Introduction Smoked tobacco is a leading risk factor for cardiopulmonary disease. Pipe and cigar use remains common among US adults, yet its risks remain insufficiently understood.Methods We analysed data from five pooled cohorts with adults enrolled from 1971 to 2011 with follow-up through 2018. Pipe/cigar use was defined by baseline self-report. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio were measured by spirometry. All-cause mortality, coronary heart disease mortality and hospitalisation, respiratory-related mortality, and chronic obstructive pulmonary disease (COPD) mortality and hospitalisation were classified via adjudication or validated algorithms. Associations were estimated with linear mixed models and Fine-Gray subdistribution hazards models adjusted for sociodemographic and clinical factors.Results Among 22 823 participants (mean (SD) age 48.0 (15.7) years; 44.9% male sex; 70.5% white, 25.4% black, 2.4% Hispanic/Latino), 2621 (11.5%) reported ever pipe/cigar use, including 518 (2.3%) exclusive users without cigarette history. Compared with never tobacco users (n=9931), exclusive pipe/cigar use was associated with faster decline in FEV1 (3.36 mL/year; 95% CI 1.99 to 4.72), FVC (3.73 mL/year; 95% CI 2.05 to 5.42) and FEV1/FVC (0.031 per year; 95% CI 0.008 to 0.054). Exclusive users had higher all-cause mortality (adjusted HR (aHR) 1.24; 95% CI 1.08 to 1.41), COPD hospitalisation/mortality (aHR 2.02; 95% CI 1.41 to 2.90) and preserved ratio impaired spirometry (aHR 1.83; 95% CI 1.24 to 2.71).Conclusion Pipe and cigar use was associated with accelerated lung function decline and increased mortality and cardiopulmonary events, including among never cigarette users. These findings underscore the need for prevention and cessation efforts targeting non-cigarette tobacco.

Background:Respiratory oscillometry can inform early-life lung function, but evidence supporting its use in Guatemala is limited. We assessed the validity and reliability of respiratory oscillometry in 3-year-old Guatemalan children and whether these improve with quality control (QC). Methods:During home visits, we measured respiratory oscillometry resistance (R) and reactance (X) at 7 Hz (R7 and X7), the frequency dependence of resistance (R7-R19) and the area of reactance (AX) in 666 children participating in the Household Air Pollution Intervention Network trial. Standard measurement QC removed artefacts using commercial software and selected the first three measurements with an R7 coefficient of variation of ≤15%. Alternative investigators' methods varied in QC procedures. We evaluated validity as the proportion of variability in tests predicted by a child's height (R2) and, in a subset of 50 children, as agreement with test results after manual QC by a paediatric pulmonologist. Reliability was assessed by the intraclass correlation coefficient (ICC) of repeated tests. Results:We collected oscillometry results from 537 children. Height explained 5-15% of the variability in R7, X7 and AX, but none in R7-R19. The correlation between standard and manually cleaned tests ranged from 0.66 to 0.97, depending on the parameter. Of the first tests, between-day ICCs using the standard method for R7, R7-R19, X7 and AX were 0.68, 0.45, 0.60 and 0.71, respectively, and the best between-day ICCs using an alternative method were 0.75, 0.57, 0.69 and 0.74, respectively. Discussion:We demonstrated good validity and reliability of respiratory oscillometry measurements collected at home from preschool-aged Guatemalan children. Investigators' automated QC methodology performed equally to or better than standard methodology.

Early pathological changes in many organ systems are difficult to detect, which creates challenges in disease prevention, diagnosis, and treatment. Here, we leverage circulating extracellular microRNAs (ex-miRNAs) to derive miRNA-based Tissue Signal (miR-TS) scores that simultaneously assess 17 tissues, including the brain, heart, liver, and lungs. Across three population-based cohorts and 10 clinical populations, miR-TS scores were robustly associated with relevant health outcomes with high tissue specificity. Using prospective data, miR-TS scores for the heart, brain, and lungs also functioned as predictive biomarkers that tracked the development of major health events, including acute myocardial infarction, cerebrovascular accidents, cognitive impairment, and airflow limitation. Finally, we demonstrated the utility of miR-TS scores in detecting tissue-specific toxicities from both acute and long-term exogenous exposures. Our results highlight the potential of circulating ex-miRNAs to function as robust biomarkers of tissue health and predict the onset of a wide range of diseases.

