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There is an urgent need for strategies to reduce the negative impacts of a warming climate on human health. Cooling urban neighborhoods by planting trees and vegetation and increasing albedo of roofs, pavements, and walls can mitigate urban heat. We used synoptic climatology to examine how different tree cover and albedo scenarios would affect heat-related morbidity in Los Angeles, CA, USA, as measured by emergency room (ER) visits. We classified daily meteorological data for historical summer heat events into discrete air mass types. We analyzed those classifications against historical ER visit data to determine both heat-related and excess morbidity. We used the Weather Research and Forecasting model to examine the impacts of varied tree cover and albedo scenarios on meteorological outcomes and used these results with standardized morbidity data algorithms to estimate potential reductions in ER visits. We tested three urban modification scenarios of low, medium, and high increases of tree cover and albedo and compared these against baseline conditions. We found that avoiding 25% to 50% of ER visits during heat events would be a common outcome if the urban environment had more tree cover and higher albedo, with the greatest benefits occurring under heat events that are moderate and those that are particularly hot and dry. We conducted these analyses at the county level and compared results to a heat-vulnerable, working-class Los Angeles community with a high concentration of people of color, and found that reductions in the rate of ER visits would be even greater at the community level compared to the county.

Abstract Microbiota imbalances are linked to inflammation and disease, as well as neurodevelopmental conditions where they may contribute to behavioral, physiological, and central nervous system dysfunction. By contrast, the role of the microbiota in Fetal Alcohol Spectrum Disorder (FASD), the group of neurodevelopmental conditions that can occur following prenatal alcohol exposure (PAE), has not received similar attention. Here we utilized a rodent model of alcohol consumption during pregnancy to characterize the impact of alcohol on the microbiota of dam-offspring dyads. Overall, bacterial diversity decreased in alcohol-consuming dams and community composition differed from that of controls in alcohol-consuming dams and their offspring. Bacterial taxa and predicted biochemical pathway composition were also altered with alcohol consumption/exposure; however, there was minimal overlap between the changes in dams and offspring. These findings illuminate the potential importance of the microbiota in the pathophysiology of FASD and support investigation into novel microbiota-based interventions.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.

Objectives Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.Design Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.Eligibility criteria Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.Data synthesis The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.Results A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI −4.00 to 9.88, I2=79.3%; %DLco −2.03, 95% CI −4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.Conclusions There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.PROSPERO registration number CRD42023423223.

