BACKGROUND Acute respiratory failure (ARF) requiring invasive mechanical ventilation affects approximately 1.5 million adult Americans annually. While acute respiratory distress syndrome (ARDS) is well-characterized, non-ARDS ARF—comprising the majority of mechanically ventilated patients—lacks systematic characterization of clinical features, biological profiles, and long-term outcomes. RESEARCH QUESTION How do ARF subtypes differ in clinical, physiologic, and biological characteristics, and long-term survival? STUDY DESIGN AND METHODS Prospective cohort study of 826 mechanically ventilated adults enrolled at a single academic center from 2011-2024. Patients were systematically classified into seven predefined ARF subtypes using consensus methodology. We compared physiology, biological subphenotypes, and 3-year survival. RESULTS Patients were classified as ARDS (36.1%), at-risk for ARDS (ARFA, 34.1%), airway controls (10.7%), other/multifactorial (7.4%), congestive heart failure (CHF, 6.2%), acute-on-chronic hypercapnic respiratory failure (AoCHRF, 3.3%), and acute exacerbation of interstitial lung disease (AEILD, 2.3%). Subtypes differed significantly in gas exchange (hypoxemia and ventilatory ratio), respiratory mechanics (normalized elastance), and radiographic severity (all p<0.01). Plasma inflammatory biomarkers were highest in ARDS and ARFA patients, with hyperinflammatory subphenotype prevalence ranging from 0% (AoCHRF) to 31% (ARFA). Three-year survival ranged from 10.5% (AEILD) to 67.0% (airway controls): 37.7% (other/multifactorial), 48.1% (AoCHRF), 56.9% (CHF), 53.2% (ARFA), 51.3% (ARDS). Hyperinflammatory subphenotype classification predicted lower survival (42.9% vs. 54.9%, p<0.01), predominantly in ARDS and ARFA, while other subtypes showed minimal subphenotype-associated survival differences. INTERPRETATION Mechanically ventilated patients with ARF demonstrate marked heterogeneity in physiology, biology, and long-term outcomes. Overall, fewer than half of patients survived to three years, but survival varied markedly across clinical subtypes beyond traditional ARDS categorization. Clinical subtype classification identifies distinct populations with divergent long-term prognoses, providing information complementary to biological subphenotyping. These findings provide quantitative outcome data to support prognostic counseling and establish a reproducible framework for clinical research in ARF from heterogeneous etiologies.

Cellular senescence is defined as an irreversible growth arrest observed when cells are exposed to a variety of stressors, including DNA damage, oxidative stress, or nutrient deprivation. Although senescence is a well-established driver of aging and age-related diseases, it is a highly heterogeneous process with significant variations across organisms, tissues, and cell types. The relatively low abundance of senescent cells in healthy aged tissues poses a major challenge to the longitudinal study of senescence in specific organs, including the human lung. To overcome this limitation, we developed a positive-unlabeled learning framework to generate a comprehensive list of senescence marker genes in human lungs (termed SenSet) using the largest publicly available single-cell lung dataset, the Human Lung Cell Atlas (HLCA). We validated SenSet in a highly complex ex vivo human 3D lung tissue culture model subjected to the senescence inducers bleomycin, doxorubicin, or irradiation, and established its sensitivity and accuracy in characterizing senescence. Using SenSet, we identified and validated cell-type-specific senescence signatures in distinct lung cell populations upon aging and environmental exposure. Our study provides a comprehensive analysis of senescent cells in the healthy aging lung, presenting fundamental implications for our understanding of major lung diseases, including cancer, fibrosis, chronic obstructive pulmonary disease, or asthma.

