Search

Lung transplantation is an elective treatment option for end-stage respiratory diseases in which all medical therapy options have been exhausted. The current study aimed to identify updated information on the postoperative conditions that may impair rehabilitation after lung transplantation and to provide specific considerations of their clinical relevance during the recovery process. The present study is a systematic review conducted by searching three primary databases: the United States National Library of Medicine PubMed system, Scopus, and the Cochrane Library. The databases were searched for articles published from database inception until May 2024; at the end of the selection process, 27 documents were included in the final analysis. The retrieved material identified 19 conditions of rehabilitative interest that potentially affect the postoperative course: graft dysfunction, dysphagia, postsurgical pain, cognitive impairment, chronic lung allograft dysfunction-bronchiolitis obliterans syndrome, phrenic nerve injury, delayed extracorporeal membrane oxygenation weaning, airway clearance, refractory hypoxemia, mediastinitis, reduced oxidative capacity, sternal dehiscence, coronavirus disease 2019 (COVID-19), gastroparesis, ossification of the elbow, Takotsubo cardiomyopathy, airway dehiscence, recurrent pleural effusion, and scapular prolapse. Although some patients are not amenable to rehabilitation techniques, others can significantly improve with rehabilitation.

Black African-Caribbean (BAC) populations are at greater risk of cardiometabolic disease than White Europeans (WE), despite lower fasting triacylglycerol (TAG) concentrations. However, limited data exist regarding postprandial fatty acid metabolism in BAC populations. This study determined the ethnic differences in postprandial fatty acid metabolism between overweight and obese WE and BAC men. WE ( n =10) and BAC ( n =9) men consumed two consecutive moderate-to-high fat meals; the first labelled with U- 13 C palmitate. The plasma concentration and appearance of meal-derived fatty acids in very-low density lipoprotein (VLDL)-TAG, chylomicron-TAG, and NEFA were determined over 8-hours. Indirect calorimetry with 13 CO 2 enrichment determined total and meal-derived fatty acid oxidation rates, and plasma b-hydroxybutyrate (3-OHB) concentration was measured to assess ketogenesis. BAC exhibited lower postprandial TAG ( P =0.006) and VLDL-TAG ( P =0.002) concentrations than WE. The appearance of meal-derived fatty acids in VLDL-TAG was lower in BAC than WE ( P =0.004). Following the second meal, BAC showed a trend for lower chylomicron-TAG concentration ( P =0.057). There were no ethnic differences in the appearance of meal-derived fatty acids in chylomicron-TAG. Cumulative fatty acid oxidation and the NEFA:3-OHB ratio were similar in WE and BAC. In conclusion, BAC exhibit lower postprandial TAG concentrations compared with WE men, driven by lower VLDL-TAG concentrations and possibly lower chylomicron-TAG in the late postprandial period. In BAC, the lower VLDL-TAG concentration was partially driven by a lower appearance of meal-derived fatty acids in VLDL-TAG. These findings suggest that postprandial fatty acid trafficking may be a less important determinant of cardiometabolic risk in BAC than WE men.

Objectives: Inspiratory muscle training is used in rehabilitation to exercise respiratory muscles in various conditions associated with limited ventilatory reserve. In this review, we investigated inspiratory muscle training in lung transplant candidates and recipients., Materials and Methods: We searched 5 primary databases from inception through April 2024. Two key word entries, "lung transplantation" and "inspiratory muscle training," were matched using the Boolean operator AND. No filters were applied for document type, age, sex, publication date, language, and subject., Results and Conclusions: The searched databases returned 119 citations. Seven articles that considered 64 patients (47% female) were included in the final analysis, with 1 study involving a pediatric patient. Lung transplant recipients used a threshold trainer at 15% to 60% of maximal inspiratory pressure and mostly exercised twice daily for 10 to 15 minutes per session. Lung transplant candidates exercised at 30% to >50% of maximal inspiratory pressure twice daily, performing 30 to 60 inspirations or for 15 minutes. The highest inspiratory muscle strength was observed in a series of adult lung transplant recipients whose mean value improved by 31.8 ± 14.6 cmH2O versus baseline after treatment. To the same extent, the highest value of maximal inspiratory pressure was detected in a pediatric patient who scored 180 cmH2O after training. Overall, participants obtained improvements in lung function (forced expiratory volume in 1 second, forced vital capacity), functional performance, dyspnea intensity, and exercise tolerance. Inspiratory muscle training is easy to perform and can be done at home without specific supervision (in adults) before or after a lung transplant. Nevertheless, additional rigorous investigations should aim to replicate the positive effects reported in the present review.