RATIONALE:Household air pollution is a risk factor for obstructive lung diseases. OBJECTIVES:We estimated the effect of an early-life liquefied petroleum gas cooking intervention on childhood lung function. METHODS:The multi-country Household Air Pollution Intervention Network trial randomized 800 pregnant women (9-19 weeks gestation, 18-34 years) in Guatemala to receive a gas cookstove and free fuel intervention or continue cooking with biomass until the child is aged 1 year. The present analysis includes only Guatemalan children. At age 3 years, we measured lung function using oscillometry at 7-41 Hertz (Tremoflo C-100, Thorasys). Outcomes were resistance and reactance at 7 Hertz, area of reactance, resistance at 19 Hertz, resistance difference between 7 and 19 Hertz, and, as exploration, resistance across frequencies. Upper airway artifacts were removed using Tremoflo software. The effect of the intervention was estimated using linear regression models, unadjusted and adjusted (height, weight, age, sex). Children with respiratory infections during a 7-day recall period were excluded. RESULTS:Valid oscillometry was obtained from 525/750 (70%) 3-year-olds. Among the 225 missed oscillometry tests, 129/750 (17%) were due to the children not being willing to perform the measurements. We did not find evidence of an effect on prespecified oscillometry outcomes. Exploratory analysis suggested that resistance across the frequency spectrum was lower in intervention than control participants (adjusted difference: -0.31 cmH2O*S/L, 95% CI: -0.59, -0.03). CONCLUSIONS:Gas cooking compared to biomass cooking from mid-gestation through infancy was not associated with improved prespecified oscillometry outcomes in 3-year-old children. However, lowered resistance across all frequencies in the intervention arm suggests the intervention may have positively impacted airway caliber. Further studies are warranted, including exposure-response analysis and lung function trajectories.

Background: Adults with interstitial lung disease (ILD) have a higher risk of developing lung cancer compared to the general population. We aimed to identify ILD-specific risk factors that can be used to improve lung cancer detection in this high-risk population. Methods: Adults >= 21 years who received at least two chest CT scans at an academic medical center between 2005 and 2020 and were found to have ILD were studied retrospectively. Lung cancer diagnoses were adjudicated based on pathology reports from lung biopsies. Logistic regression was used to evaluate associations of clinical variables with comorbid lung cancer. Results: Among 1,366 adults with ILD, the mean age was 67.2 +/- 12.4 years and 639 (46.8 %) were men. In total, 227 adults (16.6 %) had a lung nodule on CT imaging, of whom 55 (24.3 %) were diagnosed with lung cancer. Radiographic usual interstitial pneumonia (UIP) (OR 3.00, 95 % CI 1.43-6.33) was independently associated with increased odds of lung cancer. Risk factors including age, sex, smoking status, pack-years, use of immunosuppression, and radiographic fibrosis pattern collectively demonstrated high discriminative accuracy in predicting comorbid lung cancer, even among adults who would not have qualified for lung cancer screening based on current guidelines (AUC 0.80, 95 % CI 0.72-0.88). Conclusions: In a large study of adults with ILD, radiographic UIP was independently associated with comorbid lung cancer even after adjusting for established risk factors. Our results suggest radiographic UIP is an independent lung cancer risk factor and support the development of targeted lung cancer screening guidelines in adults with UIP.

