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BACKGROUND: The questions of whether the use of antibiotics that are active against atypical organisms is beneficial in the treatment of community-acquired pneumonia and of the potential mechanisms of any beneficial effects remain unresolved. Proposed mechanisms include activity against atypical organisms vs the immunomodulatory effects of these antibiotics. The study of outcomes of a large cohort of patients with bacteremic pneumonia provides a unique opportunity to address these questions by excluding patients with primary atypical infection. METHODS: We reviewed data from the charts of 2,209 Medicare patients who were admitted to hospitals across the United States from either home or a nursing facility with bacteremic pneumonia between 1998 and 2001. Patients were stratified according to the type of antibiotic treatment. Multivariate modeling was performed to assess the relationship between the class of antibiotic used and several outcome variables. RESULTS: The initial use of any antibiotic active against atypical organisms was independently associated with a decreased risk of 30-day mortality (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.59 to 0.98; p = 0.03) and hospital admission within 30 days of discharge (OR, 0.67; 95% CI, 0.51 to 0.89; p = 0.02). Further analysis revealed that the benefits of atypical treatment were associated with the use of macrolides, but not the use of fluoroquinolones or tetracyclines, with macrolides conferring lower risks of in-hospital mortality (OR, 0.59; 95% CI, 0.40 to 0.88; p = 0.01), 30-day mortality (OR, 0.61; 95% CI, 0.43 to 0.87; p = 0.007), and hospital readmission within 30 days of discharge (OR, 0.59; 95% CI, 0.42 to 0.85; p = 0.004). CONCLUSIONS: Initial antibiotic treatment including a macrolide agent is associated with improved outcomes in Medicare patients hospitalized with bacteremic pneumonia. These results have implications regarding the mechanism by which the use of a macrolide for treatment of pneumonia is associated with improved outcomes. [ABSTRACT FROM AUTHOR]

Background: Many organizations, including the Centers for Medicare & Medicaid Services, measure the percentage of patients hospitalized with pneumonia who receive antibiotics within 4 h of presentation. Because the diagnosis of pneumonia can be delayed in patients with an atypical presentation, there are concerns that attempts to achieve a performance target of 100% may encourage inappropriate antibiotic usage and the diversion of limited resources from seriously ill patients. This study was performed to determine how frequently Medicare patients with a hospital discharge diagnosis of pneumonia present in a manner that could potentially lead to diagnostic uncertainty and a resulting appropriate delay in antibiotic administration.Methods: Randomly selected charts of hospitalized Medicare patients who have received diagnoses of pneumonia were reviewed independently by three reviewers to determine whether there was a potential reason for a delay of antibiotic administration other than quality of care. Antibiotic administration timing, patient demographic, and clinical characteristics were also abstracted.Results: Nineteen of 86 patients (22%; 95% confidence interval, 13.7 to 32.2) presented in a manner that had the potential to result in delayed antibiotic treatment due to diagnostic uncertainty. Diagnostic uncertainty was significantly associated with the lack of rales, normal pulse oximetry findings, and lack of an infiltrate seen on the chest radiograph. There was a nonsignificant trend toward a longer time until antibiotic treatment in patients with diagnostic uncertainty.Conclusions: Many Medicare patients in whom pneumonia has been diagnosed present in an atypical manner. Delivering antibiotic treatment within 4 h for all patients would necessitate the treatment of many patients before a firm diagnosis can be made. [ABSTRACT FROM AUTHOR]

It is recommended that blood cultures be performed on all patients admitted to the hospital with pneumonia. Questions regarding the cost-effectiveness of this practice have emerged. We used data on 13,043 Medicare patients hospitalized with pneumonia to determine predictors of bacteremia. Predictors included recent antibiotic treatment, liver disease, and three vital-sign and three laboratory abnormalities. Patients were stratified into three groups on the basis of the likelihood of bacteremia. We then created a decision support tool that recommends performing no blood cultures on patients with low likelihood of bacteremia, one blood culture on patients with moderate likelihood of bacteremia, and two blood cultures on patients with higher likelihood of bacteremia. This tool was then applied to a validation cohort of 12,771 patients with pneumonia. Use of the decision support tool would result in 38% fewer blood cultures being performed when compared with the standard practice of performing two blood cultures for each patient and identified 88 to 89% of patients with bacteremia. A simplified tool performed similarly overall but was less sensitive than was the first tool among pneumonia severity index Class V patients. These tools may allow clinicians to target patients with pneumonia in whom blood cultures are most likely to yield a pathogen. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to compare the time course of clinical and radiographic improvement in patients with Pneumocystis carinii pneumonia (PCP), and evaluate the usefulness of early follow-up chest radiographs (CXRs) in these patients. Design: Retrospective, chart review. Methods: The medical records of 36 episodes of confirmed PCP among 28 patients were reviewed. Clinical parameters of improvement were defined as follows: (1) a decrease in temperature by 0.5 degrees C, (2) a decrease in respiratory rate by 25%, and (3) a 2% improvement in arterial oxygen saturation, as measured by pulse oximetry, in the setting of an unchanged amount of supplemental oxygen or a reduction in supplemental oxygen. A patient was defined as clinically improving when all three of these criteria were met. All CXRs were graded by radiologists, specifically for the study, as normal or abnormal and improved, worsened, or unchanged from the initial CXR. Results: Clinical improvement was noted during 30 of 36 episodes of PCP (83%) at a mean of 4.5 +/- 2.5 days (+/- SD). There was improvement in the CXR finding during the hospital stay during 15 of 36 episodes (42%), at a mean of 7.7 +/- 4.5 days. Radiographic resolution preceded clinical resolution in only four cases (11%). Excluding seven patients who received ventilatory support, the median number of CXRs per patient was four (range, two to nine CXRs). Conclusion: We conclude that radiographic improvement of PCP lags behind clinical improvement. [ABSTRACT FROM AUTHOR]

Competing Interests: Disclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0889.

Rationale: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods: Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV 1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P  < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM ( P  < 0.05). Conclusions: Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

Introduction: Antimicrobial resistance (AMR) is a global public health challenge. Global efforts to decrease AMR through antimicrobial stewardship (AMS) initiatives include education and optimising the use of diagnostic technologies and antibiotics. Despite this, economic and societal challenges hinder AMS efforts. The objective of this study was to obtain insights from healthcare professionals (HCPs) on current challenges and identify opportunities for optimising diagnostic test utilisation and AMS efforts., Methods: Three hundred HCPs from six countries (representing varied gross national incomes per capita, healthcare system structure, and AMR rates) were surveyed between November 2022 through January 2023. A targeted literature review and expert interviews were conducted to inform survey development. Descriptive statistics were used to summarise survey responses., Results: These findings suggest that the greatest challenges to diagnostic test utilisation were economic in nature; many HCPs reported that AMS initiatives were lacking investment (32.3%) and resourcing (40.3%). High resistance rates were considered the greatest barriers to appropriate antimicrobial use (52.0%). Most HCPs found local and national guidelines to be very useful (≥ 51.0%), but areas for improvement were noted. The importance of AMS initiatives was confirmed; diagnostic practices were acknowledged to have a positive impact on decreasing AMR (70.3%) and improving patient outcomes (81.0%)., Conclusion: AMS initiatives, including diagnostic technology utilisation, are pivotal to decreasing AMR rates. Interpretation of these survey results suggests that while HCPs consider diagnostic practices to be important in AMS efforts, several barriers to successful implementation still exist including patient/institutional costs, turnaround time of test results, resourcing, AMR burden, and education. While some barriers differ by country, these survey results highlight areas of opportunities in all countries for improved use of diagnostic technologies and broader AMS efforts, as perceived by HCPs. Greater investment, resourcing, education, and updated guidelines offer opportunities to further strengthen global AMS efforts., (© 2024. The Author(s).)