Importance: While β-blockers are associated with decreased mortality in cardiovascular disease (CVD), exacerbation-prone patients with chronic obstructive pulmonary disease (COPD) who received metoprolol in the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK-COPD) trial experienced increased risk of exacerbations requiring hospitalization. However, the study excluded individuals with established indications for the drug, raising questions about the overall risk and benefit in patients with COPD following acute myocardial infarction (AMI)., Objective: To investigate whether β-blocker prescription at hospital discharge is associated with increased risk of mortality or adverse cardiopulmonary outcomes in patients with COPD and AMI., Design, Setting, and Participants: This prospective, longitudinal cohort study with 6 months of follow-up enrolled patients aged 35 years or older with COPD who underwent cardiac catheterization for AMI at 18 BLOCK-COPD network hospitals in the US from June 2020 through May 2022., Exposure: Prescription for any β-blocker at hospital discharge., Main Outcomes and Measures: The primary outcome was time to the composite outcome of death or all-cause hospitalization or revascularization. Secondary outcomes included death, hospitalization, or revascularization for CVD events, death or hospitalization for COPD or respiratory events, and treatment for COPD exacerbations., Results: Among 3531 patients who underwent cardiac catheterization for AMI, prevalence of COPD was 17.1% (95% CI, 15.8%-18.4%). Of 579 total patients with COPD and AMI, 502 (86.7%) were prescribed a β-blocker at discharge. Among the 562 patients with COPD included in the final analysis, median age was 70.0 years (range, 38.0-94.0 years) and 329 (58.5%) were male; 553 of the 579 patients (95.5%) had follow-up information. Among those discharged with β-blockers, there was no increased risk of the primary end point of all-cause mortality, revascularization, or hospitalization (hazard ratio [HR], 1.01; 95% CI, 0.66-1.54; P = .96) or of cardiovascular events (HR, 1.11; 95% CI, 0.65-1.92; P = .69), COPD-related or respiratory events (HR, 0.75; 95% CI, 0.34-1.66; P = .48), or treatment for COPD exacerbations (rate ratio, 1.01; 95% CI, 0.53-1.91; P = .98)., Conclusions and Relevance: In this cohort study, β-blocker prescription at hospital discharge was not associated with increased risk of adverse outcomes in patients with COPD and AMI. These findings support use of β-blockers in patients with COPD and recent AMI.

Lung retransplantation (LRT) involves a second or subsequent lung transplant (LT) in a patient whose first transplanted graft has failed. LRT is the only treatment option for irreversible lung allograft failure caused by acute graft failure, chronic lung allograft dysfunction, or postoperative complications of bronchial anastomosis. Prehabilitation (rehabilitation before LT), while patients are on the waiting list, is recognized as an essential component of the therapeutic regimen and should be offered throughout the waiting period from the moment of listing until transplantation. LRT is particularly fraught with challenges, and prehabilitation to reduce frailty is one of the few opportunities to address modifiable risk factors (such as functional and motor impairments) in a patient population in which there is clearly room to improve outcomes. Although rehabilitative outcomes and quality of life in patients receiving or awaiting LT have gained increased interest, there is a paucity of data on rehabilitation in patients undergoing LRT. Frailty is one of the few modifiable risk factors of retransplantation that is potentially preventable. As such, it is imperative that professionals involved in the field of retransplantation conduct research specifically exploring rehabilitative techniques and outcomes of value for patients receiving LRT, because this area remains unexplored.

Introduction: Graft loss in vascularized composite allotransplantation (VCA) is more often associated with vasculopathy and chronic rejection (CR) than acute cellular rejection (ACR). We present a rat osteomyocutaneous flap model using titrated tacrolimus administration that mimics the graft rejection patterns in our clinical hand transplant program. Comparison of outcomes in these models support a role for ischemia reperfusion injury (IRI) and microvascular changes in CR of skin and large-vessel vasculopathy. The potential of the surgical models for investigating mechanisms of rejection and vasculopathy in VCA and treatment interventions is presented., Materials and Methods: Four rodent groups were evaluated: syngeneic controls (Group 1), allogeneic transient immunosuppression (Group 2), allogeneic suboptimal immunosuppression (Group 3), and allogeneic standard immunosuppression (Group 4). Animals were monitored for ACR, vasculopathy, and CR of the skin., Results: Transient immunosuppression resulted in severe ACR within 2 wk of tacrolimus discontinuation. Standard immunosuppression resulted in minimal rejection but subclinical microvascular changes, including capillary thrombosis and luminal narrowing in arterioles in the donor skin. Further reduction in tacrolimus dose led to femoral vasculopathy and CR of the skin. Surprisingly, femoral vasculopathy was also observed in the syngeneic control group., Conclusions: Titration of tacrolimus in the allogeneic VCA model resulted in presentations of rejection and vasculopathy similar to those in patients and suggests vasculopathy starts at the microvascular level. This adjustable experimental model will allow the study of variables and interventions, such as external trauma or complement blockade, that may initiate or mitigate vasculopathy and CR in VCA., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: In 2019, the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease study (BLOCK-COPD) evaluated the effect of metoprolol on exacerbation risk and mortality in a COPD population without indications for beta-blocker use. We hypothesized that an imaging metric of coronary artery disease (CAD), the coronary artery calcium (CAC) score, would predict exacerbation risk and identify a differential response to metoprolol treatment., Methods: The study population includes participants in the BLOCK-COPD study from multiple study sites. Participants underwent clinically indicated thoracic computed tomography (CT) scans ± 12 months from enrollment. The Weston scoring system quantified CAC. Adjusted Cox proportional hazards models evaluated for associations between CAC and time to exacerbation., Results: Data is included for 109 participants. The mean CAC score was 5.1±3.7, and 92 participants (84%) had CAC scores greater than 0. Over a median (interquartile range) follow-up time of 350 (280 to 352) days, there were 61 mild exacerbations and 19 severe/very severe exacerbations. No associations were found between exacerbations of any severity and CAC>0 or total CAC. Associations were observed between total CAC and CAC>0 in the left circumflex (LCx) and time to exacerbation of any severity (adjusted hazard ratio [aHR]=1.39, confidence interval [CI]: 1.08-1.79, p =0.01) and (aHR=1.96, 95% CI: 1.04-3.70, p =0.04), respectively., Conclusions: CAD is a prevalent comorbidity in COPD accounting for significant mortality. Our study confirms the high prevalence of CAD using the CAC score; however, we did not discover an association between CAC and exacerbation risk. We did find novel associations between CAC in the LCx and exacerbation risk which warrant further investigation in larger cohorts., (JCOPDF © 2024.)

