercise improves cognitive function in neurologically intact populations and may be effective in altering cognitive function post-stroke. We sought to determine if high-intensity aerobic exercise paired with motor training in individuals with chronic stroke alters cognitive-motor function and functional connectivity between the dorsolateral prefrontal cortex (DLPFC), a key region for cognitive-motor processes, and the sensorimotor network. Twenty-five participants with chronic stroke were randomly assigned to exercise (n = 14; 66 ± 11 years; 4 females), or control (n = 11; 68 ± 8 years; 2 females) groups. Both groups performed 5-days of paretic upper limb motor training after either high-intensity aerobic exercise (3 intervals of 3 min each, total exercise duration of 23-min) or watching a documentary (control). Resting-state fMRI, and trail making test part A (TMT-A) and B were recorded pre- and post-intervention. Both groups showed implicit motor sequence learning (p

Abstract Objectives In order to provide a better insight into the functional capacity of the human gut microbiome, we isolated a novel bacterium, “Candidatus Intestinicoccus colisanans” gen. nov. sp. nov., and performed whole genome sequencing. This study will provide new insights into the functional potential of this bacterium and its role in modulating host health and well-being. We expect that this data resource will be useful in providing additional insight into the diversity and functional potential of the human microbiome. Data description Here, we report the first draft genome sequences of “Candidatus Intestinicoccus colisanans” strains MH27-1 and MH27-2, recovered from faeces collected from healthy human donors. The genomes were sequenced using short-read Illumina technology and whole-genome-based comparisons and phylogenomics reconstruction indicate that “Candidatus Intestinicoccus colisanans” represents a novel genus and species within the family Acutalibacteraceae. Both genomes were estimated to be > 98% completed and to range in size from 2.9 to 3.3 Mb with a G + C content of approximately 51%. The gene repertoire of “Candidatus Intestinicoccus colisanans” indicate it is likely a saccharolytic gut bacterium.

Abstract Introduction Experiences and determinants connected with type 2 diabetes mellitus-associated erectile dysfunction (T2DMED) in health appointments are not well understood and infrequently reported. This systematic review was undertaken to synthesise evidence of the experiences, facilitators, and barriers around screening ED in men with T2DM during health service consultations. Methods The review report was based on the guidelines provided by the Joanna Briggs Institute for conducting mixed-method systematic reviews. Eight electronic databases were searched, including Web of Science, Embase via Ovid, Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCO, ProQuest, PubMed, PsychInfo via Ovid, MEDLINE via Ovid, Portal Garuda. Additionally, the review manually looked through the reference lists of the studies we included. Erectile dysfunction, type 2 diabetes mellitus, screening and barriers were initially used as keywords in the search strategy. All identified primary studies written in English and Bahasa Indonesia, and published between 2001 and 2022 were meticulously screened following an agreed set of inclusion criteria. Findings Out of 3468 papers screened, only six were chosen for the review. These included three cross-sectional studies, two qualitative studies, and one mixed-method study. The study quality of the included studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist. Based on the checklist criteria, the studies ranged between 5/10 to 9/10 in terms of quality. After synthesizing the findings, four main categories were identified including the willingness to discuss T2DMED, the barriers experienced and perceived, the limited understanding of T2DMED, and the support expected by men with T2DM. Discussion Many men kept quiet about their struggles with T2DMED, hoping to bring it up as a topic of discussion during healthcare consultations. Barriers such as embarrassment, a sense of helplessness and reluctance to seek help, financial constraints, and dismissive healthcare professionals hindered them from addressing this issue. Both the participating men and healthcare professionals lacked a comprehensive understanding of T2DMED. Recommendations It is important to provide education tailored to men's specific needs and improve awareness about T2DM-associated ED. Creating a more T2DMED-friendly environment could be a potential solution to increase early screening and management. Future research should investigate potential barriers that prevent HCPs from identifying and addressing T2MED since their absence in the identified studies highlights this need. Systematic review registration CRD42021292454.

