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Abstract Most gene functions have been discovered through phenotypic observations under loss of function experiments that lack temporal control. However, cell signaling relies on limited transcriptional effectors, having to be re-used temporally and spatially within the organism. Despite that, the dynamic nature of signaling pathways have been overlooked due to the difficulty on their assessment, resulting in important bottlenecks. Here, we have utilized the rapid and synchronized developmental transitions occurring within the zebrafish embryo, in conjunction with custom NF-kB reporter embryos driving destabilized fluorophores that report signaling dynamics in real time. We reveal that NF-kB signaling works as a clock that controls the developmental progression of hematopoietic stem and progenitor cells (HSPCs) by two p65 activity waves that inhibit cell cycle. Temporal disruption of each wave results in contrasting phenotypic outcomes: loss of HSPCs due to impaired specification versus proliferative expansion and failure to delaminate from their niche. We also show functional conservation during human hematopoietic development using iPSC models. Our work identifies p65 as a previously unrecognized contributor to cell cycle regulation, revealing why and when pro-inflammatory signaling is required during HSPC development. It highlights the importance of considering and leveraging cell signaling as a temporally dynamic entity.

Abstract Background Most rural populations experience significant health disadvantage. Community-engaged research can facilitate research activities towards addressing health issues of priority to local communities. Connecting scholars with community based frontline practices that are addressing local health and medical needs helps establish a robust pipeline for research that can inform gaps in health provision. Rural Health Projects (RHPs) are conducted as part of the Doctor of Medicine program at the University of Queensland. This study aims to describe the geographic coverage of RHPs, the health topic areas covered and the different types of RHP research activities conducted. It also provides meaningful insight of the health priorities for local rural communities in Queensland, Australia. Methods This study conducted a retrospective review of RHPs conducted between 2011 and 2021 in rural and remote Australian communities. Descriptive analyses were used to describe RHP locations by their geographical classification and disease/research categorisation using the International Classification of Diseases and Related Health Problems – 10th Revision (ICD-10) codes and the Human Research Classification System (HRCS) categories. Results There were a total of 2806 eligible RHPs conducted between 2011 and 2021, predominantly in Queensland (n = 2728, 97·2%). These were mostly conducted in small rural towns (under 5,000 population, n = 1044, 37·2%) or other rural towns up to 15,000 population (n = 842, 30·0%). Projects mostly addressed individual care needs (n = 1233, 43·9%) according to HRCS categories, or were related to factors influencing health status and contact with health services (n = 1012, 36·1%) according to ICD-10 classification. Conclusions Conducting community focused RHPs demonstrates a valuable method to address community-specific rural health priorities by engaging medical students in research projects while simultaneously enhancing their research skills.

Cool season grasses, including tall fescue, are dominant plants within managed grassland systems. A symbiotic relationship between tall fescue (Lolium arundinaceum) and the fungal endophyte Epichloë coenophiala can affect grassland response to perturbations, including changing rainfall patterns and increasing temperatures associated with climate change. Because E. coenophiala reproduces asexually, there is concern that climate change may negatively impact vertical transmission, resulting in subsequent fescue stands with lower infection frequencies and reduced grassland resiliency. This 3-year field study evaluated the impact of increased temperature, altered precipitation, and their combination on vertical transmission, seed number, and seed weight in tall fescue clones containing common toxic (CTE) or novel nonmammalian toxic (NTE) E. coenophiala. NTE clones exhibited greater transmission than CTE clones. Temperature did not affect transmission, but altered precipitation reduced transmission in CTE clones. On average, NTE clones responded to increased temperatures by reducing seed number, while CTE clones responded oppositely. NTE clones produced seeds of similar masses across all growing years, suggesting greater stability under varying environmental conditions. Our work illustrates that both plant and endophyte genetics influence vertical transmission and that climate change is unlikely to significantly impact endophyte transmission in the southeastern transition zone of the United States. [Graphic: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Integrating spatial inequality perspectives in strategic decision-making can ensure positive impacts on resource distribution for public welfare and sustainable development. This study aims to apply evidence-based approaches in deploying permanent deacons. The empirical case study has been conducted at the St Helens denary of the Liverpool archdiocese, UK. Assisting with charitable works is one of three served areas by the Roman Catholic Church facilitated by deacons. The deployment of permanent deacons could benefit from being evidence-based so that a deacon can serve to ease the socio-economic (e.g., population density, long-term health conditions, housing system, employment status, education level, social status) inequality in the most deprived area. We used geographic information system (GIS) based algorithms, Getis-Ord Gi* for hot spot analysis to find the clustered area by considering the socio-economic factors. The open/freely available government census dataset was found to help extract socio-economic parameters. Furthermore, a GIS-based multi-criteria assessment technique was conducted by applying map algebra (raster calculator) to identify the deprived area with ranks considering multiple socio-economic conditions, where served areas by the existing deacons were considered to constrain. The served areas were estimated by applying network analysis where OpenStreetMap and location existing deacons were used as input. Our empirical case study identified the central and northern parts of the deanery as the most and least deprived areas, respectively. Finally, Liverpool archdiocese could consider deploying new permanent deacons in St Helens denary based on suggested deprivation ranks. Therefore, the appropriate number of deacons in the deprived areas can quickly and effectively respond to the needy and enhance communities’ resilience and sustainable development by ensuring proportionate resource distribution.

