The Challenge Non-Typhoidal Salmonella (CHANTS) Consortium: Development of a non-typhoidal Salmonella controlled human infection model: Report from a consultation group workshop, 05 July 2022, London, UK.

Invasive non-typhoidal Salmonella disease (iNTS) is a major cause of morbidity and mortality globally, particularly as a cause of bloodstream infection in children and immunocompromised adults in sub-Saharan Africa. Vaccines to prevent non-typhoidal Salmonella (NTS) would represent a valuable public health tool in this setting to avert cases and prevent expansion of antimicrobial resistance. Several NTS and combination typhoidal-NTS vaccine candidates are in early-stage development, although the pathway to licensure is unclear due to challenges in conducting large phase III field trials. Controlled human infection models (CHIM) present an opportunity to accelerate vaccine development for a range of enteric pathogens. Several recent typhoidal Salmonella CHIMs have been conducted safely and have played pivotal roles in progressing vaccine candidates to pre-qualification and licensure. The Challenge Non-Typhoidal Salmonella (CHANTS) consortium has been formed with funding from the Wellcome Trust, to deliver the first NTS CHIM, which can act as a platform for future vaccine evaluation. This paper reports the conclusions of a consultation group workshop convened with key stakeholders. The aims of this meeting were to: (1) define the rationale for an NTS CHIM (2) map the NTS vaccine pipeline (3) refine study design and (4) establish potential future use cases.

Beyond Astana: Configuring the World Health Organization Collaborating Centres for primary health care.

The understanding of primary health care (PHC) has evolved significantly, evident in key World Health Organization (WHO) reports, promoting PHC as a means for health for all, identifying key health systems reforms and focusing on health care experience. This study explores the WHO's current framing of PHC, and its configuration of WHO Collaborating Centres (WHOCCs) on PHC using the data available on the WHOCCs Portal. We analysed the following variables: title, institutions, location, economy, date of mandate, objectives, subject, and activity. There were 13 WHOCCs on PHC, nine based in North America and Europe, and none in Africa. Only three were in Low- and Middle-Income Countries (LMICs). The WHOCCs on PHC focused on three broad subjects: five focused on human resources for health (HRH); four on health systems research (HSR) and development, with an emphasis on family medicine; four on PHC systems. Activities were related to training and education, provision of technical advice, and research. Support to WHO on implementation of PHC was an activity for two LMIC based WHOCCs. The current configuration of WHOCCs on PHC is consistent with the evolution of PHC and its intersection with Universal Health Coverage and the Sustainable Development Goals. The increasing attention to people-centred health systems aligns with WHO's commitment to PHC in all health systems, though this needs special interpretation for LMICs with their limited HRH. There has been a shift in subjects from HRH towards primary care and family medicine, and HSR highlighting primary care and PHC systems. The concern is an absence of WHOCCs in the Africa and Latin and South Americas, and under-representation in LMICs. Designating more institutions from the South with expertise in PHC is necessary to address the challenges post-Astana.

Evaluation of the short-term echocardiographic effects of two loop diuretics, furosemide and torsemide, in a group of dogs.

BACKGROUND: Two loop diuretics, torsemide and frusemide, can affect the urinary system and consequently the cardiordiovascular haemodynamics in different ways. OBJECTIVES: This study compared a number of echocardiographic parameters and systemic arterial blood pressure (ABP) changes following administration of furosemide or torsemide. METHODS: Five shelter dogs underwent transthoracic two-dimensional M-mode echocardiography to obtain the following measurements: left ventricular internal dimension at end-systole (LVIDs), left ventricular internal dimension at end-diastole (LVIDd), fractional shortening (FS), heart rate (HR) and the distance between the mitral valve socket and the ventricle wall (septal to E Point, SEP). Arterial blood pressure was measured using the oscillometric method. Measurements recorded before treatment (baseline data) were compared to those after the dogs received furosemide (5 mg/kg) or torsemide (0.5 mg/kg). RESULTS: Torsemide significantly reduced blood pressure 1 h after administration, but this was not seen with furosemide. Fractional shortening, LVIDd and SEP decreased following both treatments, but there were no significant differences between the treatment groups. Torsemide increased heart rate above that seen in the furosemide groups. CONCLUSIONS: The results of this study indicate that 1 h after administration, torsemide increases heart rate and decreases blood pressure when compared to furosemide, but both drugs have similar effects on measured cardiovascular indices.

