Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.

Recommendations for improving the working conditions and cultures of distressed junior doctors, based on a qualitative study and stakeholder perspectives.

BACKGROUND: Doctors, including junior doctors, are vulnerable to greater levels of distress and mental health difficulties than the public. This is exacerbated by their working conditions and cultures. While this vulnerability has been known for many years, little action has been taken to protect and support junior doctors working in the NHS. As such, we present a series of recommendations from the perspective of junior doctors and other relevant stakeholders, designed to improve junior doctors' working conditions and, thus, their mental health. METHODS: We interviewed 36 junior doctors, asking them for recommendations for improving their working conditions and culture. Additionally, we held an online stakeholder meeting with a variety of healthcare professionals (including junior doctors), undergraduate medical school leads, postgraduate speciality school leads and NHS policymakers where we asked what could be done to improve junior doctors' working conditions. We combined interview data with notes from the stakeholder discussions to produce this set of recommendations. RESULTS: Junior doctor participants and stakeholders made organisational and interpersonal recommendations. Organisational recommendations include the need for more environmental, staff and educational resources as well as changes to rotas. Interpersonal recommendations include changes to communication and recommendations for better support and teamwork. CONCLUSION: We suggest that NHS policymakers, employers and managers consider and hopefully implement the recommendations set out by the study participants and stakeholders as reported in this paper and that the gold standards of practice which are reported here (such as examples of positive learning environments and supportive supervision) are showcased so that others can learn from them.

Bayesian profile regression to study the ecologic associations of correlated environmental exposures with excess mortality risk during the first year of the Covid-19 epidemic in lombardy, Italy.

Many countries, including Italy, have experienced significant social and spatial inequalities in mortality during the Covid-19 pandemic. This study applies a multiple exposures framework to investigate how joint place-based factors influence spatial inequalities of excess mortality during the first year of the Covid -19 pandemic in the Lombardy region of Italy. For the Lombardy region, we integrated municipality-level data on all-cause mortality between 2015 and 2020 with 13 spatial covariates, including 5-year average concentrations of six air pollutants, the average temperature in 2020, and multiple socio-demographic factors, and health facilities per capita. Using the clustering algorithm Bayesian profile regression, we fit spatial covariates jointly to identify clusters of municipalities with similar exposure profiles and estimated associations between clusters and excess mortality in 2020. Cluster analysis resulted in 13 clusters. Controlling for spatial autocorrelation of excess mortality and health-protective agency, two clusters had significantly elevated excess mortality than the rest of Lombardy. Municipalities in these highest-risk clusters are in Bergamo, Brescia, and Cremona provinces. The highest risk cluster (C11) had the highest long-term particulate matter air pollution levels (PM2.5 and PM10) and significantly elevated NO2 and CO air pollutants, temperature, proportion ≤18 years, and male-to-female ratio. This cluster is significantly lower for income and ≥65 years. The other high-risk cluster, Cluster 10 (C10), is elevated significantly for ozone but significantly lower for other air pollutants. Covariates with elevated levels for C10 include proportion 65 years or older and a male-to-female ratio. Cluster 10 is significantly lower for income, temperature, per capita health facilities, ≤18 years, and population density. Our results suggest that joint built, natural, and socio-demographic factors influenced spatial inequalities of excess mortality in Lombardy in 2020. Studies must apply a multiple exposures framework to guide policy decisions addressing the complex and multi-dimensional nature of spatial inequalities of Covid-19-related mortality.

Relationship between working conditions and psychological distress experienced by junior doctors in the UK during the COVID-19 pandemic: a cross-sectional survey study.