In the UK, populations of Black African and Caribbean (BAC) ethnicity suffer higher rates of cardiometabolic disease than White Europeans (WE). Obesity, leading to increased visceral adipose tissue (VAT) and intrahepatic lipid (IHL), has long been associated with cardiometabolic risk, driving insulin resistance and defective fatty acid/lipoprotein metabolism. These defects are compounded by a state of chronic low-grade inflammation, driven by dysfunctional adipose tissue. Emerging evidence has highlighted associations between central complement system components and adipose tissue, fatty acid metabolism and inflammation; it may therefore sit at the intersection of various cardiometabolic disease risk factors. However, increasing evidence suggests an ethnic divergence in pathophysiology, whereby current theories fail to explain the high rates of cardiometabolic disease in BAC populations. Lower fasting and postprandial TAG has been reported in BAC, alongside lower VAT and IHL deposition, which are paradoxical to the high rates of cardiometabolic disease exhibited by this ethnic group. Furthermore, BAC have been shown to exhibit a more anti-inflammatory profile, with lower TNF-α and greater IL-10. In contrast, recent evidence has revealed greater complement activation in BAC compared to WE, suggesting its dysregulation may play a greater role in the high rates of cardiometabolic disease experienced by this population. This review outlines the current theories of how obesity is proposed to drive cardiometabolic disease, before discussing evidence for ethnic differences in disease pathophysiology between BAC and WE populations.

Aim: In this study, we aimed to provide a nationally representative estimate of the economic burden of chronic obstructive pulmonary disease (COPD) by examining direct medical costs among individuals aged 45 years and older in the USA., Methods: Medical Expenditure Panel Survey (2017-2018) data were used to estimate the direct medical costs associated with COPD. All-cause (unadjusted) cost and COPD-specific (adjusted) cost were determined for the various service categories using a regression-based approach among patients with COPD. We developed a weighted two-part model and adjusted for various demographic, socioeconomic, and clinical characteristics., Results: The study sample consisted of 23,590 patients, of which 1073 had COPD. Patients with COPD had a mean age of 67.4 years (standard error (SE): 0.41), and the total all-cause mean medical cost per patient per year (PPPY) was 2018 US $19,449 (SE: US $865), of which US $6145 (SE: US $295) was for prescription drugs. Using the regression approach, the mean total COPD-specific cost was US $4322 (SE: US $577) PPPY, with prescription drugs contributing US $1887 (SE: 216) PPPY. These results represented an annual total COPD-specific cost of US $24.0 billion, with prescription drugs contributing US $10.5 billion. The mean annual out-of-pocket spending accounted for 7.5% (mean: US $325) of the total COPD-specific cost; for COPD-specific prescription drug cost, 11.3% (mean: US $212) was out-of-pocket cost., Conclusion: COPD poses a significant economic burden on healthcare payers and patients 45 years of age and older in the USA. While prescription drugs accounted for almost half of the total cost, more than 10% of the prescription drug cost was out-of-pocket., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Severe hemorrhage is an uncommon yet potentially life-threatening complication of transbronchial lung biopsy. Lung transplantation recipients undergo multiple bronchoscopies with biopsy and are considered to be at an increased risk for bleeding from transbronchial biopsy, independent of traditional risk factors. We aimed to evaluate the efficacy and safety of endobronchial administration of prophylactic topical epinephrine in attenuating transbronchial biopsy-related hemorrhage in lung transplant recipients., Methods: The Prophylactic Epinephrine for the Prevention of Transbronchial Lung Biopsy-related Bleeding in Lung Transplant Recipients study was a 2-center, randomized, double blind, placebo-controlled clinical trial. Participants undergoing transbronchial lung biopsy were randomized to receive 1:10,000-diluted topical epinephrine vs saline placebo administered prophylactically into the target segmental airway. Bleeding was graded based on a clinical severity scale. The primary efficacy outcome was incidence of severe or very severe hemorrhage. The primary safety outcome was a composite of 3-hours all-cause mortality and an acute cardiovascular event., Results: A total of 66 lung transplantation recipients underwent 100 bronchoscopies during the study period. The primary outcome of severe or very severe hemorrhage occurred in 4 cases (8%) in the prophylactic epinephrine group and in 13 cases (24%) in the control group (p = 0.04). The composite primary safety outcome did not occur in any of the study groups., Conclusions: In lung transplantation recipients undergoing transbronchial lung biopsy, prophylactic administration of 1:10,000-diluted topical epinephrine into the target segmental airway before biopsy attenuates the incidence of significant endobronchial hemorrhage without conveying a significant cardiovascular risk. (ClinicalTrials.gov identifier: NCT03126968)., (Copyright © 2023 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: Handgrip strength is increasingly used to assess muscle strength in various conditions. In this review, we investigated handgrip strength in patients receiving or awaiting lung transplant., Materials and Methods: For this integrative review, we searched 8 databases from inception through February 2023. Two keyword entries, "handgrip strength" and "lung transplantation," were matched using the Boolean operator, AND. No filters were applied for document type, age, sex, publication date, language, and subject., Results and Conclusions: The searched databases returned 73 citations. Nine articles considering 487 patients (49% female) were included in the final analysis; 7 studies were observational, and 2 were randomized controlled trials. In 7 of 9 studies, handgrip strength was measured with a hydraulic dynamometer. In candidates for lung transplant, handgrip strength ranged from 27.1 kg (before rehabilitation) to 31.2 kg (after rehabilitation). In lung transplant recipients, handgrip strength ranged from 21.1 kg (before rehabilitation) to 35.7 kg (after rehabilitation). Handgrip strength in lung transplant candidates with chronic obstructive pulmonary disease was higher (89 ± 18% predicted) versus patients with interstitial lung disease (79 ± 18% predicted). Improvements in maximal inspiratory pressure and maximal expiratory pressure were observed in those patients whose handgrip strength improved after rehabilitation. Nonsarcopenic patients walked longer distances for the 6-minute walking test (>450 m) versus sarcopenic patients (<310 m) and had higher handgrip strength (>20 kg) versus sarcopenic patients (<20 kg). Handgrip strength testing should be implemented both in preoperative and postoperative contexts to evaluate physical potential of patients and drive rehabilitative activities toward the most impaired domains.