BACKGROUND:The health effects of smoking vary substantially between individuals. Novel strategies are needed to identify individuals with increased risk of smoking-related morbidity. Extracellular vesicle-encapsulated microRNAs (EV-miRNAs) may be viable biomarkers of smoking-related harm. Here, we measured associations of smoking status with plasma EV-miRNA expression levels. METHODS:Participants who were free of smoking-related diseases were sampled from the prospective Normative Aging Study (NAS). Smoking histories were evaluated using standardized smoking questionnaires. EV-miRNAs were measured in plasma. Vital status was monitored using death records. Associations of smoking status with EV-miRNA expression levels were modeled using linear regression. Results were validated in the Strong Heart Study (SHS). Associations of candidate EV-miRNAs with all-cause mortality were modeled using Cox proportional hazards models. RESULTS:Among 88 NAS participants (mean age 70.9 ± 8.0 years), recent smoking was associated with differential expression of 16 plasma EV-miRNAs, including decreased expression of miR-30b-5p (fold change in EV-miRNA expression: 0.26, 95 % CI 0.11-0.58). The association between smoking and low miR-30b-5p expression was replicated in the SHS cohort (fold change: 0.71, 95 % CI 0.51-0.97). A pathway analysis showed miR-30b-5p targeted genes that modulate oncogenic and pro-inflammatory signaling pathways (q-value<0.05). In the NAS cohort, low miR-30b-5p expression was associated with higher all-cause mortality (adjusted Hazard Ratio 3.36, 95 % CI 1.35-8.35). CONCLUSIONS:Recent cigarette smoking was associated with low miR-30b-5p expression in two distinct populations. Circulating miR-30b-5p is a robust biomarker of smoking-related harm and may represent a novel target for the prevention and treatment of smoking-related diseases.

Idiopathic pulmonary fibrosis (IPF) remains an incurable form of interstitial lung disease with sub-optimal treatments that merely address adverse symptoms or slow fibrotic progression. Here, inhalable hsa-miR-30a-3p-loaded liposomes (miR-30a) for the treatment of bleomycin-induced pulmonary fibrosis in mice are presented. It was previously found that exosomes (Exo) derived from lung spheroid cells are therapeutic in multiple animal models of pulmonary fibrosis and are highly enriched for hsa-miR-30a-3p. The present study investigates this miRNA as a singular factor to treat IPF. Liposomes containing miR-30a mimic can be delivered to rodents through dry powder inhalation. Inhaled miR-30a and Exo consistently lead to improved pulmonary function across six consecutive pulmonary function tests and promote de-differentiation of profibrotic myofibroblasts. The heterogenous composure of Exo also promotes reparative alveolar type I and II cell remodeling and vascular wound healing through broad transforming growth factor-beta signaling downregulation, while miR-30a targets myofibroblast de-differentiation through CNPY2/PERK/DDIT3 signaling. Overall, inhaled miR-30a represses the epithelial-mesenchymal transition of myofibroblasts, providing fibrotic attenuation and subsequent improvements in pulmonary function.

Introduction Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. Methods Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. Results Among 8252 adults (mean age 56.710.3 years, 58.1%women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (-2.44 units, 95%CI -4.42 to -0.45), though to a lesser extent than exclusive use of cigarettes (-6.01 units, 95%CI -6.01 to -4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95%CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). Conclusion Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