Background: This study aimed to evaluate the association between the number of non-cystic fibrosis bronchiectasis (bronchiectasis) exacerbations during baseline and follow-up (objective 1) and to identify longitudinal changes in FEV 1 associated with exacerbation frequency (objective 2)., Methods: This was a retrospective cohort study of adult patients enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry September 2008 to March 2020. Objective 1 outcome was association between exacerbations during baseline (24 months) and 0-to-24 month and 24-to-48 month follow-up windows. Objective 2 outcomes were change in FEV 1 and FEV 1 % predicted over 24 months stratified by baseline exacerbation frequency., Results: Objective 1 cohort (N = 520) baseline frequency of any exacerbations was 59.2%. Overall, 71.4% and 75.0% of patients with ≥1 baseline exacerbations had ≥1 exacerbations during the 0-to-24 and 24-to-48 month follow-ups. Having ≥1 exacerbation during baseline was significantly associated with ≥1 exacerbation during the 0-to-24 month (P = 0.0085) and 24-to-48 month follow-ups (P=<0.0001). Objective 2 cohort (N = 431) baseline FEV 1 was significantly lower in patients who had more exacerbations; however, decline in FEV 1 from baseline was not significantly different between patients with 0, 1, and ≥2 exacerbations. In patients with more baseline exacerbations, FEV 1 % predicted was significantly lower at baseline (P < 0.0001) and at 12 (P = 0.0002) and 24 month follow-ups (P < 0.0001)., Conclusions: Patients with frequent bronchiectasis exacerbations may be more likely than those with less frequent exacerbations to experience disease progression based on future exacerbation frequency and lower FEV 1 at baseline, although FEV 1 decline may not differ by baseline exacerbation frequency., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joseph Feliciano, Jasmanda Wu, and Sebastian Fucile are employees and shareholders of Insmed Incorporated. Timothy R. Aksamit reports no personal grant or research support from Insmed Incorporated or other pharma; clinical trial design and participation with AstraZeneca, Insmed Incorporated, Johnson & Johnson, Redhill Biopharma, Spero Therapeutics, and Zambon, with all support going to the Mayo Foundation for Medical Education and Research; and is the medical director of Bronchiectasis and NTM 360 for the COPD Foundation. Nicole C. Lapinel reports receiving consulting fees and serving on the advisory board panel for Insmed Incorporated; Louisiana State University Health Sciences Center received clinical trial support from Insmed Incorporated. Radmila Choate and Andreas Schmid have nothing to disclose. Kevin L. Winthrop reports grant and research support and consulting fees from AN2 Therapeutics, Insmed Incorporated, Paratek, Red Hill Biopharma, Renovion, and Spero Therapeutics and participation on a data safety monitoring board or advisory board for Red Hill Biopharma. Mark L. Metersky reports receiving consulting fees from AN2 Therapeutics, Boehringer Ingelheim, Insmed Incorporated, Renovion, and Zambon., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Nebulized Hypertonic saline (HS) and positive expiratory pressure device (PEP) are often used in patients with bronchiectasis. We sought to describe the clinical characteristics in patients using HS and PEP, utilizing a large national database registry., Methods: Data from the US Bronchiectasis and NTM Research Registry were used in this study. Patients with a diagnosis of bronchiectasis were included. Eligible patients were assigned to one of four mutually exclusive groups: HS only, PEP only, HS & PEP, or no airway clearance or mucoactive agent. Descriptive statistics were computed for the overall study population and stratified by the four groups. One-way ANOVA and chi-square tests were used to test the difference in the means in continuous variables and the association between categorical variables (respectively) across the four groups., Results: A total of 2195 patients were included. Of those with bronchiectasis and a productive cough, a greater number of patients utilized HS only vs PEP only (17.5 % vs 9.1 %, p < 0.001). Similar association was found in those with Pseudomonas aeruginosa (22.3 % HS only vs 6.5 % PEP only, p < 0.001). There was a higher number of patients who used HS and PEP therapy in combination vs PEP therapy alone (25.0 % vs 9.1 %, p = 0.002), in those with a productive cough., Conclusions: In patients with bronchiectasis and a productive cough or Pseudomonas aeruginosa, HS is used more often than PEP alone. There is a need for further analysis to compare these two modalities and explore the factors influencing their utilization., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ashwin Basavaraj reports a relationship with Insmed Inc that includes: consulting or advisory. Ashwin Basavaraj reports a relationship with Baxter that includes: consulting or advisory. Ashwin Basavaraj reports a relationship with Zambon SpA that includes: consulting or advisory. Ashwin Basavaraj reports a relationship with Physio-Assist that includes: consulting or advisory. Ashwin Basavaraj reports a relationship with Dymedso that includes: consulting or advisory. Ashwin Basavaraj reports a relationship with COPD Foundation that includes: funding grants. Mark Meterksy reports a relationship with COPD Foundation that includes:. Mark Metersky reports a relationship with Tactile Medical that includes: consulting or advisory. Mark Metersky reports a relationship with Insmed Inc that includes: consulting or advisory and funding grants. Mark Metersky reports a relationship with Boehringer Ingelheim Corp USA that includes: consulting or advisory. Mark Metersky reports a relationship with Renovion that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 SPLF and Elsevier Masson SAS. All rights reserved.)