Objective To evaluate the importance of rural internships to observed medical workforce distribution outcomes up to 8 years post-medical school.Design and setting Cohort study of medical graduates of The University of Queensland (UQ), Australia.Participants UQ graduates who were medical interns in Queensland’s public health system between 2014 and 2021 and observed working in Australia in 2022. Internship location was defined as being metropolitan or rural, along with other key rural exposures of whether they are of rural origin (childhood) and whether at least 1 year of clinical training at medical school was in a rural location.Primary outcome measure Current work location was collected from the Australian Health Practitioner Regulation Agency (AHPRA) in 2022, classified as either rural or metropolitan and measured in association with their internship location.Results From 1930 eligible graduates, 21.5% took up a rural internship, which was associated with rural origin (OR 1.5, 95% CI 1.2 to 2.0) and medical school rural immersions of either 1 year (OR 2.8, 95% CI 2.1 to 3.7) or 2 years (OR 5.8, 95% CI 4.4 to 7.7). Completing a rural internship was associated with currently working rural (47% vs 14%, OR 4.6, 95% CI 3.5 to 5.9), which weakened the observed (adjusted) effect of rural origin (OR 1.5, 95% CI 1.2 to 2.0) or medical school rural immersions (1 year: OR 1.4, 95% CI 1.0 to 1.9; 2 years: OR 1.7, 95% CI 1.2 to 2.3). All combinations of the key rural exposures that included rural internship had the highest proportions currently working rurally (range 32–69%) compared with the combinations with a metropolitan internship (range 12–22%).Conclusions Internship location appears to be a critical factor in shaping medical workforce distribution decisions. This evidence supports the need for strengthened and expanded rural training pathways after medical school. In particular, clearer pathways into specialty programmes via rural internships are likely to support increased numbers choosing (with confidence) to preference rural internship first and subsequently more working in rural areas long term.

Background Sources of public and private data and ways to link them continue to evolve. This offers new opportunities for research, and new reasons for data-holding organisations to form partnerships. While research using these data can be beneficial, there is also a potential for negative consequences for some individuals or groups, including unintended or unanticipated effects. It is important to consult the public on how we might achieve both opportunities to link different types of data for research purposes, and protections against the misuse of data and the possibility of negative consequences. Methods Combining data sources for research was the topic of four days of deliberation held in British Columbia, Canada in late 2019. Public deliberation events bring diverse groups of people together to give direct input to policy makers, through carefully structured in-depth discussion on issues that are controversial and/or a source of public concern. Participants discussed whether data from electronic medical records should be used for research purposes, whether it is acceptable to combine data from public and private sources, who should authorise its use in research, and how a public advisory group on data use might be structured. Results Over four days, 29 residents of BC developed 17 deliberative conclusions that can be grouped into four broad topic areas: balancing benefit and potential harms when linking data; the protections that are expected to govern use of data; the type of authorisation required; and how the public should be involved in an ongoing way. Overall, the public is very supportive of research as long as oversight and controls are in place, including ongoing input from members of the public. Conclusion Deliberative conclusions from this event provide essential public input on the use of linked data for research, in particular when those data come from multiple sources. This is important information as policy-makers continue to develop legislation and practices around the use and linkage of both public and private sources of data.