Biological heterogeneity in host inflammatory responses to severe pneumonia predicts clinical outcomes and may influence the effectiveness of immunomodulatory therapy. The upstream drivers of this heterogeneity remain poorly defined. We hypothesized that microbial translocation from the lungs to the bloodstream, detectable via multi-compartment metagenomic analysis, contributes to divergent host responses in pneumonia. In this nested case–control study of mechanically ventilated patients with severe pneumonia, we collected paired plasma and endotracheal aspirate samples at baseline. Plasma samples underwent microbial cell-free DNA (mcfDNA) sequencing, and endotracheal aspirates were analyzed by Nanopore metagenomic sequencing. Host-response biomarkers were measured in both plasma and endotracheal aspirate samples. Microbial translocation of pulmonary origin was defined by the genus-level concordance of detectable taxa between matched endotracheal aspirate and plasma samples. Among 98 patients (76 pneumonia, 22 controls), plasma mcfDNA was markedly higher in microbiologically confirmed pneumonia compared with culture-negative pneumonia (median 4015 vs. 210 molecules/μL, p = 0.0006). Pulmonary microbial translocation was identified in 31 (41

Binary inflammatory subphenotype classification (hyperinflammatory vs. hypoinflammatory) may guide trial enrollment in acute hypoxemic respiratory failure (AHRF), but assumes within-category homogeneity. We determined whether continuous probabilities reveal clinically meaningful heterogeneity. We analyzed 575 critically ill adults with AHRF (Pittsburgh Acute Lung Injury Registry) and validated findings in 1134 patients from the EDEN trial, the COVID-19 cohorts, and the RoCI registry. Continuous subphenotype probabilities were calculated using a parsimonious biomarker model (IL-6, sTNFR-1, bicarbonate; probability threshold 0.5). The primary outcome was 90-day mortality. Among 575 patients, 77 patients (13

BackgroundSocioeconomic disparities play a major role in health and disease. Growing evidence suggests that healthcare access accounts for only part of these outcomes, and additional biological mechanisms remain to be elucidated. The gut microbiome is a central component of health and disease and can be affected by environmental factors and socioeconomic disparities.MethodsUsing a large cohort with diverse comorbidities identified in the Elixhauser comorbidity index, we tested for association between area deprivation index (ADI), a neighborhood-level measurement of socioeconomic disadvantage in the United States, and taxonomic profiles of gut microbiota (16S rRNA gene sequences) to examine the effect of (1) covariates (age, sex, and smoking), ADI, and microbiota on comorbidities and (2) covariates, ADI, and comorbidities on microbiota.FindingsCovariates explained several associations, and ADI was associated with multiple comorbidities as assessed using generalized linear models (GLMs) augmented with ADI regression splines. Most associations with ADI were nonlinear, and the associations were most frequent among individuals living in more disadvantaged neighborhoods. Multivariate analysis of variance (MANOVA) revealed a significant effect of ADI on the collective microbiota of the cohort. Individual microbial taxa were identified in association with ADI, ranging from potentially more beneficial to human health to more disease-promoting, whereas microbial diversity was negatively associated with over half of the disease associations.InterpretationThese findings indicate that ADI is associated with alterations to the gut microbiome and common disease states.

Abstract Introduction Poor sleep increases peripheral inflammation, but the underlying mechanism is unclear. Extracellular adenosine (ADO) metabolism occurs via ectoenzyme CD39 and CD73 activity, and dysregulated purinergic metabolism contributes to HIV-associated inflammation. Sleep affects ADO metabolism in the central nervous system, but its effects on peripheral ADO metabolism have been understudied. We sought to evaluate how peripheral ADO metabolism differs by sleep metrics in people with HIV (PWH) and without HIV (PWOH). Methods Virally suppressed PWH with CD4+ count > 350 cells/mm3 on stable antiretroviral therapy for > 1 year and age- and sex-matched PWOH underwent 14 days of wrist actigraphy. Sleep duration, efficiency, midpoint, and regularity (standard deviation of midpoint) were derived. Blood samples were analyzed by flow cytometry to determine the percentage of T cells expressing one or both purinergic ectoenzymes (CD39 and CD73). Multivariable linear regressions adjusted for age, sex at birth, race, body mass index, and smoking status. Results Participants (94 PWH and 87 PWOH) had a mean±SD age of 56 ±11 years and 25% were female. The median (IQR) CD4+ count among PLWH was 763 (578, 982 cells/mm3). Every hour decrease in sleep duration was associated with (mean±SE) 4.1±1.8% fewer CD39+CD8+ T-lymphocytes in PLWH (p=0.03) but no association in PWOH (2.4±2.6%, p=0.35). Among PWOH, every hour increase in standard deviation of midpoint was associated with 6.9±3.4% fewer CD39+CD4+(p< 0.05) and 6.5±3.3% fewer CD39+CD8+ (p= 0.05) T-lymphocytes. In contrast, there was no association between regularity and CD39+ positivity in CD4+ (1.4±2.0%, p=0.48) or CD8+ (1.3±1.9%, p=0.52) T-cells among PWH. Neither sleep efficiency nor midpoint were associated with purinergic ectoenzyme expression in PWH or PWOH. Conclusion We identified sleep duration was associated with peripheral ADO metabolism in PWH while sleep regularity was associated with peripheral ADO metabolism in PWOH. Future research should investigate if sleep-based interventions, such as sleep extension, improves peripheral adenosine metabolism by in PWH. Support (if any) This study was supported by R01HL142118 and the AASM Physician-Scientist Training Award.

