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Abstract Many current gridded surface meteorological datasets are inadequate for quantifying near-surface spatiotemporal variability because they do not fully represent the impacts of land surface heterogeneity. Of note, explicit representation of the spatial structure and magnitude of local urban warming are usually lacking. Here we enhance the representation of spatial meteorological variability over urban areas in the conterminous United States (CONUS) by employing the High-Resolution Land Data Assimilation System (HRLDAS), which accounts for the fine-scale impacts of spatiotemporally varying land surfaces on weather. We also synthesize in situ meteorological data including local mesonets to create a 1 km grid spacing model-observation fusion product spanning 1981–2018 over the CONUS at daily temporal resolution. Daily maximum, minimum, and mean values for a variety of temperature estimates, humidity, and surface energy budget terms, among others, are included. This High-resolution Urban Meteorology for Impacts Dataset (HUMID) will be useful for studies examining spatial variability of near surface meteorology and the impacts of urban heat islands across many disciplines including epidemiology, ecology, and climatology.

Abstract Background Pre-exposure prophylaxis (PrEP) holds promise for decreasing new HIV infections among people who inject drugs (PWID), yet daily oral PrEP use is low, and PrEP modality and delivery strategy preferences in this population remain understudied. Methods From May 2022-June 2023, we conducted a discrete choice experiment (DCE) with PWID in San Diego, California. Participants viewed 18 PrEP program scenarios in sets of three and chose their preferred scenario within each set. Scenarios consisted of various combinations of five characteristics: PrEP modality (injectable, implantable, oral), frequency of use (annual, bi-monthly, daily), service location (community-based organization, clinic, telemedicine), prescription access location (on-site, street outreach, mail), and adherence supports (social support, outreach worker, phone/text reminder). Multinomial logit regression estimated probabilities of choosing PrEP program scenarios as a function of the five characteristics to estimate part-worth utility scores (PWUS; reflecting relative preferences for specific characteristic values) and relative importance scores (RIS; reflecting the relative influence of each characteristic on program choice). We also explored differences by hypothesized modifiers of preferences (i.e., sex assigned at birth, housing status, injection frequency, prior PrEP awareness). Results Among 262 participants, mean age was 43.1 years, and most reported male sex assigned at birth (69.5%), identified as non-Hispanic (60.3%), and were previously unaware of PrEP (75.2%). Frequency of use (RIS: 51.5) and PrEP modality (RIS: 35.3) had the greatest influence on PrEP program choice. Within these characteristics, participants had relative preferences for annual use (PWUS: 0.83) and oral PrEP (PWUS: 0.57), and relative aversions to daily use (PWUS: -0.76) and implantable PrEP (PWUS: -0.53). Generally, participants did not indicate preferences for specific service or prescription access locations, or adherence supports; however, among those with prior PrEP awareness, prescription access location and adherence supports had a slightly greater influence on PrEP program choices. Conclusion Our study considered diverse PrEP scenarios and highlighted potential preferences for long-acting oral modalities. Although not currently available, renewed investment in long-acting oral PrEP formulations may facilitate PrEP care engagement among PWID. Additional delivery and implementation strategy research is needed to support PrEP uptake and persistence in this population.

Abstract The southeastern Australian margin hosts a series of submarine canyons. Although the origin and evolution of canyons within the northwestern segment of the margin is relatively well studied, their quantitative morphology, interaction with longshore drift currents and slope failure remain poorly understood in the southeastern region. In this study, high-resolution bathymetry and 3D seismic reflection datasets revealed five main submarine canyons present in the central offshore Otway Basin. The canyons have V-shaped, evolving to U-shaped morphology downslope with sedimentary infill characterized by medium–high amplitudes, recognizable stratal pattern and localized chaotic seismic reflections. Analysis reveals these canyons were initiated by retrogressive slope failure on the continental slope, that once the shelf edge was reached and subsequently incised, development of the canyon heads was influenced by the shelf parallel Zeehan Current, active on the continental shelf of the region. The heads of the shelf-incised canyons preferentially migrate northwestward and were infilled by laterally accreting sedimentary packages characterized by southeast dipping seismic reflections. These indicate an early erosive phase followed by a period of deposition, a result of the prevalent eastward flowing Zeehan Current. These results have important implications for understanding of the mechanisms that control initiation and development of submarine canyons, and their morphology, both offshore southeastern Australia, and similar settings on continental margins worldwide.

Abstract Background In recognition of the burden of Perinatal Mental Health problems, NHS England invested £365 million to transform women’s access to mental health care, including investment in Community Perinatal Mental Health Services. This study examined how elements of provider care affected women’s engagement with these services. Methods Semi-structured interviews were conducted with 139 women and explored their experiences of care from 10 different Community Perinatal Mental Health Teams; including which service components participants believed made a difference to their initial and continued engagement. Realist analysis was used to create context-mechanism-outcome configurations (CMOCs) across interviews, since not all parts of the configurations were always articulated within singular interviews. Results Four key pillars for engagement were identified: perinatal competence, relationship building, accurate reassurance, and reliability. The way perinatal competencies were relayed to women mattered; compassion, understanding and consistency were critical interactional styles. The extent to which these factors affected women’s engagement varied by their context and personal characteristics. Conclusions As mental health problems increase, disproportionately affecting vulnerable populations, it is critical to continue to ensure support is not only available, but appropriately meets the needs of those individuals. Our findings suggest that key staff behaviours applied at the right time can support women’s engagement and potentially contribute to better treatment outcomes.

ABSTRACT In bacteria, if a ribosome translates an mRNA lacking a stop codon it becomes stalled at the 3′ end of the message. These ribosomes must be rescued by trans-translation or the alternative rescue factors (ArfA or ArfB). However, mounting evidence suggests that the ribosome quality control (RQC) pathway may also rescue non-stop ribosomes. Here, we surveyed the conservation of ribosome rescue pathways in >15,000 bacterial genomes. We found that trans-translation is conserved in >97% of bacterial genomes, while the other rescue pathways are restricted to particular phyla. We did not detect the gene encoding RqcH, the major mediator of RQC, in Proteobacteria (Pseudomonadota). In all Proteobacteria investigated to date, trans-translation is essential in the absence of the Arf proteins. Therefore, we tested whether expression of RQC components from Bacillus subtilis could rescue viability in the absence of trans-translation and ArfA in Escherichia coli. We found that the RQC pathway indeed functions in E. coli and rescues the well-documented synthetic lethal phenotype of ∆ssrA∆arfA. Moreover, we show that the RQC pathway in B. subtilis is essential in the absence of trans-translation and ArfA, further supporting a role for the RQC pathway in the rescue of non-stop ribosomes. Finally, we report a strong co-occurrence between RqcH and the ribosome splitting factor MutS2, but present experimental evidence that there are likely additional ribosome splitting factors beyond MutS2 in B. subtilis. Altogether, our work supports a role for RQC in non-stop ribosome rescue and provides a broad survey of ribosome rescue pathways in diverse bacteria.IMPORTANCEIn bacteria, it is estimated that 2%–4% of all translation reactions terminate with the ribosome stalled on a damaged mRNA lacking a stop codon. Mechanisms that rescue these ribosomes are essential for viability. We determined the functional overlap between the ribosome quality control pathway and the classical non-stop rescue systems [alternative rescue factor (ArfA) and trans-translation] in a representative Firmicute and Proteobacterium, phyla that are evolutionarily distinct. Furthermore, we used a bioinformatics approach to examine the conservation and overlap of various ribosome rescue systems in >15,000 species throughout the bacterial domain. These results provide key insights into ribosome rescue in diverse phyla.

