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Abstract Background Xylazine is an increasingly common adulterant in the North American unregulated drug supply that is associated with adverse health outcomes (e.g., skin infections, overdose). However, there are significant knowledge gaps regarding how xylazine was initially identified and how syringe services program (SSP) staff and clients (people who use drugs) responded to its emergence. Methods From June–July 2023, we conducted qualitative interviews with medical (e.g., clinicians) and frontline SSP staff (e.g., outreach workers) and adult clients with a history of injection drug use at a Miami-based SSP. Inductive memos identified emergent codes; thematic analysis involving team consensus established final themes. Results From interviews with SSP staff (n = 8) and clients (n = 17), xylazine emergence was identified at different times, in various ways. Initially, during summer 2022, clients identified a “tranquilizer-like substance” that worsened sedation and withdrawal and caused wounds. SSP medical staff later identified this adulterant as xylazine by treating new medical cases and through diverse information-sharing networks that included professional societies and news sources; however, frontline SSP staff and clients needed additional educational resources about xylazine and its side effects. With limited guidance on how to reduce harm from xylazine, SSP clients altered their drug consumption routes, reduced drug use, and relied on peers’ experiences with the drug supply to protect themselves. Some individuals also reported preferring xylazine-adulterated opioids and increasing their drug use, including the use of stimulants to avoid over sedation. Conclusions Xylazine’s emergence characterizes the current era of unprecedented shifts in the unregulated drug supply. We found that xylazine spurred important behavioral changes among people who use drugs (e.g., transitioning from injecting to smoking). Incorporating these experiences into early drug warning surveillance systems and scaling up drug-checking services and safer smoking supply distribution could help mitigate significant health harms caused by xylazine and other emergent adulterants.

Abstract Mosquitoes and other biting arthropods transmit diseases worldwide, causing over 700,000 deaths each year, and costing about 3 billion USD annually for Aedes species alone. Insect vectored diseases also pose a considerable threat to agricultural animals. While clothing could provide a simple solution to vector-borne diseases, modern textiles do not effectively block mosquito bites. Here we have designed three micro-resolution knitted structures, with five adjustable parameters that can block mosquito bites. These designs, which exhibit significant bite reduction were integrated into a computer numerical control knitting robot for mass production of bite-blocking garments with minimal human labor. We then quantified the comfort of blocking garments. Our knits enable individuals to protect themselves from insects amidst their day-to-day activities without impacting the environment.

Abstract Background Children with disabilities experience poorer oral health and frequently have complex needs. The accessibility of oral health care services for children with disabilities is crucial for promoting oral health and overall well-being. This study aimed to systematically review the literature to identify the barriers and facilitators to oral health care services for children with disabilities, and to propose priority research areas for the planning and provision of dental services to meet their needs. Methods This was a mixed methods systematic review. Multiple databases searched included MEDLINE, Scopus, PsycINFO, EMBASE, and CINAHL. The search strategy included Medical Subject Heading (MeSH) terms related to children, disabilities, and access to oral health. Eligibility criteria focused on studies about children with disabilities, discussing the accessibility of oral health care. Results Using Levesque’s framework for access identified barriers such as professional unwillingness, fear of the dentist, cost of treatment, and inadequate dental facilities. Facilitators of access offered insight into strategies for improving access to oral health care for children with disabilities. Conclusion There is a positive benefit to using Levesque’s framework of access or other established frameworks to carry out research on oral healthcare access, or implementations of dental public health interventions in order to identify gaps, enhance awareness and promote better oral health practices. The evidence suggests that including people with disabilities in co-developing service provision improves accessibility, alongside using tailored approaches and interventions which promote understanding of the importance of dental care and increases awareness for professionals, caregivers and children with disabilities. Trial registration Protocol has been registered online on the PROSPERO database with an ID CRD42023433172 on June 9, 2023.

uDALES is an open-source multi-physics microscale urban modelling tool, capable of performing large-eddy simulation (LES) of urban airflow, heat transfer, and pollutant dispersion. We present uDALES v2.0, which has two main new features: (1) an improved parallelisation that prepares the codebase for conducting exascale simulations and (2) a conservative immersed boundary method (IBM) suitable for an urban surface that does not need to be aligned with the underlying Cartesian grid. The urban geometry and local topography are incorporated via a triangulated surface with a resolution that is independent of the fluid grid. The IBM developed here includes the use of wall functions to apply surface fluxes, and the exchange of heat and moisture between the surface and the air is conservative by construction. We perform a number of validation simulations, ranging from neutral, coupled internal–external flows and non-neutral cases. We observe close agreement with the relevant literature, both in cases in which the buildings are aligned with the Cartesian grid and when they are at an angle. We introduce a validation case specifically for urban applications, for which we show that supporting non-grid-aligned geometries is crucial when solving surface energy balances, with errors of up to 20 % associated with using a grid-aligned geometry.