Background: High frequency chest wall oscillation (HFCWO) is a form of airway clearance therapy that has been available since the mid-1990s and is routinely used by patients suffering from retained pulmonary secretions. Patients with cystic fibrosis (CF), neuromuscular disease (NMD), and other disorders, including bronchiectasis (BE) and COPD (without BE), are commonly prescribed this therapy. Limited evidence exists describing HFCWO use in the BE population, its impact on long-term management of disease, and the specific patient populations most likely to benefit from this therapy. This study sought to characterize the clinical characteristics of patients with BE who have documented use of HFCWO at baseline and 1-year follow-up., Methods: An analysis from a large national database registry of patients with BE was performed. Demographic and clinical characteristics of all patients receiving HFCWO therapy at baseline are reported. Patients were stratified into two groups based on continued or discontinued use of HFCWO therapy at 1-year follow-up., Results: Over half (54.8 %) of patients who reported using HFCWO therapy had a Modified Bronchiectasis Severity Index (m-BSI) classified as severe, and the majority (81.4 %) experienced an exacerbation in the prior two years. Of patients with 1-year follow-up data, 73 % reported continued use of HFCWO. Compared to patients who discontinued therapy, these patients were more severe at baseline and at follow-up suggesting that patients with more severe disease are more likely to continue HFCWO therapy., Conclusions: Patients who have more severe disease and continue to experience exacerbations and hospitalizations are more likely to continue HFCWO therapy., Clinical Trial Registration: NA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ashwin Basavaraj reports writing assistance was provided by LeeAnn Phipps. AB - Consultant and Advisory Board for Baxter, Insmed, Physio-Assist, Dymedso, Zambon. Medical education consulting for Tactile Medical. Principal investigator on clinical trial sponsored by Baxter with funding to institution. Educational grant funding received from Insmed to institution. RC - No disclosures to report. BB – Employee relationship with Baxter. MM - Grant funding from Insmed and COPD foundation. Consulting fees from Insmed, Boehringer-Ingelheim, and Tactile Medical. Payment/honoraria for presentations/lectures from Insmed. Participation on data safety monitoring/advisory board for AN2, Renovion. TA - Support as medical director of the Bronchiectasis and NTM research registry. Has participated in clinical trials sponsored by Bayer, Aradigm, Zambon., (Copyright © 2024. Published by Elsevier Ltd.)

Two recent major guidelines on diagnosis and treatment of ventilator-associated pneumonia (VAP) recommend consideration of local antibiotic resistance patterns and individual patient risks for resistant pathogens when formulating an initial empiric antibiotic regimen. One recommends against invasive diagnostic techniques with quantitative cultures to determine the cause of VAP; the other recommends either invasive or noninvasive techniques. Both guidelines recommend short-course therapy be used for most patients with VAP. Although neither guideline recommends use of procalcitonin as an adjunct to clinical judgment when diagnosing VAP, they differ with respect to use of serial procalcitonin to shorten the length of antibiotic treatment., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Many patients with interstitial lung diseases (ILDs), especially fibrotic ILDs, experience chronic cough. It negatively impacts both physical and psychological well-being. Effective treatment options are limited., Areas Covered: The pathophysiology of chronic cough in IPF is complex and involves multiple mechanisms, including mechanical distortion of airways, parenchyma, and nerve fibers. The pathophysiology of cough in other fibrosing ILDs is poorly understood and involves various pathways. The purpose of this review is to highlight mechanisms of chronic cough and to present therapeutic evidence for its management in the most commonly occurring diffuse fibrosing lung diseases including idiopathic pulmonary fibrosis (IPF), connective tissue disease-related interstitial lung disease (CTD-ILD), sarcoidosis-related ILD (Sc-ILD), chronic hypersensitivity pneumonitis-related ILD (CHP-ILD), and post-COVID-19-related interstitial lung disease (PC-ILD)., Expert Opinion: This review guides the management of chronic cough in fibrosing ILDs. In this era of precision medicine, chronic cough management should be individualized in each interstitial lung disease.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV 1 , 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.

Objective: To determine change in rates of postoperative pneumonia and ventilator-associated pneumonia among patients hospitalized in the United States during 2009-2019., Design: Retrospective cohort study., Patients: Patients hospitalized for major surgical procedures, acute myocardial infarction, heart failure, and pneumonia., Methods: We conducted a retrospective review of data from the Medicare Patient Safety Monitoring System, a chart-abstraction-derived database including 21 adverse-event measures among patients hospitalized in the United States. Changes in observed and risk-adjusted rates of postoperative pneumonia and ventilator-associated pneumonia were derived., Results: Among 58,618 patients undergoing major surgical procedures between 2009 and 2019, the observed rate of postoperative pneumonia from 2009-2011 was 1.9% and decreased to 1.3% during 2017-2019. The adjusted annual risk each year, compared to the prior year, was 0.94 (95% CI, 0.92-0.96). Among 4,007 patients hospitalized for any of these 4 conditions at risk for ventilator-associated pneumonia during 2009-2019, we did not detect a significant change in observed or adjusted rates. Observed rates clustered around 10%, and adjusted annual risk compared to the prior year was 0.99 (95% CI, 0.95-1.02)., Conclusions: During 2009-2019, the rate of postoperative pneumonia decreased statistically and clinically significantly in among patients hospitalized for major surgical procedures in the United States, but rates of ventilator-associated pneumonia among patients hospitalized for major surgical procedures, acute myocardial infarction, heart failure, and pneumonia did not change.

Background: Hospitals with high mortality and readmission rates for patients with heart failure (HF) might also perform poorly in other quality concepts. We sought to evaluate the association between hospital performance on mortality and readmission with hospital performance rates of safety adverse events., Methods: This cross-sectional study linked the 2009 to 2019 patient-level adverse events data from the Medicare Patient Safety Monitoring System, a randomly selected medical records-abstracted patient safety database, to the 2005 to 2016 hospital-level HF-specific 30-day all-cause mortality and readmissions data from the United States Centers for Medicare & Medicaid Services. Hospitals were classified to one of 3 performance categories based on their risk-standardized 30-day all-cause mortality and readmission rates: better (both in <25th percentile), worse (both >75th percentile), and average (otherwise). Our main outcome was the occurrence (yes/no) of one or more adverse events during hospitalization. A mixed-effect model was fit to assess the relationship between a patient's risk of having adverse events and hospital performance categories, adjusted for patient and hospital characteristics., Results: The study included 39 597 patients with HF from 3108 hospitals, of which 252 hospitals (8.1%) and 215 (6.9%) were in the better and worse categories, respectively. The rate of patients with one or more adverse events during a hospitalization was 12.5% (95% CI, 12.1-12.8). Compared with patients admitted to better hospitals, patients admitted to worse hospitals had a higher risk of one or more hospital-acquired adverse events (adjusted risk ratio, 1.24 [95% CI, 1.06-1.44])., Conclusions: Patients admitted with HF to hospitals with high 30-day all-cause mortality and readmission rates had a higher risk of in-hospital adverse events. There may be common quality issues among these 3 measure concepts in these hospitals that produce poor performance for patients with HF., Competing Interests: Disclosures In the past 3 years, Harlan Krumholz received expenses and/or personal fees from UnitedHealth, Element Science, Eyedentifeye, and F-Prime. He is a co-founder of Refactor Health and HugoHealth, and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare & Medicaid Services and through Yale University from the Food and Drug Administration, Johnson & Johnson, Google, and Pfizer. Dr Normand, S. Eckenrode, and J. Mathew work under contract with the Centers for Medicare & Medicaid Services to develop and maintain performance measures outside this submitted work. Dr Wang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. He is the founder of Boston Deep Data LLC. Dr Metersky has worked on various quality improvement and patient safety projects with the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality. His employer has received remuneration for this work. The other authors report no conflicts.