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

Background Population data science has a long history with health care data. Some data centres are expanding to include “health-related” data, including information on other publicly funded services (e.g. education, income and housing supports), and systems (e.g. criminal justice, children in care). We describe what enabled this expansion through three examples from Health Data Research Network Canada. Methods HDRN Canada members include data centres that provide access to linkable data sets for approved research projects. We use case studies to identify similarities, differences, and lessons learned from the process of expansion in the provinces of Manitoba, New Brunswick and British Columbia. Results The Manitoba Centre for Health Policy has 30+ years of experience with linked data, with a consistent focus on population health. Data sets expanded incrementally, through partnerships across government agencies. Population Data BC has a nearly 30-year history, with recent expansion to health-related data through partnership with a program of one government ministry that operates under distinct legislative authority. The New Brunswick Institute for Research, Data and Training is newer, and helped advocate for legislation changes that enabled an expanded set of linked data to be made available for research. All embed Five Safes principles, and commitments to inclusion, diversity, equity and accessibility and Indigenous data sovereignty in data governance. Conclusion A greater variety of data enables research to answer complex research questions. This kind of expansion can be accomplished through different mechanisms, but in all cases requires attention to ethical and legal principles of population data science.

Objective Quality care for older adults living with dementia (OALwD) is a priority in Canada, nationally, and British Columbia (BC), provincially. The COVID-19 pandemic likely changed care quality, but this has not been assessed. We are examining the effect of pandemic-related policy changes on quality of care for community-dwelling OALwD in BC. Approach This population-based retrospective cohort study uses linked administrative data to examine trends in population-level indicators of quality care from 2016-2023. We will compare effects among community-dwelling BC residents aged 65+ with dementia and those without dementia. Indicators including hospitalization rate and medication use were selected, based on the Institute of Medicine’s six dimensions of quality (e.g., effectiveness, safety). Interrupted time series (ITS) analysis will examine changes between “pre-pandemic” and “in-pandemic” periods. Equity will be assessed through stratification by sociodemographic variables. Anticipated Results Percent change in the level and slope of each indicator’s trend will be reported. Single ITS will identify the effect of the pandemic on each outcome in the dementia group only. Controlled ITS will identify whether changes differ from those observed in older adults without dementia. Together, observed changes in the indicators and differences across equity factors will inform an interpretation of the overall effect of the pandemic on quality of care for community-dwelling OALwD in BC. Implications We will determine whether quality of care changed for older adults because of the pandemic and whether changes differed for OALwD. This knowledge will inform practice and policy for delivery of high quality, proactive dementia care.

Background Research and surveillance using routinely collected health data rely on algorithms to ascertain disease cases or health measures. Where algorithm validation studies are not possible due to lack of a reference standard, algorithm feasibility studies can be used to create and assess algorithms for use in more than one population or jurisdiction. Publication of the methods used to conduct feasibility studies is critical for transparency and reproducibility. Existing guidelines applicable to feasibility studies, including the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) and REporting of studies Conducted using Observational Routinely collected health Data (RECORD) statements, may benefit from additional elements to capture aspects particular to multi-jurisdiction algorithm feasibility studies and ensure full reproducibility. Methods A subcommittee of members from Health Data Research Network (HDRN) Canada’s Algorithms and Harmonized Data Working Group (AHD-WG) reviewed items within the STROBE and RECORD guidelines and compared these to published feasibility studies. Items not contained within STROBE or RECORD but recommended to ensure transparent reporting of feasibility studies were identified. The AHD-WG reviewed and approved these additional recommended elements. Results Eleven additional recommended elements were identified: one element for the title and abstract, one in the introduction, five in the methods, and four in the results sections. Elements primarily addressed reporting jurisdictional data variabilities, data harmonization methods, and algorithm implementation. Significance Implementation of these recommended elements, alongside the RECORD guidelines, is intended to encourage consistent publication of methods that support reproducibility, as well as increase comparability and international collaborations.

Background Understanding contexts of data production is necessary for using data accurately and ethically. “Biographies of data"" have developed as a complement to existing metadata as a way to critically examine and communicate social structures and power dynamics encoded in data. This project is focused on developing a “biography” of diagnostic codes, used to identify substance use disorders (SUD) in population health datasets. People with SUD regularly experience stigma and exclusion, particularly from healthcare settings. Methods Qualitative semi-structured interviews were conducted in 2024 with ""producers"" and “managers” of administrative data, including physicians and health information professionals, in British Columbia, Canada. The interviews explored processes involved with coding and billing, and the meaning of diagnostic codes from the perspective of those involved. This includes considerations of the population, social, and geographic factors, and implications of coding as inputs to decision-making. Reflexive thematic analysis was used to identify broad themes and report findings. Results Although data collection and analysis is ongoing, emerging findings have revealed structural, institutional, and social-level processes that influence coding decisions, as well as potential implications on research, policy making, and knowledge production about SUD. Conclusion Addressing the complexities of SUD and the overdose crisis will require a variety of data sources and approaches, and linked population health and administrative data will continue to be one important resource. Through better understanding the contexts and processes that inform the production and management of SUD-related population data, we will shed light on the ethical and social implications of their use.