Abstract Modifying behaviors, such as alcohol consumption, is difficult. Creating psychological distance between unhealthy triggers and one’s present experience can encourage change. Using two multisite, randomized experiments, we examine whether theory-driven strategies to create psychological distance—mindfulness and perspective-taking—can change drinking behaviors among young adults without alcohol dependence via a 28-day smartphone intervention (Study 1, N = 108 participants, 5492 observations; Study 2, N = 218 participants, 9994 observations). Study 2 presents a close replication with a fully remote delivery during the COVID-19 pandemic. During weeks when they received twice-a-day intervention reminders, individuals in the distancing interventions reported drinking less frequently than on control weeks—directionally in Study 1, and significantly in Study 2. Intervention reminders reduced drinking frequency but did not impact amount. We find that smartphone-based mindfulness and perspective-taking interventions, aimed to create psychological distance, can change behavior. This approach requires repeated reminders, which can be delivered via smartphones.

Abstract Organellar C-to-U RNA editing in plants occurs in complexes composed of various classes of nuclear-encoded proteins. DYW-deaminases are zinc metalloenzymes that catalyze hydrolytic deamination required for C-to-U modification editing. Solved crystal structures for DYW-deaminase domains display all structural features consistent with a canonical cytidine deamination mechanism. However, some recombinant DYW-deaminases from plants have been associated with ribonuclease activity in vitro. Direct ribonuclease activity by an editing factor is confounding since it is not required for deamination of cytosine, theoretically would be inimical for mRNA editing, and does not have a clear physiological function in vivo. His-tagged recombinant DYW1 from Arabidopsis thaliana (rAtDYW1) was expressed and purified using immobilized metal affinity chromatography (IMAC). Fluorescently labeled RNA oligonucleotides were incubated with recombinant AtDYW1 under different conditions. Percent relative cleavage of RNA probes was recorded at multiple time points from triplicate reactions. The effects of treatment with zinc chelators EDTA and 1, 10-phenanthroline were examined for rAtDYW1. Recombinant His-tagged RNA editing factors AtRIP2, ZmRIP9, AtRIP9, AtOZ1, AtCRR4, and AtORRM1 were expressed in E. coli and purified. Ribonuclease activity was assayed for rAtDYW1 in the presence of different editing factors. Lastly, the effects on nuclease activity in the presence of nucleotides and modified nucleosides were investigated. RNA cleavage observed in this study was linked to the recombinant editing factor rAtDYW1 in vitro. The cleavage reaction is sensitive to high concentrations of zinc chelators, indicating a role for zinc ions for activity. The addition of equal molar concentrations of recombinant RIP/MORF proteins reduced cleavage activity associated with rAtDYW1. However, addition of equal molar concentrations of purified recombinant editing complex proteins AtCRR4, AtORRM1, and AtOZ1 did not strongly inhibit ribonuclease activity on RNAs lacking an AtCRR4 cis-element. Though AtCRR4 inhibited AtDYW1 activity for oligonucleotides with a cognate cis-element. The observation that editing factors limit ribonuclease activity of rAtDYW1 in vitro, suggests that nuclease activities are limited to RNAs in absence of native editing complex partners. Purified rAtDYW1 was associated with the hydrolysis of RNA in vitro, and activity was specifically inhibited by RNA editing factors.