Brensocatib is a novel anti-inflammatory therapy in development for bronchiectasis treatment. Phase 2 WILLOW trial data demonstrate a low number needed to treat and negative number needed to harm, suggesting a favourable benefit-risk profile. https://bit.ly/3SbisW3., Competing Interests: Conflict of interest: J.D. Chalmers has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, GSK, Zambon and Insmed Incorporated; a grant from Gilead; and personal fees from Novartis and Chiesi within the past 24 months. He is an associate editor of this journal. Conflict of interest: M.L. Metersky has received consulting fees from Insmed Incorporated, Boehringer Ingelheim, California Institute for Biomedical Research and Zambon; and his institution has received clinical trial support from Insmed Incorporated. Conflict of interest: J. Feliciano, C. Fernandez, A. Teper, A. Maes, M. Hassan and A. Chatterjee are employed by Insmed Incorporated., (Copyright ©The authors 2023.)

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and rapidly fatal interstitial lung disease marked by the replacement of lung alveoli with dense fibrotic matrices. Although the mechanisms initiating IPF remain unclear, rare and common alleles of genes expressed in lung epithelia, combined with aging, contribute to the risk for this condition. Consistently, single-cell RNA sequencing (scRNA-seq) studies have identified lung basal cell heterogeneity in IPF that might be pathogenic. We used single-cell cloning technologies to generate "libraries" of basal stem cells from the distal lungs of 16 patients with IPF and 10 controls. We identified a major stem cell variant that was distinguished from normal stem cells by its ability to transform normal lung fibroblasts into pathogenic myofibroblasts in vitro and to activate and recruit myofibroblasts in clonal xenografts. This profibrotic stem cell variant, which was shown to preexist in low quantities in normal and even fetal lungs, expressed a broad network of genes implicated in organ fibrosis and showed overlap in gene expression with abnormal epithelial signatures identified in previously published scRNA-seq studies of IPF. Drug screens highlighted specific vulnerabilities of this profibrotic variant to inhibitors of epidermal growth factor and mammalian target of rapamycin signaling as prospective therapeutic targets. This profibrotic stem cell variant in IPF was distinct from recently identified profibrotic stem cell variants in chronic obstructive pulmonary disease and may extend the notion that inappropriate accrual of minor and preexisting stem cell variants contributes to chronic lung conditions.

Demographic and socioeconomic factors are recognized to contribute to disparities in healthcare outcomes. Originally, bronchiectasis was described in a population of predominantly White ethnic group of patients in which racial disparity could not be identified. The U.S. Bronchiectasis Research Registry (BRR), a centralized database of adult patients with bronchiectasis and/or NTM from 18 clinical institutions across the U.S., was created to support the research of this condition. The aim of this study is to describe the racial and ethnic distribution of patients enrolled in the BRR and evaluate factors associated with healthcare disparities within manifestations of and/or the care delivered to this population. At the time of this study, 3600 patients with bronchiectasis and/or NTM were enrolled in the BRR. Of those, 3510 participants were included in these analyses. The population was predominantly non-HispanicWhite (n = 3143, 89.5%), followed by Hispanic or Latino (n = 149, 4.3%), Asian (n = 130, 3.7%) and non-Hispanic Black (n = 88, 2.5%) participants. Testing for cystic fibrosis, immunoglobulin deficiency, and mycobacteria was not different between races, but non-Hispanic Black patients were tested less frequently for alpha-1 antitrypsin (A1AT) deficiency compared to other groups (P = 0.01). The four groups did not differ in the proportion of Pseudomonas aeruginosa or Hemophilus influenzae. There was no statistically significant difference in use of high-frequency chest wall oscillation, pulmonary rehabilitation services, or suppressive macrolide treatment across the groups (P > 0.05). There is a disproportionately high percentage of non-Hispainc White patients compared to non-Hispanic Black patients and Hispanic or Latino patients in the BRR. However, we found an overall similarity of care of BRR patients, regardless of racial and ethnic group., Competing Interests: Declaration of competing interest The authors declare no financial relationships, compensation or intellectual property related to the work in this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Since the emergence of SARS-CoV-2, maintaining healthcare worker (HCW) health and safety has been fundamental to responding to the global pandemic. Vaccination with mRNA-base vaccines targeting SARS-CoV-2 spike protein has emerged as a key strategy in reducing HCW susceptibility to SARS-CoV-2, however, neutralizing antibody responses subside with time and may be influenced by many variables. We sought to understand the dynamics between vaccine products, prior clinical illness from SARS-CoV-2, and incidence of vaccine-associated adverse reactions on antibody decay over time in HCWs at a university medical center. A cohort of 296 HCWs received standard two-dose vaccination with either bnt162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) and were evaluated after two, six, and nine months. Subjects were grouped by antibody decay curve into steep antibody decliners gentle decliners. Vaccination with mRNA-1273 led to more sustained antibody responses compared to bnt162b2. Subjects experiencing vaccine-associated symptoms were more likely to experience a more prolonged neutralizing antibody response. Subjects with clinical SARS-CoV-2 infection prior to vaccination were more likely to experience vaccination-associated symptoms after first vaccination and were more likely to have a more blunted antibody decay. Understanding factors associated with vaccine efficacy may assist clinicians in determining appropriate vaccine strategies in HCWs.

Background: Pulmonary embolism (PE) with cor pulmonale causes considerable mortality and morbidity. Randomized trials have failed to show a mortality difference between treatment modalities including anticoagulation (AC), Catheter directed thrombolysis (CDT) and systemic tPA (tissue plasminogen activator)., Methods: This is a cross-sectional retrospective case-control study utilizing the 2017 National Inpatient Sample (NIS). Patients admitted with acute PE with cor pulmonale were divided into groups based on whether they received anticoagulation, CDT or systemic tPA based on appropriate ICD-10 PCS codes. The AC group and CDT group were compared using univariate and multivariate analyses after adjusting for age, gender, race, comorbidities, insurance status and Charlson comorbidity index (CCI). Secondary outcomes included factors influencing length of stay (LOS) and total charges incurred. Similar analyses were done to compare the CDT group with the tPA group., Results: In 2017, 13240 patients were admitted with acute PE and cor pulmonale, of whom 18% underwent CDT, 10% underwent systemic tPA and 72% underwent AC alone. Patients who received CDT over AC alone were significantly younger (61.5 vs. 65.5, p = 0.00). Mortality rate overall was 4.8% with tPA group, CDT group and AC alone group having a 11.2%, 3.0% and 4.4% mortality rate respectively. On multivariate analyses, there was no significant mortality difference between the CDT and AC groups (aOR 0.61, 0.34-1.1 95%CI, p = 0.103). Patients with liver disease had significantly higher mortality while obese patients had a significantly lower mortality after adjusting for treatment strategy and confounders. Length of stay (LOS) was not significantly different between the groups however, compared to AC alone, patients who underwent CDT or tPA incurred significantly higher total hospital charges., Conclusions: CDT offers an attractive alternative to tPA therapy; however, our study does not show an in-hospital mortality benefit. More studies are required to guide patient selection prior to establishing treatment protocols.

