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Franck F Rahaghi,1 Richard Monk,2 Viswanathan Ramakrishnan,3 Tatsiana Beiko,2 Charlie Strange2 1Department of Pulmonary and Critical Care, Cleveland Clinic Florida, Weston, FL, USA; 2Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, USA; 3Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USACorrespondence: Franck F RahaghiDepartment of Pulmonary and Critical Care, Cleveland Clinic Florida, Weston, FL, USATel +1 954 659 5450Fax +1 954 6595451Email rahaghf@ccf.orgPurpose: The extent of the survival benefit of augmentation therapy for alpha-1 antitrypsin deficiency (AATD) in individuals with advanced COPD is difficult to define. We performed a retrospective analysis using all available data from the observational registry of individuals with severe deficiency of alpha-1 antitrypsin (AAT) conducted by the NHLBI investigators.Patients and Methods: Individuals (N=1129) with severe deficiency of AAT were evaluated for mortality using all data sources and stratified by 10% increments of baseline forced expiratory volume in 1 second (FEV1) percent predicted and by augmentation therapy status (ever receiving versus never receiving). Kaplan–Meier survival curves were constructed for each of the deciles comparing survival in treated vs non-treated groups. A multivariable model was performed to define the correlates of survival in individuals with FEV1 < 30% predicted.Results: Amongst all subjects, augmentation was associated with improved survival (p< 0.0001). Among the individuals ever receiving augmentation therapy, survival was better than for those not receiving augmentation at all 10% increments of FEV1% predicted from 10% to 60% (P values < 0.05 in all deciles). In subgroups of participants with hyperinflation defined as residual volume (RV)> 120% predicted and in subgroups of participants with reduced diffusing capacity for carbon monoxide (DLCO) < 70% predicted, there was significantly better survival for those ever receiving augmentation therapy than for those who never received augmentation (p< 0.001). A multivariable analysis showed that mortality benefit is influenced by age, DLCO % predicted, and augmentation therapy.Conclusion: There is a survival benefit from augmentation therapy in AATD between FEV1 values in the 10– 60% predicted range. Screening and treatment of AATD patients should therefore not be limited by the severity of illness as defined by FEV1.Keywords: alpha-1 antitrypsin deficiency, COPD, mortality, augmentation therapy, FEV1, survival

Random Forest models are widely used in genomic data analysis and can offer insights into complex biological mechanisms, particularly when features influence the target in interactive, nonlinear, or nonadditive ways. Currently, some of the most efficient Random Forest methods in terms of computational speed are implemented in Python. However, many biologists use R for genomic data analysis, as R offers a unified platform for performing additional statistical analysis and visualization. Here, we present an R package, pyRforest, which integrates Python scikit-learn "RandomForestClassifier" algorithms into the R environment. pyRforest inherits the efficient memory management and parallelization of Python, and is optimized for classification tasks on large genomic datasets, such as those from RNA-seq. pyRforest offers several additional capabilities, including a novel rank-based permutation method for biomarker identification. This method can be used to estimate and visualize P-values for individual features, allowing the researcher to identify a subset of features for which there is robust statistical evidence of an effect. In addition, pyRforest includes methods for the calculation and visualization of SHapley Additive exPlanations values. Finally, pyRforest includes support for comprehensive downstream analysis for gene ontology and pathway enrichment. pyRforest thus improves the implementation and interpretability of Random Forest models for genomic data analysis by merging the strengths of Python with R. pyRforest can be downloaded at: https://www.github.com/tkolisnik/pyRforest with an associated vignette at https://github.com/tkolisnik/pyRforest/blob/main/vignettes/pyRforest-vignette.pdf., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable., Methods: Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan-Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards., Results: Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46-0.91, p = 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class (p < 0.0001), 6MWD improvements of + 84 m (p < 0.0001), and a reduction in NT-proBNP of - 778 pg/mL (p = 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV., Conclusion: Initial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains., Clinical Trial Registration: ClinicalTrials.gov identifier NCT01560637., (© 2023. The Author(s).)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a treatable complication of acute pulmonary embolism (PE). Identification of factors that impact referral to a comprehensive CTEPH center may improve disease awareness and patient outcomes. We conducted a study of patients with acute PE. Cases were identified through a natural language processing algorithm. ICD coding was used to assess clinical documentation for dyspnea or CTEPH placed at least 90 days after their acute PE diagnosis. We analyzed characteristics of patients who were referred vs. not referred, as well as referral patterns for "at risk" patients. 2454 patients with acute PE were identified, of which 4.9% (120/2454) were referred for CTEPH evaluation. Patients who were not referred were older (61 vs. 54 years, p < 0.001), had higher rates of cancer (28% vs. 10%, p < 0.001), and lived further from the referral center (9.1 miles vs. 6.7 miles, p = 0.03). Of 175 patients identified as "at risk," 12% (21/175) were referred. In the 'at risk' cohort, distance from referral center among referred and not referred was significant (5.7 miles vs. 8.8 miles, p = 0.04). There were low rates of referral to CTEPH center in post-PE patients, and in patients with symptoms who may be at higher risk of CTEPH. Age, co-morbid conditions, distance from comprehensive center, and presence of a primary care provider contribute to differences in referral to a comprehensive CTEPH center. Clinician education about CTEPH is important to ensure optimal care to patients with or at risk for chronic complications of acute PE., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The coronavirus of 2019 (COVID-19) disrupted delivery of healthcare. Patients with pulmonary hypertension (PH), especially pulmonary arterial hypertension (PAH), require significant resources for both diagnosis and management and are at high risk for decompensation due to disruption in their care. A survey consisting of 47 questions related to the care of patients with PH was designed by the American College of Chest Physicians 2020-2021 Pulmonary Vascular Disease (PVD) NetWork Steering Committee and sent to all members of the PVD NetWork, as well as the multiple other professional networks for PH. Participation was voluntary and anonymous. Responses were collected from November 2020 through February 2021. Ninety-five providers responded to this survey. The majority (93%) believe that care of PH patients has been affected by the pandemic. Sixty-seven percent observed decreased referrals for PH evaluation. Prior to the pandemic, only 15% used telemedicine for management of PH patients compared to 84% during the pandemic. Telemedicine was used most for follow up of selected low-risk patients (49%). While 22% respondents were completely willing to prescribe new PAH therapy via telemedicine, 11% respondents were completely unwilling. Comfort levels differed based on type of medication being prescribed. Over 90% of providers experienced disruptions in obtaining testing and 31% experienced disruptions in renewal or approval of medications. Overall, providers perceived that the COVID-19 pandemic caused significant disruption of care for PH patients. Telemedicine utilization increased but was used mostly in low-risk patients. Some providers had a decreased level of comfort prescribing PAH therapy via telemedicine encounters., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest to disclose on the topic of this pulmonary hypertension survey., (Copyright © 2022. Published by Elsevier Ltd.)