Background COVID‐19 and other respiratory viral infections can cause cardiovascular complications. SARS‐CoV‐2 virions are found in the blood, and circulating viral RNA levels are associated with death. We hypothesized that viremia can induce thrombotic endotheliopathy that contributes to death and studied this relationship in patients hospitalized for COVID‐19 and enrolled in the ACTIV‐4a (Accelerating COVID‐19 Therapeutic Interventions and Vaccines) randomized trial of antithrombotic therapy. Methods We quantified SARS‐CoV‐2 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine–Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death. Results In 93 patients, SARS‐CoV‐2 RNA and N‐antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90‐day death (hazard ratio [HR], 1.31 [95% CI, 1.17–1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24–1.47]). Viral RNA more effectively predicted survivorship than N‐antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%–32.3%; P=0.048) after adjustment for age and sex of the relationship between viral RNA and the 90‐day mortality rate. Conclusions Elevated plasma SARS‐CoV‐2 RNA levels are associated with death in ACTIV‐4a, which is causally mediated in part by soluble thrombomodulin. We propose that lung–blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses. Registration URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04505774.

COPD and impairment in diffusing capacity for carbon monoxide (DLCO) are common comorbidities in people with HIV (PWH). HIV may increase susceptibility to inhaled toxins including air pollution. In PWH and people without HIV (PWoH), we investigated whether air pollution exposure was associated with within-group differences in lung function or respiratory symptoms, and whether these associations differed by HIV serostatus or the presence of underlying lung disease. We analyzed cross-sectional data from the Multicenter AIDS Cohort Study (MACS) and the Women’s Interagency HIV Study (WIHS), including participants with pulmonary function tests and accompanying standardized respiratory questionnaires in 2017–2020. The participants were linked to fine particulate matter (PM2.5) and ozone exposure data. Associations between exposures and respiratory outcomes were quantified with regression models. Two subgroup analyses were conducted, restricting to individuals with COPD (FEV1/FVC ratio < 0.7) or impaired DLCO (< 80