Importance: It is known that hospitalized patients who experience adverse events are at greater risk of readmission; however, it is unknown whether patients admitted to hospitals with higher risk-standardized readmission rates had a higher risk of in-hospital adverse events., Objective: To evaluate whether patients with pneumonia admitted to hospitals with higher risk-standardized readmission rates had a higher risk of adverse events., Design, Setting, and Participants: This cross-sectional study linked patient-level adverse events data from the Medicare Patient Safety Monitoring System (MPSMS), a randomly selected medical record abstracted database, to the hospital-level pneumonia-specific all-cause readmissions data from the Centers for Medicare & Medicaid Services. Patients with pneumonia discharged from July 1, 2010, through December 31, 2019, in the MPSMS data were included. Hospital performance on readmissions was determined by the risk-standardized 30-day all-cause readmission rate. Mixed-effects models were used to examine the association between adverse events and hospital performance on readmissions, adjusted for patient and hospital characteristics. Analysis was completed from October 2019 through July 2020 for data from 2010 to 2017 and from March through April 2022 for data from 2018 to 2019., Exposures: Patients hospitalized for pneumonia., Main Outcomes and Measures: Adverse events were measured by the rate of occurrence of hospital-acquired events and the number of events per 1000 discharges., Results: The sample included 46 047 patients with pneumonia, with a median (IQR) age of 71 (58-82) years, with 23 943 (52.0%) women, 5305 (11.5%) Black individuals, 37 763 (82.0%) White individuals, and 2979 (6.5%) individuals identifying as another race, across 2590 hospitals. The median hospital-specific risk-standardized readmission rate was 17.0% (95% CI, 16.3%-17.7%), the occurrence rate of adverse events was 2.6% (95% CI, 2.54%-2.65%), and the number of adverse events per 1000 discharges was 157.3 (95% CI, 152.3-162.5). An increase by 1 IQR in the readmission rate was associated with a relative 13% higher patient risk of adverse events (adjusted odds ratio, 1.13; 95% CI, 1.08-1.17) and 5.0 (95% CI, 2.8-7.2) more adverse events per 1000 discharges at the patient and hospital levels, respectively., Conclusions and Relevance: Patients with pneumonia admitted to hospitals with high all-cause readmission rates were more likely to develop adverse events during the index hospitalization. This finding strengthens the evidence that readmission rates reflect the quality of hospital care for pneumonia.

Objectives: This study aimed to determine whether patients in teaching hospitals are at higher risk of suffering from an adverse event during the summer trainee changeover period., Methods: We performed a retrospective analysis of data from the Medicare Patient Safety Monitoring System, a medical-record abstraction-based database in the United States. Hospital admissions from 2010 to 2017 for acute myocardial infarction, heart failure, pneumonia, or a major surgical procedure were studied. Admissions were divided into nonsurgical (acute myocardial infarction, heart failure, or pneumonia) and surgical. Adverse event rates in July/August were compared with the rest of the year. Hospitals were stratified into major teaching, minor teaching, or nonteaching. Results were adjusted for patient demographics, comorbidities, and hospital characteristics. Outcomes were the adjusted odds of having at least 1 adverse event in July/August versus the rest of the year., Results: We included 185,652 hospital admissions. The adjusted odds ratios (ORs) of suffering from at least one adverse event in a major teaching hospital in July/August was 0.83 (95% confidence interval [CI], 0.69-0.98) for nonsurgical patients and 1.09 (95% CI, 0.84-1.40) for surgical patients. In minor teaching hospitals, the adjusted ORs were 0.96 (95% CI, 0.88-1.04) for nonsurgical patients and 0.99 (95% CI, 0.87-1.12) for surgical patients. In nonteaching hospitals, the adjusted ORs were 0.98 (95% CI, 0.91-1.06) for nonsurgical patients and 1.10 (95% CI, 0.96-1.24) for surgical patients., Conclusions: Patients admitted to teaching hospitals in July/August are not at increased risk of adverse events. These findings should reassure patients and medical educators that patients are not excessively endangered by admission to the hospital during these months., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Bronchiectasis is a condition defined by permanently dilated airways and characterized by chronic cough and sputum and in many patients, recurrent exacerbations. Bronchiectasis is a heterogeneous condition, with numerous underlying risk factors and initiating conditions. These factors share in common the ability to impair the mechanisms by which the airways are protected from inflammatory or infectious insults. These underlying factors result in chronic bacterial infection of the airways, inciting a host inflammatory response in which the airways are the collateral damage. The damaged airways are unable to clear the infection, leading to ongoing inflammation and progressive damage., Competing Interests: Disclosure Dr M.L. Metersky has served as a consultant for Insmed, Zambon and International Biophysics and has served as an Investigator in a clinical trial sponsored by Insmed. Dr A.F. Barker has no financial conflicts of interest to report., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Little information is available about Stenotrophomonas maltophilia in patients with bronchiectasis. We analyzed data from the US Bronchiectasis and NTM Research Registry to determine its prevalence and association with patient characteristics and severity of disease., Methods: Baseline and follow-up data were entered into a central web-based database. Patients were grouped into four cohorts based on their baseline cultures: 1) S. maltophilia, no Pseudomonas aeruginsosa, 2) P. aeruginosa, no S. maltophilia, 3) No pathogens, 4) Pathogens other than P. aeruginosa and S. maltophilia. The association between S. maltophilia, demographic characteristics, pulmonary function, exacerbations and hospitalizations was assessed at baseline and one year follow-up., Results: Among 2659 patients, 134 (5.0%) had grown S. maltophilia at baseline. The prior exacerbation rate at baseline was similar in patients with S. maltophilia and P. aeruginosa, but significantly higher than the other two groups. Hospitalizations were more frequent in patients with S. maltophilia or P. aeruginosa. Pre-bronchodilator FEV1 among S. maltophilia patients was between that of Pseudomonas patients and patients without either organism, but was not significantly different from any of the other groups. For all risk-adjusted one-year outcomes, patients with S. maltophilia had a non-significant trend towards worse outcomes compared to patients without P. aeruginosa, but were more similar to patients with P aeruginosa., Discussion: Bronchiectasis patients with S. maltophilia may have worse outcomes than patients without this organism or without P. aeruginosa; further study is needed to determine if the non-significant trends we note are clinically significant., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The limited resources and the practice of social distancing during the COVID pandemic create a paradigm shift in the utilization of telemedicine in healthcare. However, the implementation of best practices is hampered in part by a lack of literature devoted to telehealth in bronchiectasis. In this commentary, we examine multiple approaches to structuring of telemedicine care for patients with bronchiectasis, highlight current evidence-based interventions that can be incorporated into the management of bronchiectasis, and describe our experience with telemedicine at the University of Connecticut Center for Bronchiectasis Care during the COVID-19 pandemic. The structural model must be adapted to different local dynamics and available technologies with careful attention to patient characteristics and access to technology to avoid the potential paradoxical effects of increasing patients' burden and healthcare disparities in underserved populations.