Introduction: There are no standard targeted treatment options for advanced KRAS-mutant NSCLC beyond KRAS G12C inhibitors. A computational model identified regorafenib and low-dose methotrexate as synergistic in preclinical models of KRAS-mutant NSCLC. This study evaluated the efficacy and safety of the combination in previously treated advanced KRAS-mutant NSCLC. Methods: This single-arm phase II study included regorafenib 80 to 120 mg oral daily and oral methotrexate dose escalated to tolerability from 10 to 20 mg twice weekly during the first cycle. Both agents were administered on weeks 1 to 3 of each 4-week cycle. The primary end point was progression-free survival. Results: In total, 18 patients with KRAS-mutant NSCLC were enrolled. Five patients received regorafenib at a 120 mg starting dose with four discontinuing due to toxicity; subsequently, 13 patients were treated at an 80 mg starting dose, with eight dose-escalating to 120 mg after the first cycle. Median progression-free survival was 3.7 months (95% confidence interval 1.8–8.6) and median overall survival was 10.4 months (95% confidence interval 5.2–30.3). The objective response rate was 16.7% and the 8-week disease control rate was 66.7%. Grade 3 treatment-related adverse events occurred in 11 patients, most often oral mucositis (n = 2) and asymptomatic lipase increase (n = 2). One patient developed asymptomatic grade 4 lipase increase. Conclusions: Combination treatment of regorafenib and oral methotrexate in patients with KRAS-mutant NSCLC was limited due to toxicity, and the study did not meet its primary end point. Computational modeling may aid in repurposing therapeutic options though caution must be exercised with tolerability.

Summary: In humans, dietary patterns impact weight and metabolism differentially across individuals. To uncover genetic determinants for differential dietary effects, we subjected four genetically diverse mouse strains to humanized diets (American, Mediterranean, vegetarian, and vegan) with similar macronutrient composition, and performed body weight, metabolic parameter, and RNA-seq analysis. We observed pronounced diet- and strain-dependent effects on weight, and triglyceride and insulin levels. Differences in fat mass, adipose tissue, and skeletal muscle glucose uptake, and gene expression changes in most tissues were strain-dependent. In visceral adipose tissue, ∼400 genes responded to diet in a strain-dependent manner, many of them in metabolite transport and lipid metabolism pathways and several previously identified to modify diet effects in humans. Thus, genetic background profoundly impacts metabolism, though chosen dietary patterns modify the strong genetic effects. This study paves the way for future mechanistic investigations into strain-diet interactions in mice and translation to precision nutrition in humans.

Purpose The National TeleOncology Service (NTO) is a clinical service that enables VA oncologists, from across the country, to provide services via telehealth to Veterans with cancer. We sought to understand the early experiences of medical oncologists, Veterans, and clinical staff to inform the national NTO scale–out.Materials and methods We recruited clinicians who provided and/or Veterans who received care from three early adopting NTO sites. We purposively sampled Veteran participants who were: (1) diagnosed and/or treated December 2016 – March 2021 with prostate, non-small cell lung, non-Hodgkin's lymphoma, or colorectal cancer as confirmed by ICD–10 codes, and (2) obtained NTO-delivered care in October 2016 through July 2022 at one of the included NTO sites. We used rapid qualitative analysis.Results We conducted 3 provider focus groups and interviewed 15 Veterans. Participants noted the relative advantage of NTO over in-person care. A primary advantage of NTO is that it facilitates access to oncology specialists for Veterans who travel long distances. Clinicians and Veteran participants agreed that NTO service facilitates access to specialists for Veterans living far from VA medical facilities and community care and in areas lacking specialty oncologists. Although clinicians and Veteran participants agreed that NTO largely meets patient needs, some noted that NTO may not be personable.Conclusion There was consensus among clinicians that the NTO service, with its focus on specialized and individualized oncology care and increased access to care for patients through the virtual platform, is working well to meet the needs of Veterans with cancer.

Objective/Background: Sleep problems challenge overall wellbeing. Magnesium has been implicated to benefit sleep, although the clinical evidences varied based on the magnesium source used. Magnesium L-threonate (MgT) is a promising intervention due to its brain bioavailability and effects on cognition, memory and mood. We investigated MgT supplementation on sleep quality and daily function. Patients/methods: Eighty 35–55-year-olds with self-assessed sleep problems participated in a randomized, double-blind, placebo-controlled, parallel-arm study, taking 1 g/day of MgT or placebo for 21 days. Sleep and daily behaviors were measured subjectively using standardized questionnaires including the Insomnia Severity Index, Leeds Sleep Evaluation Questionnaire, and Restorative Sleep Questionnaire, and objectively using an Oura ring. The Profile of Mood States questionnaire and a daily diary were used to evaluate mood, energy and productivity, and record any safety concerns. Results: The MgT group maintained good sleep quality and daytime functioning, while placebo declined. From objective Oura ring measurements, MgT significantly (p

Case series summary This case report describes the history and presentation of two cats with presumed gabapentin-induced myoclonus. Although this phenomenon is well documented in people, there are no previous reports in cats. Both cats in the current report had International Renal Interest Society (IRIS) stage 2 chronic kidney disease, a history of seizures (one generalized, one focal), and received gabapentin before veterinary hospital visits to alleviate anxiety (doses in the range of 11.8–16.4 mg/kg). While in the hospital, both cats were noted to have intermittent short jerks of the head that were different from the seizure activity previously noted by their owners at home. These cases appear to be the first published reports of this potential adverse effect of gabapentin in cats and risk factors in the present cases mirror those described in people. Relevance and novel information Clinicians should be aware of the potential for this phenomenon in cats receiving recommended doses of gabapentin, and future studies should focus on the role of chronic kidney disease and other neurologic conditions as risk factors for development of this condition.

ABSTRACT Hypogeous fungi (“truffles”) are challenging to study because they produce underground sporocarps that may not be located during traditional fungal surveys. Commercially valuable truffles are located using scent‐detection dogs trained on truffles. However, the dogs are not necessarily limited to commercial truffle species when trained on other taxa of interest. For example, Genea (Pyronemataceae, Ascomycota) is a genus of common but difficult to find truffles that develops small and often soil‐colored hypogeous ascomata. We used a truffle dog trained to locate Genea sporocarps in the southern Willamette Valley and associated mountains in western Oregon, USA, recording when the sporocarps were present at a wide range of elevations (113 to 1879 m). We found Genea was present in half of our surveys and noted that it rarely fruited in areas that had experienced wildfire. This study demonstrates the value of using truffle dogs in documenting truffle diversity, particularly those that are difficult to locate visually, and provides further evidence for the abundance of Genea.