Abstract The harmful effects of mining waste on human and ecosystem health make reclamation of former mine sites an environmental management priority. However, field-based monitoring of reclamation requires significant investments of time, labor, and money. Remote sensing offers a less expensive alternative to field-based monitoring, but work is still needed to determine which metrics can be reliably estimated using remote sensing techniques. This study uses remote sensing to examine over 20 years of reclamation efforts at Tar Creek Superfund Site and to assess revegetation after site restoration. Using the Normalized Difference Vegetation Index (NDVI), we quantify key factors affecting vegetation recovery and stability after reclamation across 123 surface mining waste cleanup locations within Tar Creek. Leveraging long-term imagery from Landsat and high-resolution PlanetScope imagery, we combine time series analysis of vegetation regrowth and landcover change detection for a comprehensive picture of recovery at each site. Across all reclamation sites, the average recovery duration was 3.5 years, and average recovery rate was 0.1 NDVI year−1. After vegetative growth had plateaued, reclaimed sites had an average NDVI of 0.70. All reclamation areas were converted from majority barren landcover to vegetated landcover classes after reclamation, and vegetative stability at reclamation sites was high (70% of reclaimed area saw continuous vegetative cover from 2017 to 2023). These results demonstrate a strong potential for multi-method remote sensing techniques in tracking and explaining vegetation recovery after reclamation and represent a cost-effective approach for real-time monitoring of reclamation progress and outcomes.

Abstract Background Germline genetic testing is recommended for an increasing number of conditions with underlying genetic etiologies, the results of which impact medical management. However, genetic testing is underutilized in clinics due to system, clinician, and patient level barriers. Behavioral economics provides a framework to create implementation strategies, such as nudges, to address these multi-level barriers and increase the uptake of genetic testing for conditions where the results impact medical management. Methods Patients meeting eligibility for germline genetic testing for a group of conditions will be identified using electronic phenotyping algorithms. A pragmatic, type 3 hybrid cluster randomization study will test nudges to patients and/or clinicians, or neither. Clinicians who receive nudges will be prompted to either refer their patient to genetics or order genetic testing themselves. We will use rapid cycle approaches informed by clinician and patient experiences, health equity, and behavioral economics to optimize these nudges before trial initiation. The primary implementation outcome is uptake of germline genetic testing for the pre-selected health conditions. Patient data collected through the electronic health record (e.g. demographics, geocoded address) will be examined as moderators of the effect of nudges. Discussion This study will be one of the first randomized trials to examine the effects of patient- and clinician-directed nudges informed by behavioral economics on uptake of genetic testing. The pragmatic design will facilitate a large and diverse patient sample, allow for the assessment of genetic testing uptake, and provide comparison of the effect of different nudge combinations. This trial also involves optimization of patient identification, test selection, ordering, and result reporting in an electronic health record-based infrastructure to further address clinician-level barriers to utilizing genomic medicine. The findings may help determine the impact of low-cost, sustainable implementation strategies that can be integrated into health care systems to improve the use of genomic medicine. Trial registration ClinicalTrials.gov. NCT06377033. Registered on March 31, 2024. https://clinicaltrials.gov/study/NCT06377033?term=NCT06377033&rank=1