Posting and Transfer: the experiences of public sector doctors in two Indian states.

Posting and Transfer (PT) refers to deployment of the health workforce in ways that ensure appropriate numbers and distribution. Although PT is a crucial aspect of health workforce governance, it remains under-researched from the viewpoint of implementation, health workforce and governance. The aim of this paper is to examine public sector doctors' experience of their initial postings, in the context of local policy from two Indian states. We carried out a review search for policy documentation. A total 61 in-depth interviews were conducted in both states with 33 doctors, as subjects of the study. There were 28 key informant (KI) interviews of health administrators and other policy actors to understand their perspectives of PT policies and implementation. Thematic analysis was used to analyse data. Job histories were constructed from the doctors' interviews to track their experience with the PT system, and analysed using location, duration and postings. Despite search for state policy for PT, we were unable to identify any policy documentation. However, participants referred to PT practices that suggested expectations of what the poliy meant to them. These expectations were corroborated by KI, and the job histories and interview data enabled the authors to construct a series of norms, interpreted as evidence of implied policy. The main norms identified relate to service need, native place, request, gender and posting duration. The norm related to state need had strong face validity, while other norms based on request, gender and duration were less consistent in application. In the absence of documented policies, the construction of norms from the qualitative data proved useful to examine the dynamics of health workers' interactions with the initial PT systems This construction of norms provides a methodological innovation allowing health policy and systems researchers to compensate for the absence of documented policy in exploring PT functions.

Identification and treatment of individuals with attention-deficit/hyperactivity disorder and substance use disorder: An expert consensus statement.

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with substance use (SU) and/or substance use disorder (SUD). Individuals with concurrent ADHD and SU/SUD can have complex presentations that may complicate diagnosis and treatment. This can be further complicated by the context in which services are delivered. Also, when working with young people and adults with co-existing ADHD and SU/SUD, there is uncertainty among healthcare practitioners on how best to meet their needs. In February 2022, the United Kingdom ADHD Partnership hosted a meeting attended by multidisciplinary experts to address these issues. Following presentations providing attendees with an overview of the literature, group discussions were held synthesizing research evidence and clinical experience. Topics included: (1) A review of substances and reasons for use/misuse; (2) identification, assessment and treatment of illicit SU/SUD in young people and adults with ADHD presenting in community services; and (3) identification, assessment and treatment of ADHD in adults presenting in SU/SUD community and inpatient services. Dis-cussions highlighted inter-service barriers and fragmentation of care. It was concluded that a multimodal and multi-agency approach is needed. The consensus group generated a table of practice recommendations providing guidance on: identification and assessment; pharmacological and psychological treatment; and multi-agency interventions.

UK-based multicentre cross-sectional study assessing advice requests veterinary dermatologists received from general practitioners.

BACKGROUND: There is little currently little information available regarding the nature of the advice requests veterinary dermatologists receive from general practitioners. Collation of such data could direct continuing veterinary development in the future. METHODS: Dermatologists completed hand-written recording sheets during or after enquiries. Information recorded included the route of enquiry, nature of advice, material provided, practice type and location, animal signalment, presenting signs, diagnosis/differential diagnosis, treatment and referral recommendations, time taken and if charges were made. RESULTS: Twelve dermatology services recorded 768 advice requests over a 6-month period. Most requests were submitted via email and related to canine dermatology (81%). An average of 9.5 minutes was spent replying to requests. Charges were made in 2% of cases. Advice regarding otitis was most commonly sought, followed by pruritus, alopecia and crusting. The most frequently discussed diagnoses included allergy, otitis, pyoderma, demodicosis, dermatophytosis and neoplasia. Antibiotics, anti-pruritics and topical otic medications were the most commonly discussed therapeutics. LIMITATIONS: This is an initial study and therefore there are limitations involving the depth of the data. Additional studies should be completed which identify why advice is sought, decision-making regarding referral, and if advice should be charged similarly to other disciplines. CONCLUSIONS: These findings highlight that veterinarians mostly frequently seek advice on management of common dermatological problems, including allergy, otitis and pyoderma.

