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Importance: The optimal screening frequency and spontaneous breathing trial (SBT) technique to liberate adults from ventilators are unknown., Objective: To compare the effects of screening frequency (once-daily screening vs more frequent screening) and SBT technique (pressure-supported SBT with a pressure support level that was >0-≤8 cm H2O and a positive end-expiratory pressure [PEEP] level that was >0-≤5 cm H2O vs T-piece SBT) on the time to successful extubation., Design, Setting, and Participants: Randomized clinical trial with a 2 × 2 factorial design including critically ill adults who were receiving invasive mechanical ventilation for at least 24 hours, who were capable of initiating spontaneous breaths or triggering ventilators, and who were receiving a fractional concentration of inspired oxygen that was 70% or less and a PEEP level of 12 cm H2O or less. Recruitment was between January 2018 and February 2022 at 23 intensive care units in North America; last follow-up occurred October 18, 2022., Interventions: Participants were enrolled early to enable protocolized screening (more frequent vs once daily) to identify the earliest that patients met criteria to undergo pressure-supported or T-piece SBT lasting 30 to 120 minutes., Main Outcome and Measures: Time to successful extubation (time when unsupported, spontaneous breathing began and was sustained for ≥48 hours after extubation)., Results: Of 797 patients (198 in the once-daily screening and pressure-supported SBT group, 204 in once-daily screening and T-piece SBT, 195 in more frequent screening and pressure-supported SBT, and 200 in more frequent screening and T-piece SBT), the mean age was 62.4 (SD, 18.4) years and 472 (59.2%) were men. There were no statistically significant differences by screening frequency (hazard ratio [HR], 0.88 [95% CI, 0.76-1.03]; P = .12) or by SBT technique (HR, 1.06 [95% CI, 0.91-1.23]; P = .45). The median time to successful extubation was 2.0 days (95% CI, 1.7-2.7) for once-daily screening and pressure-supported SBT, 3.1 days (95% CI, 2.7-4.8) for once-daily screening and T-piece SBT, 3.9 days (95% CI, 2.9-4.7) for more frequent screening and pressure-supported SBT, and 2.9 days (95% CI, 2.0-3.1) for more frequent screening and T-piece SBT. An unexpected interaction between screening frequency and SBT technique required pairwise contrasts that revealed more frequent screening (vs once-daily screening) and pressure-supported SBT increased the time to successful extubation (HR, 0.70 [95% CI, 0.50-0.96]; P = .02). Once-daily screening and pressure-supported SBT (vs T-piece SBT) did not reduce the time to successful extubation (HR, 1.30 [95% CI, 0.98-1.70]; P = .08)., Conclusions and Relevance: Among critically ill adults who received invasive mechanical ventilation for more than 24 hours, screening frequency (once-daily vs more frequent screening) and SBT technique (pressure-supported vs T-piece SBT) did not change the time to successful extubation. However, an unexpected and statistically significant interaction was identified; protocolized more frequent screening combined with pressure-supported SBTs increased the time to first successful extubation., Trial Registration: ClinicalTrials.gov Identifiers: NCT02399267 and NCT02969226.

