Cell division machinery drives cell-specific gene activation during differentiation in Bacillus subtilis.

When faced with starvation, the bacterium Bacillus subtilis transforms itself into a dormant cell type called a "spore". Sporulation initiates with an asymmetric division event, which requires the relocation of the core divisome components FtsA and FtsZ, after which the sigma factor σF is exclusively activated in the smaller daughter cell. Compartment-specific activation of σF requires the SpoIIE phosphatase, which displays a biased localization on one side of the asymmetric division septum and associates with the structural protein DivIVA, but the mechanism by which this preferential localization is achieved is unclear. Here, we isolated a variant of DivIVA that indiscriminately activates σF in both daughter cells due to promiscuous localization of SpoIIE, which was corrected by overproduction of FtsA and FtsZ. We propose that the core components of the redeployed cell division machinery drive the asymmetric localization of DivIVA and SpoIIE to trigger the initiation of the sporulation program.

Performance status at the time of lung retransplant predicts long-term function.

BACKGROUND: Lung retransplantation is offered to select patients with chronic allograft dysfunction. Given the increased risk of morbidity and mortality conferred by retransplantation, post-transplant function should be considered in the decision of who and when to list. The aim of this study is to identify predictors of post-operative disability in patients undergoing lung retransplantation. METHODS: Data were collected from the UNOS national dataset and included all patients who underwent lung retransplant from May 2005-March 2023. Pre- and post-operative function was reported by the Karnofsky Performance Status (KPS) and patients were stratified based on their needs. Cumulative link mixed effects models identified associations between pre-transplant variables and post-transplant function. RESULTS: A total of 1275 lung retransplant patients were included. After adjusting for between-group differences, pre-operative functional status was predictive of post-transplant function; patients requiring Total Assistance ( n = 740) were 74% more likely than No/Some Assistance patients (n = 535) to require more assistance in follow-up (OR 1.74, 95% CI 1.13-2.68, p = .012). Estimated one year survival of Total Assistance patients is lower than No/Some Assistance Recipients (72% vs. 82%, CI 69%-75%; 79%-86%) but similar to overall re-transplant survival (76%, CI 74%-79%). CONCLUSION: Both survival and regain of function in patients requiring Total Assistance prior to retransplant may be higher than previously reported. Pre-operative functional status is predictive of post-operative function and should weigh in the selection, timing and post-operative care of patients considered for lung retransplantation.

Lung transplantation in HIV seropositive recipients: An analysis of the UNOS registry.

BACKGROUND: Experience with lung transplantation (LT) in patients with human immunodeficiency virus (HIV) is limited. Many studies have demonstrated the success of kidney and liver transplantation in HIV-seropositive (HIV+) patients. Our objective was to conduct a national registry analysis comparing LT outcomes in HIV+ to HIV-seronegative (HIV-) recipients. METHODS: The United Network for Organ Sharing database was queried to identify LTs performed in adult HIV+ patients between 2016 and 2023. Patients with unknown HIV status, multiorgan transplants, and redo transplants were excluded. The primary endpoints were mortality and graft rejection. Survival time was analyzed using Kaplan-Meier analysis. RESULTS: The study included 17 487 patients, 67 of whom were HIV+. HIV+ recipients were younger (59 vs. 62 years, p = .02), had higher pulmonary arterial pressure (28 vs. 25 mm Hg, p = .04), and higher lung allocation scores (47 vs. 41, p = .01) relative to HIV- recipients. There were no differences in graft/recipient survival time between groups. HIV+ recipients had higher rates of post-transplant dialysis (18% vs. 8.4%, p = .01), but otherwise had similar post-transplant outcomes to HIV-recipients. CONCLUSIONS: This national registry analysis suggests LT outcomes in HIV+ patients are not inferior to outcomes in HIV- patients and that well-selected HIV+ recipients can achieve comparable patient and graft survival rates relative to HIV- recipients.

Single-center experience of ex vivo lung perfusion and subsequent lung transplantation.