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case–control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Background Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials. Objectives To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease. Methods This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m2 body surface area. The primary end point for the study was the change in forced vital capacity at 24 weeks. Secondary end points included safety and tolerability, corticosteroid exposure, forced vital capacity change at 48 weeks and patient-reported quality of life. A cost-effectiveness analysis was undertaken to assess the impact of rituximab use in the United Kingdom National Health Service. Results One hundred and one subjects (70 females) with a mean age of 56.3 years were randomised; 51 to rituximab and 50 to cyclophosphamide. Ninety-seven were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the cyclophosphamide group). 38.6% had scleroderma, 44.6% idiopathic inflammatory myositis and 16.8% mixed connective tissue disease. Four subjects withdrew prior to the first dose of therapy (two in each arm). At 24 weeks, both rituximab and cyclophosphamide improved forced vital capacity from baseline [(mean ± standard deviation) 97 ± 234 and 99 ± 329 ml, respectively]. Using an adjusted mixed-effects model corrected for diagnosis and baseline forced vital capacity the difference in forced vital capacity at 24 weeks between rituximab and cyclophosphamide was −40 ml (95% CI −153 to 74 ml), p = 0.49. Other physiological and quality-of-life parameters improved in both arms following treatment but were not statistically significantly different between groups. Numerically fewer adverse events were reported by subjects receiving rituximab. Corticosteroid exposure over the 48 weeks of the trial was numerically less in the rituximab arm [13,291 (±14,657) mg of hydrocortisone equivalent per subject in the cyclophosphamide arm versus 11,469 (±10,041) mg per subject in the rituximab group; these differences did not reach statistical significance]. Limitations of the study include a disproportionate number of subjects being recruited from a single centre and insufficient subjects in each subgroup to determine whether there were treatment differences between individual connective tissue diseases. Based on the results of the trial, from a UK healthcare payer perspective, rituximab is more cost-effective than cyclophosphamide as a treatment for severe or progressive connective tissue disease-interstitial lung disease. Conclusions Rituximab improved forced vital capacity and patient-reported quality of life at 24 weeks but was not superior to cyclophosphamide. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with connective tissue disease-associated interstitial lung disease requiring systemic therapy. Future work should explore the role of repeated dosing of rituximab and the use of rituximab earlier in the course of connective tissue disease-associated interstitial lung disease. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information. Plain language summary Interstitial lung disease, a condition characterised by inflammation and scarring of the lungs, is the leading cause of death in systemic sclerosis (an autoimmune disease that typically causes thickening and scarring of the skin and which is associated with internal organ problems such as interstitial lung disease and kidney failure), and a major cause of morbidity (illness) in many other connective tissue diseases; a group of conditions that are caused by over activity of the immune system. When interstitial lung disease associated with connective tissue disease gets worse over time, treatment such as intravenous cyclophosphamide is required to slow down lung scarring. Occasionally, standard immunosuppressive drugs fail to control lung inflammation and scaring and this can result in death. Rituximab, a novel therapy, has been proven to be of benefit in suppressing inflammation associated with immune system over activity. Observational studies suggest that rituximab may be an effective treatment for pulmonary inflammation in connective tissue diseases. The study was designed to determine how well rituximab works compared to cyclophosphamide in treating patients with severe connective tissue disease-associated interstitial lung disease. We recruited 101 participants from 11 hospitals throughout the UK who were randomly allocated to one of two groups. Those in the first group were given rituximab on day 1 of the study and then on day 14. They were then given a placebo every 4 weeks for the next 18 weeks. Those in the second group were given cyclophosphamide every 4 weeks from day 1 of the study to week 20. On day 14, they were given a placebo. Lung function for all participants was assessed at 24 weeks. Our results suggest that rituximab improved lung function and quality of life but was not better than cyclophosphamide. Rituximab was associated with fewer unexpected medical events and a trend towards reduction in corticosteroid use and should be considered as a therapeutic alternative to cyclophosphamide. Scientific summary Background Interstitial lung disease (ILD) is characterised by inflammation and/or fibrosis within the parenchymal compartment bounded by the alveolar epithelium and capillary endothelium and frequently results in breathlessness progressing over time to respiratory failure. Autoimmune injury to the lung is a frequent cause of ILD. As such, the connective tissue diseases (CTDs), including systemic sclerosis (SSc), the inflammatory myopathies and mixed connective tissue disease (MCTD), are important causes of ILD. For individuals with CTD the development of ILD is an important cause of morbidity and mortality; for people with scleroderma, ILD is now the leading cause of death. Despite this there are few evidence-based treatments for CTD-associated ILD. At the time of planning this research there were no approved therapies available for CTD-ILD and all of the trial data which existed had been generated in the context of scleroderma-associated ILD. The Scleroderma Lung Study I assessed the efficacy of 52 weeks of treatment with oral cyclophosphamide (CP) compared to placebo in individuals with systemic sclerosis-associated ILD and evidence of an active inflammatory cell infiltrate on bronchoalveolar lavage. The trial demonstrated a positive effect of CP at 52 weeks but the drug was poorly tolerated and the benefit compared with placebo had disappeared by 2 years. A smaller 52-week study, also conducted in individuals with scleroderma-associated ILD, compared placebo to once-monthly intravenous CP given for 6 months followed by azathioprine and low dose prednisolone for the subsequent 6 months and showed a trend towards benefit in the active treatment arm. In the absence of treatment guidelines or evidence generated in other forms of CTD-ILD, most centres in the UK were routinely using intravenous CP as first-line therapy for individuals with clinically advanced or rapidly progressive ILD arising in the context of CTD. Rituximab, a chimeric (human/mouse) monoclonal antibody with a high affinity for the CD20 surface antigen expressed on B-lymphocytes, results in rapid depletion of B cells from the peripheral circulation for 6–9 months. Evidence for the efficacy of B cell depletion exists in a number of immune-mediated conditions, including rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated vasculitis and immune thrombocytopenic purpura. Several case series suggest rituximab may also be effective in ILD occurring in the context of immunological over-activity, with favourable responses reported in antisynthetase-associated ILD and SSc-ILD. Our own clinical experience suggested that rituximab is an effective, potentially life-saving therapeutic intervention in the treatment of very severe, progressive CTD-ILD unresponsive to conventional immunosuppression. In head-to-head studies in the context of other autoimmune diseases rituximab has been shown to have a favourable safety and tolerability profile compared to CP. The absence of high-quality evidence to guide treatment of CTD-ILD provided an opportunity to assess the efficacy of rituximab compared to the accepted standard of care, CP. Objectives The primary objective of the study was to demonstrate that intravenous rituximab has superior efficacy compared to current best treatment (intravenous CP) for CTD-ILD as measured by assessment of change in forced vital capacity (FVC) at 24 weeks. Secondary objectives were: to compare the safety profile of rituximab to intravenous CP in individuals with CTD-ILD to assess the health economic benefits of rituximab compared to current standard of care for CTD-ILD – including measurements of healthcare utilisation, quality of life (QoL) and carer burden to evaluate a range of exploratory biomarkers for disease severity, prognosis and treatment response in CTD-ILD. Methods The study was a Phase IIb, UK multicentre, prospective, randomised, double-blind, double-dummy trial of intravenous rituximab compared with intravenous CP in patients with severe, progressive CTD-ILD. Patients were randomised 1 : 1 to two groups, both groups received placebo to match the different regimens. Patients were followed for 48 weeks after first treatment; after 24 weeks subjects were permitted additional immunotherapy as determined by their treating physician. Study settings The study was conducted in rheumatology or ILD units at 11 UK centres. Participant inclusion criteria A diagnosis of CTD, based on internationally accepted criteria, in one of the following categories: systemic sclerosis idiopathic interstitial myopathy (including polymyositis/dermatomyositis) MCTD. Severe and/or progressive ILD associated with the underlying CTD. Chest high-resolution computer tomography performed within 12 months of randomisation. Intention of the caring physician to treat the ILD with intravenous CP. Able to provide written informed consent. Participant exclusion criteria Previous treatment with rituximab and/or intravenous CP. Age 80 years. Known hypersensitivity to rituximab or CP or their components. Significant (in the opinion of the investigator) other organ comorbidity including cardiac, hepatic or renal impairment. Coexistent obstructive pulmonary disease (e.g. asthma, chronic obstructive pulmonary disease, emphysema) with pre-bronchodilator forced expiratory volume in 1 second (FEV1) and FVC ratio < 70%. Patients at significant risk for infectious complications following immunosuppression including those with human immunodeficiency virus positive or other immunodeficiency syndromes (including hypogammaglobulinemia). Suspected or proven untreated tuberculosis. Viral hepatitis. Infection requiring antibiotic treatment in the preceding 4 weeks. Unexplained neurological symptoms (which may be suggestive of progressive multifocal leucoencephalopathy). Neurological symptoms arising because of the underlying CTD do not necessitate exclusion. Other investigational therapy (participation in research trial) received within 8 weeks of randomisation. Immunosuppressive or CTD modifying therapy (other than corticosteroids) received within 2 weeks of the first intravenous treatment. Pregnant or breastfeeding women, or women of child-bearing potential, not using a reliable contraceptive method for up to 12 months following IMP. Unexplained haematuria, or previous bladder carcinoma. Computerised tomography scan > 12 months from randomisation. Unable to provide informed written consent. Interventions Patients were randomised to receive either: Rituximab 1000 mg for two doses at day 0 and day 14. Placebo was administered monthly from week 4 to week 20. CP given at a dose of 600 mg/m2 body surface area rounded to the nearest 100 mg every 4 weeks from day 0 to week 20. Placebo was given at day 14. Patients were pre-medicated on day 0 with hydrocortisone, paracetamol, chlorpheniramine and mesna, at day 14 with hydrocortisone, paracetamol and chlorpheniramine and at visits from week 4 to 20 with mesna. Measurements Wherever possible, even if treatment could not be given, spirometry was undertaken at the time of each planned visit and performed according to standards outlined in the American Thoracic Society/European Respiratory Society guidelines. Lung function tests (plethysmography and gas transfer) were measured at screening, baseline, week 12, week 24 and week 48. Assessment for adverse events (AEs) and clinical end points began from randomisation and continued for the individual patient until they completed their follow-up at 48 weeks. At each study visit the investigator or designee made an assessment of safety and reviewed the clinical history and investigation findings with regard to the occurrence of adverse or serious adverse events (SAEs). Peripheral blood was taken at the time of each planned visit. Collection of blood for laboratory analyses included full blood count, erythrocyte sedimentation rate, urea and electrolytes, glucose, hepatitis A, B and C serology (screening only) and liver function tests. Blood for lymphocyte subsets and biomarker analysis was taken at day 0, week 12, 24 and 48 only. Quality of life was assessed by self-administered validated questionnaires undertaken at baseline and repeated at the primary end point visit at 24 weeks and at the final follow-up visit at 48 weeks. The instruments used were: the Short Form 36 (SF36) questionnaire EuroQol-5 Dimensions (EQ-5D) St George’s Respiratory Questionnaire (SGRQ) King’s Brief Interstitial Lung Disease (K-BILD) Scleroderma Health Assessment (SHA) Questionnaire which was disease-specific. For individuals with scleroderma, assessment of skin thickening was undertaken using the modified Rodnan skin score at baseline, 24 and 48 weeks. Sample size The primary outcome was changed in FVC at 24 weeks. The trial was designed to have 90% power to detect a 5% difference in 24-week FVC between treatment groups with a significance level (alpha) of 0.05 (two-tailed). The target sample size was 116 with the anticipation that 52 patients would reach the end-of-study in each arm with an expected 10% drop out. Because of the COVID-19 pandemic and an anticipated prolonged interruption to recruitment, trial enrolment was halted in March 2020 after randomisation of 101 subjects. Statistical analysis No formal interim analysis was planned. A statistical analysis plan was produced and agreed prior to analysis. Analysis of the primary outcome was by modified intention to treat. In other words, data were included in respect of all subjects who met all the entry criteria for the trial and had been randomised and received at least one dose of study drug. Results The study recruitment period was from December 2014 until March 2020 from 11 sites. In total 145 subjects were assessed for eligibility and of these 104 participants were enrolled. Three of these failed screening and were excluded. One hundred and one subjects were therefore randomised and 97 subjects received at least one dose of study drug and were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the CP group). Overall, baseline characteristics between the rituximab and CP arms were well balanced albeit with slightly more male participants in the rituximab arm. For the total cohort the mean ± S.D. age was 56 ± 11.4 years. Seventy subjects (69.3%) were female, 70 (69.3%) were white, 16 (15.8%) Asian and 12 (11.9%) black. The most frequently encountered CTD was idiopathic inflammatory myopathy (44.6%), followed by scleroderma (38.6%) and then MCTD (16.8%). Primary outcome At week 24 the unadjusted mean [± standard deviation (SD)] change in FVC in the CP treatment arm was a gain of 99 ± 329 ml. In the rituximab arm the change was 97 ± 234 ml. The relative change from baseline for each arm was 4.35 ± 15.67% for CP and for rituximab 4.31 ± 11.80%. Using a mixed-effects model adjusted for baseline FVC and diagnosis the difference (and 95% confidence interval) at 24 weeks between rituximab and CP was −40 ml [95% confidence interval (CI) −153 to 74 ml], p = 0.49. Secondary outcomes The unadjusted change in FVC at 48 weeks was 138 ± 440 ml in the CP arm and 112 ± 249 ml in the rituximab group. In relative terms, over 48 weeks, the improvement in the CP group was 5.08 ± 19.96% and in the rituximab group 4.22 ± 10.31%. An adjusted mixed-effects model demonstrated a −58 (95% CI −178 to 62) ml difference at 48 weeks between the rituximab and CP arms (p = 0.251). At week 24 the mean relative change in diffusing capacity of the lung for carbon monoxide (DLco) in the CP arm was 1.43 ± 23.05% compared to 6.98 ± 17.19% in the rituximab arm. At 48 weeks the changes in DLco were 3.00 ± 31.35% and 7.43 ± 16.08% in the CP and rituximab arms, respectively. For 6-minute walk distance the 24-week change in the CP and rituximab arms was 10.4 ± 78.6 and 10.9 ± 74.2 m, respectively. At week 48 the changes were 15.1 ± 82.8 and −6.8 ± 69.8 m. Using an adjusted mixed-effects model the differences between the rituximab and CP arms were −0.72 (−24.76 to 23.32) m, p = 0.953 at 24 weeks and −22.46 (−48.43 to 3.51) m, p = 0.090 at 48 weeks. Quality of life was assessed using the K-BILD questionnaire. Change at 24 weeks was 9.4 ± 20.8 in the CP arm and 8.8 ± 17.0 in the rituximab arm. At 48 weeks the difference compared to baseline was 5.6 ± 25.6 and 6.4 ± 16.2 in the CP and rituximab arms, respectively. Analysis in an adjusted mixed-effects model showed the difference between rituximab and CP was 0.4 (−5.73 to 6.52) and 1.15 (−5.34 to 7.64) at weeks 24 and 48, respectively. Survival Over the 48-week course of the study there were five deaths. All were deemed to be due to complications of either CTD or ILD. Three occurred in subjects receiving rituximab and two in subjects receiving CP. There was no difference between groups in time to death as assessed by an adjusted Cox proportional hazards model [hazard ratio (HR) 1.72 (95% CI 0.311 to 9.56, p = 0.534)]. The rates of progression-free survival [HR 1.11 (95% CI 0.625 to 1.99, p = 0.715)], and time to treatment failure [HR 1.25 (95% CI 0.34 to 4.65, p = 0.742)] did not differ between treatment arms. Corticosteroids The mean per-subject total steroid exposure during the study (measured in hydrocortisone equivalents) was 13,291 (±14,657) mg in the CP and 11,469 (±10,041) mg in the rituximab group; a 12% reduction in corticosteroid exposure in the rituximab arm. The daily mean dose per patient was 42.89 mg hydrocortisone/day in the CP and 37.61 mg hydrocortisone/day in the rituximab group. Safety All subjects in both arms experienced at least one AE. There were more AEs reported in the CP arm (646) than in the rituximab arm (445). The imbalance was less marked for SAEs with 33 and 29 in the CP and rituximab arms, respectively. Gastrointestinal disorders (170 vs. 71), general disorders and administration site reactions (91 vs. 52) and nervous system disorders (72 vs. 35) were more common in the CP arm. The frequency of other AEs was balanced between groups including infections and infestations (50 vs. 46). One patient in each arm withdrew because of side effects. There were no reported cases of COVID-19 during the trial. Cost-effectiveness Over the 48-week trial period treatment with CP was associated with a cost of £94,338 compared with a cost of £93,227 for rituximab; a difference of £1110 in favour of rituximab. Rituximab was associated with a 0.022 gain in quality-adjusted life-years over that seen with CP. The incremental net monetary benefit was significantly higher in the rituximab group under a wide range of monetary values and quality-adjusted life-years. Conclusion This study demonstrated that both rituximab and CP improve FVC and QoL in patients with CTD-ILD. There were numerically fewer AEs and a trend towards reduction in corticosteroid exposure in the rituximab-treated subjects. Rituximab should therefore be considered as a treatment option in patients with severe or rapidly progressive CTD-associated ILD. Implications for health care Although this study failed to show superiority of rituximab over CP in improving FVC when used as first-line treatment for CTD-ILD, the consistent positive effects of rituximab on physiological end points, QoL, and corticosteroid requirements support the clinical use of this drug in what is a population of patients with high unmet need (especially in situations where CP is contraindicated or likely to cause deleterious effects such as gonad failure or bladder malignancy). Implications for research Further trials will be necessary to confirm whether repeated dosing with rituximab confers additional benefit as compared to a single baseline dose. Similarly, additional studies are necessary to confirm findings in individual CTDs and to assess the optimal longer-term therapeutic regimen following initial intravenous therapy. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information.