Background: Patients with group 1 pulmonary hypertension (PH) and risk factors for heart failure with preserved ejection fraction (HFpEF) demonstrate worse response to pulmonary vasodilator therapy. The mechanisms and optimal diagnostic approach to identify such patients remain unclear., Objectives: The purpose of this study was to compare exercise capacity, cardiac function, and hemodynamic responses to provocative maneuvers among patients with group 1 PH based upon pretest probability of HFpEF., Methods: Pretest probability for HFpEF was determined using the validated HFpEF-ABA algorithm based on age, body mass index, and history of atrial fibrillation among group 1 PH patients recruited to the multicenter PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) study. Functional capacity, quality of life, and dynamic pulmonary capillary wedge pressure (PCWP) responses were compared between those with low (<25%), intermediate (25%-74%), and high (≥75%) ABA score-based HFpEF probability., Results: Among 424 patients with group 1 PH, 54% (n = 228) had intermediate HFpEF probability and 15% (n = 64) had high HFpEF probability. Resting PCWP increased progressively with higher HFpEF probability (P < 0.0001), and patients with group 1 PH and high HFpEF probability had the greatest increases in PCWP with nitric oxide, fluid challenge, and exercise (P < 0.001 for all), changes that were comparable to patients with HFpEF with no pulmonary vascular disease (n = 194), but lower than those with HFpEF and combined precapillary and postcapillary PH. Left ventricular/atrial size, diastolic function, quality of life, 6-minute walk distance, and peak VO 2 were most abnormal in patients with group 1 PH and high HFpEF probability compared with those with low or intermediate HFpEF probability (P < 0.0001 for all). Increasing HFpEF probability in group 1 PH was associated with greater risk of death (HR per decile of HFpEF probability 1.09; 95% CI: 1.05-1.13; P < 0.0001)., Conclusions: Quantifying pretest probability for HFpEF in patients with group 1 PH identifies a subset of patients with worse dynamic PCWP response indicative of subclinical left heart disease, with poorer functional status, quality of life, and survival. Further study in this group 1 PH subgroup is indicated to determine whether PH therapies are effective and safe, and also whether HFpEF-specific therapies can improve functional status and outcomes., Competing Interests: Funding Support and Author Disclosures The study was supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute: U01 HL125218 (PI: Dr Rosenzweig), U01 HL125205 (PI: Dr Frantz), U01 HL125212 (PI: Dr Hemnes), U01 HL125208 (PI: Dr Rischard), U01 HL125175 (PI: Dr Hassoun), U01 HL125215 (PI: Dr Leopold), and U01 HL125177 (PI: Dr Beck), and by the Pulmonary Hypertension Association. Dr Reddy is supported by National Institutes of Health grant K23HL164901; has received research grants from Sleep Number, Bayer Accelerated Pulmonary Hypertension Award, United Jenesis Award, Merck, and the Earl Wood Career development award from Mayo Clinic. Dr Borlaug is supported by R01 HL128526, R01 HL162828, and U01 HL160226 from the National Institutes of Health/National Heart, Lung, and Blood Institute, and W81XWH2210245 from the U.S. Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (U.S. Patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Postextubation respiratory support treatment approaches, indications, and subgroups of patients with different responses to those therapies are rapidly changing. Planning optimal therapy in terms of choosing devices, timing of application and selecting settings with the goal of minimizing extubation failure is becoming a challenge. This review aims to analyze all the available evidence from a clinical point of view, trying to facilitate decision making at the bedside., Recent Findings: There is evidence for high flow nasal cannula support in patients at low risk of extubation failure. Noninvasive ventilation based strategies should be prioritized in patients at very high risk, who are obese or are hypercapnic at the end of a spontaneous breathing trial. Patients not included in the previous groups merit a tailored decision based on more variables.Optimizing the timing of therapy can include facilitation of extubation by transitioning to noninvasive respiratory support or prolonging a planned preventive therapy according to clinical condition., Summary: Planning postextubatin respiratory support must consider the risk for failing and the presence of some clinical conditions favoring noninvasive ventilation.Extubation can be safely accelerated by modifying screening criteria and spontaneous breathing trial settings, but there is room to increase the role of postextubation noninvasive respiratory support for this indication, always keeping in mind the dangers of delaying a needed intubation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: When administered as first-line intervention to patients admitted with acute hypercapnic respiratory failure secondary to COPD exacerbation in conjunction with guideline-recommended therapies, noninvasive ventilation (NIV) has been shown to reduce mortality and endotracheal intubation. Opportunities to increase uptake of NIV continue to exist despite inclusion of this therapy in clinical guidelines. Prior studies suggest that efforts to increase NIV use in acute exacerbation of COPD (AECOPD) need to account for the complex and interprofessional nature of NIV delivery and the need for interprofessional team coordination., Research Question: We sought to develop an evidence-based interprofessional algorithm to apply NIV in AECOPD to improve the appropriate utilization of NIV in AECOPD., Study Design and Methods: In this prospective qualitative descriptive study, subject matter expert physicians, nurses, and respiratory therapists practicing in a variety of clinical settings caring for patients with AECOPD were recruited for semistructured interviews. The Consolidated Criteria for Reporting Qualitative Research checklist was followed for interview development. Interview themes applicable to interprofessional collaborative practice were identified using deductive thematic analysis. An NIV algorithm based on recent society guidelines was constructed. Interprofessional team tasks appropriate for each phase of the NIV process were integrated into the algorithm., Results: We present an interprofessional team-based algorithm for delivery of NIV in AECOPD inclusive of patient selection and initiation, titration, monitoring, and weaning of NIV. The goal is to increase appropriate uptake of NIV in the AECOPD population., Interpretation: The identified roles and responsibilities of an interprofessional team could be integrated into an interprofessional education program pertaining to use and management of NIV for patients with AECOPD emphasizing collaborative best practice, interprofessional team communication, and support of professional autonomy when appropriate.