Adaptation of the islet β cell insulin-secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we have shown that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in β cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurred at sites occupied by the chromatin-modifying enzyme lysine-specific demethylase 1 (Lsd1) in islets. β Cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient-response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.

Abstract Background Timely referral of individuals with chronic kidney disease from primary care to secondary care is evidenced to improve patient outcomes, especially for those whose disease progresses to kidney failure requiring kidney replacement therapy. A shortage of specialist nephrology services plus no consistent criteria for referral and reporting leads to referral pattern variability in the management of individuals with chronic kidney disease. Objective The objective of this review was to explore the referral patterns of individuals with chronic kidney disease from primary care to specialist nephrology services. It focused on the primary-specialist care interface, optimal timing of referral to nephrology services, adequacy of preparation for kidney replacement therapy, and the role of clinical criteria vs. risk-based prediction tools in guiding the referral process. Methods A narrative review was utilised to summarise the literature, with the intent of providing a broad-based understanding of the referral patterns for patients with chronic kidney disease in order to guide clinical practice decisions. The review identified original English language qualitative, quantitative, or mixed methods publications as well as systematic reviews and meta-analyses available in PubMed and Google Scholar from their inception to 24 March 2023. Results Thirteen papers met the criteria for detailed review. We grouped the findings into three main themes: (1) Outcomes of the timing of referral to nephrology services, (2) Adequacy of preparation for kidney replacement therapy, and (3) Comparison of clinical criteria vs. risk-based prediction tools. The review demonstrated that regardless of the time frame used to define early vs. late referral in relation to the start of kidney replacement therapy, better outcomes are evidenced in patients referred early. Conclusions This review informs the patterns and timing of referral for pre-dialysis specialist care to mitigate adverse outcomes for individuals with chronic kidney disease requiring dialysis. Enhancing current risk prediction equations will enable primary care clinicians to accurately predict the risk of clinically important outcomes and provide much-needed guidance on the timing of referral between primary care and specialist nephrology services.

Abstract Objectives Arterial catheters (ACs) are critical for haemodynamic monitoring and blood sampling but are prone to complications. We investigated the incidence and risk factors of AC failure. Methods Secondary analysis of a multi-centre randomised controlled trial (ACTRN 12610000505000). Analysis included a subset of adult intensive care unit patients with an AC. The primary outcome was all-cause device failure. Secondary outcomes were catheter associated bloodstream infection (CABSI), suspected CABSI, occlusion, thrombosis, accidental removal, pain, and line fracture. Risk factors associated with AC failure were investigated using Cox proportional hazards and competing-risk models. Results Of 664 patients, 173 (26%) experienced AC failure (incidence rate [IR] 37/1000 catheter days). Suspected CABSI was the most common failure type (11%; IR 15.3/1000 catheter days), followed by occlusion (8%; IR 11.9/1,000 catheter days), and accidental removal (4%; IR 5.5/1000 catheter days). CABSI occurred in 16 (2%) patients. All-cause failure and occlusion were reduced with ultrasound-assisted insertion (failure: adjusted hazard ratio [HR] 0.43, 95% CI 0.25, 0.76; occlusion: sub-HR 0.11, 95% CI 0.03, 0.43). Increased age was associated with less AC failure (60–74 years HR 0.63, 95% CI 0.44 to 0.89; 75 + years HR 0.36, 95% CI 0.20, 0.64; referent 15–59 years). Females experienced more occlusion (adjusted sub-HR 2.53, 95% CI 1.49, 4.29), while patients with diabetes had less (SHR 0.15, 95% CI 0.04, 0.63). Suspected CABSI was associated with an abnormal insertion site appearance (SHR 2.71, 95% CI 1.48, 4.99). Conclusions AC failure is common with ultrasound-guided insertion associated with lower failure rates. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN 12610000505000); date registered: 18 June 2010.