Background: Perioperative care for total knee arthroplasty (TKA) has improved over time. We present an analysis of inpatient safety after TKA., Methods: 14,057 primary TKAs captured by the Medicare Patient Safety Monitoring System between 2010 and 2017 were retrospectively reviewed. We calculated changes in demographics, comorbidities, and adverse events (AEs) over time. Risk factors for AEs were also assessed., Results: Between 2010 and 2017, there was an increased prevalence of obesity (35.1% to 57.6%), tobacco smoking (12.5% to 17.8%), and renal disease (5.2% to 8.9%). There were reductions in coronary artery disease (17.3% to 13.4%) and chronic warfarin use (6.7% to 3.1%). Inpatient AEs decreased from 4.9% to 2.5%, ( P < .01), primarily driven by reductions in anticoagulant-associated AEs, including major bleeding and hematomas (from 2.8% to 1.0%, P < .001), catheter-associated urinary tract infections (1.1% to 0.2%, P  < .001), pressure ulcers (0.8% to 0.2%, P < .001), and venous thromboembolism (0.3% to 0.1%, P  = .04). The adjusted annual decline in the risk of developing any in-hospital AE was 14% (95% confidence interval [CI] 10%-17%). Factors associated with developing an AE were advanced age (odds ratio [OR] = 1.01, 95% CI 1.00-1.01), male sex (OR = 1.21, 95% CI 1.02-1.44), coronary artery disease (OR = 1.35, 95% CI 1.07-1.70), heart failure (OR = 1.70, 95% CI 1.20-2.41), and renal disease (OR = 1.71, 95% CI 1.23-2.37)., Conclusions: Despite increasing prevalence of obesity, tobacco smoking, and renal disease, inpatient AEs after primary TKA have decreased over the past several years. This improvement is despite the increasing complexity of the inpatient TKA population over time., (© 2021 The Authors.)

Background: This document provides evidence-based clinical practice guidelines on the diagnostic utility of nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in adults with suspected community-acquired pneumonia (CAP). Methods: A multidisciplinary panel developed a Population-Intervention-Comparison-Outcome question, conducted a pragmatic systematic review, and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations. Results: The panel evaluated the literature to develop recommendations regarding whether routine diagnostics should include nucleic acid-based testing of respiratory samples for viral pathogens other than influenza in suspected CAP. The evidence addressing this topic was generally adjudicated to be of very low quality because of risk of bias and imprecision. Furthermore, there was little direct evidence supporting a role for routine nucleic acid-based testing of respiratory samples in improving critical outcomes such as overall survival or antibiotic use patterns. However, on the basis of direct and indirect evidence, recommendations were made for both outpatient and hospitalized patients with suspected CAP. Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was not addressed in the literature at the time of the evidence review. Conclusions: The panel formulated and provided their rationale for recommendations on nucleic acid-based diagnostics for viral pathogens other than influenza for patients with suspected CAP.