Abstract Background Hypertension is a common heart condition in the United States (US) and severely impacts racial and ethnic minority populations. While the understanding of hypertension has grown considerably, there remain gaps in US healthcare research. Specifically, there is a lack of focus on undiagnosed and uncontrolled hypertension in primary care settings. Aim The present study investigates factors associated with undiagnosed and uncontrolled hypertension in primary care patients with hypertension. The study also examines whether Black/African Americans are at higher odds of undiagnosed and uncontrolled hypertension compared to White patients. Methods A cross-sectional study was conducted using electronic health records (EHR) data from the University of Utah primary care health system. The study included for analysis 24,915 patients with hypertension who had a primary care visit from January 2020 to December 2020. Multivariate logistic regression assessed the odds of undiagnosed and uncontrolled hypertension. Results Among 24,915 patients with hypertension, 28.6% (n = 7,124) were undiagnosed and 37.4% (n = 9,319) were uncontrolled. Factors associated with higher odds of undiagnosed hypertension included age 18–44 (2.05 [1.90–2.21]), Hispanic/Latino ethnicity (1.13 [1.03–1.23]), Medicaid (1.43 [1.29-1.58]) or self-pay (1.32 [1.13-1.53]) insurance, CCI 1-2 (1.79 [1.67-1.92]), and LDL-c ≥ 190 mg/dl (3.05 [1.41–6.59]). For uncontrolled hypertension, risk factors included age 65+ (1.11 [1.08–1.34]), male (1.24 [1.17–1.31]), Native-Hawaiian/Pacific Islander (1.32 [1.05-1.62]) or Black/African American race (1.24 [1.11-1.57]) , and self-pay insurance (1.11 [1.03-1.22]). Conclusion The results of this study suggest that undiagnosed and uncontrolled hypertension is prevalent in primary care. Critical risk factors for undiagnosed hypertension include younger age, Hispanic/Latino ethnicity, very high LDL-c, low comorbidity scores, and self-pay or medicaid insurance. For uncontrolled hypertension, geriatric populations, males, Native Hawaiian/Pacific Islanders, and Black/African Americans, continue to experience greater burdens than their counterparts. Substantial efforts are needed to strengthen hypertension diagnosis and to develop tailored hypertension management programs in primary care, focusing on these populations.

Abstract In this study, we evaluated and forecasted the cumulative opportunities for residents to access radiotherapy services in Cali, Colombia, while accounting for traffic congestion, using a new people-centred methodology with an equity focus. Furthermore, we identified 1–2 optimal locations where new services would maximise accessibility. We utilised open data and publicly available big data. Cali is one of South America's cities most impacted by traffic congestion. Methodology: Using a people-centred approach, we tested a web-based digital platform developed through an iterative participatory design. The platform integrates open data, including the location of radiotherapy services, the disaggregated sociodemographic microdata for the population and places of residence, and big data for travel times from Google Distance Matrix API. We used genetic algorithms to identify optimal locations for new services. We predicted accessibility cumulative opportunities (ACO) for traffic ranging from peak congestion to free-flow conditions with hourly assessments for 6–12 July 2020 and 23–29 November 2020. The interactive digital platform is openly available. Primary and secondary outcomes: We present descriptive statistics and population distribution heatmaps based on 20-min accessibility cumulative opportunities (ACO) isochrones for car journeys. There is no set national or international standard for these travel time thresholds. Most key informants found the 20-min threshold reasonable. These isochrones connect the population-weighted centroid of the traffic analysis zone at the place of residence to the corresponding zone of the radiotherapy service with the shortest travel time under varying traffic conditions ranging from free-flow to peak-traffic congestion levels. Additionally, we conducted a time-series bivariate analysis to assess geographical accessibility based on economic stratum. We identify 1–2 optimal locations where new services would maximize the 20-min ACO during peak-traffic congestion. Results: Traffic congestion significantly diminished accessibility to radiotherapy services, particularly affecting vulnerable populations. For instance, urban 20-min ACO by car dropped from 91% of Cali’s urban population within a 20-min journey to the service during free-flow traffic to 31% during peak traffic for the week of 6–12 July 2020. Percentages represent the population within a 20-min journey by car from their residence to a radiotherapy service. Specific ethnic groups, individuals with lower educational attainment, and residents on the outskirts of Cali experienced disproportionate effects, with accessibility decreasing to 11% during peak traffic compared to 81% during free-flow traffic for low-income households. We predict that strategically adding sufficient services in 1–2 locations in eastern Cali would notably enhance accessibility and reduce inequities. The recommended locations for new services remained consistent in both of our measurements. These findings underscore the significance of prioritising equity and comprehensive care in healthcare accessibility. They also offer a practical approach to optimising service locations to mitigate disparities. Expanding this approach to encompass other transportation modes, services, and cities, or updating measurements, is feasible and affordable. The new approach and data are particularly relevant for planning authorities and urban development actors.