BACKGROUND: The safety of lung transplantation using ex vivo lung perfusion (EVLP) has been confirmed in multiple clinical studies; however, limited evidence is currently available regarding the potential effects of EVLP on posttransplant graft complications and survival with mid- to long-term follow-up. In this study, we reviewed our institutional data to better understand the impact of EVLP. METHODS: Lungs placed on EVLP from 2014 through 2020 and transplant outcomes were retrospectively analyzed. Data were compared between lungs transplanted and declined after EVLP, between patients with severe primary graft dysfunction (PGD3) and no PGD3 after EVLP, and between matched patients with lungs transplanted with and without EVLP. RESULTS: In total, 98 EVLP cases were performed. Changes in metabolic indicators during EVLP were correlated with graft quality and transplantability, but not changes in physiological parameters. Among 58 transplanted lungs after EVLP, PGD3 at 72 h occurred in 36.9% and was associated with preservation time, mechanical support prior to transplant, and intraoperative transfusion volume. Compared with patients without EVLP, patients who received lungs screened with EVLP had a higher incidence of PGD3 and longer ICU and hospital stays. Lung grafts placed on EVLP exhibited a significantly higher chance of developing airway anastomotic ischemic injury by 30 days posttransplant. Acute and chronic graft rejection, pulmonary function, and posttransplant survival were not different between patients with lungs screened on EVLP versus lungs with no EVLP. CONCLUSION: EVLP use is associated with an increase of early posttransplant adverse events, but graft functional outcomes and patient survival are preserved.

Incorporating local health education priorities in HealthLAB: Learnings from very remote Australia.

ISSUE ADDRESSED: It is well-established that health education and promotion programs work best when they have been tailored to meet local contextual needs. In this brief report we describe a health education program and how it identified and incorporated local priorities into its delivery in two remote Aboriginal communities in the "Top End" of the Northern Territory. METHODS: During the first visit to each community team members met with local stakeholders and ran an inaugural HealthLAB session. Fieldnotes were taken during or directly after each interaction. At the end of each day team members debriefed regarding their fieldnotes. After both trips had been completed, priority areas were extracted from fieldnotes and synthesised. RESULTS: Although some health priorities were congruent across all groups, Community Members and Childcare staff tended to identify practical solutions while School and Clinic staff were focused on the clinical outcome. Community Members were particularly focused on the wider social and systemic factors impacting health. CONCLUSION: In response to the need for practical support, HealthLAB modified their health education packages to upskill mothers and sports coaches to provide brief health education sessions to local children and young people. SO WHAT?: It is recognised that many health promotion programs focus on individual behaviours without creating supportive environments. While it was out of scope for HealthLAB to address physical environmental factors, by building local capacity and knowledge to deliver health education, the program can contribute to a healthier and supportive social environment.

Heterogeneity in Staphylococcus aureus Bacteraemia Clinical Trials Complicates Interpretation of Findings.

We systematically evaluated randomized-controlled trials (RCTs) for Staphylococcus aureus bacteremia (SAB). There was intertrial heterogeneity in cohort characteristics, including bacteremia source, complicated SAB, and comorbidities. Reporting of cohort characteristics was itself variable, including bacteremia source and illness severity. Selection bias was introduced by exclusion criteria relating to comorbidities, illness severity, infection types, and source control. Mortality was lower in RCT control arms compared with observational cohorts. Differences in outcome definitions impedes meta-analysis. These issues complicate the interpretation and application of SAB RCT results. The value of these trials should be maximized by a standardized approach to recruitment, definitions, and reporting.

YArnhem: Co-designing a model of social and emotional wellbeing stepped care for young people of the north east Arnhem region: A development study protocol.

INTRODUCTION: More Aboriginal and Torres Strait Islander young people experience high or very high levels of psychological distress compared to their non-Indigenous counterparts. This may be partly attributed to systemic barriers resulting in lower rates of help-seeking, sub-optimal identification of psychological challenges, and undertreatment. Reducing these barriers within health systems is an important factor in reducing the Social and Emotional Wellbeing (SEWB) health burden on young Aboriginal and Torres Strait Islander people. OBJECTIVES: In partnership with Miwatj Health Aboriginal Corporation (Miwatj), this project will co-design an integrated youth Social and Emotional Wellbeing (SEWB) and mental health stepped care model for remote Aboriginal communities in the north east Arnhem region of the Northern Territory. DESIGN: A collaborative research approach using co-design methods will underpin a community-centric stepped care allocation method, to which culturally appropriate SEWB and mental health interventions and treatments are assigned. These components of the project will inform a digital platform which will facilitate access to SEWB care for young people in north east Arnhem land. This concept was co-developed in a partnership between researchers and Miwatj and builds on Miwatj's previous work to map the stepped needs of young people. The co-design of the content and features of these outputs will be facilitated through community participation and overseen by community, health, and cultural governance structures. This will ensure the solutions developed by the project are culturally responsive, fit for purpose, and will enhance self-determination while reducing systemic barriers to care.