Physicochemical properties of otic products for Canine Otitis Externa: comparative analysis of marketed products.

BACKGROUND: Otitis externa is a commonly diagnosed dermatological disorder in canines. The pathogens primarily involved in canine otitis externa (COE) include Staphylococcus pseudintermedius, Pseudomonas aeruginosa, Proteus mirabilis, and Malassezia pachydermatis. As COE tends to be superficial, medications delivered topically are often effective and practical in managing the condition. As such, there is a wide variety of approved topical products currently available in the market. The efficacy of topical dosage forms can be dependent on various factors such as the pharmacology of active constituents and the physicochemical properties of the formulation, including pH, viscosity, spreadability, and bio-adhesion. Currently, there is a lack of published literature available on the optimal properties of topical COE products. In this study, we compared the physicochemical properties of nine commercially available otic veterinarian products in Australia used clinically to manage COE. RESULTS: Based on our comparative analysis, the pH (6.26 ± 0.04) of an aqueous-based product was similar to a healthy dog's external auditory canal. Products containing polymers exhibited higher viscosity and bio-adhesion. Spreadability was inversely related to viscosity and Osurnia ® a product with high viscosity demonstrated the lowest spreadability. Aqueous-based otic products showed better syringebility whereas oil-based systems required higher force to expel the products. Variability in droplet size was noted. Derm Otic, Baytril Otic, and Aurizon Ear Drops had the lower standard deviation which indicates they would give a more consistent dose. CONCLUSIONS: Findings from this work provide considerations for industry researchers or formulation scientists working in the area of otic dosage formulations.

A Randomized Trial of Autologous Chondrocyte Implantation Versus Alternative Forms of Surgical Cartilage Management in Patients With a Failed Primary Treatment for Chondral or Osteochondral Defects in the Knee.

BACKGROUND: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee. PURPOSE: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: In total, 390 participants were randomly assigned to receive either ACI or alternative management. Patients aged 18 to 55 years with one or two symptomatic cartilage defects who had failed 1 previous therapeutic surgical procedure in excess of 6 months prior were included. Dual primary outcome measures were used: (1) patient-completed Lysholm knee score and (2) time from surgery to cessation of treatment benefit. Secondary outcome measures included International Knee Documentation Committee and Cincinnati Knee Rating System scores, as well as number of serious adverse events. Analysis was performed on an intention-to-treat basis. RESULTS: Lysholm scores were improved by 1 year in both groups (15.4 points [95% CI, 11.9 to 18.8] and 15.2 points [95% CI, 11.6 to 18.9]) for ACI and alternative, with this improvement sustained over the duration of the trial. However, no evidence of a difference was found between the groups at 5 years (2.9 points; 95% CI, -1.8 to 7.5; P = .46). Approximately half of the participants (55%; 95% CI, 47% to 64% with ACI) were still experiencing benefit at 5 years, with time to cessation of treatment benefit similar in both groups (hazard ratio, 0.97; 95% CI, 0.72 to 1.32; P > .99). There was a differential effect on Lysholm scores in patients without previous marrow stimulation compared with those with marrow stimulation (P = .03; 6.4 points in favor of ACI; 95% CI, -0.4 to 13.1). More participants experienced a serious adverse event with ACI (P = .02). CONCLUSION: Over 5 years, there was no evidence of a difference in Lysholm scores between ACI and alternative management in patients who had previously failed treatment. Previous marrow stimulation had a detrimental effect on the outcome of ACI. REGISTRATION: International Standard Randomised Controlled Trial Number: 48911177.

Gender Differences in Experiences and Expectations of Hemodialysis in a Frail and Seriously Unwell Patient Population.