Abstract The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Abstract Background Particulate matter exposure (PM) is a cause of aerodigestive disease globally. The destruction of the World Trade Center (WTC) exposed first responders and inhabitants of New York City to WTC-PM and caused obstructive airways disease (OAD), gastroesophageal reflux disease (GERD) and Barrett’s Esophagus (BE). GERD not only diminishes health-related quality of life but also gives rise to complications that extend beyond the scope of BE. GERD can incite or exacerbate allergies, sinusitis, bronchitis, and asthma. Disease features of the aerodigestive axis can overlap, often necessitating more invasive diagnostic testing and treatment modalities. This presents a need to develop novel non-invasive biomarkers of GERD, BE, airway hyperreactivity (AHR), treatment efficacy, and severity of symptoms. Methods Our observational case-cohort study will leverage the longitudinally phenotyped Fire Department of New York (FDNY)-WTC exposed cohort to identify Biomarkers of Airway Disease, Barrett’s and Underdiagnosed Reflux Noninvasively (BAD-BURN). Our study population consists of n = 4,192 individuals from which we have randomly selected a sub-cohort control group (n = 837). We will then recruit subgroups of i. AHR only ii. GERD only iii. BE iv. GERD/BE and AHR overlap or v. No GERD or AHR, from the sub-cohort control group. We will then phenotype and examine non-invasive biomarkers of these subgroups to identify under-diagnosis and/or treatment efficacy. The findings may further contribute to the development of future biologically plausible therapies, ultimately enhance patient care and quality of life. Discussion Although many studies have suggested interdependence between airway and digestive diseases, the causative factors and specific mechanisms remain unclear. The detection of the disease is further complicated by the invasiveness of conventional GERD diagnosis procedures and the limited availability of disease-specific biomarkers. The management of reflux is important, as it directly increases risk of cancer and negatively impacts quality of life. Therefore, it is vital to develop novel noninvasive disease markers that can effectively phenotype, facilitate early diagnosis of premalignant disease and identify potential therapeutic targets to improve patient care. Trial registration Name of Primary Registry: “Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BADBURN)”. Trial Identifying Number: NCT05216133 . Date of Registration: January 31, 2022.

Exponential population increases are threatening food security, particularly in mountainous areas. One potential solution is dual-use intercropped agroforestry systems such as olive (Olea europaea)–maize (Zea mays), which may mitigate risk by providing multiple market sources (oil and grain) for smallholder producers. Several studies have conducted integrated agroforestry land suitability analyses; however, few studies have used machine learning (ML) algorithms to evaluate multiple variables (i.e., soil physicochemical properties and climatic and topographic data) for the selection of suitable rainfed sites in mountainous terrain systems. The goal of this study is therefore to identify suitable land classes for an integrated olive–maize agroforestry system based on the Food and Agriculture Organization (FAO) land suitability assessment framework for 1757 km2 in Khyber Pakhtunkhwa province, Pakistan. Information on soil physical and chemical properties was obtained from 701 soil samples, along with climatic and topographic data. After determination of land suitability classes for an integrated olive–maize-crop agroforestry system, the region was then mapped through ML algorithms using random forest (RF) and support vector machine (SVM), as well as using traditional techniques of weighted overlay (WOL). Land suitability classes predicted by ML techniques varied greatly. For example, the S1 area (highly suitable) classified through RF was 9%↑ than that of SVM, and 8%↓ than that through WOL. The area of S2 (moderately suitable) classified through RF was 18%↑ than that of SWM and was 17%↓ than the area classified through WOL; similarly, the S3 (marginally suitable) class area via RF was 27%↓ than that of SVM, and 45%↓ than the area classified through WOL. Conversely, the area of N2 (permanently not suitable class) classified through RF and SVM was 6%↑ than the area classified through WOL. Model performance was assessed through overall accuracy and Kappa Index and indicated that RF performed better than SVM and WOL. Crop suitability limitations of the study area included high elevation, slope, pH, and large gravel content. Results can be used for sustainable intensification in mountainous rainfed regions by expanding intercrop agroforestry systems in developing nations to close yield gaps.