BackgroundPeople with HIV (PWH) are at increased risk for chronic lung disease and may be more susceptible to pulmonary complications following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It remains unclear whether HIV infection modifies long-term pulmonary outcomes after coronavirus disease 2019 (COVID-19). This study assessed longitudinal changes in pulmonary function and respiratory symptoms among PWH and people without HIV (PWoH) with serologically-confirmed SARS-CoV-2 infection.MethodsWe analyzed data from the Multicenter AIDS Cohort Study (MACS)/Women's Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS), a prospective US cohort of PWH and PWoH. Participants with serologic evidence of past SARS-CoV-2 infection and acceptable pre- and post-SARS-CoV-2 pulmonary function testing (PFT) including spirometry and diffusing capacity for carbon monoxide (DLCO) were included. Annualized changes in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and DLCO were compared by HIV serostatus, stratified by sex. Respiratory symptoms were assessed using the St. George's Respiratory Questionnaire (SGRQ). Linear regression estimated differences in pulmonary function change by HIV serostatus, stratifying by relevant covariates.ResultsAmong 778 participants (204 men; 574 women) exposed to SARS-CoV-2 and who underwent PFTs before and after infection, 66% were PWH. Men with HIV (MWH) had a mean annualized FEV1 decline of -44.3 mL/year versus -33.8 mL/year in men without HIV (MWoH) (mean difference -10.5 mL/year; 95% CI: -30.7, 9.7). Among women, FEV1 declined -19.8 mL/year in PWH vs. -14.8 mL/year in PWoH (mean difference -5.0 mL/year; 95% CI: -18.2, 8.2). Changes in FVC and DLCO were similar across HIV serostatus groups. No consistent differences in respiratory symptom changes were observed between PWH and PWoH. Subgroup analyses did not reveal any HIV-associated differential changes.ConclusionsAmong individuals with serologic evidence of SARS-CoV-2 infection, HIV serostatus was not associated with greater declines in pulmonary function or worsening of respiratory symptoms. Our findings suggest that having HIV alone may not increase the risk for pulmonary impairments following a SARS-CoV-2 infection. Further research is needed to understand how uncontrolled HIV infection and severity of SARS-CoV-2 infection may increase risks of adverse pulmonary outcomes following a SARS-CoV-2 infection.

RATIONALE:The Early versus Delayed Enteral Nutrition (EDEN) trial found no significant difference in mortality between trophic and full enteral nutrition strategies in acute respiratory distress syndrome (ARDS) patients. Heterogeneity of treatment effect (HTE) has been identified in prior ARDS trials. We previously identified intestine-derived incretin hormones (glucose-dependent insulinotropic peptide [GIP] and glucagon-like peptide [GLP]-1 as potential predictive biomarkers in the response to nutrition. OBJECTIVES:To investigate incretins as biomarkers predictive of HTE in EDEN. METHODS:GIP, GLP-1, and host immune response biomarkers were measured from pre-intervention EDEN plasma samples. We investigated HTE with 60-day mortality as a primary outcome by testing interaction of treatment with circulating incretin levels in analyses adjusted for demographics, severity of illness, diabetes mellitus, and circulating interleukin-6, and assessed mortality by treatment arm across incretin tertiles. We additionally tested for HTE by de novo ARDS subphenotypes and by risk of mortality. MEASUREMENTS & MAIN RESULTS:889 participants were included (452 randomized to trophic and 437 to full enteral nutrition). GIP predicted HTE to enteral nutrition strategies (adjusted interaction p-value 0.01) with lower mortality from trophic feeds (14.1% vs 27.2% in full) in patients in the highest GIP tertile but similar mortality in other tertiles. GLP-1, ARDS subphenotypes, and baseline risk of mortality did not predict HTE. CONCLUSIONS:GIP was unique among incretins in predicting HTE to enteral nutrition strategies in EDEN. Further studies are needed to validate our findings as GIP might serve as a biomarker to guide level of enteral nutrition for ARDS patients.

PURPOSE:Subphenotype classifiers for acute respiratory distress syndrome (ARDS) dichotomise patients into hyperinflammatory versus hypoinflammatory subgroups. These models demonstrated prognostic and predictive values but were developed primarily in Caucasian populations. Generalisability of these models in Asian patients, who experience worse clinical outcomes, has not been established. We aimed to profile host responses in Asian patients with ARDS and evaluate the generalisability of established classifiers in this understudied population compared with a Caucasian cohort. METHODS:We prospectively enrolled patients with ARDS from medical intensive care units in Beijing, China, and Pittsburgh, Pennsylvania, USA. In the Beijing cohort, 37 protein biomarkers were measured, with 10 overlapping biomarkers measured in the Pittsburgh cohort. Six established subphenotype models were assessed for generalisability and intermodel agreement. Sensitivity analyses, including latent class analysis, were conducted to explore biological heterogeneity within Asians. RESULTS:Between 2011 and 2020, a total of 356 patients with ARDS (83% meeting the Berlin Definition; the rest on high-flow nasal cannula (HFNC) meeting the New Global Definition) were enrolled across Beijing (97% Han Asian) and Pittsburgh (90% Caucasian) sites, with comparable baseline hypoxaemia severity but disparate outcome. While the proportion of hyperinflammatory versus hypoinflammatory subphenotypes was predicted to be overall similar across different cohorts per each model, we observed poor intermodel agreement. We observed heightened inflammation in Berlin patients with ARDS compared with HFNC-ARDS within our Asian cohort. CONCLUSION:Established subphenotype classifiers demonstrated similar distribution of subphenotypes in Asian patients with ARDS. However, poor intermodel agreement highlights the need for further investigation into model variability with models coming closer to bedside implementation. TRIAL REGISTRATION NUMBER:NCT02975908.