Although the risk of SARS-CoV-2 transmission through lung transplantation from acutely infected donors is high, the risks of virus transmission and long-term lung allograft outcomes are not as well described when using pulmonary organs from COVID-19-recovered donors. We describe successful lung transplantation for a COVID-19-related lung injury using lungs from a COVID-19-recovered donor who was retrospectively found to have detectable genomic SARS-CoV-2 RNA in the lung tissue by multiple highly sensitive assays. However, SARS-CoV-2 subgenomic RNA (sgRNA), a marker of viral replication, was not detectable in the donor respiratory tissues. One year after lung transplantation, the recipient has a good functional status, walking 1 mile several times per week without the need for supplemental oxygen and without any evidence of donor-derived SARS-CoV-2 transmission. Our findings highlight the limitations of current clinical laboratory diagnostic assays in detecting the persistence of SARS-CoV-2 RNA in the lung tissue. The persistence of SARS-CoV-2 RNA in the donor tissue did not appear to represent active viral replication via sgRNA testing and, most importantly, did not negatively impact the allograft outcome in the first year after lung transplantation. sgRNA is easily performed and may be a useful assay for assessing viral infectivity in organs from donors with a recent infection., (Copyright © 2022 American Society of Transplantation & American Society of Transplant Surgeons. All rights reserved.)

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury 1-4 . These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries 5 . Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction., (© 2022. The Author(s).)

Competing Interests: The authors declare no funding or conflicts of interest.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Aims: In populations of black African ancestry (BA), a paradox exists whereby lower visceral adipose tissue is found despite their high risk for type 2 diabetes (T2D). This systematic review investigates ethnic differences in other ectopic fat depots (intrahepatic lipid: IHL; intramyocellular lipid: IMCL and intrapancreatic lipid; IPL) to help contextualise their potential contribution to T2D risk., Methods: A systematic literature search was performed in December 2020 to identify studies reporting at least one ectopic fat comparison between BA and one/more other ethnicity. For IHL, a meta-analysis was carried out with studies considered comparable based on the method of measurement., Results: Twenty-eight studies were included (IHL: n = 20; IMCL: n = 8; IPL: n = 4). Meta-analysis of 11 studies investigating IHL revealed that it was lower in BA populations vs pooled ethnic comparators (MD -1.35%, 95% CI -1.55 to -1.16, I 2  = 85%, P < 0.00001), white European ancestry (MD -0.94%, 95% CI -1.17 to -0.70, I 2  = 79%, P < 0.00001), Hispanic ancestry (MD -2.06%, 95% CI -2.49 to -1.63, I 2  = 81%, P < 0.00001) and South Asian ancestry comparators (MD -1.92%, 95% CI -3.26 to -0.57, I 2  = 78%, P = 0.005). However, heterogeneity was high in all analyses. Most studies found no significant differences in IMCL between BA and WE. Few studies investigated IPL, however, indicated that IPL is lower in BA compared to WE and HIS., Conclusion: The discordance between ectopic fat and greater risk for T2D in BA populations raises questions around its contribution to T2D pathophysiology in BA., (© 2021. The Author(s).)

Introduction/aims: Intrathecal administration of nusinersen is challenging in patients with spinal muscular atrophy (SMA) who have spine deformities or fusions. We prospectively studied the safety and efficacy of nusinersen administration via an indwelling subcutaneous intrathecal catheter (SIC) for SMA patients with advanced disease., Methods: Seventeen participants commenced nusinersen therapy between 2.7 and 31.5 years of age and received 9 to 12 doses via SIC. Safety was assessed in all participants. A separate efficacy analysis comprised 11 nonambulatory, treatment-naive SMA patients (18.1 ± 6.8 years) with three SMN2 copies and complex spine anatomy., Results: In the safety analysis, 14 treatment-related adverse events (AEs) occurred among 12 (71%) participants; all were related to the SIC and not nusinersen. Device-related AEs interfered with 2.5% of nusinersen doses. Four SICs (24%) required surgical revision due to mechanical malfunction with or without cerebrospinal fluid leak (n = 2), and one (6%) was removed due to Staphylococcus epidermidis meningitis. In the efficacy analysis, mean performance on the nine-hole peg test improved in dominant (15.9%, P = 0.012) and nondominant (19.0%, P = 0.008) hands and grip strength increased by 44.9% (P = 0.031). We observed no significant changes in motor scales, muscle force, pulmonary function, or SMA biomarkers. All participants in the efficacy cohort reported one or more subjective improvement(s) in endurance, purposeful hand use, arm strength, head control, and/or speech., Discussion: For SMA patients with complex spine anatomy, the SIC allows for reliable outpatient administration of nusinersen that results in meaningful improvements in upper limb function, but introduces risks of technical malfunction and iatrogenic infection., (© 2021 Wiley Periodicals LLC.)