A historical overview of legislated alcohol policy in the Northern Territory of Australia: 1979-2021.

BACKGROUND: The Northern Territory (NT) has the highest levels of alcohol consumption and harms in Australia. Since the creation of the NT Liquor Act 1978, which came into effect in 1979, numerous legislated alcohol policies have been introduced to attempt to address these harms. We present a narrative historical overview of alcohol policies implemented in the NT from 1979 to 2021. METHODS: Using scoping review methodology, databases were searched from 1979 to 2021. Of 506 articles screened, 34 met inclusion criteria. Reference lists of all included articles were searched, resulting in the inclusion of another 41 articles and reports, totalling 75 final documents. Policies were organised using Babor and colleagues (2010) established framework: 1. pricing/ taxation; 2. regulating physical availability; 3. modifying drinking environments; 4. drink-driving countermeasures; 5. restrictions on marketing; 6. education/persuasion; 7. treatment/early intervention. RESULTS: Two pricing/taxation policies have been implemented, Living With Alcohol (LWA) and Minimum Unit Price, both demonstrating evidence of positive effects on health and consumption outcomes. Eight policies approaches have focused on regulating physical availability, implemented at both individual and local area levels. Several of these policies have varied by location and been amended over time. There is some evidence demonstrating reduction in harms attributable to Liquor Supply Plans, localised restrictions, and General Restricted Areas, although these have been site specific. Of the three policies which targeted modifying the drinking environment; one was evaluated, finding a relocation of social harms, rather than a reduction. The literature outlines a range of controversies, particularly regarding policies in domain 2-3, including racial discrimination and a lack of policy stability. No policies relating to restricting marketing or education/persuasion programs were found. The only drink-driving legislated policy was considered to have contributed to the success of the LWA program. Three policies relating to treatment were described; two were not evaluated and evidence showed no ongoing benefits of Alcohol Mandatory Treatment. DISCUSSION: The NT has implemented a large number of alcohol policies, several of which have evidence of positive effects. However, these policies have often existed in a context of clear politicisation of alcohol policy, frequently with an implicit focus on Aboriginal people's consumption.

How the EMERGE guideline on medication adherence can improve the quality of clinical trials.

Medication adherence in drug trials is suboptimal, affecting the quality of these studies and adding significant costs. Nonadherence in this setting can lead to null findings, unduly large sample sizes and the need for dose modification after a drug has been approved. Despite these drawbacks, adherence behaviours are not consistently measured, analysed or reported appropriately in trial settings. The ESPACOMP Medication Adherence Reporting Guideline (EMERGE) offers a solution by facilitating a sound protocol design that takes this crucial factor into account. This article summarises key evidence on traditional and newer measurements of adherence, discusses implementation in clinical trial settings and makes recommendations about the analysis and interpretation of adherence data. Given the potential benefits of this approach, the authors call on regulators and the pharmaceutical industry to endorse the EMERGE guideline.

Concepts and Instruments for Patient-Reported Outcome Assessment in Celiac Disease: Literature Review and Experts' Perspectives.

BACKGROUND: In diseases where there is a large subjective component, such as celiac disease (CD), patient reported-outcomes (PRO) endpoints are highly relevant. However, there is a gap in knowledge about which PRO endpoints and instruments should be used for clinical trials for treatment of celiac disease. OBJECTIVES: To identify patient-centered symptom, impact, and health-related quality of life (HRQoL) concepts in CD and relevant PRO instruments, and to gather expert input on concepts and instruments to inform selection of PRO endpoints for use in clinical trials of new CD treatments. METHODS: A targeted literature review was conducted to identify symptom, impact, and HRQoL concepts, including those captured in PROs further reviewed against U.S. Food and Drug Administration standards for development and validation as endpoints. US and European clinicians, payers, and a patient advocate (n = 21) were interviewed to assess the identified concepts' relative importance in measuring treatment benefit and to gauge the value of potential PROs as endpoints for market access/reimbursement. RESULTS: Thirty-four published studies were identified: 27 elucidated patient-centered concepts and 7 detailed the development or validation of PRO instruments. The Celiac Disease Symptom Diary and Celiac Disease Patient Reported Outcome instrument were deemed most appropriate for use as endpoints; however, each had limitations related to conceptual coverage, evidence for measurement properties, and feasibility for use in clinical trials. Experts reported gastrointestinal symptoms as most important to treat, with extra-intestinal symptoms burdensome from the patient perspective as well. Payers emphasized measuring both frequency and severity of symptoms and targeting patients nonresponsive to the gluten-free diet for treatment. CONCLUSIONS: With emerging treatment options for CD, further work is needed to operationalize PRO symptom endpoints that are meaningful to patients, valued by payers, and acceptable to regulators in demonstrating efficacy.