BackgroundAdult day programs provide critical supports to older adults and their family or friend caregivers. High-quality care in the community for as long as possible and minimizing facility-based continuing care are key priorities of older adults, their caregivers, and health care systems. While most older adults in need of care live in the community, about 10% of newly admitted care home residents have relatively low care needs that could be met in the community with the right supports. However, research on the effects of day programs is inconsistent. The methodological quality of studies is poor, and we especially lack robust, longitudinal research. ObjectiveOur research objectives are to (1) compare patterns of day program use (including nonuse) by province (Alberta, British Columbia, and Manitoba) and time; (2) compare characteristics of older adults by day program use pattern (including nonuse), province, and time; and (3) assess effects of day programs on attendees, compared with a propensity score–matched cohort of older nonattendees in the community. MethodsIn this population-based retrospective cohort study, we will use clinical and health administrative data of older adults (65+ years of age) who received publicly funded continuing care in the community in the Canadian provinces of Alberta, British Columbia, and Manitoba between January 1, 2012, and December 31, 2024. We will compare patterns of day program use between provinces and assess changes over time. We will then compare characteristics of older adults (eg, age, sex, physical or cognitive disability, area-based deprivation indices, and caregiver availability or distress) by pattern of day program use or nonuse, province, and time. Finally, we will create a propensity score–matched comparison group of older adults in the community, who have not attended a day program. Using time-to-event models and general estimating equations, we will assess whether day program attendees compared with nonattendees enter care homes later; use emergency, acute, or primary care less frequently; experience less cognitive and physical decline; and have better mental health. ResultsThis will be a 3-year study (July 1, 2024, to June 30, 2027). We received ethics approvals from the relevant ethics boards. Starting on July 1, 2024, we will work with the 3 provincial health systems on data access and linkage, and we expect data analyses to start in early 2025. ConclusionsThis study will generate robust Canadian evidence on the question whether day programs have positive, negative, or no effects on various older adult and caregiver outcomes. This will be a prerequisite to improving the quality of care provided to older adults in day programs, ultimately improving the quality of life of older adults and their caregivers. Trial RegistrationClinicalTrials.gov NCT06440447; https://clinicaltrials.gov/study/NCT06440447 International Registered Report Identifier (IRRID)PRR1-10.2196/60896

Context: There is growing evidence supporting a shift towards 'grow your own' approaches to recruiting, training and retaining health professionals from and for rural communities. To achieve this, there is a need for sound methodologies by which universities can describe their area of geographic focus in a precise way that can be utilised to recruit students from their region and evaluate workforce outcomes for partner communities. In Australia, Deakin University operates a Rural Health Multidisciplinary Training (RHMT) program funded Rural Clinical School and University Department of Rural Health, with the purpose of producing a graduate health workforce through the provision of rural clinical placements in western and south-western Victoria. The desire to establish a dedicated Rural Training Stream within Deakin's Doctor of Medicine course acted as a catalyst for us to describe our 'rural footprint' in a way that could be used to prioritise local student recruitment as well as evaluate graduate workforce outcomes specifically for this region. Issue: In Australia, selection of rural students has relied on the Australian Statistical Geography Standard Remoteness Areas (ASGS-RA) or Modified Monash Model (MMM) to assign rural background status to medical course applicants, based on a standard definition provided by the RHMT program. Applicants meeting rural background criteria may be preferentially admitted to any medical school according to admission quotas or dedicated rural streams across the country. Until recently, evaluations of graduate workforce outcomes have also used these rurality classifications, but often without reference to particular geographic areas. Growing international evidence supports the importance of place-based connection and training, with medical graduates more likely to work in a region that they are from or in which they have trained. For universities to align rural student recruitment more strategically with training in specific geographic areas, there is a need to develop precise geographical definitions of areas of rural focus that can be applied during admissions processes. Lessons learned: As we strived to describe our rural activity area precisely, we modelled the application of several geographical and other frameworks, including the MMM, ASGS-RA, Primary Healthcare Networks (PHN), Local Government Areas (LGAs), postcodes and Statistical Areas. It became evident that there was no single geographical or rural framework that (1) accurately described our area of activity, (2) accurately described our desired workforce focus, (3) was practical to apply during the admissions process. We ultimately settled on a bespoke approach using a combination of the PHN and MMM to achieve the specificity required. This report provides an example of how a rural activity footprint can be accurately described and successfully employed to prioritise students from a geographical area for course admission. Lessons learned about the strengths and limitations of available geographical measures are shared. Applications of a precise footprint definition are described including student recruitment, evaluation of workforce outcomes for a geographic region, benefits to stakeholder relationships and an opportunity for more nuanced RHMT reporting.