Introduction: Surprisingly few studies have explored the experiences of seriously unwell people with kidney disease on hemodialysis therapy: we conducted a mixed-methods study to investigate gender differences in illness experience, symptom burden, treatment considerations or expectations in this cohort. Methods: Seriously unwell people on hemodialysis (1-year mortality risk of >20%) at 3 hospital-based units were invited to take part in a structured interview or to complete the same questions independently via a questionnaire. A total of 54 people took part (36 males, 18 females); data analysis was undertaken using a thematic approach. Results: "Desire to keep living" is the most important and basic thought process when starting dialysis. Fear also predominates influencing risk assessment and decision-making. Once fear is managed, there are physical, social, practical and emotional issues to rationalize, but choice only seems possible if shared decision-making is part of the consultation.Gender differences were seen in perceived hopes and expectations of treatment. Males were more likely to prioritize achievement of physical goals, with females prioritizing a wish to feel well. Both genders reported significantly higher symptom scores than their health care provider perceived, however this difference was more marked in females. Dialysis regret existed in >50% of participants and 6 out of 54 (11%) stated that they would have chosen no dialysis at all. Females were more likely to report feeling depressed (P = 0.001). Conclusion: Different genders approach treatment decisions and prioritize treatment expectations differently. Recognizing this will allow personalized care plans to be developed and improve the experiences of seriously unwell people with kidney disease.

Multisite implementation of a workflow-integrated machine learning system to optimize COVID-19 hospital admission decisions.

Demand has outstripped healthcare supply during the coronavirus disease 2019 (COVID-19) pandemic. Emergency departments (EDs) are tasked with distinguishing patients who require hospital resources from those who may be safely discharged to the community. The novelty and high variability of COVID-19 have made these determinations challenging. In this study, we developed, implemented and evaluated an electronic health record (EHR) embedded clinical decision support (CDS) system that leverages machine learning (ML) to estimate short-term risk for clinical deterioration in patients with or under investigation for COVID-19. The system translates model-generated risk for critical care needs within 24 h and inpatient care needs within 72 h into rapidly interpretable COVID-19 Deterioration Risk Levels made viewable within ED clinician workflow. ML models were derived in a retrospective cohort of 21,452 ED patients who visited one of five ED study sites and were prospectively validated in 15,670 ED visits that occurred before (n = 4322) or after (n = 11,348) CDS implementation; model performance and numerous patient-oriented outcomes including in-hospital mortality were measured across study periods. Incidence of critical care needs within 24 h and inpatient care needs within 72 h were 10.7% and 22.5%, respectively and were similar across study periods. ML model performance was excellent under all conditions, with AUC ranging from 0.85 to 0.91 for prediction of critical care needs and 0.80-0.90 for inpatient care needs. Total mortality was unchanged across study periods but was reduced among high-risk patients after CDS implementation.

Lessons Learned From Rapid Deployment of 100% Mortality Review for Patients With COVID-19 Across a Health System.

Mortality review is one approach to systematically examine delivery of care and identify areas for improvement. Health system leaders sought to ensure hospitals were adapting to the rapidly changing medical guidance for COVID-19 and delivering high-quality care. Thus, all patients with a COVID-19 diagnosis within the 6-hospital system who died between March and July 2020 were reviewed within 72 hours. Concerns for preventability advanced review to level 2 (content experts) or 3 (hospital leadership). Reviews included available autopsy and cardiac arrest data. Overall health system mortality for COVID-19 patient admissions was 12.5% and mortality for mechanically ventilated patients was 34.4%. Significant differences in mortality rates were observed among hospitals due to demographic variations in patient populations at hospitals. Mortality reviews resulted in the dissemination of evolving knowledge among sites using an electronic medical record order set, implementation of proning teams, and development of checklists for converting COVID-19 floors and units.

Tangible Experiences of Grace: A Qualitative Investigation of Divine Grace in Roman Catholics.