OBJECTIVES: This paper explored the self-reported prevalence of depression, anxiety and stress among junior doctors during the COVID-19 pandemic. It also reports the association between working conditions and psychological distress experienced by junior doctors. DESIGN: A cross-sectional online survey study was conducted, using the 21-item Depression, Anxiety and Stress Scale and Health and Safety Executive scale to measure psychological well-being and working cultures of junior doctors. SETTING: The National Health Service in the UK. PARTICIPANTS: A sample of 456 UK junior doctors was recruited online during the COVID-19 pandemic from March 2020 to January 2021. RESULTS: Junior doctors reported poor mental health, with over 40% scoring extremely severely depressed (45.2%), anxious (63.2%) and stressed (40.2%). Both gender and ethnicity were found to have a significant influence on levels of anxiety. Hierarchical multiple linear regression analysis outlined the specific working conditions which significantly predicted depression (increased demands (ß=0.101), relationships (ß=0.27), unsupportive manager (ß=-0.111)), anxiety (relationships (ß=0.31), change (ß=0.18), demands (ß=0.179)) and stress (relationships (ß=0.18), demands (ß=0.28), role (ß=0.11)). CONCLUSIONS: The findings illustrate the importance of working conditions for junior doctors' mental health, as they were significant predictors for depression, anxiety and stress. Therefore, if the mental health of junior doctors is to be improved, it is important that changes or interventions specifically target the working environment rather than factors within the individual clinician.

Patterns of Kdr-L995F Allele Emergence Alongside Detoxifying Enzymes Associated with Deltamethrin Resistance in Anopheles gambiae s.l. from North Cameroon.

Understanding how multiple insecticide resistance mechanisms occur in malaria vectors is essential for efficient vector control. This study aimed at assessing the evolution of metabolic mechanisms and Kdr L995F/S resistance alleles in Anopheles gambiae s.l. from North Cameroon, following long-lasting insecticidal nets (LLINs) distribution in 2011. Female An. gambiae s.l. emerging from larvae collected in Ouro-Housso/Kanadi, Be-Centre, and Bala in 2011 and 2015, were tested for susceptibility to deltamethrin + piperonyl butoxide (PBO) or SSS-tributyl-phosphoro-thrithioate (DEF) synergists, using the World Health Organization's standard protocol. The Kdr L995F/S alleles were genotyped using Hot Ligation Oligonucleotide Assay. Tested mosquitoes identified using PCR-RFLP were composed of An. arabiensis (68.5%), An. coluzzii (25.5%) and An. gambiae (6%) species. From 2011 to 2015, metabolic resistance increased in Ouro-Housso/Kanadi (up to 89.5% mortality to deltametnrin+synergists in 2015 versus <65% in 2011; p < 0.02), while it decreased in Be-Centre and Bala (>95% mortality in 2011 versus 42-94% in 2015; p < 0.001). Conversely, the Kdr L995F allelic frequencies slightly decreased in Ouro-Housso/Kanadi (from 50% to 46%, p > 0.9), while significantly increasing in Be-Centre and Bala (from 0-13% to 18-36%, p < 0.02). These data revealed two evolutionary trends of deltamethrin resistance mechanisms; non-pyrethroid vector control tools should supplement LLINs in North Cameroon.

What challenges did junior doctors face while working during the COVID-19 pandemic? A qualitative study.

OBJECTIVES: This paper reports findings exploring junior doctors' experiences of working during the COVID-19 pandemic in the UK. DESIGN: Qualitative study using in-depth interviews with 15 junior doctors. Interviews were audio-recorded, transcribed, anonymised and imported into NVivo V.12 to facilitate data management. Data were analysed using reflexive thematic analysis. SETTING: National Health Service (NHS) England. PARTICIPANTS: A purposive sample of 12 female and 3 male junior doctors who indicated severe depression and/or anxiety on the DASS-21 questionnaire or high suicidality on Paykel's measure were recruited. These doctors self-identified as having lived experience of distress due to their working conditions. RESULTS: We report three major themes. First, the challenges of working during the COVID-19 pandemic, which were both personal and organisational. Personal challenges were characterised by helplessness and included the trauma of seeing many patients dying, fears about safety and being powerless to switch off. Work-related challenges revolved around change and uncertainty and included increasing workloads, decreasing staff numbers and negative impacts on relationships with colleagues and patients. The second theme was strategies for coping with the impact of COVID-19 on work, which were also both personal and organisational. Personal coping strategies, which appeared limited in their usefulness, were problem and emotion focused. Several participants appeared to have moved from coping towards learnt helplessness. Some organisations reacted to COVID-19 collaboratively and flexibly. Third, participants reported a positive impact of the COVID-19 pandemic on working practices, which included simplified new ways of working-such as consistent teams and longer rotations-as well as increased camaraderie and support. CONCLUSIONS: The trauma that junior doctors experienced while working during COVID-19 led to powerlessness and a reduction in the benefit of individual coping strategies. This may have resulted in feelings of resignation. We recommend that, postpandemic, junior doctors are assigned to consistent teams and offered ongoing support.