Abstract Hypertension disparities persist and remain high among racial and ethnic minority populations in the United States (US). Data‐driven approaches based on electronic health records (EHRs) in primary care are seen as a strong opportunity to address this situation. This qualitative study evaluated the development, sustainability, and usability of an EHR‐integrated hypertension disparities dashboard for health care professionals in primary care. Ten semi‐structured interviews, exploring the approach and sustainability, as well as eight usability interviews, using the think aloud protocol were conducted with quality improvement managers, data analysts, program managers, evaluators, and primary care providers. For the results, dashboard development steps include having clear goals, defining a target audience, compiling data, and building multidisciplinary teams. For sustainability, the dashboard can enhance understanding of the social determinants of health or to inform QI projects. In terms of dashboard usability, positive aspects consisted of the inclusion of summary pages, patient's detail pages, and hover‐over interface. Important design considerations were refining sorting functions, gender inclusivity, and increasing dashboard visibility. In sum, an EHR‐driven dashboard can be a novel tool for addressing hypertension disparities in primary care. It offers a platform where clinicians can identify patients for culturally tailored interventions. Factors such as physician time constraints, data definitions, comprehensive patient demographic information, end‐users, and future sustenance, should be considered before implementing a dashboard. Additional research is needed to identify practices for integrating a dashboard into clinical workflow for hypertension.

Abstract Viral mutations frequently outpace technologies used to detect harmful variants. Given the continual emergence of SARS-CoV-2 variants, platforms that can identify the presence of a virus and its propensity for infection are needed. Our electronic biomembrane sensing platform recreates distinct SARS-CoV-2 host cell entry pathways and reports the progression of entry as electrical signals. We focus on two necessary entry processes mediated by the viral Spike protein: virus binding and membrane fusion, which can be distinguished electrically. We find that closely related variants of concern exhibit distinct fusion signatures that correlate with trends in cell-based infectivity assays, allowing us to report quantitative differences in their fusion characteristics and hence their infectivity potentials. We use SARS-CoV-2 as our prototype, but we anticipate that this platform can extend to other enveloped viruses and cell lines to quantifiably assess virus entry.

Abstract The field of exercise physiology has undergone significant technological advancements since the pioneering works of exercise physiologists in the early to mid‐20th century. Historically, the ability to detect metabolites in biofluids from exercising participants was limited to single‐metabolite analyses. However, the rise of metabolomics, a discipline focused on the comprehensive analysis of metabolites within a biological system, has facilitated a more intricate understanding of metabolic pathways and networks in exercise. This review explores some of the pivotal technological and bioinformatic advancements that have propelled metabolomics to the forefront of exercise physiology research. Metabolomics offers a unique ‘fingerprint’ of cellular activity, offering a broader spectrum than traditional single‐metabolite assays. Techniques, including mass spectrometry and nuclear magnetic resonance spectroscopy, have significantly improved the speed and sensitivity of metabolite analysis. Nonetheless, challenges persist, including study design and data interpretation issues. This review aims to serve as a guide for exercise physiologists to facilitate better research design, data analysis and interpretation within metabolomics. The potential of metabolomics in bridging the gap between genotype and phenotype is emphasised, underscoring the critical importance of careful study design and the selection of appropriate metabolomics techniques. Furthermore, the paper highlights the need to deeply understand the broader scientific context to discern meaningful metabolic changes. The emerging field of fluxomics, which seeks to quantify metabolic reaction rates, is also introduced as a promising avenue for future research.

Abstract Background Asthma is the most common chronic respiratory illness among children in Australia. While childhood asthma prevalence varies by region, little is known about variations at the small geographic area level. Identifying small geographic area variations in asthma is critical for highlighting hotspots for targeted interventions. This study aimed to investigate small area-level variation, spatial clustering, and sociodemographic risk factors associated with childhood asthma prevalence in Australia. Methods Data on self-reported (by parent/carer) asthma prevalence in children aged 0–14 years at statistical area level 2 (SA2, small geographic area) and selected sociodemographic features were extracted from the national Australian Household and Population Census 2021. A spatial cluster analysis was used to detect hotspots (i.e., areas and their neighbours with higher asthma prevalence than the entire study area average) of asthma prevalence. We also used a spatial Bayesian Poisson model to examine the relationship between sociodemographic features and asthma prevalence. All analyses were performed at the SA2 level. Results Data were analysed from 4,621,716 children aged 0–14 years from 2,321 SA2s across the whole country. Overall, children’s asthma prevalence was 6.27%, ranging from 0 to 16.5%, with significant hotspots of asthma prevalence in areas of greater socioeconomic disadvantage. Socioeconomically disadvantaged areas had significantly higher asthma prevalence than advantaged areas (prevalence ratio [PR] = 1.10, 95% credible interval [CrI] 1.06–1.14). Higher asthma prevalence was observed in areas with a higher proportion of Indigenous individuals (PR = 1.13, 95% CrI 1.10–1.17). Conclusions We identified significant geographic variation in asthma prevalence and sociodemographic predictors associated with the variation, which may help in designing targeted asthma management strategies and considerations for service enhancement for children in socially deprived areas.