Two cases of imported respiratory diphtheria in Edinburgh, Scotland, October 2019.

We report two cases of respiratory toxigenic Corynebacterium diphtheriae infection in fully vaccinated UK born adults following travel to Tunisia in October 2019. Both patients were successfully treated with antibiotics and neither received diphtheria antitoxin. Contact tracing was performed following a risk assessment but no additional cases were identified. This report highlights the importance of maintaining a high index of suspicion for re-emerging infections in patients with a history of travel to high-risk areas outside Europe.

Global Burden of Atherosclerotic Cardiovascular Disease in People Living With HIV: Systematic Review and Meta-Analysis.

BACKGROUND: With advances in antiretroviral therapy, most deaths in people with HIV are now attributable to noncommunicable illnesses, especially cardiovascular disease. We determine the association between HIV and cardiovascular disease, and estimate the national, regional, and global burden of cardiovascular disease attributable to HIV. METHODS: We conducted a systematic review across 5 databases from inception to August 2016 for longitudinal studies of cardiovascular disease in HIV infection. A random-effects meta-analysis across 80 studies was used to derive the pooled rate and risk of cardiovascular disease in people living with HIV. We then estimated the temporal changes in the population-attributable fraction and disability-adjusted life-years (DALYs) from HIV-associated cardiovascular disease from 1990 to 2015 at a regional and global level. National cardiovascular DALYs associated with HIV for 2015 were derived for 154 of the 193 United Nations member states. The main outcome measure was the pooled estimate of the rate and risk of cardiovascular disease in people living with HIV and the national, regional, and global estimates of DALYs from cardiovascular disease associated with HIV. RESULTS: In 793 635 people living with HIV and a total follow-up of 3.5 million person-years, the crude rate of cardiovascular disease was 61.8 (95% CI, 45.8-83.4) per 10 000 person-years. In comparison with individuals without HIV, the risk ratio for cardiovascular disease was 2.16 (95% CI, 1.68-2.77). Over the past 26 years, the global population-attributable fraction from cardiovascular disease attributable to HIV increased from 0.36% (95% CI, 0.21%-0.56%) to 0.92% (95% CI, 0.55%-1.41%), and DALYs increased from 0.74 (95% CI, 0.44-1.16) to 2.57 (95% CI, 1.53-3.92) million. There was marked regional variation with most DALYs lost in sub-Saharan Africa (0.87 million, 95% CI, 0.43-1.70) and the Asia Pacific (0.39 million, 95% CI, 0.23-0.62) regions. The highest population-attributable fraction and burden were observed in Swaziland, Botswana, and Lesotho. CONCLUSIONS: People living with HIV are twice as likely to develop cardiovascular disease. The global burden of HIV-associated cardiovascular disease has tripled over the past 2 decades and is now responsible for 2.6 million DALYs per annum with the greatest impact in sub-Saharan Africa and the Asia Pacific regions. CLINICAL TRIAL REGISTRATION: URL: https://www.crd.york.ac.uk/prospero . Unique identifier: CRD42016048257.

Governing for Health: Advancing Health and Equity through Policy and Advocacy.

In an age of wellness peddled to the predominantly white middle-class by the overwhelmingly white upper-class, Baum's book is a firm reminder of the systemic and structural issues which detrimentally impact an individual's health. As Gwyneth Paltrow charges approximately $8000 a ticket for entry to her 'In Goop Health summit' (Bryant, 2019), and lifestyle influencers brand their perfectly styled, plastic free, free range, organic, sustainable lifestyles as authentic and achievable (Chocano, 2019), Baum's distaste for the neoliberal naval gazing (and subsequent individual blaming) is a refreshing addition to the conversation.

Emergence of Nonfalciparum Plasmodium Infection Despite Regular Artemisinin Combination Therapy in an 18-Month Longitudinal Study of Ugandan Children and Their Mothers.