Disk-fed accretion onto neutron stars can power a wide range of astrophysical sources ranging from X-ray binaries, to accretion-powered millisecond pulsars, ultraluminous X-ray sources, and gamma-ray bursts. A crucial parameter controlling the gas–magnetosphere interaction is the strength of the stellar dipole. In addition, coherent X-ray pulsations in many neutron star systems indicate that the star's dipole moment is oblique relative to its rotation axis. Therefore, it is critical to systematically explore the 2D parameter space of the star's magnetic field strength and obliquity, which is what this work does, for the first time, in the framework of 3D general-relativistic magnetohydrodynamics. If the accretion disk carries its own vertical magnetic field, this introduces an additional factor: the relative polarity of the disk and stellar magnetic fields. We find that depending on the strength of the stellar dipole and the star–disk relative polarity, the neutron star's jet power can either increase or decrease with increasing obliquity. For weak dipole strength (equivalently, high accretion rate), the parallel polarity results in a positive correlation between jet power and obliquity, whereas the antiparallel orientation displays the opposite trend. For stronger dipoles, the relative-polarity effect disappears, and jet power always decreases with increasing obliquity. The influence of the relative polarity gradually disappears as obliquity increases. Highly oblique pulsars tend to have an increased magnetospheric radius, a lower mass accretion rate, and enter the propeller regime at lower magnetic moments than aligned stars.