The tumor suppressor gene, TP53 , has the highest rate of mutation among all genes in human cancer. This transcription factor plays an essential role in the regulation of many cellular processes. Mutations in TP53 result in loss of wild-type p53 function in a dominant negative manner. Although TP53 is a well-studied gene, the transcriptome modifications caused by the mutations in this gene have not yet been explored in a pan-cancer study using both primary and metastatic samples. In this work, we used a random forest model to stratify tumor samples based on TP53 mutational status and detected a p53 transcriptional signature. We hypothesize that the existence of this transcriptional signature is due to the loss of wild-type p53 function and is universal across primary and metastatic tumors as well as different tumor types. Additionally, we showed that the algorithm successfully detected this signature in samples with apparent silent mutations that affect correct mRNA splicing. Furthermore, we observed that most of the highly ranked genes contributing to the classification extracted from the random forest have known associations with p53 within the literature. We suggest that other genes found in this list including GPSM2, OR4N2, CTSL2, SPERT, and RPE65 protein coding genes have yet undiscovered linkages to p53 function. Our analysis of time on different therapies also revealed that this signature is more effective than the recorded TP53 status in detecting patients who can benefit from platinum therapies and taxanes. Our findings delineate a p53 transcriptional signature, expand the knowledge of p53 biology and further identify genes important in p53 related pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Keshavarz-Rahaghi, Pleasance, Kolisnik and Jones.)