Rationale Obstructive lung disease is increasingly common among persons living with HIV (PLWH). There are currently no validated biomarkers that identify individuals at risk of developing obstructive lung disease (OLD), and specific mechanisms contributing to HIV-associated OLD remain elusive, independent of smoking. We sought to identify biomarkers and biological pathways associated with OLD using a broad proteomic approach. Methods We performed tandem mass tagging and mass spectrometry (MS) analysis on bronchoalveolar lavage fluid samples from persons living with HIV with OLD (n=26) and without OLD (n=26). We combined untargeted MS with a targeted SomaScan aptamer-based approach. We used Pearson correlation tests to identify associations between each protein and lung function (forced expiratory volume in 1 s (FEV1) % pred). We adjusted for multiple comparisons using a false discovery rate adjustment. Significant proteins were entered into a pathway over-representation analysis. Protein-driven endotypes were constructed using K-means clustering. Measurements and main results We identified over 3800 proteins by MS and identified 254 proteins that correlated with FEV1 % pred when we combined the MS and SomaScan proteomes when adjusting for smoking status. Pathway analysis revealed cell adhesion molecules as significant. Conclusions Protein expression differs in the lung of PLWH and decreased lung function (FEV1 % pred). Pathway analysis reveals cell adhesion molecules having potentially important roles in this process.

Rationale: Recovery of Candida species from lower respiratory tract (LRT) secretions of critically ill patients has historically been considered harmless airway colonization. However, recent observational evidence associates adverse clinical outcomes with Candida colonization in mechanically ventilated patients. We examined the role of LRT Candida on lung injury with complementary murine, in vitro, and human observational studies. Methods: To investigate the role of Candida in the LRT during lung injury, we used a sterile two-hit murine model of intratracheal C. albicans (day 0) followed by intratracheal lipopolysaccharide (LPS, day 2) with lung injury endpoints measured on day 4. Additionally, we delivered intratracheal C. albicans alone in wild-type and neutrophil-ablated (PMNDTR) mice and observed lung injury endpoints on day 2. To investigate mechanisms of lung injury, we performed bulk RNA sequencing of non-lavaged lungs harvested on day 1 after intratracheal C. albicans insult. In vitro, we administered wild-type and mutant C. albicans strains to murine and human alveolar epithelial cells for assays of cytotoxicity and transepithelial resistance (TEER). Finally, we analyzed lung injury biomarkers and endpoints in a prospective cohort of critically ill patients with acute respiratory failure (ARF). Results:C. albicans potentiated LPS-induced lung injury marked by air-blood barrier disruption and neutrophilic airspace recruitment. Intratracheal C. albicans alone was sufficient to produce lung injury in mice, with lung transcriptomics demonstrating strong signatures of neutrophil activation. Importantly, neutrophil-ablated PMNDTR mice exposed to C. albicans developed extra-pulmonary fungal dissemination and increased mortality with severe lung injury, showing that neutrophils are essential for host defense. C. albicans induced murine and human lung epithelial cytotoxicity in vitro, which was attenuated with heat-killed or yeast-locked (TNRG1) C. albicans strains that cannot form hyphae. Wild-type C. albicans caused significant barrier disruption in human alveolar epithelial cells at air-liquid interface, which was markedly attenuated in the yeast-locked strain. In a prospective cohort of critically ill humans with ARF on mechanical ventilation, individuals with Candida growth on respiratory cultures had increased LRT soluble receptor for advanced glycation end-products (sRAGE) and neutrophil elastase as well as an association with worse lung injury endpoints when compared to patients with bacterial growth on respiratory cultures. Conclusions: Our study challenges the belief that LRT Candida is harmless, demonstrating that C. albicans induces lung injury in mice and associates with lung injury endpoints in mechanically-ventilated humans. Understanding this complex host-pathogen interaction may uncover new therapies in the management of ARF in critically ill patients.