Objective: Leptin (LEP) is an obesity-associated adipokine associated with tumor cell growth. We examined the relevance of genetic variants of LEP and leptin receptor (LEPR) to colorectal cancer (CRC) survival by using data from the Newfoundland Familial Colorectal Cancer Study. Methods: A total of 532 patients newly diagnosed with CRC between 1997 and 2003 were followed up until April 2010. Data on their demographics and lifestyles were collected via questionnaires. Genotyping of blood samples was performed with the Illumina Human Omni-Quad Bead chip. Multivariable Cox models were used to assess the relationships of 35 tag single-nucleotide polymorphisms (SNPs) in LEP and LEPR with overall survival (OS), disease-free survival (DFS), and CRC-specific survival. Results: At the gene level, LEP was associated with DFS (P = 0.017), and LEPR was associated with both DFS (P = 0.021) and CRC-specific survival (P = 0.013) in patients with CRC. In single-SNP analysis, LEP rs11763517, LEPR rs9436301, and LEPR rs7602 were associated with DFS after adjustment for multiple testing. The LEPR haplotypes G-C-T (rs7534511-rs9436301-rs1887285) and A-A-G (rs7602-rs970467-rs9436748) were associated with prolonged OS among patients with CRC overall (G-C-T: HR, 0.63; 95% CI, 0.43–0.93; A-A-G: HR, 0.59; 95% CI, 0.38–0.91) and those diagnosed with colon cancer (G-C-T: HR, 0.54; 95% CI, 0.34–0.86; A-A-G: HR, 0.49; 95% CI, 0.29–0.83). Similar results were observed for DFS. Moreover, significant interactions were found among LEPR rs7602 (A vs. G), LEPR rs1171278 (T vs. C), red meat intake, and BMI status: the associations between these variants and prolonged DFS were limited to patients with below-median red meat consumption and body mass index (BMI) < 25 kg/m2. Conclusions: Polymorphic variations in the LEP and LEPR genes were associated with survival of patients after CRC diagnosis. The LEP/LEPR-CRC survival association was modified by participants’ red meat intake and BMI.