Introduction Despite greater needs in rural areas, occupational therapists are maldistributed to urban spaces which limits service access and health outcomes for rural people and communities. Preparation of students for rural practice may improve rural workforce recruitment and retention; however, the range and scope of preparation strategies employed by education providers are unclear. This scoping review aims to understand and describe the range of strategies education services use to prepare occupational therapy students for rural practice across the globe.Methods and analysis The study will include all publications about strategies used to prepare occupational therapy students for future rural practice, prior to enrolment, during the programme or on graduation. MEDLINE (Ovid), Emcare (Ovid), APA PsychInfo (Ovid), CINAHL (EBSCOhost), Health Source: Nursing/Academic (EBSCOHost), Educational Resources Information Centre (ERIC), Open Access Theses and Dissertations (OATD), and Scientific Electronic Library Online (SciELO) databases will be systematically searched in English, Spanish, French and Portuguese languages. Citations will be screened by two or more independent researchers against inclusion criteria and data extracted from included publications using a customised extraction tool. Frequency counts will be provided for study type, student location and sociodemographics, and the timing/educational strategy. The extracted data will be analysed using a matrix framework and presented in diagrammatic/tabular form and accompanied by a narrative summary which will describe how the results relate to the reviews’ questions.Ethics and dissemination This study will not involve human/animal subjects and does not require ethics approval. Results will be disseminated to relevant groups in peer-reviewed journal(s) and at relevant occupational therapy, higher education and/or rural health conferences. Results will also be translated and shared in blogs/social media to support access for non-research audiences and shared with other regional universities to influence curriculum design.

Summary: Background: Epidemic waves of coronavirus disease 2019 (COVID-19) infections have often been associated with the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Rapid detection of growing genomic variants can therefore serve as a predictor of future waves, enabling timely implementation of countermeasures such as non-pharmaceutical interventions (social distancing), additional vaccination (booster campaigns), or healthcare capacity adjustments. The large amount of SARS-CoV-2 genomic sequence data produced during the pandemic has provided a unique opportunity to explore the utility of these data for generating early warning signals (EWS). Methods: We developed an analytical pipeline (Transmission Fitness Polymorphism Scanner – designated in an R package mrc-ide/tfpscanner) for systematically exploring all clades within a SARS-CoV-2 virus phylogeny to detect variants showing unusually high growth rates. We investigated the use of these cluster growth rates as the basis for a variety of statistical time series to use as leading indicators for the epidemic waves in the UK during the pandemic between August 2020 and March 2022. We also compared the performance of these phylogeny-derived leading indicators with a range of non-phylogeny-derived leading indicators. Our experiments simulated data generation and real-time analysis. Findings: Using phylogenomic analysis, we identified leading indicators that would have generated EWS ahead of significant increases in COVID-19 hospitalisations in the UK between August 2020 and March 2022. Our results also show that EWS lead time is sensitive to the threshold set for the number of false positive (FP) EWS. It is often possible to generate longer EWS lead times if more FP EWS are tolerated. On the basis of maximising lead time and minimising the number of FP EWS, the best performing leading indicators that we identified, amongst a set of 1.4 million, were the maximum logistic growth rate (LGR) amongst clusters of the dominant Pango lineage and the mean simple LGR across a broader set of clusters. In the case of the former, the time between the EWS and wave inflection points (a conservative measure of wave start dates) for the seven waves ranged between a 20-day lead time and a 7-day lag, with a mean lead time of 5.4 days. The maximum number of FP EWS generated prior to a true positive (TP) EWS was two and this only occurred for two of the seven waves in the period. The mean simple LGR amongst a broader set of clusters also performed well in terms of lead time but with slightly more FP EWS. Interpretation: As a result of the significant surveillance effort during the pandemic, early detection of SARS-CoV-2 variants of concern Alpha, Delta, and Omicron provided some of the first examples where timely detection and characterisation of pathogen variants has been used to tailor public health response. The success of our method in generating early warning signals based on phylogenomic analysis for SARS-CoV-2 in the UK may make it a worthwhile addition to existing surveillance strategies. In addition, the method may be translatable to other countries and/or regions, and to other pathogens with large-scale and rapid genomic surveillance. Funding: This research was funded in whole, or in part, by the Wellcome Trust (220885_Z_20_Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. KOD, OB, VBF and EMV acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/X020258/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. RMC acknowledges funding from the Wellcome Trust Collaborators Award (206298/Z/17/Z).