BACKGROUND:Shortened telomere length (TL) is a genomic risk factor for fibrotic interstitial lung disease (ILD), but its role in clinical management is unknown. RESEARCH QUESTION:What is the clinical impact of TL testing on the management of ILD? STUDY DESIGN AND METHODS:Patients were evaluated in the Columbia University ILD clinic and underwent Clinical Laboratory Improvement Amendments-certified TL testing by flow cytometry and fluorescence in situ hybridization (FlowFISH) as part of clinical treatment. Short TL was defined as below the 10th age-adjusted percentile for either granulocytes or lymphocytes by FlowFISH. Patients were offered genetic counseling and testing if they had short TL or a family history of ILD. FlowFISH TL was compared with research quantitative polymerase chain reaction (qPCR) TL measurement. RESULTS:A total of 108 patients underwent TL testing, including those with clinical features of short telomere syndrome such as familial pulmonary fibrosis (50%) or extrapulmonary manifestations in the patient (25%) or a relative (41%). The overall prevalence of short TL was 46% and was similar across clinical ILD diagnoses. The number of short telomere clinical features was independently associated with detecting short TL (OR, 2.00; 95% CI, 1.27-3.32). TL testing led to clinical treatment changes for 35 patients (32%), most commonly resulting in reduction or avoidance of immunosuppression. Of the patients who underwent genetic testing (n = 34), a positive or candidate diagnostic finding in telomere-related genes was identified in 10 patients (29%). Inclusion of TL testing below the 1st percentile helped reclassify eight of nine variants of uncertain significance into actionable findings. The quantitative polymerase chain reaction test correlated with FlowFISH, but age-adjusted percentile cutoffs may not be equivalent between the two assays. INTERPRETATION:Incorporating TL testing in ILD impacted clinical management and led to the discovery of new actionable genetic variants.

BACKGROUND:American Indian populations have experienced marked disparities in respiratory disease burden. Extracellular vesicle-encapsulated microRNAs (EV-miRNAs) are a novel class of biomarkers that may improve recognition of lung damage in indigenous populations in the United States. RESEARCH QUESTION:Are plasma EV-miRNAs viable biomarkers of respiratory health in American Indian populations? STUDY DESIGN AND METHODS:The Strong Heart Study is a prospective cohort study that enrolled American Indian patients aged 45 to 74 years. EV-miRNA expression was measured in plasma (1993-1995). Respiratory health outcomes, including prebronchodilator FEV1, FVC, and respiratory symptom burden, were ascertained in the same study visit. Club cell secretory protein (CC-16), an antiinflammatory pneumoprotein implicated in COPD pathogenesis, was measured in serum. Linear and logistic regression were used for statistical analyses. Biological pathway analyses were used to elucidate gene targets of significant EV-miRNAs. RESULTS:Among 853 American Indian adults, three EV-miRNAs were associated with FEV1, four EV-miRNAs were associated with FVC, and one EV-miRNA was associated with FEV1/FVC (P < .05). Increased miR-1294 expression was associated with higher odds of airflow limitation (OR, 1.29; 95% CI, 1.07-1.55), whereas increased expression of miR-1294 (OR, 1.32; 95% CI, 1.07-1.63) and miR-532-5p (OR, 1.57; 95% CI, 1.02-2.40) was associated with higher odds of restriction. Increased miR-451a expression was associated with lower odds of exertional dyspnea (OR, 0.71; 95% CI, 0.59-0.85). Twenty-two EV-miRNAs were associated with serum CC-16 levels (q < 0.05), suggesting that EV-miRNAs may play a role in the pathway linking CC-16 to COPD pathogenesis. A pathway analysis showed key EV-miRNAs targeted biological pathways that modulate inflammation, immunity, and structural integrity in the lungs. INTERPRETATION:Circulating EV-miRNAs are novel mechanistic biomarkers of respiratory health and may facilitate the early detection and treatment of lung damage in American Indian populations that have been disproportionately affected by chronic lung diseases.