Maintaining ERCP capacity and high quality key performance quality indicators during the challenge of COVID-19

IntroductionCOVID-19 has negatively impacted on the delivery of endoscopy services worldwide. In the UK, national endoscopy database (NED) indicated activity was dramatically reduced by 80-95% during the first wave in 2020, due to redeployment of staff, challenges with personal protective equipment (PPE), room air-change cycle and patients’ unwillingness to attend during lockdown restrictions. ERCP is a higher-risk procedure often performed in patients with an urgent indication such as cancer obstruction or gallstone-related biliary sepsis or pancreatitis. We aimed to define the impact of COVID-19 on our ERCP service delivery, clinical outcomes, patient safety and endoscopists’ KPIs.MethodsWe examined Nottingham ERCP outcomes during the COVID-19 pandemic in 2020 compared to those before in 2019 at a high-volume HPB endoscopy centre serving a local population of 750,000 and tertiary HPB MDT population of 2.3 million. Technical success, comfort rates and complications according to RCP JAG and ESGE quality standards, including 8- and 30-day readmission rates and deaths were recorded. We also assessed the incidence of Covid-19 infection among the population who underwent ERCP.ResultsPre-pandemic, during 2019, 686 ERCP procedures were performed. Of these, 433 (63.1%) were cases of first ever ERCP. In 2020, 614 ERCPs were performed including 390 (63.5%) cases of first ever ERCP. During the COVID-19 pandemic in 2020, compared to 2019, there was no significant reduction in any of: total number of ERCP procedures (619 vs. 686);virgin ERCP successful cannulation of the intended duct (91.3% vs. 89.6%;p=0.8);complete CBD stone clearance (80% vs. 81%;p=0.9);successful stent placement across extrahepatic stricture (91.9% vs. 97.3%;p=0.6);obtaining stricture cytology (85.6% vs. 84.4%;p=0.9). The sensitivity of biliary cytology for cancer (C5 or C4 with compatible imaging/tumour markers or clinical follow up) was 68% vs. 70%;p=0.6.Patient comfort score was recorded as moderate/severe in 6% of cases in 2019 vs. 7.1% in 2020 (p=0.4). Following ERCP, the number of patients re-admitted within 8- and 30-days was 22 (3.2%) and 37 (5.4%) in 2019, versus 30 (4.9%) and 42 (6.8%) in 2020;p= 0.15 and p= 0.3, respectively. All-cause and procedure-related mortality within 30 days from ERCP was 1.6% and 0.14% in 2019 vs. 1.79% and 0.65% in 2020;p=0.8 and p=0.15, respectively.In total, 25/9500 (0.26%) of all patients undergoing any endoscopy tested positive for COVID-19 within 14 days of endoscopy. However, none tested positive following ERCP.ConclusionsOur provision of clinically urgent ERCP during 2020 and the COVID-19 pandemic did not significantly fall due to combination of senior prioritisation of all referrals, accessing unused operating theatres and reducing training lists. Patients underwent ERCP in a safe environment, keeping comfort levels within accepted limits and post-operative Covid-19 infection levels to zero. The endoscopists’ KPIs of successful outcome and adverse events were similar despite the challenges of PPE and staff anxieties or exhaustion.

Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult outpatients: CONTAIN phase II randomised controlled trial.

OBJECTIVE: To determine if inhaled and intranasal ciclesonide are superior to placebo at decreasing respiratory symptoms in adult outpatients with covid-19. DESIGN: Randomised, double blind, placebo controlled trial. SETTING: Three Canadian provinces (Quebec, Ontario, and British Columbia). PARTICIPANTS: 203 adults aged 18 years and older with polymerase chain reaction confirmed covid-19, presenting with fever, cough, or dyspnoea. INTERVENTION: Participants were randomised to receive either inhaled ciclesonide (600 µg twice daily) and intranasal ciclesonide (200 µg daily) or metered dose inhaler and nasal saline placebos for 14 days. MAIN OUTCOME MEASURES: The primary outcome was symptom resolution at day 7. Analyses were conducted on the modified intention-to-treat population (participants who took at least one dose of study drug and completed one follow-up survey) and adjusted for stratified randomisation by sex. RESULTS: The modified intention-to-treat population included 203 participants: 105 were randomly assigned to ciclesonide (excluding two dropouts and one loss to follow-up) and 98 to placebo (excluding three dropouts and six losses to follow-up). The median age was 35 years (interquartile range 27-47 years) and 54% were women. The proportion of participants with resolution of symptoms by day 7 did not differ significantly between the intervention group (42/105, 40%) and control group (34/98, 35%); absolute adjusted risk difference 5.5% (95% confidence interval -7.8% to 18.8%). Results might be limited to the population studied, which mainly included younger adults without comorbidities. The trial was stopped early, therefore could have been underpowered. CONCLUSION: Compared with placebo, the combination of inhaled and intranasal ciclesonide did not show a statistically significant increase in resolution of symptoms among healthier young adults with covid-19 presenting with prominent respiratory symptoms. As evidence is insufficient to determine the benefit of inhaled and intranasal corticosteroids in the treatment of covid-19, further research is needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT04435795.

The first month of the COVID-19 outbreak in 46 sub-Saharan African countries; a comparative analysis of growth rates (preprint)

Background The COVID-19 outbreak in sub-Saharan African countries started after those in Asia, Europe and North America, on 28th February 2020. The susceptibility to infection of populations in that region has been debated. Outbreaks on the scale of those seen elsewhere would pose substantial challenges. There are reasons for concern that transmission may be high and difficult to control, rapidly exceeding capacity to meet the needs for hospitalization and critical care. Methods We obtained data on daily new confirmed cases for all 46 countries from the World Health Organization, and used these to model and visualize growth trajectories using an AutoRegressive Integrated Moving Average (ARIMA) model. We then estimated doubling times from growth rates estimated from Poisson regression models, and by back counting from the most recent observation. We also calculated the time from 1st to 50th case, and the time from 5th to 100th case. These indicators were compared with the same summary indicators of growth at the same stage of the outbreak in highly affected European countries. Results Kenya was the only country with clear evidence of exponential growth. Nineteen countries had either reported no cases, were in the first few days of the outbreak, or had reported fewer than 10 cases over a period of two or more weeks. For the remaining 27 countries we identified four growth patterns: slow linear growth, more rapid linear growth, variable growth patterns over the course of the outbreak, and early signs of possible exponential growth. For those in the last three groups, doubling times ranged from 3 to 4 days, times from 1st to 50th case from 12 to 29 days, and from 5th to 100th case from eight to 15 days. These early indicators are comparable to those in European countries that have gone on to have substantial outbreaks, and time to 50th case was shorter suggesting lesser effectiveness of contact-tracing and quarantine in the early phase. Conclusion The 46 sub-Saharan African countries, home to over one billion people, are at a tipping point with clear potential for the outbreak to follow a similar course as in HIC in the global north. Radical population-level physical distancing measures may be required, but their impact on poor, disadvantaged and vulnerable people and communities need mitigating. Health systems in the region need urgent technical and material support, with testing, personal protection, and hospital/ critical care.