According to Catholic theology, God offers a gift of love, known as divine grace, to all of humanity. This gift of divine grace is the gift of redemption and forgiveness of sins from God that is offered to everyone who decides to acknowledge and accept it. Grace is central to the lived experience of many Christians. This qualitative study examined how Catholics perceive and experience divine grace using interviews that assessed perceptions of divine grace in 29 practicing adult Catholics. A grounded theory analysis resulted in themes indicating that these Catholics view God's divine grace as a tangible gift that is undeserved though continuously offered. The participants' experience of God's grace is not just an abstract theological concept but an embodied aspect of religious life with which believers can interact in many powerful ways. Three characteristics of God's divine grace (i.e., salvific grace, cooperation through free will, primacy of conscience and the afterlife) and three mechanisms to experiencing God's grace (i.e., sacraments, prayer and meditation, saints) are presented.

The vulnerable versatility of Salmonella antibiotic persisters during infection.

Tolerance and persistence are superficially similar phenomena by which bacteria survive bactericidal antibiotics. It is assumed that the same physiology underlies survival of individual tolerant and persistent bacteria. However, by comparing tolerance and persistence during Salmonella Typhimurium infection, we reveal that these two phenomena are underpinned by different bacterial physiologies. Multidrug-tolerant mutant Salmonella enter a near-dormant state protected from immune-mediated genotoxic damages. However, the numerous tolerant cells, optimized for survival, lack the capabilities necessary to initiate infection relapse following antibiotic withdrawal. In contrast, persisters retain an active state. This leaves them vulnerable to accumulation of macrophage-induced dsDNA breaks but concurrently confers the versatility to initiate infection relapse if protected by RecA-mediated DNA repair. Accordingly, recurrent, invasive, non-typhoidal Salmonella clinical isolates display hallmarks of persistence rather than tolerance during antibiotic treatment. Our study highlights the complex trade-off that antibiotic-recalcitrant Salmonella balance to act as a reservoir for infection relapse.

Two Novel Adenoviruses in Free-Living British lizards.

In this study, we describe two novel adenoviruses isolated from (i) a common lizard (Zootoca vivipara) found dead and examined post-mortem and (ii) pooled samples from free-living sand lizards (Lacerta agilis agilis). Sequencing indicated the two were closely related atadenovirus strains which were distinct from previously recorded adenoviruses in lizards. Adenoviruses are not always associated with disease in squamates, but morbidity and mortality have been reported. These are the first known cases of adenovirus infection in free-living native British lizards, and further monitoring will be necessary to elucidate the implications of these possible pathogens for vulnerable populations of native reptiles.

Antibiotic persistence and tolerance: not just one and the same.

Distinguished by their penetrance within a population, antibiotic tolerance and persistence are superficially similar phenomena by which growth-restricted bacteria survive treatment with bactericidal antibiotics. Owing to their apparent similarity, it is often assumed that the same physiological states and molecular mechanisms underlie the ability of individual antibiotic tolerant and persistent bacteria to survive treatment. Experimentally, antibiotic persistence is an extremely challenging phenomenon to study due to both its transience and the co-existence of persisters with non-persisters in the population of interest. In contrast, antibiotic tolerance operates at the whole population level as a result of bacteria acquiring genetic mutations or encountering environmental conditions that result in growth restriction. Therefore, studying antibiotic tolerance is often used as a convenient way to understand the molecular mechanisms governing antibiotic persistence. In this opinion, we discuss our current understanding of these two phenomena, outlining how tolerance and persistence can be distinguished experimentally. We argue that this approach will help avoid controversies in the field, especially in instances where the two phenomena co-exist. Finally, we evaluate the clinical evidence implicating tolerance and persistence in recalcitrance and relapse of bacterial infections.

Building a sustainable rural physician workforce.