Introduction: In metastatic colorectal cancer (mCRC), RAS mutations impart inferior survival and resistance to anti-epidermal growth factor receptor (EGFR) antibodies. KRAS G12C inhibitors have been developed and we evaluated how KRAS G12C differs from other RAS mutations., Patients and Methods: This retrospective review evaluated patients in British Columbia, Canada with mCRC and RAS testing performed between 1 January 2016 and 31 December 2018. Sequencing information from The Cancer Genome Analysis (TCGA) was also obtained and analysed., Results: Age at diagnosis, sex, anatomic location and stage at diagnosis did not differ by RAS mutation type. Progression free survival on first chemotherapy for patients with metastatic KRAS G12C tumours was 11 months. Median overall survival did not differ by RAS mutation type but was worse for both KRAS G12C (27 months) and non-G12C alterations (29 months) than wildtype (43 months) ( p  = 0.01). Within the TCGA, there was no differential gene expression between KRAS G12C and other RAS mutations. However, eight genes with copy number differences between the G12C and non-G12C RAS mutant groups were identified after adjusting for multiple comparisons ( FITM2 , PDRG1 , POFUT1 , ERGIC3 , EDEM2 , PIGU , MANBAL and PXMP4) . We also noted that other RAS mutant mCRCs had a higher tumour mutation burden than those with KRAS G12C mutations (median 3.05 vs 2.06 muts/Mb, p  = 4.2e-3) and that KRAS G12C/other RAS had differing consensus molecular subtype distribution from wildtype colorectal cancer (CRC) ( p  < 0.0001) but not each other ( p  = 0.14)., Conclusion: KRAS G12C tumours have similar clinical presentation to other RAS mutant tumours, however, are associated with differential copy number alterations., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Stephen Yip is a member of the advisory boards for Amgen, AstraZeneca, Bayer, Merck, Novartis and Roche. Jonathan Loree is a member of advisory boards for Amgen, Bayer, Novartis, Roche, Ipsen, Eisai and Pfizer and has received research funding from Ipsen, AstraZeneca and Amgen., (© The Author(s), 2022.)

Background: Pulmonary endothelial damage has been shown to precede the development of emphysema in animals, and vascular changes in humans have been observed in COPD and emphysema., Research Question: Is intraparenchymal vascular pruning associated with longitudinal progression of emphysema on CT imaging or decline in lung function over 5 years?, Study Design and Methods: The Genetic Epidemiology of COPD Study enrolled ever smokers with and without COPD from 2008 through 2011. The percentage of emphysema-like lung, or "percent emphysema," was assessed at baseline and after 5 years on noncontrast CT imaging as the percentage of lung voxels < -950 Hounsfield units. An automated CT imaging-based tool assessed and classified intrapulmonary arteries and veins. Spirometry measures are postbronchodilator. Pulmonary arterial pruning was defined as a lower ratio of small artery volume (< 5 mm 2 cross-sectional area) to total lung artery volume. Mixed linear models included demographics, anthropomorphics, smoking, and COPD, with emphysema models also adjusting for CT imaging scanner and lung function models adjusting for clinical center and baseline percent emphysema., Results: At baseline, the 4,227 participants were 60 ± 9 years of age, 50% were women, 28% were Black, 47% were current smokers, and 41% had COPD. Median percent emphysema was 2.1 (interquartile range, 0.6-6.3) and progressed 0.24 percentage points/y (95% CI, 0.22-0.26 percentage points/y) over 5.6 years. Mean FEV 1 to FVC ratio was 68.5 ± 14.2% and declined 0.26%/y (95% CI, -0.30 to -0.23%/y). Greater pulmonary arterial pruning was associated with more rapid progression of percent emphysema (0.11 percentage points/y per 1-SD increase in arterial pruning; 95% CI, 0.09-0.16 percentage points/y), including after adjusting for baseline percent emphysema and FEV 1 . Arterial pruning also was associated with a faster decline in FEV 1 to FVC ratio (-0.04%/y per 1-SD increase in arterial pruning; 95% CI, -0.008 to -0.001%/y)., Interpretation: Pulmonary arterial pruning was associated with faster progression of percent emphysema and more rapid decline in FEV 1 to FVC ratio over 5 years in ever smokers, suggesting that pulmonary vascular differences may be relevant in disease progression., Trial Registry: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Alpha-1 antitrypsin deficiency (AATD) is a common but highly underdiagnosed genetic disorder that may lead to chronic obstructive pulmonary disease (COPD), bronchiectasis, and liver disease. Early diagnosis is key to altering the course of disease as well as informing family members of potential risk. This randomized, prospective observational study compares the different testing modalities for AATD testing of at-risk patients initiated in the pulmonary function testing (PFT) laboratory. Providing a recommendation with a prescription for serologic testing, providing a finger-stick testing method (AlphaKit), and providing a buccal swab testing method (AlphaID) were compared to the community standard of referring the patient back to the PFT-ordering provider only. Results show that testing directly in the PFT laboratory has an odds ratio (OR) for completing testing of 35.14 (5.33 - 999.99), p -value of <0.0001, for buccal swab testing and an OR of 17.09 (2.58 - 729.99), p -value of 0.0002, for finger-stick testing compared to the community standard. Providing a prescription was no better than referral back to the PFT-ordering provider with an OR of 2.61(0.33 - 119.36), p -value of 0.6412. Resources needed to have testing performed by the Respiratory Therapy department were minimal with an average time of 1 to 5 minutes per patient tested. Causes of testing refusal were also identified. In conclusion, direct testing for AATD by respiratory therapists at the conclusion of PFT testing shows a significant improvement in rates of testing, especially with testing that utilizes buccal swab sample collection., (JCOPDF © 2021.)