OBJECTIVE:People with HIV (PWH) have increased risk for worse pulmonary function and increased emphysema. HIV has been proposed as a risk factor for respiratory patient-reported outcomes (PROs). We assessed the association of HIV with respiratory symptoms, respiratory health status, and functional exercise capacity. DESIGN:Systematic review and meta-analysis. METHODS:We searched PubMed, EMBASE, CENTRAL, CDSR, WoS, Scopus, CINAHL, and GIM through November 2023 for studies of PWH and people without HIV (PWOH) reporting respiratory PROs. Primary outcomes were activity-limiting dyspnea (defined as Modified Medical Research Council Dyspnea Scale score ≥2), respiratory health status by St. George's Respiratory Questionnaire (SGRQ), and exertional capacity by 6-min walking distance (6MWD). We performed random-effects meta-analyses estimating odds ratios (ORs) and mean differences with 95% confidence intervals (CIs). RESULTS:We included 89 publications corresponding to 56 studies. HIV was associated with activity-limiting dyspnea (OR 1.67; 95% CI 1.05-2.65), worse respiratory health status (SGRQ mean difference 2.9 units; 95% CI 0.6-5.2), worse exertional capacity (6MWD mean difference -58.9 m; 95% CI -115.3 to -2.4), and chronic cough, dyspnea, phlegm, and wheeze (OR 1.38-1.78). Respiratory symptom and adverse respiratory health status risk was greatest in European PWH. Certainty of evidence was very low, primarily due to studies' observational design and inconsistency. CONCLUSION:PWH have increased risk for worse respiratory PROs. Systematic respiratory PRO assessment should be incorporated into routine clinical care to facilitate active case-finding of chronic lung disease in PWH. Future studies should longitudinally co-assess objective physiologic measures and respiratory PROs.

Background: Pulmonary hypertension (PH) is a fatal condition characterized by elevated pressure in pulmonary artery which could be partly caused by dysfunctional nitric oxide (NO) signaling. Previous studies identified that nitrate is actively concentrated in saliva and could be reduced to nitrite by bacterial nitrate reductase enzymes, which are rarely found in human genomes. Oral nitrate reduction (NR) capacity was previously reported to be predictive of blood pressure in systemic circulation; however, the role of the oral microbiome in oral NR and NO signaling in PH remains unclear. Hypothesis: We hypothesize that loss of nitrate reductase-expressing bacteria in oral microbiota leads to decreased NR capacity and is associated with worse PH phenotype. Method: We prospectively enrolled patients who underwent RHC at University of Pittsburgh Medical Center, following the ERS 2022 PH hemodynamic classification. Oral wash [OW] samples were collected&underwent 16S rRNA sequencing then analyzed with Qiime2 (v2024.10; SILVA). We predicted bacterial NR capacity in silico by Picrust2 (v2.6). Differential abundance analyses were done with ANCOMBC2. Plasma nitrate&nitrite levels were quantified. In a subset, NR capacity was verified by measuring ex vivo nitrite formation rate with NO analyzer (Sievers) after adding KNO 3 substrate to OW. Results: We enrolled n=184 patients who underwent RHC in 2014-2020. Of these, 144 (78%) had mPAP over 20mmHg (PH) with mPAP of 32.4 [10.2] mmHg (mean [SD]) and PVR of 3.6 [1.9] Wood Units. Between PH vs non-PH patients, alpha diversity, beta diversity and microbial load (16S qPCR) were similar in the oral microbiome (all p>0.05). Veillonella, Rothia, Neisseria etc are major NR capacity contributors, but their abundances did not differ between PH vs non-PH. NR index, defined as the ratio of sum abundance of NR contributors over non-contributors, was significantly associated with the predicted abundance of bacterial nitrate reductase genes, and also verified with the NR enzyme activity (p=0.016) measured in vitro . Increased NR index is associated with lower mPAP (R=-0.21, p=0.0129, adjusted for diastolic systematic blood pressure [DBP] and smoking history) and lower PVR (R= -0.19, adjusted p=0.019) among PH patients. Conclusions: We confirmed that predicted nitrate reduction capacity by the oral microbiome reflects functional nitrate reduction in vitro and is associated with PH severity. The oral microbiome represents a modifiable target in PH.