Background: Previous meta-analyses suggested that treating hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP), with empiric carbapenems was associated with lower mortality rates but higher rates of clinical failure for pseudomonal pneumonia. This study was an updated meta-analysis with sensitivity analyses and meta-regression to better understand the impact of carbapenem use in HAP/VAP., Research Question: What is the efficacy of carbapenems for empiric treatment of nosocomial pneumonia?, Study Design and Methods: Databases were searched for randomized controlled studies evaluating empiric treatment for HAP and/or VAP, and studies were included comparing carbapenem- vs non-carbapenem-containing regimens. The primary outcome was all-cause mortality. Secondary outcomes included subgroup stratification and resistance development., Results: Of 9,140 references, 20 trials enrolling 5,489 patients met inclusion criteria. For mortality, carbapenem use had a risk ratio (RR) of 0.84 (95% CI, 0.74-0.96; P = .01). Stratified according to VAP proportion (< 33%, 33%-66%, and > 66%), RRs were 0.95 (95% CI, 0.77-1.17; P = .66), 0.78 (95% CI, 0.57-1.07; P = .13), and 0.81 (95% CI, 0.65-0.99; P = .04), respectively. Stratified according to severity, only groups with Acute Physiology and Chronic Health Evaluation II scores < 14 and between 14 and 17 showed mortality benefit (RRs of 0.64 [95% CI, 0.45-0.92; P = .01] and 0.77 [95% CI, 0.61-0.97; P = .03]). Meta-regression did not show an association between Pseudomonas prevalence and mortality (P = .44). Carbapenem use showed a trend toward developing resistance (RR, 1.40; 95% CI, 0.95-2.06; P = .09) and a 96% probability of resistance emergence., Interpretation: Carbapenem-based empiric regimens were associated with lower mortality rates compared with non-carbapenems, largely driven by trials of VAP. The mortality effect was not observed in trials with high disease severity and was not associated with Pseudomonas. The mortality difference was observed mainly in studies that used ceftazidime as control. There was a trend toward increasing resistance associated with carbapenems., Trial Registry: International Prospective Register of Systematic Reviews; No. CRD42018093602; URL: https://www.crd.york.ac.uk/prospero/., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Non-cystic fibrosis bronchiectasis (NCFB) is characterized by dilated bronchi, poor mucus clearance and susceptibility to bacterial infection. Pseudomonas aeruginosa (PA) is one of the most frequently isolated pathogens in patients with NCFB. The purpose of this study was to evaluate the association between presence of PA and disease severity in patients within the US Bronchiectasis and Nontuberculous mycobacteria (NTM) Research Registry (BRR)., Methods: Baseline US BRR data from adult patients with NCFB collected between 2008 and 2018 was used for this study. The presence of PA was defined as one or more positive PA cultures within two years prior to enrollment. Modified Bronchiectasis Severity Index (m-BSI) and modified FACED (m-FACED) were computed to evaluate severity of bronchiectasis. Unadjusted and multivariable multinomial regression models were used to assess the association between presence of PA and severity of bronchiectasis., Results: Average age of the study participants (n = 1831) was 63.7 years (SD = 14.1), 91.5% white, and 78.8% female. Presence of PA was identified in 25.4% of the patients. Patients with presence of PA had significantly lower mean pre-bronchodilator FEV1% predicted compared to those without PA (62.8% vs. 73.7%, p < .0001). In multivariate analyses, patients with presence of PA had significantly greater odds for having high (OR adj  = 6.15 (95%CI:3.98-9.50) and intermediate (OR adj  = 2.06 (95%CI:1.37-3.09) severity vs. low severity on m-BSI., Conclusion: The presence of PA is common in patients with NCFB within the Bronchiectasis and NTM Research Registry. Severity of bronchiectasis is significantly greater in patients with PA which emphasizes high burden of the disease., Competing Interests: Declaration of competing interest DA-H has served on a research protocol advisory board for AIT Therapeutics and has served in an educational lecture series sponsored by Insmed. TRA has participated in clinical trials sponsored by Bayer, Aradigm, Zambon, and Insmed but has not received any personal or research support. ABarker has received grant support from COPD Foundation for participation in the Bronchiectasis and NTM Research Registry. ABasavaraj has received grant support from COPD Foundation for participation in the Bronchiectasis and NTM Research Registry, has served on the advisory board and consultant for Insmed, and consultant for Hill-Rom. AS has served on the Speaker Bureau and Advisory Board for Insmed. CLD has received grant support from COPD Foundation and Insmed. DM is a former employee and a current shareholder of GlaxoSmithKline. MLAD has served on Speaker Bureau/Advisory Boards for Spark Partners and Insmed and participated in clinical trials for Zambon and Parion/Vertex. MLM has received grant support from COPD Foundation. PGN has received grant support from Aradigm/Grifols, Insmed, Parion/ Vertex and Bayer, and consultancy fees from Bayer, Grifols, and Smartvest. AEO has received grant support from Parion, Insmed, Aradigm, Grifols, and COPD Foundation. KNO has a Cooperative Research and Development Award with AIT Therapeutics (Beyond Air) and Matinas Biopharma and has participated on advisory panels with Insmed, Inc. MAS has received grant support from COPD Foundation, Parion, Bayer Healthcare, and Aradigm. BMT has received personal fees for serving on advisory boards for GlaxoSmithKline and AstraZeneca and helped cofound the COPD Foundation and served as the Foundation’s Board Chairman for ten years. GT has received grant support from the COPD Foundation for participation in the Bronchiectasis and NTM Research Registry and has received personal fees for serving on Advisory Boards for Bayer, Grifols, Aradigm, and Cipla. KLW has received grant support and personal fees from Insmed and Bayer. No conflicts declared from RC, AD, EE, KF, DG, MMJ, MRK and GS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases., Methods: In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed., Results: Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo., Conclusions: In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Increasing numbers of patients are being diagnosed with bronchiectasis, yet much remains to be elucidated about this heterogeneous patient population. We sought to determine the relationship between nutrition and health outcomes in non-cystic fibrosis (non-CF) bronchiectasis, using data from the U.S. Bronchiectasis Nontuberculous Mycobacterial Research Registry (U.S. BRR)., Methods: This was a retrospective, observational, longitudinal study using 5-year follow-up data from the BRR. Bronchiectasis was confirmed on computed tomography (CT). We stratified patients into nutrition categories using body mass index (BMI), and correlated BMI to markers of disease severity., Results: Overall, n = 496 patients (mean age 64.6- ± 13 years; 83.3% female) were included. At baseline 12.3% (n = 61) were underweight (BMI < 18.5kg/m 2 ), 63.9% (n = 317) had normal weight (BMI ≥ 18.5kg/m 2 and <25.0kg/m 2 ), 17.3% (n = 86) were overweight (BMI ≥ 25.0kg/m 2 and < 30.0kg/m 2 ), and 6.5% (n= 32) were obese (BMI ≥ 30kg/m 2 ). Men were overrepresented in the overweight and obese groups (25.6% and 43.8% respectively, p < 0.0001). Underweight patients had lower lung function (forced expiratory volume in 1 second [FEV 1 ] % predicted) than the other weight groups (64.5 ± 22, versus 73.5 ± 21, 68.5 ± 20, and 76.5 ± 21 in normal, overweight, and obese groups respectively, p = 0.02). No significant differences were noted between BMI groups for other markers of disease severity at baseline, including exacerbation frequency or hospitalization rates. No significant differences were noted in BMI distribution between patients with and without Pseudomonas , non-tuberculous mycobacteria, or by cause of bronchiectasis. The majority of patients demonstrated stable BMI over 5 years., Conclusions: Although underweight patients with bronchiectasis have lower lung function, lower BMI does not appear to relate to other markers of disease severity in this patient population., Competing Interests: Dr. Addrizzo-Harris reports consultant work from Insmed, advisory board work from AIT, outside the submitted work. Dr. Basavaraj reports grants from the COPD Foundation, personal fees from Hill-Rom, and personal fees from Insmed, outside the submitted work. Dr. Daley reports grants from the COPD Foundation, during the conduct of the study and grants from Insmed, outside the submitted work. Dr. Daniels reports grants and personal fees from Insmed, personal fees from Spark Healthcare, personal fees from International Biophysics Corporation, grants from Zambon, and grants from Parion/Vertex, outside the submitted work. Dr. Noone has received grant support from Aradigm/Grifols, Insmed, Parion/ Vertex and Bayer, and consultancy fees from Bayer, Grifols, and Smartvest. Dr. O'Donnell reports grants from the COPD Foundation/U.S. Bronchiectasis Research Registry, grants and personal fees from Insmed Inc, personal fees from Electromed and Merck, grants and personal fees from Bayer, personal fees from Xellia, and grants from Zambon, Aradigm, and Parion, outside the submitted work. Dr. Olivier reports grants from Beyond Air, Inc, and Matinas Biopharma, outside the submitted work. Dr. Philley reports personal fees from Insmed, Bayer, and Janssen, grants from REPORT trial, outside the submitted work. Dr. Tino reports grants from the U.S. BRR/COPD Foundation, advisory board work from Bayer, Grifols, Aradigm and Cipla, outside the submitted work. Dr. Salathe reports grants from the COPD Foundation (registry), during the conduct of the study; grants and personal fees from the National Institutes of Health, the Flight Attendant Medical Research Institute, and Arrowhead Pharmaceuticals and grants from the James and Esther King Florida Biomedical Research Program, outside the submitted work. Dr. Thomashow reports personal fees from GSK and Astra Zeneca, outside the submitted work. Dr. Winthrop reports grants and personal fees from Insmed, personal fees from Johnson and Johnson, Paratek, Red Hill Biopharma, and Horizon, outside the submitted work. Drs. Aksamit, Barker, Despotes, Choate, DiMango, Eden, Fennelly, Johnson, Knowles, McShane, Metersky, and Schmid have no conflicts of interest to disclose., (JCOPDF © 2020.)