Abstract Identifying how species respond to system drivers such as weather, climate, habitat, and resource availability is critical for understanding population change. In coastal areas, the transfer of nutrients across the marine and terrestrial interface increases complexity. Nesting populations of bald eagles (Haliaeetus leucocephalus) along the Pacific coast of North America, although terrestrial, are largely dependent on marine resources during the breeding season and therefore represent a good focal species for understanding the linkages of nutrients between terrestrial and marine systems. Due to their location, coastal eagle populations are susceptible to a variety of climate‐induced perturbations, from both land and sea. The northeast Pacific Marine Heatwave (PMH) of 2014–2016 had wide‐ranging impacts on the marine ecosystem and provided an opportunity to explore how marine conditions can impact terrestrial wildlife populations. We used a spatially explicit multistate occupancy modeling framework to analyze >30 years of bald eagle nest occupancy data collected in four large national parks along a coastal interior gradient in Alaska, USA. We assessed occupancy state in relation to weather conditions, salmon abundance, access to alternate prey resources, and the PMH event to help elucidate the factors affecting bald eagle occupancy dynamics over time. We found that occupancy probability was higher in areas where prey resources were concentrated (e.g., near seabird colonies, where bears facilitate access to salmon carcasses). We also found that the probability of reproductive success was higher during warmer, drier springs with higher‐than‐average salmon abundance. After the onset of the PMH, success declined in the areas most dependent on non‐salmon marine resources. These findings confirm the importance of spring weather conditions and access to salmon resources during the critical chick‐rearing period, but also reveal that marine heatwaves may have important secondary effects through a reduction in the overall quantity or quality of prey available to bald eagles. Given ongoing warming at high latitudes and the expectation that marine heatwaves will become more common, our findings are useful for understanding ongoing and future changes in the transfer of nutrients from marine to terrestrial ecosystems and how such changes may impact terrestrial species such as bald eagles.

Cardiac ventricular pressure overload affects patients with congenital heart defects and can cause cardiac insufficiency. Grafts of stem cell–derived cardiomyocytes are proposed as a complementary treatment to surgical repair of the cardiac defect, aiming to support ventricular function. Here, we report successful engraftment of human induced pluripotent stem cell–derived cardiac lineage cells into the heart of immunosuppressed rhesus macaques with a novel surgical model of right ventricular pressure overload. The human troponin+ grafts were detected in low-dose (2 × 10 6 cells/kg) and high-dose (10 × 10 6 cells/kg) treatment groups up to 12 weeks post-injection. Transplanted cells integrated and progressively matched the organization of the surrounding host myocardium. Ventricular tachycardia occurred in five out of 16 animals receiving cells, with episodes of incessant tachycardia observed in two animals; ventricular tachycardia events resolved within 19 days. Our results demonstrate that grafted cardiomyocytes mature and integrate into the myocardium of nonhuman primates modeling right ventricular pressure overload.

This paper evaluates the potential effect that operation lifetime could have on the accuracy and reproducibility of the Condor reflectometer. For this purpose, three Condors with different operation lifetimes have been used and compared in this study. In addition to the device’s operation lifetimes, reproducibility and the repeatability of the measurements have also been evaluated. Silvered glass mirrors at different states have been used, e.g., clean, soiled and eroded in order to evaluate the effect of the surface properties on the difference reported using different devices. The obtained results have shown that the difference in specular reflectance reported by the three different Condors is more noticeable in case of soiled and eroded glass mirrors compared to clean sample. This could be linked to the surface roughness more than to the years of operation of the device itself.

Background Whether cardiovascular dysfunction is associated with preeclampsia in women without fetal growth restriction (FGR) is unclear. Our objective was to investigate associations between third‐trimester cardiac output (CO) and systemic vascular resistance and risk of hypertensive disorders of pregnancy in women with and without FGR. Methods and Results A case–cohort study in 906 pregnant women in Denmark with repeated third‐trimester cardiac function assessments was performed using the Ultrasound Cardiac Output Monitor 1A. Using Cox regression, we compared rates of hypertensive disorders of pregnancy in women with low, normal, and high CO and normal and high systemic vascular resistance, by FGR status and gestational age, and evaluated associations between a third‐trimester drop in CO or increase in systemic vascular resistance and preeclampsia risk in women without FGR. The analysis included 249 women with preeclampsia (42 with FGR) and 119 women with gestational hypertension. Low CO was strongly associated with preeclampsia at 75th percentile and preeclampsia in women without FGR (odds ratio, 1.91 [95% CI, 0.84–4.36]). High systemic vascular resistance was strongly associated with increased rates of all forms of hypertensive disorders of pregnancy. Conclusions Low CO is associated with preeclampsia risk in women with and without FGR, particularly before 37 weeks. Repeated measurements of third‐trimester cardiovascular function might identify women without FGR for monitoring for preeclampsia, but this result needs to be confirmed in other studies.

Purpose Despite the volume of accumulating knowledge from prospective Aboriginal cohort studies, longitudinal data describing developmental trajectories in health and well-being is limited. The linkage of child and carer cohorts from a historical cross-sectional survey with longitudinal health-service and social-service administrative data has created a unique and powerful data resource that underpins the Western Australian Aboriginal Child Health Survey (WAACHS) linked data study. This study aims to provide evidence-based information to Aboriginal communities across Western Australia, governments and non-government agencies on the heterogeneous life trajectories of Aboriginal children and families.Participants This study comprises data from a historical cross-sectional household study of 5289 Aboriginal children from the WAACHS (2000–2002) alongside their primary (N=2113) and other (N=1040) carers, and other householders. WAACHS data were linked with Western Australia (WA) government administrative datasets up to 2020 including health, education, child protection, police and justice system contacts. The study also includes two non-Aboriginal cohorts from WA, linked with the same administrative data sources allowing comparisons of outcomes across cohorts in addition to between-group comparisons within the Aboriginal population.Findings to date Linked data coverage rates are presented for all WAACHS participants. Child health outcomes for the WAACHS children (Cohort 1) are described from birth into adulthood along with other outcomes including child protection and juvenile justice involvement.Future plans Analysis of data from both the child and carer cohorts will seek to understand the contribution of individual, family (intergenerational) and community-level influences on Aboriginal children’s developmental and health pathways, identify key developmental transitions or turning points where interventions may be most effective in improving outcomes, and compare service pathways for Aboriginal and non-Aboriginal children. All research is guided by Aboriginal governance processes and study outputs will be produced with Aboriginal leadership to guide culturally appropriate policy and practice for improving health, education and social outcomes.

Abstract Introduction People who use drugs (PWUD) are at increased risk for HIV infection. HIV self-testing (HIVST) is a promising method for identifying new infections, but optimal distribution strategies remain understudied. Methods To characterize PWUD by HIVST distribution strategy (peers vs. mail), we examined data from July 2022 to June 2023 collected from a real-world HIVST program led by the non-profit, Florida Harm Reduction Collective. We used descriptive statistics and Poisson regressions with robust error variance to compare those who received HIVST through peers or via mail by socio-demographics, Ending the HIV Epidemic (EHE) county designation, and HIV testing experience. Results Among 728 participants, 78% received HIVST from peers, 47% identified as cisgender female, 48% as heterosexual, and 45% as non-White; 66% resided in an EHE county, and 55% had no HIV testing experience. Compared to those who received an HIV self-test from peers, those who received tests via mail were less likely to be cisgender male (vs. cisgender female; prevalence ratio [PR] = 0.59, 95% confidence interval [CI]: 0.43, 0.81), non-Hispanic Black (vs. non-Hispanic White; PR = 0.57, 95% CI: 0.36, 0.89) or from EHE counties (vs. non-EHE counties; PR = 0.33, 95% CI: 0.25, 0.44). Those who received tests via mail were also more likely to identify their sexual orientation as “Other/Undisclosed” (vs. straight/heterosexual; PR = 2.00, 95% CI: 1.51, 2.66). Conclusion Our findings support the role of community-based HIVST distribution strategies in increasing HIV testing coverage among PWUD. Additional research could help inform the equitable reach of HIVST.