BACKGROUND:Several studies have reported lung function impairment following COVID-19. Less is known about the subsequent recovery. RESEARCH QUESTION:What is the recovery in lung function after COVID-19 during the first year after infection? METHODS:We conducted a systematic review and meta-analysis of studies that monitored individuals' lung function from the time of infection to at least 1 year after infection. Primary outcomes were change in percent predicted forced expiratory volumes in 1 s (FEV1), forced vital capacity (FVC) and diffusing capacity for carbon monoxide (D LCO). Mean differences (MDs) with 95% confidence intervals were estimated using a random effects model. RESULTS:We included 23 studies (n=3347 participants). 20 (86.9%) studies had their first follow-up 3 months after infection and 21 (91.3%) had their second follow-up 12 months after infection. The MDs between the second and first follow-up visits of FEV1, FVC and D LCO were 3.1% (95% CI 1.8-4.5; p<0.01), 4.4% (95% CI 2.7-6.0; p<0.01) and 6.6% (95% CI 4.4-8.9; p<0.01), respectively. Recovery of FEV1, FVC and D LCO was greater in mechanically ventilated patients compared to individuals with less severe disease. Current smoking status, pre-existing chronic lung disease and age did not impact recovery during the first year after infection. INTERPRETATION:Recovery in lung function was evident during the first year after COVID-19, with the largest improvement in patients with the most severe infection. Further follow-up and large-scale studies are warranted to establish recovery trajectories of COVID-19 and other respiratory infections to identify patient subgroups needing additional follow-up to ascertain modifiable factors influencing pulmonary recovery.

Background:People living with HIV (PLWH) commonly have sleep disturbances, but little is known about their habitual sleep patterns and rest-activity rhythms (RARs). We sought to compare sleep and RAR metrics between people living with and without HIV. Methods:Adult participants with (n = 106) and without HIV (n = 105) underwent evaluation with 14 days of wrist actigraphy. PLWH were virally suppressed and on stable antiretroviral therapy for at least 1 year before evaluation. Sleep duration, timing, regularity, and RAR metrics were derived from actigraphy. Differences in sleep and RAR metrics by HIV status were compared using multivariable regression adjusting for age, sex, race, body mass index, education, employment, smoking, alcohol, and sleep apnea severity. Results:In adjusted analyses, PLWH had later timing of sleep and activity compared with those without HIV (sleep midpoint 38.9 ± 12.7 minutes later, P = .003, acrophase 44.3 ± 13.1 minutes later, P = .0009) and less consolidated nighttime sleep (sleep efficiency 2.4 ± 0.9% lower, P = .007; daytime napping 10.5 ± 3.9 minutes greater, P = .007). In addition, PLWH had less robust rhythms with more variable nightly sleep (standard deviation of nocturnal sleep duration 18.1 ± 5.3 minutes greater, P = .0007; standard deviation of sleep midpoint 26.0 ± 7.8 minutes greater, P = .001), lower RAR peak (relative amplitude 0.07 ± 0.02 lower, P = .002), and less regular rhythm (pseudo-F statistic 858 ± 426 lower, P = .046; interdaily stability 0.06 ± 0.02 lower, P = .003). Conclusions:PLWH have delayed, less consolidated, and less robust sleep and RARs compared with those without HIV, suggesting intrinsic differences in circadian rhythms. Future research should evaluate the impact of these abnormalities on long-term health outcomes in PLWH.