Background: Chronic obstructive pulmonary disease (COPD) is an age-related condition that has been associated with early telomere attrition; the clinical implications of telomere shortening in COPD are not well known. In this study we aimed to determine the relationship of the epigenetic regulation of telomeric length in peripheral blood with the risk of exacerbations and hospitalization in patients with COPD., Methods: Blood DNA methylation profiles were obtained from 292 patients with COPD enrolled in the placebo arm of the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) Study and who were followed for 1-year. We calculated telomere length based on DNA methylation markers (DNAmTL) and related this biomarker to the risk of exacerbation and hospitalization and health status (St. George Respiratory Questionnaire [SGRQ]) score over time using a Cox proportional hazards model. We also used linear models to investigate the associations of DNAmTL with the rates of exacerbation and hospitalization (adjusted for chronological age, lung function, race, sex, smoking, body mass index and cell composition)., Results: Participants with short DNAmTL demonstrated increased risk of exacerbation (P = 0.02) and hospitalization (P = 0.03) compared to those with longer DNAmTL. DNAmTL age acceleration was associated with higher rates of exacerbation (P = 1.35 × 10 -04 ) and hospitalization (P = 5.21 × 10 -03 ) and poor health status (lower SGRQ scores) independent of chronological age (P = 0.03)., Conclusion: Telomeric age based on blood DNA methylation is associated with COPD exacerbation and hospitalization and thus a promising biomarker for poor outcomes in COPD., (© 2021. The Author(s).)

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma are common respiratory diseases that impose a significant economic burden on Medicaid. Inhalers are the mainstay treatment for relieving symptoms and improving outcomes for COPD and asthma patients. OBJECTIVE: To describe the total spending and trends of Medicaid expenditures on inhalers between 2012 and 2018 in the United States. METHODS: We analyzed the deidentified data from the Medicaid Drug Spending Dashboard and utilization datasets from 2012 to 2018. We identified 9 classes of inhalers and described the Medicaid total spending on and relative annual changes for those inhalers. We also described the spending on available generic inhalers and compared the Medicaid spending by manufacturers during this time frame. RESULTS: Medicaid spent $26.2 billion on inhalers from 2012 to 2018. This spending increased by $2.5 billion (120%) over this time frame. During this specified period, the highest Medicaid spending was on the group of inhaled corticosteroid (ICS)-containing inhalers ($14.9 billion). Within this group, the inhaler class of ICS/long-acting beta-2 adrenoceptor agonists contributed to the highest Medicaid spending (53%), with a growth of 607% between 2012 and 2018. Of the $26.2 billion that Medicaid spent on inhalers, $35.5 million (less than 0.01%) was spent on 2 generic inhalers: fluticasone propionate with salmeterol and levalbuterol tartrate hydrofluoroalkane. CONCLUSIONS: Between 2012 and 2018, on average, $3.5 billion per year was spent by Medicaid on inhalers. Decreasing the price of inhalers by introducing more generic inhalers in the market can potentially reduce the cost burden on Medicaid. DISCLOSURES : This study was funded by the American Foundation for Pharmaceutical Education (AFPE). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflicts of interest.

Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE., Objective: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901)., Methods: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data., Results: We identified 6 loci at genome-wide significance (P < 5 × 10 -9 ), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (P discovery  = 2 × 10 -4 ; P replication  = 5 × 10 -4 ; P discovery+replication  = 4 × 10 -7 ), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (P Hispanic/Latino discovery+replication  = 8 × 10 -8 )., Conclusion: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Coronavirus disease 2019 (COVID-19) pandemic has led to widespread implementation of public health measures, such as stay-at-home orders, social distancing, and masking mandates. In addition to decreasing spread of severe acute respiratory syndrome coronavirus 2, these measures also impact the transmission of seasonal viral pathogens, which are common triggers of chronic obstructive pulmonary disease (COPD) exacerbations. Whether reduced viral prevalence mediates reduction in COPD exacerbation rates is unknown., Methods: We performed retrospective analysis of data from a large, multicenter health care system to assess admission trends associated with community viral prevalence and with initiation of COVID-19 pandemic control measures. We applied difference-in-differences analysis to compare season-matched weekly frequency of hospital admissions for COPD prior to and after implementation of public health measures for COVID-19. Community viral prevalence was estimated using regional Centers for Disease Control and Prevention test positivity data and correlated to COPD admissions., Results: Data involving 4422 COPD admissions demonstrated a season-matched 53% decline in COPD admissions during the COVID-19 pandemic, which correlated to community viral burden (r = 0.73; 95% confidence interval, 0.67-0.78) and represented a 36% greater decline over admission frequencies observed in other medical conditions less affected by respiratory viral infections (incidence rate ratio 0.64; 95% confidence interval, 0.57-0.71, P < .001). The post-COVID-19 decline in COPD admissions was most pronounced in patients with fewer comorbidities and without recurrent admissions., Conclusion: The implementation of public health measures during the COVID-19 pandemic was associated with decreased COPD admissions. These changes are plausibly explained by reduced prevalence of seasonal respiratory viruses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: While forced expiratory volume in 1 s (FEV 1 ) is a hallmark of disease progression in chronic obstructive lung diseases, little is known about the relationship between baseline FEV 1 and future risks of other medical conditions., Objective: The aim of this study was to investigate the association between baseline FEV 1 and future risks of diabetes, asthma, myocardial infarction, hypertension and all-cause mortality., Methods: We used data from the National Health and Nutrition Examination Survey and its Epidemiological Follow-Up Study. Our data provided longitudinal follow-up of the original cohort for up to 12 years. We used two competing risks approaches, the cause-specific hazard model and the Fine-Gray sub-distribution hazard model, to measure the associations between baseline FEV 1 and future risks of the outcomes of interest. All models were adjusted for major confounding factors., Results: The final sample included 3020 participants (mean±sd baseline age 44.64±13.44 years). In the cause-specific hazard model, for every per cent increase in the baseline per cent predicted FEV 1 , the hazard of the event reduced by 2.5% (HR 0.975; 95% CI 0.958-0.994) for diabetes, 4.3% (HR 0.957; 95% CI 0.932-0.983) for asthma and 1.8% (HR 0.982; 95% CI 0.971-0.992) for all-cause mortality. There was no statistically significant association between baseline per cent predicted FEV 1 and future risks of myocardial infarction (HR 0.987; 95% CI 0.970-1.004) and hypertension (HR 0.998; 95% CI 0.992-1.005). Consistent results were observed for the Fine-Gray sub-distribution hazard model., Conclusion: Our data suggest that lower per cent predicted FEV 1 values at baseline were significantly associated with higher future risks of diabetes, asthma and all-cause mortality., Competing Interests: Conflict of interest: C.H. Shah has nothing to disclose. Conflict of interest: R.M. Reed has nothing to disclose. Conflict of interest: Y. Liang has nothing to disclose. Conflict of interest: Z. Zafari reports that his research has been funded by the American Lung Association, the Institute for Clinical and Translation Research, the US Food and Drug Administration, the Maryland Dept of Transportation and GSK Pharmaceutical., (Copyright ©The authors 2021.)