The ESG literature suggests that the relationship between a firm's environmental, social, and governance (ESG) performance and a firm's financial performance is positive, but the causal link between these two variables is ambiguous. The results in this study mirrored that sentiment of the ESG literature; thus, the purpose of this article is to frame the causal ambiguity in ESG research that accounts for ambiguous conclusions in ESG literature. This study found that firms with complete Bloomberg ESG ratings had higher abnormal returns than firms without complete ESG ratings, but the actual rating did not correlate with abnormal returns. Similarly, this study found that firms with higher ESG disclosure scores (regardless of whether the disclosures were good or bad) were associated with higher abnormal returns, which further illustrates the ambiguity and suggests transparency as a clarifying factor. While much of the literature notes challenges in ESG research, this study is one of the first that frames the confusing causal link between ESG performance and financial performance as the key conclusion of the study.

The Industrial Metrology Business Unit of Nikon Corporation, on behalf of ScottishPower Renewables and Maritime Archaeology (MA), Southampton, UK, has employed X-ray CT (computed tomography) to visualise the internal structure of an anchor found in the North Sea. The non-destructive method of internal inspection and measurement has helped to determine approximately when it was made. The results indicate that the artefact, initially thought to be potentially Roman, is probably more recent, likely dating to between the late 16th and early 17th centuries CE. This paper presents the discovery, recovery, analysis and interpretation of a significant find from a UK offshore wind farm and underscores the valuable role that non-destructive X-ray CT played in the investigation.

Abstract Background The Veterans Health Administration (VHA) is the United States largest learning health system. The Diffusion of Excellence (DoE) program is a large-scale model of diffusion that identifies and diffuses evidence-informed practices across VHA. During the period of 2016-2021, 57 evidence-informed practices were implemented across 82 VHA facilities. This setting provides a unique opportunity to understand sustainment determinants and pathways. Our objective was to characterize the longitudinal pathways of practices as they transition from initial implementation to long-term sustainment at each facility. Methods A longitudinal, mixed-methods evaluation of 82 VHA facilities. Eighty-two facility representatives, chosen by leadership as points-of-contact for 57 DoE practices, were eligible for post-implementation interviews and annual sustainment surveys. Primary outcomes (implementation, sustainment), and secondary outcomes (institutionalization, effectiveness, anticipated sustainment) at four time-points were collected. We performed descriptive statistics and directed content analysis using Hailemariam et al.’s factors influencing sustainment. Results After approximately five years post-implementation (e.g., 2021 sustainment outcomes), of the 82 facilities, about one-third fully sustained their practice compared to one-third that did not fully sustain their practice because it was in a “liminal” stage (neither sustained nor discontinued) or permanently discontinued. The remaining one-third of facilities had missing 2021 sustainment outcomes. A higher percentage of facilities (70%) had inconsistent primary outcomes (changing over time) compared to facilities (30%) with consistent primary outcomes (same over time). Thirty-four percent of facilities with sustained practices reported resilience since they overcame implementation and sustainment barriers. Facilities with sustained practices reported more positive secondary outcomes compared to those that did not sustain their practice. Key factors facilitating practice sustainment included: demonstrating practice effectiveness/benefit, sufficient organizational leadership, sufficient workforce, and adaptation/alignment with local context. Key factors hindering practice sustainment included: insufficient workforce, not able to maintain practice fidelity/integrity, critical incidents related to the COVID-19 pandemic, organizational leadership did not support sustainment of practice, and no ongoing support. Conclusions We identified diverse pathways from implementation to sustainment, and our data underscore that initial implementation outcomes may not determine long-term sustainment outcomes. This longitudinal evaluation contributes to understanding impacts of the DoE program, including return on investment, achieving learning health system goals, and insights into achieving high-quality healthcare in VHA.

Antibiotic prophylaxis for extremity gunshot wounds (GSWs) is highly variable. The objective of the present study is to quantify the adherence rate to a protocol for single-dose cephalosporin prophylaxis for extremity GSWs and the impacts on post-injury infection rates. We reviewed patients presenting to a level 1 trauma center with an extremity gunshot wound between 2019 and 2021. Infection rates were compared for patients following the protocol or not, and for patients presenting before or after the protocol’s implementation. Overall, 94% of patients received antibiotic treatment at presentation, but only 34% followed the single-dose antibiotic protocol. The rate of protocol adherence increased from 15% to 39% after the protocol was implemented in the hospital in January 2020 (p = 0.081). Infection rates were not different before and after the protocol implementation (25% vs. 18%, p = 0.45). Infection rates were also not different between patients who did and did not follow the protocol (15% vs. 20%, p = 0.52). The implementation of a single-dose cephalosporin protocol increased adherence to the protocol in a level 1 trauma center without increasing infection rates. These findings support conservative treatment along with a single dose of first-generation cephalosporin antibiotic for uncomplicated extremity GSWs in order to decrease healthcare costs without compromising infection risk.

Abstract Background A transformation towards healthy diets through a sustainable food system is essential to enhance both human and planet health. Development of a valid, multidimensional, quantitative index of a sustainable diet would allow monitoring progress in the US population. We evaluated the content and construct validity of a sustainable diet index for US adults (SDI-US) based on data collected at the individual level. Methods The SDI-US, adapted from the SDI validated in the French population, was developed using data on US adults aged 20 years and older from the National Health and Nutrition Examination Survey, 2007–2018 (n = 25,543). The index consisted of 4 sub-indices, made up of 12 indicators, corresponding to 4 dimensions of sustainable diets (nutritional quality, environmental impacts, affordability (economic), and ready-made product use behaviors (sociocultural)). A higher SDI-US score indicates greater alignment with sustainable diets (range: 4–20). Validation analyses were performed, including the assessment of the relevance of each indicator, correlations between individual indicators, sub-indices, and total SDI-US, differences in scores between sociodemographic subgroups, and associations with selected food groups in dietary guidelines, the alternative Mediterranean diet (aMed) score, and the EAT-Lancet diet score. Results Total SDI-US mean was 13.1 (standard error 0.04). The correlation between SDI-US and sub-indices ranged from 0.39 for the environmental sub-index to 0.61 for the economic sub-index (Pearson Correlation coefficient). The correlation between a modified SDI-US after removing each sub-index and the SDI-US ranged from 0.83 to 0.93. aMed scores and EAT-Lancet diet scores were significantly higher among adults in the highest SDI-US quintile compared to the lowest quintile (aMed: 4.6 vs. 3.2; EAT-Lancet diet score: 9.9 vs. 8.7 p

Genetically diverse simian arteriviruses (simarteriviruses) naturally infect geographically and phylogenetically diverse monkeys, and cross-species transmission and emergence are of considerable concern. Characterization of most simarteriviruses beyond sequence analysis has not been possible because the viruses fail to propagate in the laboratory. We attempted to isolate 4 simarteriviruses, Kibale red colobus virus 1, Pebjah virus, simian hemorrhagic fever virus, and Southwest baboon virus 1, by inoculating an immortalized grivet cell line (known to replicate simian hemorrhagic fever virus), primary macaque cells, macrophages derived from macaque induced pluripotent stem cells, and mice engrafted with macaque CD34+-enriched hematopoietic stem cells. The combined effort resulted in successful virus isolation; however, no single approach was successful for all 4 simarteriviruses. We describe several approaches that might be used to isolate additional simarteriviruses for phenotypic characterization. Our results will expedite laboratory studies of simarteriviruses to elucidate virus-host interactions, assess zoonotic risk, and develop medical countermeasures.

