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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.

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: 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.)

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).)

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: 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.)

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.

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.)

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.

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.)

We present the case of a critically ill woman whose dialysis line was noted to be circulating bright red blood. Located in the right internal jugular vein, the line had previously been working normally with the change occurring shortly after the patient was liberated from positive pressure mechanical ventilation. An arterial malposition was ruled out and subsequent investigations revealed the presence of a left-sided partial anomalous pulmonary venous connection (PAPVC) that had been previously undiagnosed. The identification of a left-sided PAPVC from blood gas measurements taken from a right internal jugular vein dialysis catheter in this case provides an informative opportunity to consider the intricate physiological relationship between the respiratory and cardiovascular systems in critically ill patients requiring invasive procedures and treatments., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The literature is scarce regarding the prevalence and clinical impact of IgG subclass deficiency in COPD. We investigated the prevalence of IgG subclass deficiencies and their association with exacerbations and hospitalizations using subjects from two COPD cohorts., Methods: We measured IgG subclass levels using immunonephelometry in serum samples from participants enrolled in two previous COPD trials: Macrolide Azithromycin for Prevention of Exacerbations of COPD (MACRO; n = 976) and Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD (STATCOPE; n = 653). All samples were collected from clinically stable participants upon entry into both studies. IgG subclass deficiency was diagnosed when IgG subclass levels were below their respective lower limit of normal: IgG1 < 2.8 g/L; IgG2 < 1.15 g/L; IgG3 < 0.24 g/L; and IgG4 < 0.052 g/L. To investigate the impact of IgG subclass levels on time to first exacerbation or hospitalization, we log-transformed IgG levels and performed Cox regression models, with adjustments for confounders., Results: One or more IgG subclass deficiencies were found in 173 (17.7%) and 133 (20.4%) participants in MACRO and STATCOPE, respectively. Lower IgG1 or IgG2 levels resulted in increased risk of exacerbations with adjusted hazard ratios (HR) of 1.30 (95% CI, 1.10-1.54, p < 0.01) and 1.19 (95% CI, 1.05-1.35, p < 0.01), respectively in the MACRO study, with STATCOPE yielding similar results. Reduced IgG1 or IgG2 levels were also associated with increased risk of hospitalizations: the adjusted HR for IgG1 and IgG2 was 1.52 (95% CI: 1.15-2.02, p < 0.01) and 1.33 (95% CI, 1.08-1.64, p < 0.01), respectively for the MACRO study; in STATCOPE, only IgG2 was an independent predictor of hospitalization. In our multivariate Cox models, IgG3 and IgG4 levels did not result in significant associations for both outcomes in either MACRO or STATCOPE cohorts., Conclusions: Approximately 1 in 5 COPD patients had one or more IgG subclass deficiencies. Reduced IgG subclass levels were independent risk factors for both COPD exacerbations (IgG1 and IgG2) and hospitalizations (IgG2) in two COPD cohorts., Trial Registration: This study used serum samples from participants of the MACRO ( NCT00325897 ) and STATCOPE ( NCT01061671 ) trials.

Introduction: The obesity paradox in chronic obstructive pulmonary disease (COPD), whereby patients with higher body mass index (BMI) fare better, is poorly understood. Higher BMIs are associated with lower lung volumes and greater lung elastic recoil, a key determinant of expiratory airflow. The forced expiratory flow (25-75) (FEF 25-75 )/forced vital capacity (FVC) ratio reflects effort-independent expiratory airflow in the context of lung volume and could be modulated by BMI., Methods: We analysed data from the COPDGene study, an observational study of 10 192 subjects, with at least a 10 pack-year smoking history. Data were limited to subjects with BMI 20-40 kg/m 2 (n=9222). Subjects were stratified according to forced expiratory volume in 1 s (FEV 1 ) (%predicted)-quintiles. In regression analyses and Cox proportional hazard models, we analysed the association between BMI, the FEF 25-75 /FVC ratio, the imaging phenotype, COPD exacerbations, hospitalisations and death., Results: There was no correlation between BMI and FEV 1 (%predicted). However, a higher BMI is correlated with a higher FEF 25-75 /FVC ratio. In CT scans, a higher BMI was associated with less emphysema and less air trapping. In risk-adjusted models, the quintile with the highest FEF 25-75 /FVC ratio was associated with a 46% lower risk of COPD exacerbations (OR 0.54, p<0.001) and a 40% lower risk of death (HR 0.60, p=0.02), compared with the lowest quintile. BMI was not independently associated with these outcomes., Conclusions: A higher BMI is associated with lower lung volumes and higher expiratory airflows when normalised for lung volume, as quantified by the FEF 25-75 /FVC ratio. A higher FEF 25-75 /FVC ratio is associated with a lower risk of COPD exacerbations and death and might quantify functional aspects of the paradoxical effect of higher BMIs on COPD., Competing Interests: Competing interests: None declared.