CHAPTER 1: CHARACTERISING AUSTRALIA'S RURAL SPECIALIST PHYSICIAN WORKFORCE: THE PROFESSIONAL PROFILE AND PROFESSIONAL SATISFACTION OF JUNIOR DOCTORS AND CONSULTANTS: Objective: To assess differences in the demographic characteristics, professional profile and professional satisfaction of rural and metropolitan junior physicians and physician consultants in Australia. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional, population level national survey of the Medicine in Australia: Balancing Employment and Life longitudinal cohort study (collected 2008-2016). Participants were specialist physicians from four career stage groups: pre-registrars (physician intent); registrars; new consultants (< 5 years since Fellowship); and consultants. MAIN OUTCOME MEASURES: Level of professional satisfaction across various job aspects, such as hours worked, working conditions, support networks and educational opportunities, comparing rural and metropolitan based physicians. RESULTS: Participants included 1587 pre-registrars (15% rural), 1745 physician registrars (9% rural), 421 new consultants (20% rural) and 1143 consultants (13% rural). Rural physicians of all career stages demonstrated equivalent professional satisfaction across most job aspects, compared with metropolitan physician counterparts. Some examples of differences in satisfaction included rural pre-registrars being less likely to agree they had good access to support and supervision from qualified consultants (odds ratio [OR], 0.6; 95% CI, 0.3-0.9) and rural consultants being more likely to agree they had a poorer professional support network (OR, 1.9; 95% CI, 1.2-2.9). In terms of demographics, relatively more rural physicians had a rural background or were trained overseas. Although most junior physicians were women, female consultants were less likely to be working in a rural location (OR, 0.6; 95% CI, 0.4-0.8). CONCLUSION: Junior physicians in metropolitan or rural settings have a similar professional experience, which is important in attracting future trainees. Increased opportunities for rural training should be prioritised, along with addressing concerns about the professional isolation and poorer support network of those in rural areas, not only among junior doctors but also consultants. Finally, making rural practice more attractive to female junior physicians could greatly improve the consultant physician distribution. CHAPTER 2: GENERAL PHYSICIANS AND PAEDIATRICIANS IN RURAL AUSTRALIA: THE SOCIAL CONSTRUCTION OF PROFESSIONAL IDENTITY: Objective: To explore the construction of professional identity among general physicians and paediatricians working in non-metropolitan areas. DESIGN, SETTING AND PARTICIPANTS: In-depth qualitative interviews were conducted with general physicians and paediatricians, plus informants from specialist colleges, government agencies and academia who were involved in policy and programs for the training and recruitment of specialists in rural locations across three states and two territories. This research is part of the Training Pathways and Professional Support for Building a Rural Physician Workforce Study, 2018-19. MAIN OUTCOME MEASURES: Individual and collective descriptors of professional identity. RESULTS: We interviewed 36 key informants. Professional identity for general physicians and paediatricians working in regional, rural and remote Australia is grounded in the breadth of their training, but qualified by location - geographic location, population served or specific location, where social and cultural context specifically shapes practice. General physicians and paediatricians were deeply engaged with their local community and its economic vulnerability, and they described the population size and dynamics of local economies as determinants of viable practice. They often complemented their practice with formal or informal training in areas of special interest, but balanced their practice against subspecialist availability, also dependent on demographics. While valuing their professional roles, they showed limited inclination for industrial organisation. CONCLUSION: Despite limited consensus on identity descriptors, rural general physicians and paediatricians highly value generalism and their rural engagement. The structural and geographic bias that preferences urban areas will need to be addressed to further develop coordinated strategies for advanced training in rural contexts, for which collective identity is integral. CHAPTER 3: SUSTAINABLE RURAL PHYSICIAN TRAINING: LEADERSHIP IN A FRAGILE ENVIRONMENT: Objectives: To understand Royal Australasian College of Physicians (RACP) training contexts, including supervisor and trainee perspectives, and to identify contributors to the sustainability of training sites, including training quality. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional mixed-methods design was used. A national sample of RACP trainees and Fellows completed online surveys. Survey respondents who indicated willingness to participate in interviews were purposively recruited to cover perspectives from a range of geographic, demographic and training context parameters. MAIN OUTCOME MEASURES: Fellows' and trainees' work and life satisfaction, and their experiences of supervision and training, respectively, by geographic location. RESULTS: Fellows and trainees reported high levels of satisfaction, with one exception - inner regional Fellows reported lower satisfaction regarding opportunities to use their abilities. Not having a good support network was associated with lower satisfaction. Our qualitative findings indicate that a culture of undermining rural practice is prevalent and that good leadership at all levels is important to reduce negative impacts on supervisor and trainee availability, site accreditation and viability. Trainees described challenges in navigating training pathways, ensuring career development, and having the flexibility to meet family needs. The small number of Fellows in some sites poses challenges for supervisors and trainees and results in a blurring of roles; accreditation is an obstacle to provision of training at rural sites; and the overlap between service and training roles can be difficult for supervisors. CONCLUSION: Our qualitative findings emphasise the distinctive nature of regional specialist training, which can make it a fragile environment. Leadership at all levels is critical to sustaining accreditation and support for supervisors and trainees. CHAPTER 4: PRINCIPLES TO GUIDE TRAINING AND PROFESSIONAL SUPPORT FOR A SUSTAINABLE RURAL SPECIALIST PHYSICIAN WORKFORCE: Objective: To draw on research conducted in the Building a Rural Physician Workforce project, the first national study on rural specialist physicians, to define a set of principles applicable to guiding training and professional support action. DESIGN: We used elements of the Delphi approach for systematic data collection and codesign, and applied a hybrid participatory action planning approach to achieve consensus on a set of principles. RESULTS: Eight interconnected foundational principles built around rural regions and rural people were identified: FP1, grow your own "connected to" place; FP2, select trainees invested in rural practice; FP3, ground training in community need; FP4, rural immersion - not exposure; FP5, optimise and invest in general medicine; FP6, include service and academic learning components; FP7, join up the steps in rural training; and FP8, plan sustainable specialist roles. CONCLUSION: These eight principles can guide training and professional support to build a sustainable rural physician workforce. Application of the principles, and coordinated action by stakeholders and the responsible organisations, are needed at national, state and local levels to achieve a sustainable rural physician workforce.