Introduction: Guns were one of the leading causes of death in children and youth aged 0–24 years in the U.S. over the last decade, with large variations by sex, race, region, and income. This paper examines the rates of gun involvement for a group of youth and young adults in the U.S. from ages 10 years to 34 years across major demographic and background factors. Methods: This is a cross-sectional nationally representative survey of participants recruited through an ongoing national research panel. Completed surveys were collected from 5,311 participants from September 2023 to January 2024. Results: Lifetime rates for carrying guns were 26.7%, gun violence victimization rates were 9.5%, and gun violence perpetration rates were 3.3%. High levels of past-year involvement with guns and gun violence were observed, with 13.9% carrying guns, gun violence victimization of 2.5%, and gun violence perpetration of 0.9%. Even more concerning, data indicate that 7.6% of the participants reported carrying a gun before age 18 years, 5.2% experienced gun violence victimization, and 1.8% perpetrated gun violence. Gun carrying and violence were higher by demographics, with a statistically significant difference for all demographic subgroups on at least 1 gun outcome. Conclusions: High levels of exposure to guns and gun violence are experienced among a nationally representative population of young Americans, with rates varying considerably by demographic factors. On the basis of these demographic disparities in gun involvement, more work is needed to address community and other risk and protective factors across different levels of the social ecology, such as structural inequities associated with gun violence.

Background: Group work is employed in higher education institutions to foster communication, collaborative learning, leadership qualities and teamwork skills. The rationale behind group work as a learning strategy is to ensure that graduates are equipped with teamwork skills. Aim: The aim of this study was to establish whether the final-year radiography students of the National Diploma curriculum in three universities in South Africa were exposed to effective group work. Setting: The study was conducted in three universities in South Africa, all of which offer diagnostic radiography programmes. Methods: This study used a non-experimental descriptive design to collect data. A purposive sampling technique was used to select participants. This was an attempt to conduct a census on 167 students, out of which 124 students responded to the questionnaire, giving a response rate of 74.25%. Results: The findings show that the majority (n = 81; 66.9%) of students did not enjoy group work, as 101 (81.5%) of them preferred less group projects. The results further demonstrated that participants rated factors such as co-operation, leadership, choice, diversity and effectiveness of group work neutral on the Likert scale. Conclusion: The study results imply that factors that contribute towards the effectiveness of group work should be incorporated into group activities in order for student radiographers to be exposed to effective group work. The gaps identified in this study indicate the need for a follow-up study within the current 4-year bachelor’s degree in radiography. Contribution: Identification of a gap in radiography education, which group work needs to be facilitated effectively.

Objective & Approach Routine optometry examinations, which may include retinal images, have been free to everyone in Scotland since 2006. Images and patient data are stored locally on non-interoperable systems, usually without unique identifiers. The Scottish Collaborative Optometry-Ophthalmology Network for e-research (SCONe) aimed to create a secure, longitudinal repository collating community-acquired images linked to national, routinely-collected healthcare data. We developed bulk export processes to retrieve images and patient data from current and archived systems and a series of deterministic and probabilistic algorithms to match images to patients. Results We successfully exported images and patient data from several commonly used systems. Exact matching of available data between image and clinical systems within practices linked 78% of images (IQR 71.2-84.1). Our algorithms increased match rate to 90% (IQR 83.5-98.6) of images, efficiently reducing risk of systemic bias in the cohort. Match method is included in the repository metadata to facilitate quality assurance checks after national linkage and pseudonymisation. To date over 600k images have been processed and delivered to the National Safe Haven for linkage to healthcare data. Conclusions & Implications Breakthrough research into early detection and pre-symptomatic disease can be facilitated by harnessing community-acquired retinal images which capture normal ageing and disease progression. Rather than await interoperability and widespread use of unique identifiers, this has been achieved through innovative solutions to real-world issues around time-pressured clinical data entry and non-standardised data storage. The SCONe repository continues to grow. It is currently supporting ocular disease prediction research and offers the potential for much more.

Organophosphorus nerve agents (OPNA) are hazardous environmental exposures to the civilian population and have been historically weaponized as chemical warfare agents (CWA). OPNA exposure can lead to several neurological, sensory, and motor symptoms that can manifest into chronic neurological illnesses later in life. There is still a large need for technological advancement to better understand changes in brain function following OPNA exposure. The human-relevant in vitro multi-electrode array (MEA) system, which combines the MEA technology with human stem cell technology, has the potential to monitor the acute, sub-chronic, and chronic consequences of OPNA exposure on brain activity. However, the application of this system to assess OPNA hazards and risks to human brain function remains to be investigated. In a concentration-response study, we have employed a human-relevant MEA system to monitor and detect changes in the electrical activity of engineered neural networks to increasing concentrations of the sarin surrogate 4-nitrophenyl isopropyl methylphosphonate (NIMP). We report a biphasic response in the spiking (but not bursting) activity of neurons exposed to low (i.e., 0.4 and 4 μM) versus high concentrations (i.e., 40 and 100 μM) of NIMP, which was monitored during the exposure period and up to 6 days post-exposure. Regardless of the NIMP concentration, at a network level, communication or coordination of neuronal activity decreased as early as 60 min and persisted at 24 h of NIMP exposure. Once NIMP was removed, coordinated activity was no different than control (0 μM of NIMP). Interestingly, only in the high concentration of NIMP did coordination of activity at a network level begin to decrease again at 2 days post-exposure and persisted on day 6 post-exposure. Notably, cell viability was not affected during or after NIMP exposure. Also, while the catalytic activity of AChE decreased during NIMP exposure, its activity recovered once NIMP was removed. Gene expression analysis suggests that human iPSC-derived neurons and primary human astrocytes resulted in altered genes related to the cell’s interaction with the extracellular environment, its intracellular calcium signaling pathways, and inflammation, which could have contributed to how neurons communicated at a network level.

Conventional diagnostic images from Magnetic Resonance Imaging (MRI) are typically qualitative and require subjective interpretation. Alternatively, quantitative MRI (qMRI) methods have become more prevalent in recent years with multiple clinical and preclinical imaging applications. Quantitative MRI studies on preclinical MRI scanners are being used to objectively assess tissues and pathologies in animal models and to evaluate new molecular MRI contrast agents. Low-field preclinical MRI scanners (≤3.0T) are particularly important in terms of evaluating these new MRI contrast agents at human MRI field strengths. Unfortunately, these low-field preclinical qMRI methods are challenged by long acquisition times, intrinsically low MRI signal levels, and susceptibility to motion artifacts. In this study, we present a new rapid qMRI method for a preclinical 3.0T MRI scanner that combines a Spiral Acquisition with a Matching-Based Algorithm (SAMBA) to rapidly and quantitatively evaluate MRI contrast agents. In this initial development, we compared SAMBA with gold-standard Spin Echo MRI methods using Least Squares Fitting (SELSF) in vitro phantoms and demonstrated shorter scan times without compromising measurement accuracy or repeatability. These initial results will pave the way for future in vivo qMRI studies using state-of-the-art chemical probes.