Purpose: Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF), which slows disease progression. Management of patients with IPF receiving nintedanib can be complicated by tolerability issues, comorbidities, and concomitant medications. We developed consensus recommendations on the management of dosing, adverse events and comorbidities in patients with IPF treated with nintedanib., Methods: A modified Delphi process using 3 questionnaires was used to survey 14 pulmonologists experienced in using nintedanib. Panelists rated their agreement with statements on a Likert scale from -5 (strongly disagree) to +5 (strongly agree). Consensus was predefined as a mean score of ⩽-2.5 or ⩾+2.5 with a standard deviation not crossing zero., Results: The panelists' recommendations were largely aligned with clinical trial data, real-world evidence, and the prescribing information, and provided additional guidance regarding minimizing gastrointestinal effects, periodic monitoring for liver dysfunction, caution with respect to concomitant administration of cytochrome P450 3A4 and P-glycoprotein 1 inhibitors and inducers and anticoagulants, and management of comorbidities. The panelists unanimously agreed that adverse event management should be individualized, based on careful consideration of the risks and benefits of each possible intervention and discussion with the patient., Conclusions: These consensus recommendations provide additional guidance on the appropriate management of IPF with nintedanib, for use alongside evidence-based literature and the prescribing information., Competing Interests: Declaration of conflicting interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FFR reports personal fees from Boehringer Ingelheim (BI) and Genentech. JAB has no competing interests to disclose. JF has no competing interests to disclose. MG reports grants, non-financial support, and other support from BI; personal fees, non-financial support, and other support from the France Foundation; personal fees from Genentech; and grants, non-financial support, and other support from the Pulmonary Fibrosis Foundation. RH has no competing interests to disclose. KBH reports grants and personal fees from Actelion Pharmaceuticals, BI, and United Therapeutics; personal fees from Bayer; and grants from Genentech, Eiger Pharmaceuticals, and Reata Pharmaceuticals. TJH reports research support from BI and Promedior and writing support funded by BI. HJK has no competing interests to disclose. MK reports grants and personal fees from BI, Gilead, GlaxoSmithKline, Prometic, and Roche; and personal fees from AstraZeneca, Covance, Galapagos NV, Indalo, and Third Pole Inc. JAL reports personal fees from Biogen, BI, Galecto, Roche/Genentech, and Veracyte. BDS reports grants from Genentech and personal fees from BI. JJS has no competing interests to disclose. JAD reports personal fees from BI., (© The Author(s) 2021.)

The COVID-19 pandemic created a global health emergency that has changed the practice of medicine and has shown the need for palliative care as an essential element of hospital care. In our small South Florida hospital, a palliative care service was created to support the frontline caregivers. Thanks to the hospital support, our team was formed rapidly. It consisted of 3 advanced care practitioners, a pulmonary physician with palliative care experience and the cooperation of community resources such as hospice and religious support. We were able to support patients and their families facilitating communication as visitation was not allowed. We also addressed goals of care, providing comfort care transition when appropriate, and facilitating allocation of scarce resources to patients who were most likely to benefit from them. With this article we describe a simplified framework to replicate the creation of a Palliative Care Team for other hospitals that are experiencing this need.