PURPOSE:Growing evidence suggests plasma extracellular-vesicle encapsulated microRNAs (EV-miRNAs) regulate signaling networks that promote lung fibrosis and may be modifiable drivers of idiopathic pulmonary fibrosis (IPF).However, no prior studies have characterized the role of total plasma EV-miRNAs in IPF.We aimed to evaluate associations of plasma EV-miRNAs with IPF pathology and markers of IPF severity in a case-control study of adults with IPF.METHODS: This single-center case-control study enrolled adults with IPF who were diagnosed according to established clinical practice guidelines.Control participants with no known lung disease were recruited from family members of adults with IPF and were matched on age and sex.Plasma EV-miRNAs were measured in all participants using a non-targeted approach.EV-miRNAs that were detectable in $80% of study samples were retained for analyses.Spirometry was collected in all adults with IPF.Associations of IPF case status and the forced vital capacity (FVC, in liters) with plasma EV-miRNAs were modeled in separate linear regression models adjusted for age, sex, smoking status, and smoking pack-years.Benjamini-Hochberg false discovery rate (FDR) correction was used to account for multiple comparisons.Biological functions of significant EV-miRNAs were explored using pathway analyses.RESULTS: This pilot study included 10 adults with IPF and 5 control participants.The study population mean age was 68 AE 6.6 years, 12 (80%) were men, and 12 (80%) were White.In total, 872 EV-miRNAs were detected in at least 80% of plasma samples.IPF case status was associated with increased expression of 1 plasma EV-miRNA (miR-346) and decreased expression of 3 (FDR q<0.05).Among adults with IPF, higher levels of 20 EV-miRNAs and lower levels of 2 EV-miRNAs were associated with lower FVC (FDR q<0.05).A biological pathway analysis showed the EV-miRNAs that were associated with FVC interact with genes that modulate the extracellular matrix, fatty acid metabolism, and the TGF-beta signaling pathway (FDR q<0.05), which are heavily implicated in IPF pathogenesis.CONCLUSIONS: Adults with IPF exhibited differential expression of plasma EV-miRNAs that were associated with markers of IPF severity.Plasma EV-miRNAs may represent easily accessible mechanistic biomarkers of IPF pathology.Future research should determine if plasma EV-miRNAs can be used to screen for IPF and should provide a detailed characterization of the role of EV-miRNAs in IPF to maximize potential to re-engineer EVs into vehicles for IPF treatment.CLINICAL IMPLICATIONS: Plasma EV-miRNAs may represent novel mechanistic biomarkers of IPF pathology that may help optimize IPF diagnosis and may be targetable factors for IPF treatment.

Rationale: Early detection of respiratory diseases is critical to facilitate delivery of disease-modifying interventions. Extracellular vesicle-enriched microRNAs (EV-miRNAs) may represent reliable markers of early lung injury. Objectives: Evaluate associations of plasma EV-miRNAs with lung function. Methods: The prospective NAS (Normative Aging Study) collected plasma EV-miRNA measurements from 1996-2015 and spirometry every 3-5 years through 2019. Associations of EV-miRNAs with baseline lung function were modeled using linear regression. To complement the individual miRNA approach, unsupervised machine learning was used to identify clusters of participants with distinct EV-miRNA profiles. Associations of EV-miRNA profiles with multivariate latent longitudinal lung function trajectories were modeled using log binomial regression. Biological functions of significant EV-miRNAs were explored using pathway analyses. Results were replicated in an independent sample of NAS participants and in the HEALS (Health Effects of Arsenic Longitudinal Study). Measurements and Main Results: In the main cohort of 656 participants, 51 plasma EV-miRNAs were associated with baseline lung function (false discovery rate-adjusted P value, 0.05), 28 of which were replicated in the independent NAS sample and/or in the HEALS cohort. A subset of participants with distinct EV-miRNA expression patterns had increased risk of declining lung function over time, which was replicated in the independent NAS sample. Significant EV-miRNAs were shown in pathway analyses to target biological pathways that regulate respiratory cellular immunity, the lung inflammatory response, and airway structural integrity. Conclusions: Plasma EV-miRNAs may represent a robust biomarker of subclinical lung injury and may facilitate early identification and treatment of patients at risk of developing overt lung disease.

A substantial proportion of disease risk for common complex disorders is attributable to environmental exposures and pollutants. An appreciation of how environmental pollutants act on our cells to produce deleterious health effects has led to advances in our understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases, including cancer and cardiovascular, neurodegenerative and respiratory diseases. Here, we discuss emerging research on the interplay of environmental pollutants with the human genome and epigenome. We review evidence showing the environmental impact on gene expression through epigenetic modifications, including DNA methylation, histone modification and non-coding RNAs. We also highlight recent studies that evaluate recently discovered molecular processes through which the environment can exert its effects, including extracellular vesicles, the epitranscriptome and the mitochondrial genome. Finally, we discuss current challenges when studying the exposome — the cumulative measure of environmental influences over the lifespan — and its integration into future environmental health research. Environmental pollutants have been shown to disrupt molecular mechanisms underlying common complex diseases. The authors review the interplay of environmental stressors with the human genome and epigenome as well as other molecular processes, such as production of extracellular vesicles, epitranscriptomic changes and mitochondrial changes, through which the environment can exert its effects.