Background: In patients with bronchiectasis, airway clearance techniques (ACTs) are important management strategies., Research Question: What are the differences in patients with bronchiectasis and a productive cough who used ACTs and those who did not? What was the assessment of bronchiectasis exacerbation frequency and change in pulmonary function at 1-year follow up?, Study Design and Methods: Adult patients with bronchiectasis and a productive cough in the United States Bronchiectasis and NTM Research Registry were included in the analyses. ACTs included the use of instrumental devices and manual techniques. Stratified analyses of demographic and clinical characteristics were performed by use of ACTs at baseline and follow up. The association between ACT use and clinical outcomes was assessed with the use of unadjusted and adjusted multinomial logistic regression models., Results: Of the overall study population (n = 905), 59% used ACTs at baseline. A greater proportion of patients who used ACTs at baseline and follow up continuously had Pseudomonas aeruginosa (47% vs 36%; P = .021) and experienced an exacerbation (81% vs 59%; P < .0001) or hospitalization for pulmonary illness (32% vs 22%; P = .001) in the prior two years, compared with those patients who did not use ACTs. Fifty-eight percent of patients who used ACTs at baseline did not use ACTs at 1-year follow up. There was no significant change in pulmonary function for those who used ACTs at follow up, compared with baseline. Patients who used ACTs at baseline and follow up had greater odds for experiencing exacerbations at follow up compared with those patients who did not use ACTs., Interpretation: In patients with bronchiectasis and a productive cough, ACTs are used more often if the patients have experienced a prior exacerbation, hospitalization for pulmonary illness, or had P aeruginosa. There is a significant reduction in the use of ACTs at 1-year follow up. The odds of the development of a bronchiectasis exacerbation are higher in those patients who use ACTs continuously, which suggests more frequent use in an ill bronchiectasis population., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a progressive condition of chronic bronchitis, small airway obstruction, and emphysema that represents a leading cause of death worldwide. While inflammation, fibrosis, mucus hypersecretion, and metaplastic epithelial lesions are hallmarks of this disease, their origins and dependent relationships remain unclear. Here we apply single-cell cloning technologies to lung tissue of patients with and without COPD. Unlike control lungs, which were dominated by normal distal airway progenitor cells, COPD lungs were inundated by three variant progenitors epigenetically committed to distinct metaplastic lesions. When transplanted to immunodeficient mice, these variant clones induced pathology akin to the mucous and squamous metaplasia, neutrophilic inflammation, and fibrosis seen in COPD. Remarkably, similar variants pre-exist as minor constituents of control and fetal lung and conceivably act in normal processes of immune surveillance. However, these same variants likely catalyze the pathologic and progressive features of COPD when expanded to high numbers., Competing Interests: Declaration of Interests W.X., F.D.M., W.R., S.W., J.X., M.D., and M.V. have filed patents related to technologies used in the present work. M.V., F.D.M., and W.X. have financial interests in Nüwa Medical Systems, Houston, TX, USA and Tract pharmaceuticals, Houston, TX, USA. Nuwa Medical Systems is a trade name of Tract Pharmaceuticals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Intensive care units (ICUs) are an appropriate focus of antibiotic stewardship program efforts because a large proportion of any hospital's use of parenteral antibiotics, especially broad-spectrum, occurs in the ICU. Given the importance of antibiotic stewardship for critically ill patients and the importance of critical care practitioners as the front line for antibiotic stewardship, a workshop was convened to specifically address barriers to antibiotic stewardship in the ICU and discuss tactics to overcome these. The working definition of antibiotic stewardship is "the right drug at the right time and the right dose for the right bug for the right duration." A major emphasis was that antibiotic stewardship should be a core competency of critical care clinicians. Fear of pathogens that are not covered by empirical antibiotics is a major driver of excessively broad-spectrum therapy in critically ill patients. Better diagnostics and outcome data can address this fear and expand efforts to narrow or shorten therapy. Greater awareness of the substantial adverse effects of antibiotics should be emphasized and is an important counterargument to broad-spectrum therapy in individual low-risk patients. Optimal antibiotic stewardship should not focus solely on reducing antibiotic use or ensuring compliance with guidelines. Instead, it should enhance care both for individual patients (by improving and individualizing their choice of antibiotic) and for the ICU population as a whole. Opportunities for antibiotic stewardship in common ICU infections, including community- and hospital-acquired pneumonia and sepsis, are discussed. Intensivists can partner with antibiotic stewardship programs to address barriers and improve patient care.

Importance: Studies have shown that adverse events are associated with increasing inpatient care expenditures, but contemporary data on the association between expenditures and adverse events beyond inpatient care are limited., Objective: To evaluate whether hospital-specific adverse event rates are associated with hospital-specific risk-standardized 30-day episode-of-care Medicare expenditures for fee-for-service patients discharged with acute myocardial infarction (AMI), heart failure (HF), or pneumonia., Design, Setting, and Participants: This cross-sectional study used the 2011 to 2016 hospital-specific risk-standardized 30-day episode-of-care expenditure data from the Centers for Medicare & Medicaid Services and medical record-abstracted in-hospital adverse event data from the Medicare Patient Safety Monitoring System. The setting was acute care hospitals treating at least 25 Medicare fee-for-service patients for AMI, HF, or pneumonia in the United States. Participants were Medicare fee-for-service patients 65 years or older hospitalized for AMI, HF, or pneumonia included in the Medicare Patient Safety Monitoring System in 2011 to 2016. The dates of analysis were July 16, 2017, to May 21, 2018., Main Outcomes and Measures: Hospitals' risk-standardized 30-day episode-of-care expenditures and the rate of occurrence of adverse events for which patients were at risk., Results: The final study sample from 2194 unique hospitals included 44 807 patients (26.1% AMI, 35.6% HF, and 38.3% pneumonia) with a mean (SD) age of 79.4 (8.6) years, and 52.0% were women. The patients represented 84 766 exposures for AMI, 96 917 exposures for HF, and 109 641 exposures for pneumonia. Patient characteristics varied by condition but not by expenditure category. The mean (SD) risk-standardized expenditures were $22 985 ($1579) for AMI, $16 020 ($1416) for HF, and $16 355 ($1995) for pneumonia per hospitalization. The mean risk-standardized rates of occurrence of adverse events for which patients were at risk were 3.5% (95% CI, 3.4%-3.6%) for AMI, 2.5% (95% CI, 2.5%-2.5%) for HF, and 3.0% (95% CI, 2.9%-3.0%) for pneumonia. An increase by 1 percentage point in the rate of occurrence of adverse events was associated with an increase in risk-standardized expenditures of $103 (95% CI, $57-$150) for AMI, $100 (95% CI, $29-$172) for HF, and $152 (95% CI, $73-$232) for pneumonia per discharge., Conclusions and Relevance: Hospitals with high adverse event rates were more likely to have high 30-day episode-of-care Medicare expenditures for patients discharged with AMI, HF, or pneumonia.

Guideline implementation tools are designed to improve uptake of guideline recommendations in clinical settings but do not uniformly accompany the clinical practice guideline documents. Performance measures are a type of guideline implementation tool with the potential to catalyze behavior change and greater adherence to clinical practice guidelines. However, many performance measures suffer from serious flaws in their design and application, prompting the American Thoracic Society (ATS) to define its own performance measure development standards in a previous workshop in 2012. This report summarizes the proceedings of a follow-up workshop convened to advance the ATS's work in performance measure development and guideline implementation. To illustrate the application of the ATS's performance measure development framework, we used the example of a low-tidal volume ventilation performance measure created de novo from the 2017 ATS/European Society of Intensive Care Medicine/Society of Critical Care Medicine mechanical ventilation in acute respiratory distress syndrome clinical practice guideline. We include a detailed explanation of the rationale for the specifications chosen, identification of areas in need of further validity testing, and a preliminary strategy for pilot testing of the performance measure. Pending additional resources and broader performance measure expertise, issuing "preliminary performance measures" and their specifications alongside an ATS clinical practice guideline offers a first step to further the ATS's guideline implementation agenda. We recommend selectively proceeding with full performance measure development for those measures with positive early user feedback and the greatest potential impact in accordance with ATS leadership guidance.