Rationale and Objectives: Bronchiectasis (BE) is associated with chronic obstructive pulmonary disease (COPD), but emphysema and small airways disease, main pathologic features of COPD, have been sparsely studied in BE. We aimed to objectively assess those features in smokers with and without radiographic BE and examine its relationships to airflow obstruction and exercise capacity., Material and Methods: We measured emphysema and small airways disease on paired inspiratory-expiratory computed tomography (CT) scans with the parametric response map (PRM EMPH and PRM SAD ) method in 1184 smokers with and without radiographic BE. PRM SAD and PRM EMPH are expressed as the percentage of lung area. Clinical, spirometry, and exercise capacity data were measured with standardized methods. The differences in PRM SAD and PRM EMPH between subjects with and without radiographic BE were assessed using multivariable linear regression analysis, and their associations with FEV 1 and six-minute walk test (6MWT) were assessed with generalized linear models., Results: Out of 1184 subjects, 383 (32%) had radiographic BE. PRM EMPH but not PRM SAD was higher in subjects with radiographic BE than those without radiographic BE in adjusted models. Subjects with radiographic BE and PRM EMPH (defined as ≥5% on paired CTs) had lower FEV 1 (least square mean, 1479 mL vs. 2350 mL p < 0.0001) and 6MWT (372 m vs. 426 m p = 0.0007) than those with radiographic BE alone in adjusted models., Conclusion: Smokers with radiographic BE have an increased burden of emphysema on paired CTs, and those with radiographic BE and emphysema have lower airflow and exercise capacity., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Pulmonary hypertension currently has minimal guidelines for outpatient disease management. Congestive heart failure studies, however, have shown effectiveness of disease management plans in reducing all-cause mortality and all-cause and congestive heart failure-related hospital readmissions. Heart failure exacerbation is a common reason for readmission in both pulmonary hypertension and congestive heart failure. Our aim was to review individual studies and comprehensive meta-analyses to identify effective congestive heart failure interventions that can be used to develop similar disease management plans for pulmonary hypertension. A comprehensive literature review from 1993 to 2019 included original articles, systematic reviews, and meta-analyses. We reviewed topics of outpatient congestive heart failure interventions to decrease congestive heart failure mortality and readmission and patient management strategies in congestive heart failure. The most studied interventions included case management, multidisciplinary intervention, structured telephone strategy, and tele-monitoring. Case management showed decreased all-cause mortality at 12 months, all-cause readmission at 12 months, and congestive heart failure readmission at 6 and 12 months. Multidisciplinary intervention resulted in decreased all-cause readmission and congestive heart failure readmission. There was some discrepancy on effectiveness of tele-monitoring programs in individual studies; however, meta-analyses suggest tele-monitoring provided reduced all-cause mortality and risk of congestive heart failure hospitalization. Structured telephone strategy had similar results to tele-monitoring including decreased risk of congestive heart failure hospitalization, without effect on mortality. Extrapolating from congestive heart failure data, it seems strategies to improve the health of pulmonary hypertension patients and development of comprehensive care programs should include structured telephone strategy and/or tele-monitoring, case management strategies, and multidisciplinary interventions., (© The Author(s) 2020.)

Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg-maximum ( N  = 131 pretreated patients) and placebo ( N  = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: -8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies., (© The Author(s) 2020.)

Alpha-1 Antitrypsin Deficiency (AATD) is a progressive pulmonary disease under-recognized or misdiagnosed by clinicians. Patients with AATD can develop a variety of organ-specific complications and as a result, often require hospitalization and treatment within critical care and ICU settings. Due to the complexity of AATD there are minimal guidelines in place to address the specific and highly variable needs of these patients in the critical care setting. This review presents clinical considerations with respect to the management of patients with AATD and provides treatment recommendations for these patients in the critical care setting. In addition, we have outlined certain aspects of the care of this patient population that may be of interest to critical care practitioners. With greater disease awareness and earlier diagnosis the onset of symptoms can be delayed, which will ultimately reduce the frequency of deleterious health consequences., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

There are few studies looking at the pulmonary circulation in subjects with bronchiectasis. We aimed to evaluate the intraparenchymal pulmonary vascular structure, using noncontrast chest computed tomography (CT), and its clinical implications in smokers with radiographic bronchiectasis. Visual bronchiectasis scoring and quantitative assessment of the intraparenchymal pulmonary vasculature were performed on CT scans from 486 smokers. Clinical, lung function and 6-min walk test (6MWT) data were also collected. The ratio of blood vessel volume in vessels <5 mm 2 in cross-section (BV5) to total blood vessel volume (TBV) was used as measure of vascular pruning, with lower values indicating more pruning. Whole-lung and lobar BV5/TBV values were determined, and regression analyses were used to assess the differences in BV5/TBV between subjects with and without bronchiectasis. 155 (31.9%) smokers had bronchiectasis, which was, on average, mild in severity. Compared to subjects without bronchiectasis, those with lower-lobe bronchiectasis had greater vascular pruning in adjusted models. Among subjects with bronchiectasis, those with vascular pruning had lower forced expiratory volume in 1 s and 6MWT distance compared to those without vascular pruning. Smokers with mild radiographic bronchiectasis appear to have pruning of the distal pulmonary vasculature and this pruning is associated with measures of disease severity., Competing Interests: Conflict of interest: A.A. Diaz received research grants from the NIH and Brigham and Women's Hospital, and speaker fees from Novartis Inc. outside of the submitted work. Conflict of interest: D.J. Maselli has nothing to disclose. Conflict of interest: F. Rahaghi has nothing to disclose. Conflict of interest: C.E. Come received NIH/NHLBI grant K23HL114735 during the conduct of the study. Conflict of interest: A. Yen reports receiving salary support from the NIH under COPDGene R01-HL089897 during the conduct of the study. Conflict of interest: E.S. Maclean has nothing to disclose. Conflict of interest: Y. Okajima reports receiving grants from Canon Medical Systems, grants from Ziosoft, outside the submitted work. Conflict of interest: C.H. Martinez has nothing to disclose. Conflict of interest: T. Yamashiro has nothing to disclose. Conflict of interest: D.A. Lynch reports receiving grants from the NHLBI, research supports from Parexel and Veracyte, and personal fees from Boehringer Ingelheim and Genentech/Roche, outside the submitted work. Conflict of interest: W. Wang has nothing to disclose. Conflict of interest: G.L. Kinney has nothing to disclose. Conflict of interest: G.R. Washko reports receiving grants from the NIH, grants and other support from Boehringer Ingelheim, and other support from Genentech, Quantitative Imaging Solutions and PulmonX, during the conduct of the study. G.R. Washko's spouse works for Biogen, which is focused on developing therapies for fibrotic lung disease. Conflict of interest: R. San José Estépar reports receiving grants from the NHLBI during the conduct of the study. He is founder and co-owner of Quantitative Imaging Solutions, which is a company that provides image-based consulting and develops software to enable data sharing.