Background and Objective: Formative research studies can inform stated-preference instrument development to quantify the importance of various attributes of healthcare treatments. The objective of this study was to elicit from patients with chronic obstructive pulmonary disease the prioritization of an established set of patient-informed value elements., Methods: Using an iterative mixed-methods study design, we engaged individuals living with chronic obstructive pulmonary disease in Phase 1 value element elicitation and Phase 2 language refinement. Study participants were recruited from March to July 2019. Four guided activities, administered in an online instrument, elicited individual preferences for 40 disease-agnostic value elements that were aligned with treatment, outcomes, or care process. Responses from the guided activities were summarized and then presented to a patient advocate and additional patient participants for further refinement of the value elements and the phrasing., Results: Twenty-three participants, 18 male and five female, mean age of 66 years (standard deviation = 7) were enrolled in Phase 1. Participant responses informed the selection of eight elements as the key candidates for the Phase 2 language refinement: Side Effects, New Therapeutic Option, Available Treatment, Appropriateness of Care, Predictable Healthcare Needs, Physical Activities: Endurance and Symptom Control, and Explanation of Treatment. With feedback from a patient advocate and additional patient participants, elements were refined, rephrased, or modified and this list was narrowed to six value elements (Side Effects, New Therapeutic Option, Willingness to Pay, Physical Activities, Explanation of Treatment, and Access to Care) to serve as attributes in a conceptual framework for a future quantitative stated-preference instrument., Conclusions: This patient-engaged formative work identified patients with chronic obstructive pulmonary disease key attributes of value-based decision making that underpin benefit-risk trade-offs between physical endurance, treatment side effects, care access, and cost. This study illustrates an iterative process for eliciting and refining a comprehensive list of value elements, resulting in a subgroup of elements important to a specific patient population., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

Background: In the United States, COPD is a leading cause of mortality, with a substantial societal health and economic burden. With anticipated population growth, it is important for various stakeholders to have an estimate for the projected burden of disease., Research Question: The goal of this study was to model the 20-year health and economic burden of COPD, from 2019 to 2038, in the United States., Study Design and Methods: Using country-specific data from published literature and publicly available datasets, a dynamic open cohort Markov model was developed in a probabilistic Monte Carlo simulation. Population growth was modeled across different subgroups of age, sex, and smoking. The COPD prevalence rates were calibrated for different subgroups, and distributions of severity grades were modeled based on smoking status. Direct costs, indirect absenteeism costs, losses of quality-adjusted life years (QALYs), and number of exacerbations and deaths associated with COPD were projected., Results: The 20-year discounted direct medical costs attributable to COPD were estimated to be $800.90 billion (95% credible interval [CrI], 565.29 billion-1,081.29 billion), with an expected $337.13 billion in male subjects and $463.77 billion in female subjects. The 20-year discounted indirect absenteeism costs were projected to be $101.30 billion (70.82 billion-137.41 billion). The 20-year losses of QALYs, number of exacerbations, and number of deaths associated with COPD were 45.38 million (8.63 million-112.07 million), 315.08 million (228.59 million-425.33 million), and 9.42 million (8.93 million-9.93 million), respectively. The proportion of disease burden attributable to continued smoking was 34% in direct medical costs, 35% in indirect absenteeism costs, and 37% in losses of QALYs over 20 years., Interpretation: This study projects the substantial burden of COPD that the American society is expected to incur with current patterns for treatments and smoking rates. Mitigating such burden requires targeted budget appropriations and cost-effective interventions., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: The metabolic syndrome (MetS) is a systemic disorder associated with reduced atheroprotective gynoid fat and bone mineral content (BMC). The goal of this pilot study was to assess whether administration of icosapent ethyl (IPE), a purified formulation of eicosapentaenoic acid, would maintain gynoid fat and BMC over a 9-month treatment period., Methods: Patients with MetS aged ≥40 years were randomly assigned to receive 4 g daily of IPE (2 g BID with food) or placebo (paraffin oil 2 g BID with food) for 9 months. Data were collected at baseline and 9 months later. The data included anthropometric measures, biochemical analysis, and whole body fat mass, including gynoid fat. Bone mineral density and BMC were measured by using dual-energy X-ray absorptiometry. A two-tailed P value ≤ 0.05 was considered statistically significant., Findings: The study sample consisted of 13 patients with MetS (mean age, 61.6 years; age range, 44-77 years; 77% female and 23% male). Compared with the IPE group, the placebo group experienced statistically significant mean reductions in percent gynoid fat (pre/post, 46.8%-43.5%; P = 0.02), BMC (pre/post, 2461 g-2423 g; P = 0.02), and bone mineral density (pre/post, 1.24 g/cm 2 to 1.22 g/cm 2 ; P = 0.05) over the 9-month study period., Implications: The results of this pilot study raise the possibility that IPE supplementation may preserve gynoid fat distribution and bone mineral health in patients with MetS. Larger, randomized longitudinal studies are necessary to determine the potential long-term metabolic benefits of IPE treatment., (Published by Elsevier Inc.)