Abstract Background Identifying meaningful ecological associations between host and components of the microbiome is challenging. This is especially true for hosts such as marine macroalgae where the taxonomic composition of the microbiome is highly diverse and variable in space and time. Identifying core taxa is one way forward but there are many methods and thresholds in use. This study leverages a large dataset of microbial communities associated with the widespread brown macroalga, Fucus distichus, across sites and years on one island in British Columbia, Canada. We compare three different methodological approaches to identify core taxa at the amplicon sequence variant (ASV) level from this dataset: (1) frequency analysis of taxa on F. distichus performed over the whole dataset, (2) indicator species analysis (IndVal) over the whole dataset that identifies frequent taxa that are enriched on F. distichus in comparison to the local environment, and (3) a two-step IndVal method that identifies taxa that are consistently enriched on F. distichus across sites and time points. We then investigated a F. distichus time-series dataset to see if those core taxa are seasonally consistent on another remote island in British Columbia, Canada. We then evaluate host-specificity of the identified F. distichus core ASVs using comparative data from 32 other macroalgal species sampled at one of the sites. Results We show that a handful of core ASVs are consistently identified by both frequency analysis and IndVal approaches with alternative definitions, although no ASVs were always present on F. distichus and IndVal identified a diverse array of F. distichus indicator taxa across sites on Calvert Island in multiple years. Frequency analysis captured a broader suit of taxa, while IndVal was better at identifying host-specific microbes. Finally, two-step IndVal identified hundreds of indicator ASVs for particular sites/timepoints but only 12 that were indicators in a majority (> 6 out of 11) of sites/timepoints. Ten of these ASVs were also indicators on Quadra Island, 250 km away. Many F. distichus-core ASVs are generally found on multiple macroalgal species, while a few ASVs are highly specific to F. distichus. Conclusions Different methodological approaches with variable set thresholds influence core identification, but a handful of core taxa are apparently identifiable as they are widespread and temporally associated with F. distichus and enriched in comparison to the environment. Moreover, we show that many of these core ASVs of F. distichus are found on multiple macroalgal hosts, indicating that most occupy a macroalgal generalist niche rather than forming highly specialized associations with F. distichus. Further studies should test whether macroalgal generalists or specialists are more likely to engage in biologically important exchanges with host.