Background: Adults with cognitive impairment are prone to living alone in large numbers but receive relatively little attention. This study aimed to evaluate whether living alone with cognitive impairment was associated with a higher burden of functional disability but lack of informal care. Methods: 982 observations of adults living alone with cognitive impairment and 50,695 observations of adults living with others and with normal cognition were identified from 4 waves (2011/2012, 2013, 2015, and 2018) of the China Health and Retirement Longitudinal Study (CHARLS). A matched comparator was selected using propensity score matching (1:2). Functional disability included disability in Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), and mobility. The time of receiving informal care was measured in monthly hours. Results: Adults living alone with cognitive impairment demonstrated significantly higher odds ratio of ADL disability (OR = 1.59, 95 % CI: 1.30, 1.95), IADL disability (OR = 1.19, 95 % CI: 1.00, 1.44), mobility disability (OR = 1.38, 95 % CI: 1.12, 1.70), but received fewer hours of informal care (β = −127.7 h per month, standard error = 25.83, P

The resilience of coral reefs in oligotrophic, (sub)tropical oceans is largely due to the symbiotic relationship between scleractinian corals and Symbiodiniaceae algae, which enables efficient internal nutrient recycling. Investigating the history of this coral symbiosis can provide insights into its role in sustaining the health of both present and future coral reefs. The isotopic composition of organic nitrogen (15N/14N or δ15N) bound within coral skeletons has been utilized to trace the existence of symbiosis in fossil corals, suggesting that coral symbiosis dates back to at least 210 million years ago. The basis of this proxy is that symbiotic corals are expected to exhibit lower δ15N compared to their non-symbiotic (aposymbiotic) counterparts within the same environments, owing to internal nitrogen recycling between the coral host and algal symbiont, and reduced leakage of low-δ15N ammonium into seawater. However, this hypothesis has not been adequately tested in contemporary settings. In a laboratory experiment, we examined the δ15N differences between the symbiotic and aposymbiotic branches within the same genetic backgrounds of the facultatively symbiotic coral Oculina arbuscula under well-fed conditions. Across five different genotypes in two separate experiments, symbiotic branches consistently showed lower δ15N than their aposymbiotic counterparts. These findings corroborate the use of δ15N as a proxy for identifying coral symbiosis in the past, particularly when multiple species of corals coexisted in the same environments.

Background/purpose Sepsis is a leading cause of morbidity, mortality and healthcare utilisation for children worldwide, particularly in resource-limited regions. In Kumasi, Ghana, organ system failure and mortality in children who present to the emergency department (ED) with symptoms of sepsis are often due to late presentation and lack of recognition and implementation of time-critical evidence-based interventions. The purpose of this study was to assess the barriers and facilitators for families in seeking healthcare for their septic children; and to understand the barriers and facilitators for ED providers in Kumasi to recognise and implement sepsis bundle interventions.Design Single-centre qualitative interviews of 39 caregivers and 35 ED providers in a teaching hospital in Kumasi, Ghana.Results Thematic analysis of data from caregivers about barriers included: fear of hospital, finances, transportation, delay from referring hospital, cultural/spiritual differences, limited autonomy and concerns with privacy and confidentiality. Negative impacts on family life included financial strain and neglect of other children. ED providers reported barriers included: lack of training, poor work environment and accessibility of equipment. Facilitators from caregivers and providers included some support from the National Health Insurance. Caregivers reported having positive experiences with frontline clinicians, which encouraged them to return to seek health services.Implications Qualitative structured interviews identified facilitator and critical barrier themes about seeking healthcare, and sepsis identification/management in the paediatric population arriving for care in our centre in Kumasi, Ghana. This study highlights significant deficiencies in healthcare systems that make sepsis management challenging in these settings.

IntroductionDegenerin proteins, such as βENaC and ASIC2, have been implicated in cardiovascular function. However, their role in metabolic syndrome have not been studied. To begin to assess this interaction, we evaluated the impact of a high fat diet (HFD) on mice lacking normal levels of ASIC2 (ASIC2-/-) and βENaC (βENaCm/m).MethodsTwenty-week-old male and female mice were placed on a 60% HFD for 12 weeks. Body weight was measured weekly, and body composition by non-invasive ECHO MRI and fasting blood glucose were measured at 0, 4, 8 and 12 weeks. A glucose tolerance test was administered after 12 weeks. Differences between ASIC2-/-/βENaCm/m and WT groups were compared using independent t-tests or ANOVA where appropriate within each sex. Data are presented as mean ± SEM and ASIC2-/-/βENaCm/m vs. WT. ResultsAt 20 weeks of age, ASIC2-/-/βENaCm/m mice (n=9F/10M) weighed less and gained less weight than WT (n=12F/16M). Total body fat and lean body masses were reduced in female and male ASIC2-/-/βENaCm/m mice. Total body fat and lean body masses as % control were identical at the end of 12 weeks. Fasting blood glucoses were lower in female and male ASIC2-/-/βENaCm/m vs. WT mice after 12 weeks HFD. The area under the curve for the glucose tolerance test was reduced in female and tended (p=.079) to decrease in male ASIC2-/-/βENaCm/m. Plasma leptin and insulin were reduced in female and male ASIC2-/-/βENaCm/m vs. WT mice. Plasma insulin in female ASIC2-/-/βENaCm/m mice remained unchanged throughout the HFD period. Liver and liver fat masses, as well as percent liver fat, were reduced in both female and male ASIC2-/-/βENaCm/m mice after HFD. Plasma triglycerides, cholesterol, LDL- and HDL-cholesterols were markedly improved in male and/or female ASIC2-/-/βENaCm/m following the HFD.DiscussionThese novel findings suggest that loss of ASIC2 and βENaC offer a significant protection against HFD-induced metabolic syndrome.

Background: Anti-citrullinated protein antibodies (ACPA) are a specific serological biomarker used in the diagnosis of rheumatoid arthritis (RA). In clinical practice ACPA can be identified using immunoassays targeting synthetic cyclic citrullinated peptides (CCP). The 3rd generation anti-CCP IgG antibody (CCP3) offers improved sensitivity compared to the earlier versions. Recently, CCP3.1, capable of detecting both IgG and IgA antibodies, was introduced to enhance sensitivity, especially in patients with early RA. Methods: We assessed serum CCP3.1 against CCP3 in 331 subjects undergoing RA panel serology, comprising 136 patients with RA and 195 patients without RA. Sera were tested for anti-CCP IgG (CCP3) and anti-CCP IgG/IgA (CCP3.1) antibodies. Clinical performance of these tests was compared at manufacturer-suggested cutoffs. A separate set of 81 patients with a diagnosis of RA by 2010 criteria and whose samples were obtained from within 1-year of RA diagnosis was similarly assessed to evaluate assay performance in an independent clinical RA cohort. Results: Overall diagnostic accuracy was similar; CCP3 had an area under the curve (AUC) of 0.88, CCP3.1 had an AUC of 0.89. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for CCP3 were 79 %, 91 %, 86 %, and 86 %, respectively. For CCP3.1, sensitivity was 78 %, specificity 93 %, PPV 89 %, NPV 86 %. Both assays demonstrated excellent agreement; positive percent agreement of 94 % and negative percent agreement of 99 %. Conclusion: Our findings indicate comparable diagnostic accuracy between CCP3 and CCP3.1 assays in these clinical cohorts.

