Annals of the American Thoracic Society最新文献

Rationale: To identify barriers and opportunities for Ph.D., basic and translational scientists to be fully integrated into clinical units. Objectives: In 2022, an ad hoc committee of the American Thoracic Society developed a project proposal and workshop to identify opportunities and barriers for scientists who do not practice medicine to develop successful careers and achieve tenure-track faculty positions in clinical departments and divisions within academic medical centers (AMCs) in the United States. Methods: This document focuses on results from a survey of adult and pediatric pulmonary, critical care, and sleep medicine division chiefs as well as a survey of workshop participants, including faculty in departmental and school leadership roles in both basic science and clinical units within U.S. AMCs. Results: We conclude that full integration of non-clinically practicing basic and translational scientists into the clinical units, in addition to their traditional placements in basic science units, best serves the tripartite mission of AMCs to provide care, perform research, and educate the next generation. Evidence suggests clinical units do employ Ph.D. scientists in large numbers, but these faculty are often hired into non-tenure track positions, which do not provide the salary support, start-up funds, research independence, or space often associated with hiring in basic science units within the same institution. These barriers to success of Ph.D. faculty in clinical units are largely financial. Conclusions: Our recommendation is for AMCs to consider and explore some of our proposed strategies to accomplish the goal of integrating basic and translational scientists into clinical units in a meaningful way.

Rationale: Disparities in patient selection for advanced therapeutics in health care have been identified in multiple studies, but it is unclear if disparities exist in patient selection for extracorporeal membrane oxygenation (ECMO), a rapidly expanding critical care resource. Objectives: To determine if disparities exist in patient selection for ECMO based on sex, primary insurance, and median income of the patient's neighborhood. Methods: In a retrospective cohort study using the Nationwide Readmissions Database 2016-2019, we identified patients treated with mechanical ventilation (MV) and/or ECMO with billing codes. Patient sex, insurance, and income level for patients receiving ECMO were compared with the patients treated with MV only, and hierarchical logistic regression with the hospital as a random intercept was used to determine odds of receiving ECMO based on patient demographics. Results: We identified 2,170,752 MV hospitalizations with 18,725 cases of ECMO. Among patients treated with ECMO, 36.1% were female compared with 44.5% of patients treated with> MV only (adjusted odds ratio [aOR] for ECMO, 0.73; 95% confidence interval [CI], 0.70-0.75). Of patients treated with ECMO, 38.1% had private insurance compared with 17.4% of patients treated with MV only. Patients with Medicaid were less likely to receive ECMO than patients with private insurance (aOR, 0.55; 95% CI, 0.52-0.57). Patients treated with ECMO were more likely to live in the highest-income neighborhoods compared with patients treated with MV only (25.1% vs. 17.3%). Patients living in the lowest-income neighborhoods were less likely to receive ECMO than those living in the highest-income neighborhoods (aOR, 0.63; 95% CI, 0.60-0.67). Conclusions: Significant disparities exist in patient selection for ECMO. Female patients, patients with Medicaid, and patients living in the lowest-income neighborhoods are less likely to be treated with ECMO. Despite possible unmeasured confounding, these findings were robust to multiple sensitivity analyses. On the basis of previous work describing disparities in other areas of health care, we speculate that limited access in some neighborhoods, restrictive/biased interhospital transfer practices, differences in patient preferences, and implicit provider bias may contribute to the observed differences. Future studies with more granular data are needed to identify and modify drivers of observed disparities.

Rationale: Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for F508del-CFTR in a Phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index_2.5 (LCI_2.5), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment. Objective: To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI). Methods: This Phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for F508del-CFTR received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). The results from Part 1 are reported. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI_2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index-for-age z-scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the chest MRI global score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics. Results: Fifty-one children were enrolled and received LUM/IVA (n = 35) or placebo (n = 16). For the change in chest MRI global score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference, <0; higher score indicates greater abnormality) was 76%; the mean treatment difference was -1.5 (95% credible interval, -5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI_2.5, growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA. Conclusions: This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years of age. Clinical trial registered with www.clinicaltrials.gov (NCT03625466).

Rationale: Central sleep apnea (CSA) is pervasive during sleep at high altitude, disproportionately impacting men and associated with increased peripheral chemosensitivity. Objectives: We aimed to assess whether biological sex affects loop gain (LGn) and CSA severity during sleep over 9-10 days of acclimatization to 3,800 m. We hypothesized that CSA severity would worsen with acclimatization in men but not in women because of greater increases in LGn in men. Methods: Sleep studies were collected from 20 (12 male) healthy participants at low altitude (1,130 m, baseline) and after ascent to (nights 2/3, acute) and residence at high altitude (nights 9/10, prolonged). CSA severity was quantified as the respiratory event index (REI) as a surrogate of the apnea-hypopnea index. LGn, a measure of ventilatory control instability, was quantified using a ventilatory control model fit to nasal flow. Linear mixed models evaluated effects of time at altitude and sex on respiratory event index and LGn. Data are presented as contrast means with 95% confidence intervals. Results: REI was comparable between men and women at acute altitude (4.1 [-9.3, 17.5] events/h; P = 0.54) but significantly greater in men at prolonged altitude (23.7 [10.3, 37.1] events/h; P = 0.0008). Men had greater LGn than did women for acute (0.08 [0.001, 0.15]; P = 0.047) and prolonged (0.17 [0.10, 0.25]; P < 0.0001) altitude. The change in REI per change in LGn was significantly greater in men than in women (107 ± 46 events/h/LGn; P = 0.02). Conclusions: The LGn response to high altitude differed between sexes and contributed to worsening of CSA over time in men but not in women. This sex difference in acclimatization appears to protect females from high altitude-related CSA. These data provide fundamental sex-specific physiological insight into high-altitude acclimatization in healthy individuals and may help to inform sex differences in sleep-disordered breathing pathogenesis in patients with cardiorespiratory disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV₁ decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV₁ in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery β = 0.0561, Q = 4.05 × 10^-10; β  = 0.0421, Q = 1.12 × 10^-3; and β = 0.0358, Q = 1.67 × 10^-3, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV₁ decline (Q < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; β = -4.3 ml/yr, Q = 0.049; β = -6.1 ml/yr, Q = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV₁ decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.

As fossil fuel combustion continues to power the global economy, the rate of climate change is accelerating, causing severe respiratory health impacts and large disparities in the degree of human suffering. Hotter and drier climates lead to longer and more severe wildland fire seasons, impairing air quality around the globe. Hotter temperatures lead to higher amounts of ozone and particles, causing the exacerbation of chronic respiratory diseases and premature mortality. Longer pollen seasons and higher pollen concentrations provoke allergic airway diseases. In arid regions, accelerated land degradation and desertification are promoting dust pollution and impairing food production and nutritional content that are essential to respiratory health. Extreme weather events and flooding impede healthcare delivery and can lead to poor indoor air quality due to mold overgrowth. Climate and human activities that harm the environment and ecosystem may also affect the emergence and spread of viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and associated morbidity and mortality exacerbated by air pollution. Children and elderly individuals are more susceptible to the adverse health effects of climate change. Geographical and socioeconomic circumstances, together with a decreased capacity to adapt, collectively increase vulnerability to the adverse effects of climate change. Successful mitigation of anthropogenic climate change is dependent on the commitment of energy-intensive nations to manage greenhouse gas emissions, as well as societal support and response to aggravating factors. In this review, we focus on the respiratory health impacts of global climate change, with an emphasis on susceptible and vulnerable populations and low- and middle-income countries.