Background: Right ventricular (RV) dysfunction and heart failure with preserved ejection fraction may contribute to exercise intolerance in obesity. To further define RV exercise responses, we investigated RV-arterial coupling in obesity with and without development of exercise pulmonary venous hypertension (ePVH)., Methods: RV-arterial coupling defined as RV end-systolic elastance/pulmonary artery elastance (Ees/Ea) was calculated from invasive cardiopulmonary exercise test data in 6 controls, 8 obese patients without ePVH (Obese-ePVH) and 8 obese patients with ePVH (Obese+ePVH) within a larger series. ePVH was defined as a resting pulmonary arterial wedge pressure < 15 mmHg but ≥ 20 mmHg on exercise. Exercise haemodynamics were further evaluated in 18 controls, 20 Obese-ePVH and 17 Obese+ePVH patients., Results: Both Obese-ePVH and Obese+ePVH groups developed exercise RV-arterial uncoupling (peak Ees/Ea = 1.45 ± 0.26 vs 0.67 ± 0.18 vs 0.56 ± 0.11, p < 0.001, controls vs Obese-ePVH vs Obese+ePVH respectively) with higher peak afterload (peak Ea = 0.31 ± 0.07 vs 0.75 ± 0.32 vs 0.88 ± 0.62 mL/mmHg, p = 0.043) and similar peak contractility (peak Ees = 0.50 ± 0.16 vs 0.45 ± 0.22 vs 0.48 ± 0.17 mL/mmHg, p = 0.89). RV contractile reserve was highest in controls (ΔEes = 224 ± 80 vs 154 ± 39 vs 141 ± 34% of baseline respectively, p < 0.001). Peak Ees/Ea correlated with peak pulmonary vascular compliance (PVC, r = 0.53, p = 0.02) but not peak pulmonary vascular resistance (PVR, r = - 0.20, p = 0.46). In the larger cohort, Obese+ePVH patients on exercise demonstrated higher right atrial pressure, lower cardiac output and steeper pressure-flow responses. BMI correlated with peak PVC (r = - 0.35, p = 0.04) but not with peak PVR (r = 0.24, p = 0.25)., Conclusions: Exercise RV-arterial uncoupling and reduced RV contractile reserve further characterise obesity-related exercise intolerance. RV dysfunction in obesity may develop independent of exercise LV filling pressures.

Background: Systemic sclerosis is a chronic debilitating autoimmune disease characterized by endothelial dysfunction and multi-organ fibrosis. Interstitial lung disease, a common manifestation of SSc, is termed scleroderma-related interstitial lung disease (SSc-ILD) and along with pulmonary hypertension contributes to a majority of deaths in SSc. SSc-ILD patients frequently develop pulmonary hypertension, which prognosticates a poorer outcome. We investigated pulmonary artery dimensions as an outcome predictor in patients with SSc-ILD., Methods: A retrospective chart review abstracting data from SSc-ILD patients evaluated at a large tertiary care center was performed. HRCT imaging was reviewed and pulmonary artery (PA) and ascending aorta (Ao) diameters were measured for calculation of the PA:Ao ratio. Additionally, demographics, vital signs, spirometric parameters, comorbidities, and mean pulmonary artery pressures were collected when available. Outcome analysis with lung transplant or death events within 4 years based on pulmonary artery size as well as PA:Ao ratio was performed., Results: 70 SSc-ILD patients were identified. Mean pulmonary artery diameter and PA:Ao ratio was 31.17 and 1.07 mm, respectively. Patients with a pulmonary artery diameter ≥32 mm had higher risk of lung transplantation or death (p < 0.001) within 4 years. Patients with a PA:Ao ratio ≥1.1 also had higher risk of lung transplantation or death (p < 0.001) within 4 years. Unadjusted outcomes analyses also identified PA:Ao ratio ≥1.1 as an independent outcome predictor (hazard ratio 3.30, p < 0.001)., Conclusions/clinical Implications: In SSc-ILD patients, a PA:Ao ratio ≥1.1 is associated with higher risk of lung transplant or death. These data suggest that PA:Ao dimension may be used for prognostication in SSc-ILD.