This paper describes experimental work that has been carried out to assess the durability of glass and polymer mirrors against erosion and soiling phenomena. Both outdoor and indoor tests have been performed and the results show that polymer mirrors are quickly degraded in comparison to glass. Soiling deposition has been simulated using a soiling test rig developed for laboratory use. Results show that polymer mirrors, due to their high roughness and their surface energy properties, can accumulate more soiling on their surface generating a higher drop in specular reflectance compared to glass mirrors. Contact cleaning processes have also been simulated on polymer mirrors and the results show that using a hard brush, even at low speed with rotational motion, causes significantly more degradation than a soft brush.

The Newark Community Collaborative Board (NCCB) is in its fourteenth year of operation with nine successful research projects and more than six million dollars in funding. The NCCB began with a community needs assessment in Newark, New Jersey, that led to the subsequent establishment of a community collaborative board (CCB) of consumers, researchers, service providers, and residents committed to advocating for health equity through community engagement and research informed by critical thinking. This paper explores the NCCB’s history and processes that allowed conducting community-based participatory research (CBPR) to reduce inequities related to social determinants of health (SDH). This conceptual manuscript draws on data from NCCB meeting minutes and a group interview with three of the five founding members. We detail the collaborative process used to develop and assess Community Wise, a multilevel, group-based intervention designed to reduce substance use among formerly incarcerated men in Newark, funded by the National Institutes of Health. Review of documentation and interview transcripts revealed the following key ingredients for success: 1) Having a north star; 2) Functional diversity; 3) Challenges as learning opportunities; 4) Board structure and healthy relationships; and 5) Funding and resources. The NCCB has undergone multiple transformations, including a name change to the New Jersey Critical Consciousness Collaborative Board (NJ-3CB), representing its growth from being a small local board to becoming part of a network of community collaborative boards across the United States and a chapter of the global campaign against racism. These and future transitions will help sustain the collaborative journey.

Abstract The monocyte–macrophage system plays an important role in phagocytosis of pathogens and cellular debris following infection or tissue injury in several pathophysiological conditions. We examined ENaC/ASIC subunit transcript expression and the importance of select subunits in migration of bone marrow derived monocytes (freshly isolated) and macrophages (monocytes differentiated in culture). We also examined the effect of select subunit deletion on macrophage phenotype. BM monocytes were harvested from the femurs of male and female WT and KO mice (6–12 weeks of age). Our results show that α, β, γENaC, and ASIC1‐5 transcripts are expressed in BM macrophages and monocytes to varying degrees. At least αENaC, βENaC, and ASIC2 subunits contribute to chemotactic migration responses in BM monocyte–macrophages. Polarization markers (CD86, soluble TNFα) in BM macrophages from mice lacking ASIC2a plus βENaC were shifted towards the M1 phenotype. Furthermore, select M1 phenotypic markers were recovered with rescue of βENaC or ASIC2. Taken together, these data suggest that βENaC and ASIC2 play an important role in BM macrophage migration and loss of βENaC and/or ASIC2 partially polarizes macrophages to the M1 phenotype. Thus, targeting ENaC/ASIC expression in BM macrophages may regulate their ability to migrate to sites of injury.

Dense seismic arrays such as EarthScope’s Transportable Array (TA) have enabled high-resolution seismic observations that show the structure of cratonic lithosphere is more heterogeneous and complex than previously assumed. In this study, we pair TA data with data from the Bighorn Arch Seismic Experiment and the Crust and lithosphere Investigation of the Easternmost expression of the Laramide Orogeny (CIELO) to provide unprecedented detail on the seismic anisotropic structure of the eastern margin of the Wyoming Craton, where several orogens emerged from nominally strong cratonic lithosphere during the Laramide Orogeny. In this study, we use the splitting of teleseismic shear waves to characterize fabrics associated with deformation in the Earth’s crust and mantle. We constrain distinct anisotropic domains in the study area, and forward modeling shows that each of these domains can be explained by a single layer of anisotropy. Most significantly, we find a fast direction in the southern part of the Powder River Basin, which we refer to as the Thunder Basin Block (TBB), that deviates from absolute plate motion (APM). This change in splitting behavior coincides with changes in other modeled geophysical observations, such as active source P-wave velocity models, potential field modeling, and seismic attenuation analysis, which all show a significant change moving from the Bighorn Mountains to the TBB. We argue that these results correspond to structure predating the Laramide Orogeny, and most likely indicate a Neoarchean boundary preserved within the lithosphere.

Summary: Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.

Abstract Introduction Depression is one of the most disabling diseases globally, with a high disease burden that generates high direct and indirect costs. The incidence of depression is twofold higher in adult women than in men. Biological and psychosocial factors constitute the pathophysiological bases of the condition and due to the complexity of the condition, current understanding is that the “treatment strategy must be multimodal”. The objective of this study was to measure the effect of introducing the frequent use of makeup on improving depressive symptoms in adult women of medium–low purchasing power Methods Participants with the targeted profile who did not frequently use makeup were selected and randomised to receive (test group) or not (control group) stimuli and makeup products intended for encouraging the frequent use of makeup. The Zung Depression Self-Assessment Scale was used to assess depressive symptoms, with additional assessments on self-image perception using the mirror test and salivary cortisol level. Results The results demonstrated a sustained reduction in depressive symptoms (8.3 percentage points reduction in the Average Zung Index; P

Abstract Analysis of DNA methylation in cell-free DNA reveals clinically relevant biomarkers but requires specialized protocols such as whole-genome bisulfite sequencing. Meanwhile, millions of cell-free DNA samples are being profiled by whole-genome sequencing. Here, we develop FinaleMe, a non-homogeneous Hidden Markov Model, to predict DNA methylation of cell-free DNA and, therefore, tissues-of-origin, directly from plasma whole-genome sequencing. We validate the performance with 80 pairs of deep and shallow-coverage whole-genome sequencing and whole-genome bisulfite sequencing data.

Abstract Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that treatment with immunotherapy containing arms (nivolumab or a combination of nivolumab plus capecitabine) leads to an increase in PIS from baseline to week 6 compared with capecitabine alone, meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Abstract Background People who use drugs (PWUD) experience elevated HIV risk and numerous barriers to facility-based HIV testing. HIV self-testing (HIVST) could circumvent many of those barriers and is acceptable among PWUD, yet HIVST implementation for PWUD is limited. Service providers’ perspectives on specific HIVST delivery strategies could help increase availability for PWUD. Methods From April–November 2021, we interviewed 16 health, harm reduction, and social service providers working with PWUD in San Diego, CA. Interviews and rapid thematic analysis explored perspectives on HIVST’s utility and appropriateness, as well as the feasibility of and anticipated challenges with specific HIVST delivery strategies, including peer or secondary distribution. Results Participants viewed HIV as a significant threat to PWUD health and confirmed the presence of numerous barriers to local facility-based HIV testing. Participants viewed HIVST as a promising and potentially empowering solution. Based on community familiarity with secondary distribution of harm reduction supplies (i.e., naloxone) and information, participants viewed secondary distribution of HIVST kits as an appropriate and feasible strategy for increasing the reach of HIVST, but also described potential barriers (e.g., engaging socially disconnected individuals, ensuring linkages to services following HIVST) and provided suggestions for alternative HIVST kit delivery models (e.g., harm reduction vending machines). Conclusions Service providers viewed secondary distribution of HIVST kits among PWUD as promising, appropriate, and feasible, yet specialized efforts may be needed to reach the most marginalized individuals and ensure consistent provision of educational information and referral supports that maximize the impact of this approach.