Abstract Gammaherpesviruses are oncogenic viruses that establish lifelong infections and are significant causes of morbidity and mortality. Vaccine strategies to limit gammaherpesvirus infection and disease are in development, but there are no FDA-approved vaccines for Epstein-Barr or Kaposi sarcoma herpesvirus. As a new approach to gammaherpesvirus vaccination, we developed and tested a replication-deficient virus (RDV) platform, using murine gammaherpesvirus 68 (MHV68), a well-established mouse model for gammaherpesvirus pathogenesis studies and preclinical therapeutic evaluations. We employed codon-shuffling-based complementation to generate revertant-free RDV lacking expression of the essential replication and transactivator protein encoded by ORF50 to arrest viral gene expression early after de novo infection. Inoculation with RDV-50.stop exposes the host to intact virion particles and leads to limited lytic gene expression in infected cells yet does not produce additional infectious particles. Prime-boost vaccination of mice with RDV-50.stop elicited virus-specific neutralizing antibody and effector T cell responses in the lung and spleen. In contrast to vaccination with heat-inactivated WT MHV68, vaccination with RDV-50.stop resulted in a near complete abolishment of virus replication in the lung 7 days post-challenge and reduction of latency establishment in the spleen 16 days post-challenge with WT MHV68. Ifnar1 −/− mice, which lack the type I interferon receptor, exhibit severe disease and high mortality upon infection with WT MHV68. RDV-50.stop vaccination of Ifnar1 −/− mice prevented wasting and mortality upon challenge with WT MHV68. These results demonstrate that prime-boost vaccination with a gammaherpesvirus that is unable to undergo lytic replication offers protection against acute replication, impairs the establishment of latency, and prevents severe disease upon the WT virus challenge. Our study also reveals that the ability of a gammaherpesvirus to persist in vivo despite potent pre-existing immunity is an obstacle to obtaining sterilizing immunity.

Abstract In a pivotal trial (EPIC-HR), a 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days of symptoms onset), decreased hospitalization and death by 89.1% and nasal viral load by 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis in a trial, and frequent viral rebound has been observed in subsequent cohorts. We develop a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulates viral loads from this and another clinical trial (PLATCOV). Our results suggest that nirmatrelvir’s in vivo potency is significantly lower than in vitro assays predict. According to our model, a maximally potent agent would reduce the viral load by approximately 3.5 logs relative to placebo at 5 days. The model identifies that earlier initiation and shorter treatment duration are key predictors of post-treatment rebound. Extension of treatment to 10 days for Omicron variant infection in vaccinated individuals, rather than increasing dose or dosing frequency, is predicted to lower the incidence of viral rebound significantly.

Abstract Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with > 21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. This study represents the first systematic exploration of DNA methylation patterns during human fetal pancreas development and confirms the prenatal period as a time of major epigenomic plasticity.