Abstract Very short duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) has recently attracted a lot of attention with the introduction of newer generations stents. This is appealing, especially in patients at high bleeding risk. However, none of the trials were powered for the individual ischemic and bleeding endpoints. All randomised controlled trials (RCTs) investigating one-month versus routine duration of DAPT in patients undergoing PCI and reporting outcomes from the time of cessation of DAPT (1 month) to 1 year were eligible for inclusion in the meta-analysis. The pooled risk ratios (RR) with their 95% confidence interval (CI) were calculated with the random-effects model using the Mantel-Haenszel method. Four RCTs involving 26,576 patients were included in this meta-analysis. Cessation of DAPT after 1 month was associated with significantly less major bleeding [RR 0.70, 95%CI (0.51–0.95), P = 0.02, heterogeneity (I2) = 42%]. There was no statistically significant difference in all-cause mortality [RR 0.84 (95%CI 0.69–1.03), P = 0.10, I2 = 0%] and stroke [RR 0.71 (95%CI 0.45–1.13), P = 0.15, I2 = 42%] when compared to routine duration of DAPT. There was also no difference in myocardial infarction (MI) [RR 1.12 (95%CI 0.91–1.39), P = 0.28, I2 = 0%], and definite or probable stent thrombosis [RR 1.49 (95%CI 0.92–2.41), P = 0.11, I2 = 0%] with cessation of DAPT after 1 month. Cessation of DAPT 1 month after PCI was associated with significantly less major bleeding, but there was no difference in the rate of all-cause mortality, stroke, MI and stent thrombosis.

Accreting neutron stars differ from black holes by the presence of the star’s own magnetic field, whose interaction with the accretion flow is a central component in understanding these systems’ disk structure, outflows, jets, and spin evolution. It also introduces an additional degree of freedom, as the stellar dipole can have any orientation relative to the inner disk’s magnetic field. We present a suite of 3D general-relativistic magnetohydrodynamic simulations in which we investigate the two extreme polarities, with the dipole field being either parallel or antiparallel to the initial disk field, in both the accreting and propeller states. When the magnetosphere truncates the disk near or beyond the corotation radius, most of the system’s properties, including the relativistic jet power, are independent of the star–disk relative polarity. However, when the disk extends well inside the corotation radius, in the parallel orientation the jet power is suppressed and the inner disk is less dense and more strongly magnetized. We suggest a physical mechanism that may account for this behavior—the interchange slingshot—and discuss its astrophysical implications. When the star is in the rapidly accreting regime, which in most cases will be associated with strong spin-up, we expect large observational differences between the two magnetic orientations. This may be reflected in increased variability as the accretion flow drags in successive magnetic structures of varying polarity.

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

Summary: Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research.

BackgroundInteractions among genetic variants are rarely studied but may explain a part of the variability in patient outcomes.ObjectivesIn this study, we aimed to identify 1 to 3 way interactions among SNPs from five Wnt protein interaction networks that predict the 5-year recurrence risk in a cohort of stage I-III colorectal cancer patients.Methods423 patients recruited to the Newfoundland Familial Colorectal Cancer Registry were included. Five Wnt family member proteins (Wnt1, Wnt2, Wnt5a, Wnt5b, and Wnt11) were selected. The BioGRID database was used to identify the proteins interacting with each of these proteins. Genotypes of the SNPs located in the interaction network genes were retrieved from a genome-wide SNP genotype data previously obtained in the patient cohort. The GMDR 0.9 program was utilized to examine 1-, 2-, and 3-SNP interactions using a 5-fold cross validation step. Top GMDR 0.9 models were assessed by permutation testing and, if significant, prognostic associations were verified by multivariable logistic regression models.ResultsGMDR 0.9 has identified novel 1, 2, and 3-way SNP interactions associated with 5-year recurrence risk in colorectal cancer. Nine of these interactions were multi loci interactions (2-way or 3-way). Identified interaction models were able to distinguish patients based on their 5-year recurrence-free status in multivariable regression models. The significance of interactions was the highest in the 3-SNP models. Several of the identified SNPs were eQTLs, indicating potential biological roles of the genes they were associated with in colorectal cancer recurrence.ConclusionsWe identified novel interacting genetic variants that associate with 5-year recurrence risk in colorectal cancer. A significant portion of the genes identified were previously linked to colorectal cancer pathogenesis or progression. These variants and genes are of interest for future functional and prognostic studies. Our results provide further evidence for the utility of GMDR models in identifying novel prognostic biomarkers and the biological importance of the Wnt pathways in colorectal cancer.

We aimed to examine the associations of a genome‐wide set of single nucleotide polymorphisms (SNPs) and 254 copy number variations (CNVs) and/or insertion/deletions (INDELs) with clinical outcomes in colorectal cancer patients (n = 505). We also aimed to investigate whether their associations changed (e.g., appeared, diminished) over time. Multivariable Cox proportional hazards and piece‐wise Cox regression models were used to examine the associations. The Cancer Genome Atlas (TCGA) datasets were used for replication purposes and to examine the gene expression differences between tumor and nontumor tissue samples. A common SNP (WBP11‐rs7314075) was associated with disease‐specific survival with P‐value of 3.2 × 10−8. Association of this region with disease‐specific survival was also detected in the TCGA patient cohort. Two expression quantitative trait loci (eQTLs) were identified in this locus that were implicated in the regulation of ERP27 expression. Interestingly, expression levels of ERP27 and WBP11 were significantly different between colorectal tumors and nontumor tissues. Three SNPs predicted the risk of recurrent disease only after 5 years postdiagnosis. Overall, our study identified novel variants, one of which also showed an association in the TCGA dataset, but no CNVs/INDELs, that associated with outcomes in colorectal cancer. Three SNPs were candidate predictors of long‐term recurrence/metastasis risk.