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

Background: Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations., Research Question: To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD., Study Design and Methods: Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status., Results: The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001., Interpretation: Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) is a heterogenous condition. This study aims to quantify the heterogeneity of Health-related Quality of Life (HRQoL), and identify subgroups with the lowest HRQoL, in COPD patients in the United States (US). Methods Data from 2008-2015 Medical Expenditure Panel Survey were used to examine the heterogeneity of HRQoL between different COPD subgroups using mixed-effects modeling and G-computation. The Physical Composite Summary (PCS) and Mental Composite Summary (MCS) scores from the Short-Form-12 questionnaire were utilized. We also compared the heterogeneity of HRQoL in our COPD cohort against that in a matched non-COPD cohort. Results The final sample consisted of 1,866 (weighted = 19,952,143) COPD patients with a mean age of 63.2 years (Standard error (SE):0.38), mean MCS score of 46.84 (SE:0.35), and mean PCS score of 35.65 (SE:0.32). The adjusted MCS and PCS scores ranged from 36.19 to 53.06, and from 25.52 to 48.27, respectively, for COPD subgroups. COPD patients had statistically significantly lower MCS and PCS scores by 4.61, and 5.86 points, respectively, compared to the matched non-COPD cohort, and MCS scores showed a wider variability in the COPD cohort. Conclusion Our study quantifies substantial heterogeneity of HRQoL in COPD in the US and provides evidence for prioritizing COPD subgroups with the lowest HRQoL for targeted interventions.

Evidence-based depression treatment in primary care is well established. However, clinicians are less likely to be trained to diagnose and treat anxiety disorder, which is frequently comorbid, poses an independent risk for suicidality, and complicates disease management. The University of North Carolina's Internal Medicine Clinic developed a measurement-guided approach to identifying and treating anxiety disorder using the seven-item Generalized Anxiety Disorder Scale, treatment algorithms, medication charts, case-based training for best practices, onsite behavioral counseling, and psychiatric consultation. NAMASTE (new anxiety management algorithm standardizing treatment experience) offers a treatment approach for primary care and addresses a major unmet need in public health and medical education.

Background: Atmospheric particulate matter (PM) has been associated with endothelial dysfunction, an early marker of cardiovascular risk. Our aim was to extend this research to a genetically homogenous, geographically stable rural population using location-specific moving-average air pollution exposure estimates indexed to the date of endothelial function measurement., Methods: We measured endothelial function using brachial artery flow-mediated dilation (FMD) in 615 community-dwelling healthy Amish participants. Exposures to PM < 2.5 μm (PM 2.5 ) and PM < 10 μm (PM 10 ) were estimated at participants' residential addresses using previously developed geographic information system-based spatio-temporal models and normalized. Associations between PM exposures and FMD were evaluated using linear mixed-effects regression models, and polynomial distributed lag (PDL) models followed by Bayesian model averaging (BMA) were used to assess response to delayed effects occurring across multiple months., Results: Exposure to PM 10 was consistently inversely associated with FMD, with the strongest (most negative) association for a 12-month moving average (- 0.09; 95% CI: - 0.15, - 0.03). Associations with PM 2.5 were also strongest for a 12-month moving average but were weaker than for PM 10 (- 0.07; 95% CI: - 0.13, - 0.09). Associations of PM 2.5 and PM 10 with FMD were somewhat stronger in men than in women, particularly for PM 10 ., Conclusions: Using location-specific moving-average air pollution exposure estimates, we have shown that 12-month moving-average estimates of PM 2.5 and PM 10 exposure are associated with impaired endothelial function in a rural population.

Post-transplantation lymphoproliferative disorder (PTLD) is uncommon following solid organ transplantation. We present a case of PTLD presenting as hematochezia and abdominal pain in a 66-year-old man, who had undergone bilateral lung transplantation with alemtuzumab induction 7 months prior to presentation. The transplant serologic status was "high-risk" for the presence of both Epstein-Barr virus (EBV) serologies in the donor and negative serologies in the recipient. Biopsies taken during colonoscopy stained strongly positive for EBV-encoded RNA. Mediastinal lymph node biopsies also showed atypical, EBV-positive lymphohistiocytic infiltration with focal necrosis. The patient's hospital course was complicated by treatment side effects, most notably bowel perforation following rituximab. In this case report the topic of PTLD is reviewed and consideration is given to whether alemtuzumab induction may have contributed to the patient's development of PTLD., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials., Methods: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol., Results: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV 1 ) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group., Conclusions: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.)., (Copyright © 2019 Massachusetts Medical Society.)

Pulmonary hypertension (PH) is a frequently encountered complication of chronic obstructive pulmonary disease (COPD) and is associated with worsened clinical symptoms and prognosis. The prevalence of PH-COPD is not concretely established as classification criteria vary historically, but the presence of severe disease out of proportion to underlying COPD is relatively rare. Right heart catheterization, the gold standard in diagnosis of PH, is infrequently performed in COPD, and the overlap in the clinical symptoms of PH and COPD presents diagnostic challenges. Proven treatments are limited. Trials exploring the use of vasodilator therapy in this patient group generally demonstrate improvements in hemodynamics accompanied by worsening gas exchange without clearly demonstrated improvements in clinically meaningful outcomes. In-depth workup of underlying pulmonary hypertension and use of pulmonary vasodilator medications may be appropriate on an individual basis. We present a case study and a review and discussion of the pertinent literature on this topic.