Abstract Background In all organisms, the innate immune system defends against pathogens through basal expression of molecules that provide critical barriers to invasion and inducible expression of effectors that combat infection. The adenosine deaminase that act on RNA (ADAR) family of RNA-binding proteins has been reported to influence innate immunity in metazoans. However, studies on the susceptibility of ADAR mutant animals to infection are largely lacking. Results Here, by analyzing adr-1 and adr-2 null mutants in well-established slow-killing assays, we find that both Caenorhabditis elegans ADARs are important for organismal survival to gram-negative and gram-positive bacteria, all of which are pathogenic to humans. Furthermore, our high-throughput sequencing and genetic analysis reveal that ADR-1 and ADR-2 function in the same pathway to regulate collagen expression. Consistent with this finding, our scanning electron microscopy studies indicate adr-1;adr-2 mutant animals also have altered cuticle morphology prior to pathogen exposure. Conclusions Our data uncover a critical role of the C. elegans ADAR family of RNA-binding proteins in promoting cuticular collagen expression, which represents a new post-transcriptional regulatory node that influences the extracellular matrix. In addition, we provide the first evidence that ADAR mutant animals have altered susceptibility to infection with several opportunistic human pathogens, suggesting a broader role of ADARs in altering physical barriers to infection to influence innate immunity.

Using multipathogen PCR testing, we identified 195 students with adenovirus type 4 infections on a university campus in South Carolina, USA, during January–May 2022. We co-detected other respiratory viruses in 43 (22%) students. Continued surveillance of circulating viruses is needed to prevent virus infection outbreaks in congregate communities.

Abstract Background HIV self-testing (HIVST) could increase HIV testing access among people who inject drugs (PWID), and secondary distribution (i.e., peer-delivery) of HIVST kits in PWID social networks could further expand coverage. We assessed willingness to use and distribute HIVST kits among PWID in the San Diego–Tijuana border region. Methods From 2020 to 2021, HIV-negative PWID in San Diego, USA, and Tijuana, Mexico, completed surveys and provided data on individual (N = 539) and social network (N = 366) characteristics. We used modified Poisson regression to examine the effects of individual and social network characteristics on willingness to use and distribute HIVST kits. Results Most participants were willing to use (81%) and distribute (81%) HIVST kits. At the individual level, prior HIV testing was positively associated with willingness to use (adjusted prevalence ratio [aPR] = 1.24, 95% confidence interval [CI] 1.10–1.40) and distribute (aPR = 1.27, 95% CI 1.12–1.43) HIVST kits, while perceiving oneself to be at higher HIV risk than others was negatively associated with willingness to use HIVST kits (aPR = 0.83, 95% CI 0.74–0.93). At the network level, willingness to distribute HIVST kits was positively associated with network size (aPR = 1.04 per member, 95% CI 1.01–1.08) and greater proportions of one’s network encouraging them to use drugs (aPR = 1.29, 95% CI 1.16–1.44) and having a history of homelessness (aPR = 1.51, 95% CI 1.31–1.74) or detention/arrest (aPR = 1.57, 95% CI 1.36–1.82), and negatively associated with a greater proportion of one’s network including “very close” persons (aPR = 0.80, 95% CI 0.69–0.94). Conclusions We found high potential for HIVST kits and their secondary distribution to increase HIV testing among PWID who face the greatest barriers to facility-based testing.

Abstract Background Chronic primary low back pain (CPLBP) and other musculoskeletal conditions represent a sizable attribution to the global burden of disability, with rates greatest in older age. There are multiple and varied interventions for CPLBP, delivered by a wide range of health and care workers. However, it is not known if these are acceptable to or align with the values and preferences of care recipients. The objective of this synthesis was to understand the key factors influencing the acceptability of, and values and preferences for, interventions/care for CPLBP from the perspective of people over 60 and their caregivers. Methods We searched MEDLINE, CINAHL and OpenAlex, for eligible studies from inception until April 2022. We included studies that used qualitative methods for data collection and analysis; explored the perceptions and experiences of older people and their caregivers about interventions to treat CPLBP; from any setting globally. We conducted a best fit framework synthesis using a framework developed specifically for this review. We assessed our certainty in the findings using GRADE-CERQual. Results All 22 included studies represented older people’s experiences and had representation across a range of geographies and economic contexts. No studies were identified on caregivers. Older people living with CPLBP express values and preferences for their care that relate to therapeutic encounters and the importance of therapeutic alliance, irrespective of the type of treatment, choice of intervention, and intervention delivery modalities. Older people with CPLBP value therapeutic encounters that validate, legitimise, and respect their pain experience, consider their context holistically, prioritise their needs and preferences, adopt a person-centred and tailored approach to care, and are supported by interprofessional communication. Older people valued care that provided benefit to them, included interventions beyond analgesic medicines alone and was financially and geographically accessible. Conclusions These findings provide critical context to the implementation of clinical guidelines into practice, particularly related to how care providers interact with older people and how components of care are delivered, their location and their cost. Further research is needed focusing on low- and middle-income settings, vulnerable populations, and caregivers.

The parallel evolution of lateral plates and body shape in the threespine stickleback (Gasterosteus aculeatus) is an iconic example of adaptation. We test a case of contemporary evolutionary transition in a recently isolated population of marine G. aculeatus in British Columbia, Canada. We investigate Ectodysplasin (Eda) genotypes, plate counts, neutral genetic divergence, and whole-body phenotypes to determine the genetic and phenotypic distance between this population and nearby comparative populations. Our focal population is in the process of adapting both genetically and phenotypically to a freshwater environment, and we provide an example of the genetic basis for parallel evolution on a contemporary timescale. The frequency of Eda genotypes and lateral plate phenotypes in our focal population is not consistent with those of marine or fully freshwater populations. Although our focal population is genetically distinct from nearby marine populations, these fish still more closely resemble marine populations in overall body shape while demonstrating an intriguing intermediate phenotype. Eda frequency and lateral plate phenotype change faster than body shape in response to freshwater conditions, suggesting that the pace of adaptation differs across traits in response to the same environmental conditions. Our results further bolster the case for G. aculeatus as a key model of contemporary evolution.

Biodiversity genomics research requires reliable organismal identification, which can be difficult based on morphology alone. DNA-based identification using DNA barcoding can provide confirmation of species identity and resolve taxonomic issues but is rarely used in studies generating reference genomes. Here, we describe the development and implementation of DNA barcoding for the Darwin Tree of Life Project (DToL), which aims to sequence and assemble high quality reference genomes for all eukaryotic species in Britain and Ireland. We present a standardised framework for DNA barcode sequencing and data interpretation that is then adapted for diverse organismal groups. DNA barcoding data from over 12,000 DToL specimens has identified up to 20% of samples requiring additional verification, with 2% of seed plants and 3.5% of animal specimens subsequently having their names changed. We also make recommendations for future developments using new sequencing approaches and streamlined bioinformatic approaches.