Abstract Background Zip codes classified by the Food Insecurity Index with moderate and high food insecurity (FI) risk can be a threat to the health and well-being of children during the first 1,000 days (from pregnancy to 2 years). The presence of nurturing care assets (i.e., stable environments that promote health and nutrition, learning opportunities, security and safety, and responsive relationships) can contribute to supporting families and their communities, and ultimately reduce systemic barriers to food security. We aimed to identify and characterize nurturing care assets in under-resourced communities with moderate and high FI risk. Methods Four steps were used to conduct a Community Asset Mapping (CAM): (1) review of community documents across five zip codes in Clark County, Nevada (2), engagement of community members in identifying community assets (3), definition of the assets providing nurturing care services, and (4) classification of assets to nurturing care components, i.e., good health, adequate nutrition, safety and security, opportunities for early learning, and responsive caregiving. The Food Insecurity Index was used to determine FI risk in each zip code. Analyses explored whether disparities in nurturing care assets across zip codes with moderate and high FI exist. Results We identified 353 nurturing care assets across zip codes. A more significant number of nurturing care assets were present in zip codes with high FI risk. The adequate nutrition component had the most assets overall (n = 218, 61.8%), while the responsive caregiving category had the least (n = 26, 7.4%). Most of the adequate nutrition resources consisted of convenience stores (n = 96), food pantries (n = 33), and grocery stores (n = 33). Disparities in the number and type of good health, early learning, and security and safety assets were identified within zip codes with high FI risk compared to moderate FI risk. Conclusions The quantity and type of nurturing care assets can exacerbate existing demographic disparities across zip codes, which are tied to barriers to access to food in under-resourced communities in Clark County, Nevada. Co-creating a nurturing care asset-based zip code strategy to address high FI risk will require strengthening systems across existing nurturing care assets.

Teaching is a stressful profession, and teacher stress has been shown to be associated with job dissatisfaction, attrition from the field, and negative outcomes for teachers and their students. A major contributor to teacher stress is disruptive student behavior. Given that students with or at-risk for attention-deficit/hyperactivity disorder (ADHD) demonstrate high rates of disruptive behaviors and are present in nearly every classroom, studying the connection between student ADHD symptoms and teacher stress may provide useful insights for better supporting teachers and their students. Aims of this study were to (1) assess the replicability of a previous finding that teachers rate their students with elevated ADHD symptoms to be more stressful to teach than students without these symptoms and (2) explore the extent to which key factors (i.e., overall work-related stress and student--teacher relationship quality) moderate the relationship between student ADHD symptoms and related teacher stress. Participants were 97 K-2nd grade teachers who completed an online survey about themselves and two male students in their classroom. Results showed that teachers report students with elevated levels of ADHD symptoms and impairment to be more stressful to work with than students who do not exhibit these symptoms (d = 1.52). Additionally, overall work-related stress and conflict in the student--teacher relationship exacerbated the relationship between student ADHD symptom severity and related teacher stress, whereas closeness in the student--teacher relationship mitigated this association. Implications of these findings and directions for future research are discussed.

This paper reports on research conducted with staff employed in the Australian higher education sector during the COVID-19 pandemic. The sector has been significantly impacted, particularly those institutions heavily reliant on revenue from international student enrolments. Universities moved swiftly to introduce cost-savings measures such as, deferring capital works spending and reducing non-salary expenditure, scaling back casual and fixed term staff and cuts to executive staff salaries, followed by rounds of redundancies, early retirement offers and termination of staff, often framed as organisational restructuring. However, financial data for the 2021-22 period indicate that some institutions have actioned disproportionate staff cuts related to net income, often badging this downsizing as organisational restructure. This information is discussed in terms of the potential implications for the higher education sector in planning for, and meeting workforce needs, as it seeks to regenerate a sustainable business model post-pandemic.

The purpose of this article is to explore SI's alignment to theories of adult learning and development which are the underpinnings of developmental education. We begin by identifying adult learning and development theories that have influenced the field of developmental education and then examine descriptions of SI in the literature to explore SI's utility as a student support strategy within developmental education contexts. We conclude by providing examples from our own application of SI, including pragmatic tools for helping both instructors and SIL be successful in the classroom. We demonstrate how these SI practices are consistent with adult learning and development research. The tools we describe were developed with a developmental education context in mind but can be applied in any SI context.

This investigation uses conversation analysis (CA) to document, in very close detail, how participants-in-interaction manage and organize repair practices in moments when linguistic repair becomes conditionally relevant in conversational or 'chatting' phases of online dyadic L2-learning interactions between a tutor and tutee. Specifically, this study focuses on the phenomena of precluding linguistic repair when it becomes relevant (by making it conditional on quick uptake and completion, and by deploying turn-taking devices to hold the turn when other-correction becomes or seems relevant) and abandoning it when it is in progress. Analysis framed these phenomena not as individual strategies, but as collaborative accomplishments realized through the interactional competence (IC) of the participants, and showed that participants oriented to both pedagogical and social concerns in moments of linguistic repair. Therefore, such moments were key sites for co-construction and configuration of the interactional space as primarily social or pedagogical, or as a complex and conditional interweaving of the two.