In The Lancet Infectious Diseases, James Welker and colleagues1Welker J Pulido JD Catanzaro AT et al.Efficacy and safety of CD24Fc in hospitalised patients with COVID-19: a randomised, double-blind, placebo-controlled, phase 3 study.Lancet Infect Dis. 2022; (published online March 11.)https://doi.org/10.1016/S1473-3099(22)00058-5Summary Full Text Full Text PDF PubMed Scopus (20) Google Scholar report a randomised, double-blind, placebo-controlled, phase 3 study of intravenous CD24Fc (480 mg over 60 min on day 1) versus placebo in adults hospitalised with COVID-19 at nine medical centres in the USA. The primary endpoint was time to clinical improvement, defined as time elapsed between a baseline National Institute of Allergy and Infectious Diseases 8-point ordinal scale (NIAID-OS) score of 2–4 and a score of 5 or higher or hospital discharge.2Marshall JC Murthy S Diaz J et al.A minimal common outcome measure set for COVID-19 clinical research.Lancet Infect Dis. 2020; 20: e192-e197Summary Full Text Full Text PDF PubMed Scopus (952) Google Scholar Among all 234 participants who were randomly assigned to a treatment group (of whom 62% were male and 38% female, 47% were non-Hispanic White, and median age was 59 years [IQR 48–68]), time to clinical improvement was accelerated among participants who received CD24Fc (median 6·0 days) compared with those who received placebo (10·5 days) over the 28-day study period (hazard ratio [HR] 1·40, 95% CI 1·02–1·92). The study was well designed, with near-complete protocol adherence and minimal loss to follow-up. However, the trial enrolled participants between April and September, 2020, and preceded landmark clinical trials of dexamethasone,3Horby P Lim WS Emberson JR et al.Dexamethasone in hospitalized patients with COVID-19.N Engl J Med. 2021; 384: 693-704Crossref PubMed Scopus (6601) Google Scholar remdesivir,4Beigel JH Tomashek KM Dodd LE et al.Remdesivir for the treatment of COVID-19—final report.N Engl J Med. 2020; 383: 1813-1826Crossref PubMed Scopus (4757) Google Scholar and interleukin-6 (IL-6) receptor antagonists5Gordon AC Mouncey PR Al-Beidh F et al.Interleukin-6 receptor antagonists in critically ill patients with COVID-19.N Engl J Med. 2021; 384: 1491-1502Crossref PubMed Scopus (1147) Google Scholar in the treatment of severe COVID-19. As a result, CD24Fc infusion was compared with an outdated standard of care that included a combination of experimental corticosteroids, remdesivir, and convalescent plasma given at the discretion of the treating physician. Since the enrolment period ended, trials have shown that convalescent plasma was not associated with reduced time to clinical improvement,6O'Donnell MR Grinsztejn B Cummings MJ et al.A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19.J Clin Invest. 2021; 131150646PubMed Google Scholar and IL-6 receptor antagonists have emerged as an important part of the COVID-19 treatment framework.5Gordon AC Mouncey PR Al-Beidh F et al.Interleukin-6 receptor antagonists in critically ill patients with COVID-19.N Engl J Med. 2021; 384: 1491-1502Crossref PubMed Scopus (1147) Google Scholar A key component of clinical trial design is ensuring the control group reflects the current standard of care. For example, when baricitinib was evaluated in a phase 3 clinical trial, the study showed that baricitinib plus remdesivir was superior to remdesivir alone in the treatment of severe COVID-19 infection.7Kalil AC Patterson TF Mehta AK et al.Baricitinib plus remdesivir for hospitalized adults with COVID-19.N Engl J Med. 2021; 384: 795-807Crossref PubMed Scopus (1142) Google Scholar Global collaborations have enabled accelerated clinical trial enrolment during the COVID-19 pandemic, which has resulted in a rapidly evolving standard of care that incorporates emerging effective therapies. Welker and colleagues effectively recorded background treatments and showed that, among participants who received the current standard daily dose of dexamethasone (6·0 mg; n=61 in the CD24Fc group, n=59 in the placebo group), time to clinical improvement was still accelerated in the CD24Fc group compared with the placebo group (HR 1·64, 95% CI 1·05–2·55). The trial findings show promise, but do not conclusively show that CD24Fc improves time to clinical improvement relative to the current COVID-19 treatment framework, consisting of dexamethasone, remdesivir, or IL-6 receptor antagonists, or a combination of these treatments. The evolving use of background therapies during the enrolment period might also partially account for the weakened association that was observed after the prespecified interim analysis. In the interim analysis, after 146 time to clinical improvement events were accrued among 197 randomised participants, CD24Fc showed an improved clinical improvement rate compared with placebo (HR 1·61, 95% CI 1·16–2·23). After the interim analysis, the protocol was amended to allow inclusion of participants requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (NIAID-OS score of 2), and an additional 37 participants were enrolled. In the entire randomised population, CD24Fc was still associated with accelerated time to clinical improvement compared with placebo, but the magnitude of the association was slightly reduced. The inclusion of participants with an NIAID-OS score of 2 after the interim analysis might account for the reduced strength of the association between CD24Fc and time to clinical improvement. Participants with an NIAID-OS score of 2 or 3 appeared to derive minimal benefit from CD24Fc treatment, although larger studies are required to evaluate the effectiveness of CD24Fc in subgroups defined by severity of illness. An alternative explanation is that evolving background therapies after the interim analysis led to reduced efficacy of CD24Fc therapy. An additional trial evaluating CD24Fc in combination with the current COVID-19 treatment framework would help elucidate whether CD24Fc improves time to clinical improvement over the current standard of care. Another explanation for the weakened association in the entire randomised population is that CD24Fc might be most effective in subgroups of patients with a heightened inflammatory response to COVID-19. An observational study in patients with critical COVID-19 has identified two distinct subgroups using latent class analysis.8Sinha P Furfaro D Cummings MJ et al.Latent class analysis reveals COVID-19-related acute respiratory distress syndrome subgroups with differential responses to corticosteroids.Am J Respir Crit Care Med. 2021; 204: 1274-1285Crossref PubMed Scopus (87) Google Scholar The hyperinflammatory phenotype had higher proinflammatory markers and showed improved overall survival after treatment with corticosteroids compared with patients who did not receive corticosteroids. By contrast, the hypoinflammatory phenotype had increased mortality after corticosteroid treatment. It is possible that CD24Fc, an anti-inflammatory therapy that suppresses production of inflammatory cytokines,9Song NJ Allen C Vilgelm AE et al.Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology.J Hematol Oncol. 2022; 15: 5Crossref PubMed Scopus (19) Google Scholar might be most effective in patients with a heightened inflammatory response. In general, identifying subphenotypes of critical illness might facilitate discovery of interventions that are most effective in specific subgroups with distinct biological characteristics.10Reddy K Sinha P O'Kane CM Gordon AC Calfee CS McAuley DF Subphenotypes in critical care: translation into clinical practice.Lancet Respir Med. 2020; 8: 631-643Summary Full Text Full Text PDF PubMed Scopus (94) Google Scholar However, the optimal methods for identifying subphenotypes in severe COVID-19 remain unknown and require further investigation. CD24Fc has shown promise as a COVID-19 therapy with systemic effects that might persist against emerging viral variants. CD24Fc treatment accelerated time to clinical improvement compared with placebo in a diverse patient population and might represent an emerging addition to the COVID-19 treatment armamentarium. We declare no competing interests. Efficacy and safety of CD24Fc in hospitalised patients with COVID-19: a randomised, double-blind, placebo-controlled, phase 3 studyCD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19. Full-Text PDF