Background: Beta-blockers are commonly prescribed for patients with cardiovascular disease. Providers have been wary of treating chronic obstructive pulmonary disease (COPD) patients with beta-blockers due to concern for bronchospasm, but retrospective studies have shown that cardio-selective beta-blockers are safe in COPD and possibly beneficial. However, these benefits may reflect symptom improvements due to the cardiac effects of the medication. The purpose of this study is to evaluate associations between beta-blocker use and both exacerbation rates and longitudinal measures of lung function in two well-characterized COPD cohorts., Methods: We retrospectively analyzed 1219 participants with over 180 days of follow up from the STATCOPE trial, which excluded most cardiac comorbidities, and from the placebo arm of the MACRO trial. Primary endpoints were exacerbation rates per person-year and change in spirometry over time in association with beta blocker use., Results: Overall 13.9% (170/1219) of participants reported taking beta-blockers at enrollment. We found no statistically significant differences in exacerbation rates with respect to beta-blocker use regardless of the prevalence of cardiac comorbidities. In the MACRO cohort, patients taking beta-blockers had an exacerbation rate of 1.72/person-year versus a rate of 1.71/person-year in patients not taking beta-blockers. In the STATCOPE cohort, patients taking beta-blockers had an exacerbation rate of 1.14/person-year. Patients without beta-blockers had an exacerbation rate of 1.34/person-year. We found no detrimental effect of beta blockers with respect to change in lung function over time., Conclusion: We found no evidence that beta-blocker use was unsafe or associated with worse pulmonary outcomes in study participants with moderate to severe COPD.

Background: Helicobacter pylori (HP) infection is associated with reduced lung function and systemic inflammation in chronic obstructive pulmonary disease (COPD) patients. Azithromycin (AZ) is active against HP and reduces the risk of COPD exacerbation. We determined whether HP infection status modifies the effects of AZ in COPD patients., Methods: Plasma samples from 1018 subjects with COPD who participated in the Macrolide Azithromycin (MACRO) in COPD Study were used to determine the HP infection status at baseline and 12 months of follow-up using a serologic assay. Based on HP infection status and randomization to either AZ or placebo (PL), the subjects were divided into 4 groups: HP+/AZ, HP-/AZ, HP+/PL, and HP-/PL. Time to first exacerbation was compared across the 4 groups using Kaplan-Meier survival analysis and a Cox proportional hazards model. The rates of exacerbation were compared using both the Kruskal-Wallis test and negative binomial analysis. Blood biomarkers at enrolment and at follow-up visits 3, 12, and 13 (1 month after treatment was stopped) months were measured., Results: One hundred eighty one (17.8%) patients were seropositive to HP. Non-Caucasian participants were nearly three times more likely to be HP seropositive than Caucasian participants (37.4% vs 13.6%; p < 0.001). The median time to first exacerbation was significantly different across the four groups (p = 0.001) with the longest time in the HP+/AZ group (11.2 months, 95% CI; 8.4-12.5+) followed by the HP-/AZ group (8.0 months, 95% CI; 6.7-9.7). Hazard ratio (HR) for exacerbations was lowest in the HP+/AZ group after adjustment for age, sex, smoking status, ethnicity, history of peptic ulcer, dyspnea, previous hospital admission, GOLD grade of severity, and forced vital capacity (HR, 0.612; 95% CI, 0.442-0.846 vs HR, 0.789; 95% CI, 0.663-0.938 in the HP-/AZ group). Circulating levels of soluble tumor necrosis factor receptor-75 were reduced only in the HP+/AZ group after 3 months of AZ treatment (-0.87 ± 0.31 μg/L; p = 0.002); levels returned to baseline after discontinuing AZ., Conclusions: AZ is effective in preventing COPD exacerbations in patients with HP seropositivity, possibly by modulating TNF pathways related to HP infection.