Gene Expression Profiling in Kidney Transplants with Immune Checkpoint Inhibitor-Associated Adverse Events.

BACKGROUND AND OBJECTIVES: Immune checkpoint inhibitors are increasingly used to treat various malignancies, but their application in patients with kidney transplants is complicated by high allograft rejection rates. Immune checkpoint inhibitor-associated rejection is a novel, poorly understood entity demonstrating overlapping histopathologic features with immune checkpoint inhibitor-associated acute interstitial nephritis, which poses a challenge for diagnosis and clinical management. We sought to improve the understanding of these entities through biopsy-based gene expression analysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: NanoString was used to measure and compare the expression of 725 immune-related genes in 75 archival kidney biopsies, including a 25-sample discovery cohort comprising pure T cell-mediated rejection and immune checkpoint inhibitor-associated acute interstitial nephritis and an independent 50-sample validation cohort comprising immune checkpoint inhibitor-associated acute interstitial nephritis, immune checkpoint inhibitor-associated T cell-mediated rejection, immune checkpoint inhibitor-associated crescentic GN, drug-induced acute interstitial nephritis, BK virus nephropathy, and normal biopsies. RESULTS: Significant molecular overlap was observed between immune checkpoint inhibitor-associated acute interstitial nephritis and T cell-mediated rejection. Nevertheless, IFI27, an IFN-α-induced transcript, was identified and validated as a novel biomarker for differentiating immune checkpoint inhibitor-associated T cell-mediated rejection from immune checkpoint inhibitor-associated acute interstitial nephritis (validation cohort: P<0.001, area under the receiver operating characteristic curve =100%, accuracy =86%). Principal component analysis revealed heterogeneity in inflammatory gene expression patterns within sample groups; however, immune checkpoint inhibitor-associated T cell-mediated rejection and immune checkpoint inhibitor-associated acute interstitial nephritis both demonstrated relatively more molecular overlap with drug-induced acute interstitial nephritis than T cell-mediated rejection, suggesting potential dominance of hypersensitivity mechanisms in these entities. CONCLUSIONS: These results indicate that, although there is significant molecular similarity between immune checkpoint inhibitor-associated rejection and acute interstitial nephritis, biopsy-based measurement of IFI27 gene expression represents a potential biomarker for differentiating these entities.