Abstract The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R15A has been explored in lung epithelial cells, the role of this UPR resolving factor has yet to be explored in lung mesenchymal cells. The objective of the current study was to determine the expression and role of PPP1R15A in IPF fibroblasts and in a bleomycin-induced lung fibrosis model. A survey of IPF lung tissue revealed that PPP1R15A expression was markedly reduced. Targeting PPP1R15A in primary fibroblasts modulated TGF-β-induced fibroblast to myofibroblast differentiation and exacerbated pulmonary fibrosis in bleomycin-challenged mice. Interestingly, the loss of PPP1R15A appeared to promote lung fibroblast senescence. Taken together, our findings demonstrate the major role of PPP1R15A in the regulation of lung mesenchymal cells, and regulation of PPP1R15A may represent a novel therapeutic strategy in IPF.

Background: As a result of the COVID-19 pandemic first wave, reductions in ST-elevation myocardial infarction (STEMI) invasive care, ranging from 23% to 76%, have been reported from various countries. Whether this change had any impact on coronary angiography (CA) volume or on mechanical support device use for STEMI and post-STEMI mechanical complications in Canada is unknown. Methods: We administered a Canada-wide survey to all cardiac catheterization laboratory directors, seeking the volume of CA use for STEMI performed during the period from March 1 2020 to May 31, 2020 (pandemic period), and during 2 control periods (March 1, 2019 to May 31, 2019 and March 1, 2018 to May 31, 2018). The number of left ventricular support devices used, as well as the number of ventricular septal defects and papillary muscle rupture cases diagnosed, was also recorded. We also assessed whether the number of COVID-19 cases recorded in each province was associated with STEMI-related CA volume. Results: A total of 41 of 42 Canadian catheterization laboratories (98%) provided data. There was a modest but statistically significant 16% reduction (incidence rate ratio [IRR] 0.84; 95% confidence interval 0.80-0.87) in CA for STEMI during the first wave of the pandemic, compared to control periods. IRR was not associated with provincial COVID-19 caseload. We observed a 26% reduction (IRR 0.74; 95% confidence interval 0.61-0.89) in the use of intra-aortic balloon pump use for STEMI. Use of an Impella pump and mechanical complications from STEMI were exceedingly rare. Conclusions: We observed a modest 16% decrease in use of CA for STEMI during the pandemic first wave in Canada, lower than the level reported in other countries. Provincial COVID-19 caseload did not influence this reduction. Résumé: Introduction: Après la première vague de la pandémie de COVID-19, de nombreux pays ont déclaré une réduction de 23 % à 76 % des soins invasifs de l'infarctus du myocarde avec élévation du segment ST (STEMI). On ignore si ce changement a entraîné des répercussions sur le volume d'angiographies coronariennes (AC) ou sur l'utilisation des dispositifs d'assistance mécanique lors de STEMI et des complications mécaniques post-STEMI au Canada. Méthodes: Nous avons réalisé un sondage pancanadien auprès de tous les directeurs de laboratoire de cathétérisme cardiaque pour obtenir le volume d'utilisation des AC lors des STEMI réalisées durant la période du 1er mars 2020 au 31 mai 2020 (période de pandémie) et durant 2 périodes témoins (1er mars 2019 au 31 mai 2019 et 1er mars 2018 au 31 mai 2018). Le nombre de dispositifs d'assistance ventriculaire gauche utilisés et le nombre de cas de communications interventriculaires et de ruptures du muscle papillaire diagnostiqués ont également été enregistrés. Nous avons aussi évalué si le nombre de cas de COVID-19 enregistrés dans chaque province était associé au volume d'AC liées aux STEMI. Résultats: Au total, 41 des 42 laboratoires canadiens de cathétérisme (98 %) ont fourni des données. Lors de la comparaison de la première vague de la pandémie aux périodes témoins, nous avons noté une réduction modeste, mais significative, sur le plan statistique de 16 % (ratio du taux d'incidence [RTI] 0,84; intervalle de confiance à 95 % 0,80-0,87) des AC lors de STEMI. Le RTI n’était pas associé au nombre provincial de cas de COVID-19. Nous avons observé une réduction de 26 % (RTI 0,74; intervalle de confiance à 95 % 0,61-0,89) de l'utilisation de pompes à ballonnet intra-aortique lors de STEMI. L'utilisation d'une pompe Impella et les complications mécaniques après les STEMI étaient extrêmement rares. Conclusions: Nous avons observé une diminution modeste de 16 % de l'utilisation des AC lors de STEMI durant la première vague de la pandémie au Canada, soit une diminution plus faible que ce que les autres pays ont signalé. Le nombre provincial de cas de COVID-19 n'a pas influencé cette réduction.