Due to their relatively homogeneous lifestyle and living environment, the Amish offer a novel opportunity to study the health associations of tobacco smoke exposure, particularly secondhand smoke. We hypothesized that secondhand smoke exposure is associated with worse pulmonary and cardiometabolic health. We examined cross-sectional data on 3568 Amish study participants, including tobacco use and secondhand smoke exposure from family members included in the study. Thirty-four percent of Amish men reported ever smoking. Of this proportion, 64% used cigars, 46% cigarettes, and 21% pipes. Less than 1% of women reported ever smoking. Smoking was associated with lower spirometric lung function, higher body mass index, lower HDL cholesterol, higher heart rate, lower ankle-brachial index, and larger aortic diameter in men. A greater number of sources of secondhand smoke exposure (defined from the total of spouses, parents, and siblings who smoke) was associated with higher body mass index (p = 0.03) and with higher fasting glucose in men (p = 0.01), but not in women (p = 0.007 for sex*secondhand smoke interaction). Secondhand smoke exposure was also associated with reduced HDL cholesterol only in women (p = 0.002) and a lower heart rate only in men (p = 0.006). Smoking habits among the Old Order Amish are notable for the absence of female participation and a high proportion of cigar and pipe use. Smoking is associated with decreased spirometric indices of lung function and increased cardiovascular risk in this population and secondhand smoke exposure is associated with a greater burden of risk factors for cardiovascular disease. Sex differences in correlations could reflect differences in exposure patterns, mechanisms, or susceptibilities.

Aim: To demonstrate a direct inhibitory effect of cigarette smoke exposure on paraoxonase 1 activity in a murine in vivo model., Methods: At 8 weeks old, we randomized 10 C57/bl6 mice to an environment consisting of either filtered air or cigarette smoke for 6 months. Smoke exposure (7 hours per day, 5 days per week) was standardized using a model TE-10 smoking machine and adjusted to maintain constant sidestream and mainstream smoke. After 6 months of exposure, we assessed differences in lung air space, cholesterol, lipid, and lipoprotein profiles, as well as paraoxonase activity in mice exposed to cigarette smoke extract compared to unexposed control mice., Results: Cigarette smoke exposure by the protocol used was sufficient to result in pathologic changes in lung architecture consistent with emphysema. Specifically, we observed that mice exposed to cigarette smoke had a significantly higher mean linear chord length compared to animals that were exposed to filtered air ( p <0.02). Despite this exposure, no differences in total HDL-cholesterol levels or HDL-cholesterol sub-fractions (i.e. HDL2 and HDL3 fractions) were noted between smoke-exposed and unexposed animals ( p =1.00, 0.6, and 0.4, respectively). Notably, mean HDL-cholesterol levels were identical between groups (92.8 vs 92.8 mg/dL, p =1.0). Paraoxonase activity, however, was markedly reduced in mice exposed to cigarette smoke compared to those who were not exposed (102, SD=9.6 vs 144, SD=4.1 units of activity, respectively, p =0.002)., Conclusion: In this murine model, tobacco smoke exposure directly inhibits paraoxonase activity independently of HDL-cholesterol levels rather than indirectly via reduction in HDL-cholesterol levels.

Aim: To systematically review reports on deceased-donor-lobar lung transplantation (ddLLTx) and uniformly describe size matching using the donor-to-recipient predicted-total lung-capacity (pTLC) ratio., Methods: We set out to systematically review reports on ddLLTx and uniformly describe size matching using the donor-to-recipient pTLC ratio and to summarize reported one-year survival data of ddLLTx and conventional-LTx. We searched in PubMed, CINAHL via EBSCO, Cochrane Database of Systematic Reviews via Wiley (CDSR), Database of Abstracts of Reviews of Effects via Wiley (DARE), Cochrane Central Register of Controlled Trials via Wiley (CENTRAL), Scopus (which includes EMBASE abstracts), and Web of Science for original reports on ddLLTx., Results: Nine observational cohort studies reporting on 301 ddLLTx met our inclusion criteria for systematic review of size matching, and eight for describing one-year-survival. The ddLLTx-group was often characterized by high acuity; however there was heterogeneity in transplant indications and pre-operative characteristics between studies. Data to calculate the pTLC ratio was available for 242 ddLLTx (80%). The mean pTLCratio before lobar resection was 1.25 ± 0.3 and the transplanted pTLCratio after lobar resection was 0.76 ± 0.2. One-year survival in the ddLLTx-group ranged from 50%-100%, compared to 72%-88% in the conventional-LTx group. In the largest study ddLLTx ( n = 138) was associated with a lower one-year-survival compared to conventional-LTx ( n = 539) (65.1% vs 84.1%, P < 0.001)., Conclusion: Further investigations of optimal donor-to-recipient size matching parameters for ddLLTx could improve outcomes of this important surgical option., Competing Interests: Conflict-of-interest statement: The authors of this manuscript have no conflicts of interest to disclose.