Vascularized composite allotransplantation (VCA) is a relatively new field in the reconstructive surgery. Clinical achievements in human VCA include hand and face transplants and, more recently, abdominal wall, uterus, and urogenital transplants. Functional outcomes have exceeded initial expectations, and most recipients enjoy an improved quality of life. However, as clinical experience accumulates, chronic rejection and complications from the immunosuppression must be addressed. In many cases where grafts have failed, the causative pathology has been ischemic vasculopathy. The biological mechanisms of the acute and chronic rejection associated with VCA, especially ischemic vasculopathy, are important areas of research. However, due to the very small number of VCA patients, the evaluation of proposed mechanisms is better addressed in an experimental model. Multiple groups have used animal models to address some of the relevant unsolved questions in VCA rejection and vasculopathy. Several model designs involving a variety of species are described in the literature. Here we present a reproducible model of VCA heterotopic hindlimb osteomyocutaneous flap in the rat that can be utilized for translational VCA research. This model allows for the serial evaluation of the graft, including biopsies and different imaging modalities, while maintaining a low level of morbidity.

Introduction: Transbronchial lung biopsy (TBLB) is frequently performed in single-lung and double-lung transplant recipients for evaluation of clinical and radiological findings as well as routine surveillance for acute cellular rejection. While rates of clinically significant TBLB-related haemorrhage are <1% for all comers, the incidence in lung transplant recipients is reported to be higher, presumably due to persistent allograft inflammation and alterations in allograft blood flow. While routinely performed by some bronchoscopists, the efficacy and safety profile of prophylactic administration of topical intrabronchial diluted epinephrine for the prevention of TBLB-related haemorrhage has not been explored in a prospective manner., Methods and Analysis: In this randomised, double-blind, placebo-controlled multicentre trial (PROPHET Study), single-lung and double-lung transplant adult recipients from participating institutions who are scheduled for bronchoscopy with TBLB for clinical indications will be identified. Potential participants who meet inclusion and exclusion criteria and sign an informed consent will be randomised to receive either diluted epinephrine or placebo prior to performance of TBLB. The degree of TBLB-related haemorrhage will be graded by the performing bronchoscopist as well as independent observers. The primary analysis will compare the rates of severe and very severe bleeding in participants treated with epinephrine or placebo. The study will also evaluate the safety profile of prophylactic topical epinephrine including the occurrence of serious cardiovascular and haemodynamic adverse events. Additional secondary outcomes to be explored include rates of non-severe TBLB-related haemorrhage, overall yield of the bronchoscopic procedure and non-serious cardiovascular and haemodynamic adverse effects., Ethics and Dissemination: The study procedures were reviewed and approved by institutional review boards in participating institutions. This study is being externally monitored, and a data and safety monitoring committee has been assembled to monitor patient safety and to evaluate the efficacy of the intervention. The results of this study will be published in peer-reviewed scientific journals and presented at relevant academic conferences., Trial Registration Number: NCT03126968; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: The pleiotropic anti-inflammatory effects of statins that have proven to improve outcomes in cardiovascular disease have also been of interest in the treatment of COPD, a disease with considerable morbidity and little available treatment that improves mortality. In-vitro and animal studies have supported biologic plausibility of statin therapy for lung health and function. Retrospective observational studies in humans have echoed this potential as well but confirmatory data from randomized studies are limited and somewhat disappointing., Recent Findings: Despite discouraging clinical trial results, the possibility remains that statins can help patients with COPD characterized by systemic inflammation. At the same time, increasing recognition of the considerable cardiovascular disease burden and its suboptimal treatment in patients with COPD has also contributed to continued enthusiasm for statin use in COPD., Summary: When it comes to defining the role for statins as a disease-modifying therapy, the jury is still out; however, the importance of more careful cardiovascular risk stratification that includes assessing levels of inflammatory markers in patients with COPD and the benefit of statins in those with increased risk is gaining increasing recognition.

Objectives: Anticipatory grief, the experience of grief before the death of a mourned individual, is common among people with seriously ill loved ones and associated with impaired social problem solving. We sought to evaluate anticipatory grief in the Intensive Care Unit setting., Research Methodology/design: Cross-sectional study of surrogate decision-makers of patients admitted to an intensive care unit, incorporating survey methodology., Setting: Intensive care units at a tertiary care centre., Main Outcome Measures: Surrogates completed a 78-question, self-administered questionnaire consisting of demographic and clinical data, as well as three validated instruments: Anticipatory Grief Scale (AGS), Hospital Anxiety and Depression Scale (HADS), and Social Problem Solving Inventory Revised Short Form (SPSI-R:S)., Main Results: Surveys were completed by 50 surrogate decision-makers, among whom anticipatory grief was elevated and associated with anxiety and depression. Anticipatory grief was also significantly associated with worsened overall problem solving (Spearman's Rho -0.32, p value 0.02). Surrogates with loved ones who were older or admitted to a trauma unit experienced anticipatory grief at lower levels. Prior admission and Charlson Comorbidity Index scores were not associated with anticipatory grief., Conclusion: Levels of anticipatory grief in the intensive care unit are high and associated with concurrent anxiety and depression. Association of anticipatory grief with worsened social problem solving may worsen decision making ability in surrogates., (Copyright © 2018 Elsevier Ltd. All rights reserved.)