Environmental pollutants contribute to the pathogenesis of numerous diseases including chronic cardiovascular, respiratory, and neurodegenerative diseases, among others. Emerging evidence suggests that extracellular vesicles (EVs) may mediate the association of environmental exposures with chronic diseases. The purpose of this review is to describe the impact of common environmental exposures on EVs and their role in linking environmental pollutants to the pathogenesis of chronic systemic diseases. Common environmental pollutants including particulate matter, tobacco smoke, and chemical pollutants trigger the release of EVs from multiple systems in the body. Existing research has focused primarily on air pollutants, which alter EV production and release in the lungs and systemic circulation. Air pollutants also impact the selective loading of EV cargo including microRNA and proteins, which modify the cellular function in recipient cells. As a result, pollutant-induced EVs often contribute to a pro-inflammatory and pro-thrombotic milieu, which increases the risk of pollutant-related diseases including obstructive lung diseases, cardiovascular disease, neurodegenerative diseases, and lung cancer. Common environmental exposures are associated with multifaceted changes in EVs that lead to functional alterations in recipient cells and contribute to the pathogenesis of chronic systemic diseases. EVs may represent emerging targets for the prevention and treatment of diseases that stem from environmental exposures. However, novel research is required to expand our knowledge of the biological action of EV cargo, elucidate determinants of EV release, and fully understand the impact of environmental pollutants on human health.