Donor-to-recipient organ size matching is a critical aspect of thoracic transplantation. In the United States potential recipients for lung transplant and heart transplant are listed with limitations on donor height and weight ranges, respectively. Height is used as a surrogate for lung size and weight is used as a surrogate for heart size. While these measures are important predictors of organ size, they are crude surrogates that fail to incorporate the influence of sex on organ size. Independent of other measures, a man's thoracic organs are approximately 20% larger than a woman's. Lung size can be better estimated using the predicted total lung capacity, which is derived from regression equations correcting for height, sex and age. Similarly, heart size can be better estimated using the predicted heart mass, which adjusts for sex, age, height, and weight. These refined organ sizing measures perform better than current sizing practice for the prediction of outcomes after transplantation, and largely explain the outcome differences observed after sex-mismatch transplantation. An undersized allograft is associated with worse outcomes. In this review we examine current data pertaining to size-matching in thoracic transplantation. We advocate for a change in the thoracic allocation mechanism from a height-or-weight-based strategy to a size-matching process that utilizes refined estimates of organ size. We believe that a size-matching approach based on refined estimates of organ size would optimize outcomes in thoracic transplantation without restricting or precluding patients from thoracic transplantation.

Vasoactivity, an important aspect of tissue healing, is often compromised in disease and tissue injury. Dysfunction in the smaller vasoactive arteries is most impactful, given the role of these vessels in controlling downstream tissue perfusion. The adipose stromal vascular fraction (SVF) is a mix of homeostatic cells shown to promote tissue healing. Our objective was to test the hypothesis that autologous SVF cells therapeutically modulate peripheral artery vasoactivity in syngeneic mouse models of small artery function. Analysis of vasoactivity of saphenous arteries isolated from normal mice 1 week after intravenous injection of freshly isolated SVF cells revealed that pressure-dependent artery vasomotor tone was decreased by the SVF cell isolate, but not one depleted of CD11b(+) cells. Scavenging hydrogen peroxide in the vessel wall abrogated the artery relaxation promoted by the SVF cell isolate. Consistent with a CD11b(+) cell being the relevant cell type, SVF-derived F4/80-positive macrophages were present within the adventitia of the artery wall coincident with vasorelaxation. In a model of artery inflammation mimicking a common disease condition inducing vasoactive dysfunction, the SVF cells potentiated relaxation of saphenous arteries without structurally remodeling the artery via a CD11b(+) cell-dependent manner. Our findings demonstrate that freshly isolated, adipose SVF cells promote vasomotor relaxation in vasoactive arteries via a hydrogen peroxide-dependent mechanism that required CD11b(+) cells (most likely macrophages). Given the significant impact of small artery dysfunction in disease, we predict that the intravenous delivery of this therapeutic cell preparation would significantly improve tissue perfusion, particularly in diseases with diffuse vascular involvement., (©AlphaMed Press.)

Novel anticoagulants are increasingly utilised in lieu of warfarin to treat non-valvular atrial fibrillation. Their clinical use in other non-FDA approved settings is also increasing. We present a case in which a patient abruptly stopped taking dabigatran due to a small bowel obstruction and shortly thereafter suffered a myocardial infarction complicated by left ventricular thrombosis with fatal embolisation to the superior mesenteric artery. In this context, we discuss the possibility of a rebound phenomenon of hypercoagulability with abrupt cessation of novel anticoagulants., (2014 BMJ Publishing Group Ltd.)

A Caucasian woman in her late 30s was evaluated after a period of binge drinking and found to have hyperbilirubinaemia for which she was referred for consideration of cholecystectomy. After exclusion of other possibilities, Zieve's syndrome was diagnosed. This is a condition of hyperbilirubinaemia, Coombs' negative haemolytic anaemia and hyperlipidaemia associated with alcoholism. Abstinence from alcohol remains the only known effective treatment, and appreciation of the entity can prevent unnecessary biliary procedures. The patient improved with supportive measures and was discharged in stable condition.