Background: SNP interactions may explain the variable outcome risk among colorectal cancer patients. Examining SNP interactions is challenging, especially with large datasets. Multifactor Dimensionality Reduction (MDR)-based programs may address this problem.Objectives: 1) To compare two MDR-based programs for their utility; and 2) to apply these programs to sets of MMP and VEGF-family gene SNPs in order to examine their interactions in relation to colorectal cancer survival outcomes.Methods: This study applied two data reduction methods, Cox-MDR and GMDR 0.9, to study one to three way SNP interactions. Both programs were run using a 5-fold cross validation step and the top models were verified by permutation testing. Prognostic associations of the SNP interactions were verified using multivariable regression methods. Eight datasets, including SNPs from MMP family genes (n = 201) and seven sets of VEGF-family interaction networks (n = 1,517 SNPs) were examined.Results: ∼90 million potential interactions were examined. Analyses in the MMP and VEGF gene family datasets found several novel 1- to 3-way SNP interactions. These interactions were able to distinguish between the patients with different outcome risks (regression p-values 0.03–2.2E-09). The strongest association was detected for a 3-way interaction including CHRM3.rs665159_EPN1.rs6509955_PTGER3.rs1327460 variants.Conclusion: Our work demonstrates the utility of data reduction methods while identifying potential prognostic markers in colorectal cancer.

Introduction: Several jurisdictions have adopted a more conservative approach to anemia in patients receiving dialysis amid safety concerns from target hemoglobin studies. It is largely unknown if this has contributed to a change in clinical outcomes. Methods: A national registry was used to identify 35,945 adult patients who initiated and were maintained on dialysis for ≥90 days in Canada from January 2007 to December 2015. Outcomes were ascertained until March 2017 via linkage with hospital discharge diagnoses. Cox proportional hazards models were used to investigate the association between the era of dialysis initiation and the primary composite outcome (acute myocardial infarction [AMI], stroke, or mortality). Results: The mean hemoglobin at dialysis initiation decreased from 102.9 g/l in 2007 to 95.5 g/l in 2015, corresponding with a higher prevalence of hemoglobin

Stunting and environmental enteric dysfunction (EED) may be responsible for altered gut and systemic immune responses. However, their impact on circulating immune cell populations remains poorly characterized during early life. A detailed flow cytometry analysis of major systemic immune cell populations in 53 stunted and 52 non-stunted (2 to 5 years old) children living in Antananarivo (Madagascar) was performed. Compared to age-matched non-stunted controls, stunted children aged 2-3 years old had a significantly lower relative proportion of classical monocytes. No significant associations were found between stunting and the percentages of effector T helper cell populations (Th1, Th2, Th17, Th1Th17, and cTfh). However, we found that HLA-DR expression (MFI) on all memory CD4+ or CD8+ T cell subsets was significantly lower in stunted children compared to non-stunted controls. Interestingly, in stunted children compared to the same age-matched non-stunted controls, we observed statistically significant age-specific differences in regulatory T cells (Treg) subsets. Indeed, in 2- to 3-year-old stunted children, a significantly higher percentage of memory Treg, whilst a significantly lower percentage of naive Treg, was found. Our results revealed that both innate and adaptive systemic cell percentages, as well as activation status, were impacted in an age-related manner during stunting. Our study provides valuable insights into the understanding of systemic immune system changes in stunted children.

Bats are geographically widespread and play an important role in many ecosystems, but relatively little is known about the ecology of their associated microbial communities and the role microbial taxa play in bat health, development, and evolution. Moreover, few vertebrate animal skin microbiomes have been comprehensively assessed, and thus characterizing the bat skin microbiome will yield valuable insight into the variability of vertebrate skin microbiomes as a whole. The recent emergence of the skin fungal disease white-nose syndrome highlights the potentially important role bat skin microbial communities could play in bat health. Understanding the determinant of bat skin microbial communities could provide insight into important factors allowing individuals to persist with disease. We collected skin swabs from a total of 11 bat species from the eastern United States (n = 45) and Colorado (n = 119), as well as environmental samples (n = 38) from a subset of sites, and used 16S rRNA marker gene sequencing to observe bacterial communities. In addition, we conducted a literature survey to compare the skin microbiome across vertebrate groups, including the bats presented in this study. Host species, region, and site were all significant predictors of the variability across bat skin bacterial communities. Many bacterial taxa were found both on bats and in the environment. However, some bacterial taxa had consistently greater relative abundances on bat skin relative to their environments. Bats shared many of their abundant taxa with other vertebrates, but also hosted unique bacterial lineages such as the class Thermoleophilia (Actinobacteria). A strong effect of site on the bat skin microbiome indicates that the environment very strongly influences what bacteria are present on bat skin. Bat skin microbiomes are largely composed of site-specific microbiota, but there do appear to be important host-specific taxa. How this translates to differences in host-microbial interactions and bat health remains an important knowledge gap, but this work suggests that habitat variability is very important. We identify some bacterial groups that are more consistent on bats despite site differences, and these may be important ones to study in terms of their function as potential core microbiome members.

Skin bacterial communities can protect amphibians from a fungal pathogen; however, little is known about how these communities are maintained. We used a neutral model of community ecology to identify bacteria that are maintained on salamanders by selection or by dispersal from a bacterial reservoir (soil) and ecological drift. We found that 75% (9/12) of bacteria that were consistent with positive selection,

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.