Rationale: Earlymobilization of extracorporealmembrane oxygenation (ECMO)-supported patients is increasingly common, but it remains unknownwhether there are factors predictive of achieving higher intensitymobilization among those able to participate in physical therapy. Additionally, data regarding the safety and feasibility of earlymobilization with femoral cannulation, particularly ambulation, are sparse. Objectives: To determine whether there are factors associated with achieving out-of-bed versus in-bed physical therapy in ECMO-supported patients participating in physical therapy, and whether mobilization with femoral cannulation is safe and feasible. Methods: This large, single-center, retrospective study evaluated adult patients who performed active physical therapy while receiving ECMO. Mixed effects modeling was used to identify predictors of out-of-bed versus in-bed activity. Rates of mobilization with femoral cannulation and adverse events were also reported. Results: Between April 2009 and January 2020, 511 patients were supported with ECMO in a single medical intensive care unit, of whom 177 (35%) underwent active physical therapy and were included in the analysis, including 124 of 141 (88%) bridge to lung transplantation and 53 of 370 (14%) bridge to recovery. These 177 patients accounted for 2,706 active physical therapy sessions, with 138 patients (78%) achieving out-of-bed activity. In total, 108 (61%) patients ambulated (1,284 sessions), 34 of whom had femoral cannulae (250 sessions). Bridge-to-transplant (odds ratio [OR], 17.2; 95% confidence interval [CI], 4.12-72.1), venovenous ECMO (OR, 2.83; 95% CI, 1.29-6.22), later cannulation year (OR, 1.65; 95% CI, 1.37-1.98) and higher Charlson comorbidity index (OR, 1.53; 95% CI, 1.07-2.19) were associated with increased odds of achieving out-of-bed versus in-bed physical therapy, whereas invasive mechanical ventilation (OR, 0.11; 95% CI, 0.05-0.25) and femoral cannulation (OR, 0.19; 95% CI, 0.04-0.92) were associated with decreased odds of performing outof-bed activities. Adverse events occurred in 2% of sessions. Conclusions: Several patient- and ECMO-related factors were associated with achieving higher intensity of early mobilization in patients participating in rehabilitation. Physical therapy with femoral cannulation was safe and feasible, and complications related to mobilization were uncommon.

AIMSThe aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF).METHODS AND RESULTSData were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking.CONCLUSIONLung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.