Introduction Digital technology is increasingly being adopted within primary healthcare services to improve service delivery and health outcomes; however, the scope for digital innovation within primary care services in rural areas is currently unknown. This systematic review aims to synthesise existing research on the use and integration of digital health technology within primary care services for rural populations across the world.Methods and analysis A systematic approach to the search strategy will be conducted. Relevant medical and healthcare-focused electronic databases will be searched using key search terms between January 2013 and December 2023. Searches will be conducted using specific inclusion and exclusion criteria. A systematic study selection and data extraction process will be implemented, using standardised templates. Outcomes will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses- Protocol statement guidelines. Quality assessment and risk of bias appraisal will be conducted using the Mixed Methods Appraisal Tool.Ethics and dissemination Ethical approval will not be required because there is no individual patient data collected or reviewed. The finding of this review will be disseminated through peer-reviewed publications and conference presentations. Outcomes will help to understand existing knowledge and identify gaps in delivering digital healthcare services, while also providing potential future practice and policy recommendations.PROSPERO registration number CRD42023477233.

Objective This study aims to determine the associations between specialty type and practice location at postgraduate year 10 (PGY10), matched with PGY5 and PGY8 work locations, and earlier rural exposure/experience.Design and setting A cohort study of medicine graduates from nine Australian universities.Participants 1220 domestic medicine graduates from the class of 2011.Outcome measures Practice location recorded by the Australian Health Practitioner Regulation Agency in PGY10; matched graduate movement between PGYs 5, 8 and 10 as classified by the Modified Monash Model, stratified by specialty type (predominantly grouped as general practitioner (GP) or non-GP).Results At PGY10, two-thirds (820/1220) had achieved fellowship. GPs were 2.8 times more likely to be in non-metropolitan practice (28% vs 12%; 95% CI 2.0 to 4.0, p

Abstract Background Medical internship is a key transition point in medical training from student to independent (junior) doctor. The national Regional Training Hubs (RTH) policy began across Australia in late 2017, which aims to build medical training pathways for junior doctors within a rural region and guide students, interns and trainees towards these. This study aims to explore preferencing and acceptance trends for rural medical internship positions in Queensland. Moreover, it focuses on internship preference and acceptance outcomes prior to and following the establishment of RTHs, and their association with key covariates such as rural training immersions offered by medical schools. Methods Data from all applicants to Queensland Health intern positions between 2014–2021 were available, notably their preference order and location of accepted internship position, classified as rural or metropolitan. Matched data from Queensland’s medical schools were added for rural training time and other key demographics. Analyses explored the statistical associations between these factors and preferencing or accepting rural internships, comparing pre-RTH and post-RTH cohorts. Results Domestic Queensland-trained graduates first preferencing rural intern positions increased significantly (pre-RTH 21.1% vs post-RTH 24.0%, p = 0.017), reinforced by a non-significant increase in rural acceptances (27.3% vs 29.7%, p = 0.070). Rural interns were more likely to have previously spent ≥ 11-weeks training in rural locations within medical school, be rurally based in the year applying for internship, or enrolled in the rural generalist pathway. Conclusions The introduction of the RTH was associated with a moderate increase of graduates both preferencing and accepting a rural internship, though a richer understanding of the dominant reasons for and against this remain less clear. An expansion of graduates who undertook longer periods of undergraduate rural training in the same period did not diminish the proportion choosing a rural internship, suggesting there remains an appetite for these opportunities. Overall, domestic graduates are identified as a reliable source of intern recruitment and retention to rural hospitals across Queensland, with entry to the rural generalist pathway and extended rural placement experiences enhancing uptake of rural practice.

Abstract Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.

Abstract Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are currently underappreciated, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of three-dimensional chromatin organization in mediating host-viral interaction. Furthermore, we discover another anti-viral regulator KLF5, a transcriptional factor involved in sphingolipid metabolism, which is up-regulated, and harbors genetic variations linked to COVID-19 patients with severe symptoms. Anti-viral effects of three identified candidates (DAZAP2/VTA1/KLF5) are confirmed individually. Molecular characterization of DAZAP2/VTA1/KLF5-knockout cells highlights the involvement of genes related to the coagulation system in determining the severity of COVID-19. Together, our results provide further resources for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies.