Perceptions of Illness Severity, Treatment Goals, and Life Expectancy: The ePISTLE Study.

INTRODUCTION: A better understanding of factors influencing perceived life expectancy (PLE), interactions between patient prognostic beliefs, experiences of illness, and treatment behavior is urgently needed. METHODS: Case-notes at 3 hemodialysis units were screened: patients with ≥20% 1-year mortality risk were included. Patients and their health care professionals (HCPs) were invited to complete a structured interview or mixed-methods questionnaire. Four hundred eleven patient notes were screened. Seventy-seven eligible patients were approached and 51 were included. RESULTS: Patients predicted significantly higher life expectancies than HCPs (P < 0.0001). Documented cognitive impairment, gender, or increasing age did not affect 1- or 5-year PLE. PLE influenced priorities of care: one-fifth of patients who estimated themselves to have >95% 1-year survival preferred "care focusing on relieving pain and discomfort," compared with nearly three-quarters of those reporting a ≤50% chance of 1-year survival. Twenty of 51 (39%) patients believed transplantation was an option for them, despite only 4 being waitlisted at the time of the interview. Patients who thought they were transplant candidates were significantly more confident they would be alive at 1 and 5 years and to want resuscitation attempted. Cognitive impairment had no effect on perceived transplant candidacy. A high symptom burden was present and underrecognized by HCPs. High symptom burden was associated with significantly lower PLE at both 1 and 5 years, increased anxiety/depression scores, and treatment choices more likely to prioritize relief of suffering. CONCLUSION: There is a disparity between patient PLE and those of their HCPs. Severity of symptom burden and beliefs regarding PLE or transplant candidacy affect patient treatment preferences.

Patient Trajectories Among Persons Hospitalized for COVID-19 : A Cohort Study.

BACKGROUND: Risk factors for progression of coronavirus disease 2019 (COVID-19) to severe disease or death are underexplored in U.S. cohorts. OBJECTIVE: To determine the factors on hospital admission that are predictive of severe disease or death from COVID-19. DESIGN: Retrospective cohort analysis. SETTING: Five hospitals in the Maryland and Washington, DC, area. PATIENTS: 832 consecutive COVID-19 admissions from 4 March to 24 April 2020, with follow-up through 27 June 2020. MEASUREMENTS: Patient trajectories and outcomes, categorized by using the World Health Organization COVID-19 disease severity scale. Primary outcomes were death and a composite of severe disease or death. RESULTS: Median patient age was 64 years (range, 1 to 108 years); 47% were women, 40% were Black, 16% were Latinx, and 21% were nursing home residents. Among all patients, 131 (16%) died and 694 (83%) were discharged (523 [63%] had mild to moderate disease and 171 [20%] had severe disease). Of deaths, 66 (50%) were nursing home residents. Of 787 patients admitted with mild to moderate disease, 302 (38%) progressed to severe disease or death: 181 (60%) by day 2 and 238 (79%) by day 4. Patients had markedly different probabilities of disease progression on the basis of age, nursing home residence, comorbid conditions, obesity, respiratory symptoms, respiratory rate, fever, absolute lymphocyte count, hypoalbuminemia, troponin level, and C-reactive protein level and the interactions among these factors. Using only factors present on admission, a model to predict in-hospital disease progression had an area under the curve of 0.85, 0.79, and 0.79 at days 2, 4, and 7, respectively. LIMITATION: The study was done in a single health care system. CONCLUSION: A combination of demographic and clinical variables is strongly associated with severe COVID-19 disease or death and their early onset. The COVID-19 Inpatient Risk Calculator (CIRC), using factors present on admission, can inform clinical and resource allocation decisions. PRIMARY FUNDING SOURCE: Hopkins inHealth and COVID-19 Administrative Supplement for the HHS Region 3 Treatment Center from the Office of the Assistant Secretary for Preparedness and Response.