The primary aim was to explore the safety and tolerability of inhaled treprostinil when used in patients with pulmonary hypertension (PH) with concomitant chronic obstructive pulmonary disease (COPD). Patients with a diagnosis of pre-capillary PH (defined as pulmonary artery mean pressure of ≥ 25 mmHg and pulmonary artery wedge pressure or left ventricular end diastolic pressure of ≤ 15 mmHg) who were being initiated on inhaled treprostinil and had concomitant COPD (defined as FEV1/FVC ratio ≤ 70% with FEV1 ≥ 40% predicted) were considered for inclusion in this pilot study. Assessments included adverse events, physical exam, World Health Organization (WHO) functional class, 6-minute walk test (6MWT), modified Borg dyspnea score, and concomitant medication. At baseline and week 16 St. George's Respiratory Questionnaire (SGRQ), arterial blood gas (ABG), and pulmonary function test (PFT) were assessed. The median age was 65 years (age range, 56-80 years) and five patients (56%) were men. Among the nine patients, a majority had an increase in 6MWT from baseline to week 16 (median change, 19 m). Only three of the nine patients (33%) had an increase in A-a gradient at week 16 (median change, -7). There was no difference in any of the following: arterial blood gases, WHO functional class, 6MWT results, or SGRQ scores from baseline to week 16. There was a statistically significant decline in several of the PFT measures, including FEV1 (median change, -0.18 L; P  = 0.004; median change, -7% of predicted; P  = 0.016), FVC (median change, -0.23 L; P  = 0.027), and diffusion capacity for carbon monoxide (DLCO) (median change, -5% of predicted; P  = 0.023). The small number of patients limits firm conclusions; however, inhaled treprostinil did not seem to adversely impact oxygenation in the majority of the study patients with pre-capillary PH and COPD. While there may have an adverse impact on some pulmonary function parameters, the clinical significance is unclear.

Cement pulmonary embolism is a rare complication of cement kyphoplasty. These emboli are often asymptomatic and commonly detected many years after the procedure as incidental findings on radiographic imaging. We herein report a case of a 32-year-old professional diver who was diagnosed with asymptomatic cement pulmonary emboli during his annual diving physical exam. After two years of follow-up the patient remained asymptomatic and resumed his career in professional diving, which included deep sea diving activities with no evidence of respiratory limitations or long-term complications.

Exogenous lipoid pneumonia (ELP) is a rare type of inflammatory lung disease caused by aspiration and/or inhalation of fatty substances and characterized by a chronic foreign body-type reaction to intra-alveolar lipid deposits. The usual clinical presentation occurs with insidious onset of nonspecific respiratory symptoms and radiographic findings that can mimic other pulmonary diseases. Diagnosis of ELP is often missed or delayed as it requires a high index of suspicion and familiarity with the constellation of appropriate history and radiologic and pathologic features. We herein report a case of occupational exposure to tabletop "Teppanyaki" entertainment cooking as a cause of ELP, confirmed by surgical lung biopsies in a 63-year-old Asian woman who worked as a Hibachi-Teppanyaki chef for 25 years., Competing Interests: Dr. Franck Rahaghi is a Consultant, Speaker, and Researcher for United Therapeutics Corporation, Actelion Pharmaceuticals, Gilead Sciences, Bayer Healthcare Pharmaceuticals, and Lung Therapeutics Inc. The remaining authors have indicated that they have no conflict of interests to disclose.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by severe remodeling of the pulmonary artery resulting in increased pulmonary artery pressure and right ventricular hypertrophy and, ultimately, failure. Bone marrow-derived progenitor cells play a critical role in vascular homeostasis and have been shown to be involved in the pathogenesis of PAH. A proliferation of c-Kit(+) hematopoietic progenitors and mast cells has been noted in the remodeled vessels in PAH. Imatinib, a tyrosine kinase inhibitor that targets c-Kit, has been shown to be beneficial for patients with PAH. Here we hypothesize that the clinical benefit of imatinib in PAH could be related to c-Kit inhibition of progenitor cell mobilization and maturation into mast cells. As a corollary to the phase 3 study using imatinib in PAH, blood samples were collected from 12 patients prior to starting study drug (baseline) and while on treatment at weeks 4 and 24. Eight were randomized to imatinib and 4 to placebo. Circulating c-Kit(+) and CD34(+)CD133(+) hematopoietic progenitors as well as biomarkers of mast cell numbers and activation were measured. Circulating CD34(+)CD133(+) and c-Kit(+) progenitor cells as well as c-Kit(+)/CD34(+)CD133(+) decreased with imatinib therapy (all P < 0.05). In addition, total tryptase, a marker of mast cell load, dropped with imatinib therapy (P = 0.02) and was related to pulmonary vascular resistance (R = 0.7, P = 0.02). The findings support c-Kit inhibition as a potential mechanism of action of imatinib in PAH and suggest that tryptase is a potential biomarker of response to therapy.