Abstract Background Caribbean Latino adults are at high risk for osteoporosis yet remain underrepresented in bone research. This increased risk is attributed to genetics, diet, and lifestyle known to drive inflammation and microbial dysbiosis. Objective The primary objective of this study was to determine whether consuming 5 oz of yogurt daily for 8wks improves bone turnover markers (BTMs) among Caribbean Latino adults > 50 years; and secondarily to determine the impact on the gut microbiota and markers of intestinal integrity and inflammation. Methods Following a 4wk baseline period, participants were randomized to an 8wk whole fat yogurt intervention (n = 10) daily, containing only Streptococcus thermophilus and Lactobacillus bulgaricus, or to an untreated control group that did not consume yogurt (n = 10). Blood and stool samples collected at week-0 and week-8 were used to assess BTMs, inflammation, intestinal integrity biomarkers, and gut microbiota composition, short chain fatty acids (SCFAs), respectively. Data were evaluated for normality and statistical analyses were performed. Results Participants were 55% women, with a mean age of 70 ± 9 years, BMI 30 ± 6 kg/m2, and serum C-reactive protein 4.8 ± 3.6 mg/L, indicating chronic low-grade inflammation. Following 8wks of yogurt intake, absolute change in BTMs did not differ significantly between groups (P = 0.06–0.78). Secondarily, absolute change in markers of inflammation, intestinal integrity, and fecal SCFAs did not differ significantly between groups (P range 0.13–1.00). Yogurt intake for 8wks was significantly associated with microbial compositional changes of rare taxa (P = 0.048); however, no significant alpha diversity changes were observed. Conclusions In this study, daily yogurt did not improve BTMs, inflammation, intestinal integrity, nor SCFAs. However, yogurt did influence beta diversity, or the abundance of rare taxa within the gut microbiota of the yogurt group, compared to controls. Additional research to identify dietary approaches to reduce osteoporosis risk among Caribbean Latino adults is needed. Trial registration This study is registered to ClinicalTrials.gov, NCT05350579 (28/04/2022).

Abstract Background Major depressive disorder (MDD) is one of the world’s leading causes of disability. Our purpose was to characterize the total costs of MDD and evaluate the degree to which the British Columbia provincial health system meets its objective to protect people from the financial impact of illness. Methods We performed a population-based cohort study of adults newly diagnosed with MDD between 2015 and 2020 and followed their health system costs over two years. The expenditure proportion of MDD-related, patient paid costs relative to non-subsistence income was estimated, incidences of financial hardship were identified and the slope index of inequality (SII) between the highest and lowest income groups compared across regions. Results There were 250,855 individuals diagnosed with MDD in British Columbia over the observation period. Costs to the health system totalled >$1.5 billion (2020 CDN), averaging $138/week for the first 12 weeks following a new diagnosis and $65/week to week 52 and $55/week for weeks 53–104 unless MDD was refractory to treatment ($125/week between week 12–52 and $101/week over weeks 53–104). The proportion of MDD-attributable costs not covered by the health system was 2-15x greater than costs covered by the health system, exceeding $700/week for patients with severe MDD or MDD that was refractory to treatment. Population members in lower-income groups and urban homeowners had disadvantages in the distribution of financial protection received by the health system (SII reached − 8.47 and 15.25, respectively); however, financial hardship and inequities were mitigated province-wide if MDD went into remission (SII − 0.07 to 0.6). Conclusions MDD-attributable costs to health systems and patients are highest in the first 12 weeks after a new diagnosis. During this time, lower income groups and homeowners in urban areas run the risk of financial hardship.

Abstract Background Inequities of health outcomes persist in rural populations globally. This is strongly associated with there being less health coverage in rural and underserviced areas. Increasing health care coverage in rural area requires rural health system strengthening, which subsequently necessitates having tools to guide action. Objective This mapping review aimed to describe the range of tools, frameworks and resources (hereafter called tools) available globally for rural health system capacity building. Methods This study collected peer-reviewed materials published in 15-year period (2005–2020). A systematic mapping review process identified 149 articles for inclusion, related to 144 tools that had been developed, implemented, and/or evaluated (some tools reported over multiple articles) which were mapped against the World Health Organization’s (WHO’s) six health system building blocks (agreed as the elements that need to be addressed to strengthen health systems). Results The majority of tools were from high- and middle-income countries (n = 85, 59% and n = 43, 29%, respectively), and only 17 tools (12%) from low-income countries. Most tools related to the health service building block (n = 57, 39%), or workforce (n = 33, 23%). There were a few tools related to information and leadership and governance (n = 8, 5% each). Very few tools related to infrastructure (n = 3, 2%) and financing (n = 4, 3%). This mapping review also provided broad quality appraisal, showing that the majority of the tools had been evaluated or validated, or both (n = 106, 74%). Conclusion This mapping review provides evidence that there is a breadth of tools available for health system strengthening globally along with some gaps where no tools were identified for specific health system building blocks. Furthermore, most tools were developed and applied in HIC/MIC and it is important to consider factors that influence their utility in LMIC settings. It may be important to develop new tools related to infrastructure and financing. Tools that have been positively evaluated should be made available to all rural communities, to ensure comprehensive global action on rural health system strengthening.