As part of a longitudinal cohort investigation of intestinal schistosomiasis and malaria in Ugandan children and their mothers on the shorelines of Lakes Victoria and Albert, we documented risk factors and morbidity associated with nonfalciparum Plasmodium infections and the longitudinal dynamics of Plasmodium species in children. Host age, household location, and Plasmodium falciparum infection were strongly associated with nonfalciparum Plasmodium infections, and Plasmodium malariae infection was associated with splenomegaly. Despite regular artemisinin combination therapy treatment, there was a 3-fold rise in P. malariae prevalence, which was not accountable for by increasing age of the child. Worryingly, our findings reveal the consistent emergence of nonfalciparum infections in children, highlighting the complex dynamics underlying multispecies infections here. Given the growing body of evidence that nonfalciparum malaria infections cause significant morbidity, we encourage better surveillance for nonfalciparum Plasmodium infections, particularly in children, with more sensitive DNA detection methods and improved field-based diagnostics.

Patient-Reported Outcome Assessments as Endpoints in Studies in Infectious Diseases.

The goal of administering medical interventions is to help patients live longer or live better. In keeping with this goal, there has been increasing interest in taking the "voice" of the patient into account during the development process, specifically in the evaluation of treatment benefits of medical interventions, and use of patient-centered outcome data to justify reimbursement. Patient-reported outcomes (PROs) are outcome assessments (OAs) used to define endpoints that can provide direct evidence of treatment benefit on how patients feel or function. When PROs are appropriately developed, they can increase the efficiency and clinical relevance of clinical trials. Several PROs have been developed for OA in specific infectious diseases indications, and more are under development. PROs also hold promise for use in evaluating adherence, adverse effects, satisfaction with care, and routine clinical practice.

COVID-19 as a catalyst for alcohol policy change: A case study of the Gove Peninsula.

In many ways, the COVID-19 pandemic provided a natural experiment for alternate ways of living and working. Although alcohol supply was one of many aspects impacted by COVID-19 restrictions, few of those alcohol-related measures have been continued. This commentary presents a unique case study from the Gove Peninsula in northern Australia, where pandemic restrictions acted as a catalyst for a review of an established alcohol management system. A permit system was introduced on the Gove Peninsula in 2008 to control who can purchase takeaway alcohol and how much they could buy each day. Development of the system was rooted in the principles of community development and self-determination. This commentary describes how COVID-19 and associated changes in levels of alcohol harms mobilised community support for a review of the system, that had operated unchanged for the past decade. COVID-19 was adventitious in revealing compelling localised information which encouraged examination of potential improvements to the system. An updated regime is now being trialled, which sets daily limits on the alcohol purchases of everyone in the area. This experience illustrates the benefits of timely and relevant data to assist communities in formulating local solutions to local problems.

Police-recorded adult sexual assault in the Northern Territory, Australia: Alcohol involvement and alcohol policy effects.

INTRODUCTION: Between 2017 and 2018 three major alcohol policy changes were introduced in the Northern Territory (NT): the Banned Drinker Register, an individual-level ban enforced via ID scanners at takeaway outlets; a Minimum Unit Price on alcohol; and Police Auxiliary Liquor Inspectors, who monitor takeaway outlets to prevent purchase by people who do not have a legal place to consume alcohol. We aimed to: (i) describe alcohol-involved adult sexual assault in the NT; and (ii) estimate the impacts of these alcohol policies on police-recorded adult sexual assault. METHODS: We used victim records for sexual assault where victims were aged 15 years and over. We undertook descriptive analyses for the NT from 2014 to 2020 and used interrupted time series analysis to assess policy impacts across the NT and in Greater Darwin. RESULTS: In 2020, the NT adult victimisation rate was 105 per 100,000. A large minority (40%) of adult sexual assaults involved alcohol. Interrupted time series analyses showed no effect of the Banned Drinker Register or Minimum Unit Price on sexual assault across the NT or in Greater Darwin. DISCUSSION AND CONCLUSIONS: The rate of adult sexual assaults in the NT is extremely high and many involve alcohol. Neither the Banned Drinker Register or Minimum Unit Price were associated with changes in police-recorded adult sexual assault in Greater Darwin or across the NT. Due to small counts, we were unable to assess policy impacts in three of the four main towns, highlighting the challenges of assessing impacts of policies on sexual assault in small population areas.