Heterologous viruses may transactivate or suppress human immunodeficiency virus (HIV)-1 replication. An adenovirus type 5 gene transfer vector (Ad5) HIV-1 vaccine was recently evaluated in a clinical trial, without efficacy. In this context, it is relevant to ask what effect Ad vectors have on HIV-1 replication, particularly in cells that are part of the innate immune system. Infection of HIV-1-infected human alveolar macrophages (AMs) obtained from HIV-1(+) individuals with an Ad vector containing no transgene (AdNull) resulted in dose-responsive inhibition of endogenous HIV-1 replication. HIV-1 replication in normal AMs infected with HIV-1 in vitro was inhibited by AdNull with a similar dose response. Ad reduced AM HIV-1 replication up to 14 days after HIV-1 infection. Fully HIV-1-infected AMs were treated with 3'-azido-3'-deoxythymidine, after which Ad infection still inhibited HIV-1 replication, suggesting a postentry step was affected. Substantial HIV-1 DNA was still produced after Ad infection, as quantified by TaqMan real-time PCR, suggesting that the replication block occurred after reverse transcription. AdNull blocked HIV-1 long terminal repeat (LTR) transcription, as assessed by an vesicular stomatitis virus G protein pseudotyped HIV-1 LTR luciferase construct. The formation of HIV-1 DNA integrated into the host chromosome was not inhibited by Ad, as quantified by a two-step TaqMan real-time PCR assay, implying a postintegration block to HIV-1 replication. These data indicate that Ad vectors are inhibitory to HIV-1 replication in human AMs based, in part, on their ability to inhibit LTR-driven transcription.

Alpha-1 antitrypsin deficiency (AATD) is under-recognized by clinicians, with long diagnostic delays between patients' first symptom and initial diagnosis. Recent recommendations by official societies encourage testing for AATD in all symptomatic adults with spirometric evidence of COPD, though compliance with this recommendation has been variable. For 6 months, the following physician alert was added to PFT reports of patients with airflow obstruction of GOLD Stage II or higher: "The American Thoracic Society recommends testing for AATD in all patients with FEV1 < 80% predicted and FEV1/FVC less than 0.70, if clinically indicated. Appropriate counseling suggested." During the "Pre-alert Period," 821 spirometry tests were performed; 178 of these 821 unique patients (22%) satisfied spirometric criteria of > GOLD Stage II and 11 (6%) were tested for AATD. In contrast, during the "Physician Alert" intervention period, 689 spirometry tests were performed on 689 unique patients, of whom 140 (20%) satisfied criteria for > GOLD II airflow obstruction; AAT testing was done more frequently (18 [13%], p = 0.04). The overall rate of misclassifying patients' reports for testing by the respiratory therapists was very low (3.3%). An analysis of "number needed to test" suggests that 98-290 patients must be tested to have 95% certainty to identify a single patient with severe AATD. In conclusion, implementing a physician alert on PFT reports of patients with COPD can increase physicians' testing for AATD. The incomplete rate of testing suggests the need for additional strategies to enhance clinicians' detection of individuals with AATD.

To define the patterns of referral of adult patients with obstructive sleep apnea syndrome (OSAS) for diagnostic sleep testing, we studied 97 consecutive patients with OSAS (Apnea/Hypopnea Index >/= 20) referred to the Center for Sleep and Ventilatory Disorders, an American Sleep Disorders Association-accredited university sleep center. Chart review and semi-structured patient telephone interview quantified the time between the onset of any major feature of OSAS and referral to the sleep center, as well as the time between the first OSAS complaint to a health care provider and referral to the center. The average time elapsed between first recognition by the patient of a major feature of OSAS to sleep center referral was 87.5 months (range, 1 to 480 months). Only 4% of referrals were made as a result of the clinician eliciting a history of sleep-related complaints. Once OSAS-related features were apparent to the clinician, the average time to referral for diagnostic testing was 7.9 months (range, 0 to 128 months). These data suggest that both a lack of reporting of symptoms by OSAS patients and a lack of obtaining appropriate sleep history by health care providers contribute to a significant delay in diagnosis of OSA.