Abstract Fusion oncoproteins (FOs) arise from chromosomal translocations in ~17% of cancers and are often oncogenic drivers. Although some FOs can promote oncogenesis by undergoing liquid-liquid phase separation (LLPS) to form aberrant biomolecular condensates, the generality of this phenomenon is unknown. We explored this question by testing 166 FOs in HeLa cells and found that 58% formed condensates. The condensate-forming FOs displayed physicochemical features distinct from those of condensate-negative FOs and segregated into distinct feature-based groups that aligned with their sub-cellular localization and biological function. Using Machine Learning, we developed a predictor of FO condensation behavior, and discovered that 67% of ~3000 additional FOs likely form condensates, with 35% of those predicted to function by altering gene expression. 47% of the predicted condensate-negative FOs were associated with cell signaling functions, suggesting a functional dichotomy between condensate-positive and -negative FOs. Our Datasets and reagents are rich resources to interrogate FO condensation in the future.

The objective of the review is to identify factors related to how East and Southeast Asian immigrant youth aged 12-24 and their families access mental health and substance use (MHSU) services. To address how East and Southeast Asian youth and their families access mental health and substance use services, a scoping review was conducted to identify studies in these databases: PubMed, MEDLINE (Ovid), EMBASE (Ovid), PsychINFO, CINAHL, and Sociology Collection. Qualitative content analysis was used to deductively identify themes and was guided by Bronfenbrenner's Ecological Systems Theory, the process-person-context-time (PPCT) model, and the five dimensions of care accessibility (approachability, acceptability, availability and accommodation, appropriateness, affordability). Seventy-three studies met the inclusion criteria. The dimensions of healthcare accessibility shaped the following themes: 1) Acceptability; 2) Appropriateness; 3) Approachability; 4) Availability and Accommodation. Bronfenbrenner's Ecological Systems Theory and the PPCT model informed the development of the following themes: 1) Immediate Environment/Proximal Processes (Familial Factors, Relationships with Peers; 2) Context (School-Based Services/Community Resources, Discrimination, Prevention, Virtual Care); 3) Person (Engagement in Services/Treatment/Research, Self-management); 4) Time (Immigration Status). The study suggests that there is a growing body of research (21 studies) focused on identifying acceptability factors, including Asian cultural values and the model minority stereotype impacting how East and Southeast Asian immigrant youth access MHSU services. This review also highlighted familial factors (16 studies), including family conflict, lack of MHSU literacy, reliance on family as support, and family-based interventions, as factors affecting how East and Southeast Asian immigrant youth access MHSU care. However, the study also highlighted a dearth of research examining how East and Southeast Asian youth with diverse identities access MHSU services. This review emphasizes the factors related to the access to MHSU services by East and Southeast Asian immigrant youth and families while providing insights that will improve cultural safety.

Objectives To assess the impact of the COVID-19 pandemic on prescription drug use and costs.Design Interrupted time series analysis of comprehensive administrative health data linkages in British Columbia, Canada, from 1 January 2018 to 28 March 2021.Setting Retrospective population-based analysis of all prescription drugs dispensed in community pharmacies and outpatient hospital pharmacies and irrespective of the drug insurance payer.Participants Between 4.30 and 4.37 million individuals (52% women) actively registered with the publicly funded medical services plan.Intervention COVID-19 pandemic and associated mitigation measures.Main outcome measures Weekly dispensing rates and costs, both overall and stratified by therapeutic groups and pharmacological subgroups, before and after the declaration of the public health emergency related to the COVID-19 pandemic. Relative changes in post-COVID-19 outcomes were expressed as ratios of observed to expected rates.Results After the onset of the pandemic and subsequent COVID-19 mitigation measures, overall medication dispensing rates dropped by 2.4% (p