Background: Sex-based differences are important in the development and progression of pulmonary arterial hypertension. However, it is not established whether these differences are generalizable to all forms of pulmonary hypertension (PH)., Research Question: What are the sex-based differences in right ventricle (RV) function and transplant-free survival in patients with PH from the Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort?, Study Design and Methods: Patients with PH enrolled in the PVDOMICS cohort study underwent right heart catheterization, cardiac MRI, and echocardiography. A multivariable linear regression model was used to investigate the interactive effect between sex and pulmonary vascular resistance (PVR) on RV ejection fraction (RVEF). Effects of sex, RVEF, and PVR on transplant-free survival were assessed using a Cox proportional hazards model., Results: Seven hundred fifty patients with PH (62.8% female) were enrolled, including 397 patients with groups 2 through 5 PH. Patients with group 1 PH were predominantly female (73.4%). Male patients showed multiple markers of worse RV function with significantly lower RVEF (adjusted difference, 5.5%; 95% CI, 3.2%-7.8%; P < .001) on cardiac MRI and lower RV fractional shortening (adjusted difference, 4.0%; 95% CI, 2.3%-5.8%; P < .001) and worse RV free-wall longitudinal strain (adjusted difference, 2.4%; 95% CI, 1.2%-3.6%; P < .001) on echocardiography. Significant interaction was noted between PVR and sex on RVEF, with the largest sex-based differences in RVEF noted at mild to moderate PVR elevation. Male sex was associated with decreased transplant-free survival (adjusted hazard ratio, 1.46; 95% CI, 1.07-1.98; P = .02), partially mediated by differences in RVEF ( P = .003)., Interpretation: In patients with PH in the PVDOMICS study, female sex was more common, whereas male sex was associated with worse RV function and decreased transplant-free survival, most notably at mild to moderate elevation of PVR.

Aims: The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved., Methods and Results: We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular-pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660-0.737, p < 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656-0.734, p < 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference -0.072, 95% CI -0.123 to -0.020, p = 0.006, and -0.043, 95% CI -0.067 to -0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p > 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p < 0.05 for all)., Conclusions: Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH., (© 2024 European Society of Cardiology.)

Background: Aging-associated left ventricular dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in a left ventricular dysfunction model., Methods and Results: Left ventricular dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone mice, a subset of mice that received sham surgery. Three weeks after surgery, mice underwent simultaneous PET-MRI at 4.7 T. Collagen-targeted PET and fibrogenesis magnetic resonance (MR) probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio. Percent signal intensity increase and Δ lung-to-muscle ratio were computed from the pre-/postinjection magnetic resonance images. Elevated allysine in the heart ( P =0.02) and lungs ( P =0.17) of TAC mice corresponded to an increase in myocardial magnetic resonance imaging percent signal intensity increase ( P <0.0001) and Δlung-to-muscle ratio ( P <0.0001). Hydroxyproline in the heart ( P <0.0001) and lungs ( P <0.01) were elevated in TAC mice, which corresponded to an increase in heart (myocardium-to-muscle ratio, P =0.02) and lung (lung-to-muscle ratio, P <0.001) PET measurements. Pressure-volume loop and echocardiography demonstrated adverse left ventricular remodeling, function, and increased right ventricular systolic pressure in TAC mice., Conclusions: Administration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-magnetic resonance imaging signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-magnetic resonance imaging protocol.

Group 5 pulmonary hypertension (PH) encompasses diverse diseases, with a few cases linking it to T-cell large granular lymphocytic (LGL) leukemia. We report a case of a 76-year-old woman, diagnosed with LGL leukemia and concomitant PH, treated with oral triple pulmonary arterial hypertension (PAH) therapy. She initially presented with dyspnea on exertion; evaluation revealed severe precapillary PH. Implementing cyclophosphamide for leukemia along with tadalafil and macitentan for PH led to sustained symptomatic and hemodynamic improvement for over 3 years. At that time, deterioration in PH prompted the addition of selexipag, resulting in sustained clinical improvement for an additional 5 years. This case exemplifies the potential for sustained benefits of PAH therapy in leukemia-associated PH and highlights the need for continued research on the mechanistic relationship between LGL leukemia and PH, with the hope of identifying new management strategies., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. J. S.: consulting fee/travel reimbursement relationship with Actelion Pharmaceuticals US Inc. H. W. F.: advisory committee member relationship with Actelion and Liberate Medical; consulting fee/advisory committee member relationship with Atlavant, Acceleron, Aerovate, United Therapeutics, and Aerami. N. S. H.: consulting fee/consultant relationship with 4D medical, Breas, Philips Respironics, and Fisher Paykel; consulting fee/advisory committee member relationship with Inogen and Altavant; consulting fee/scientific medical advisor relationship with Liquidia and Aerovate; grant/research support advisory committee member relationship with Acceleron. I. R. P.: PI relationship with United Therapeutics, Liquidia, Bayer, and Acceleron; grant/research support/advisory committee member relationship with United Therapeutics, Liquidia, Acceleron, and Actelion; honoraria adjudecation committee member relationship with Pfizer; consultant relationship with Respira; consulting fee/PI relationship with PhaseBio, Complexa, and Actelion; scientific Medical Advisor relationship with Gilead. None declared (N. M. P., B. M.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

When administered as first-line intervention to patients admitted with acute hypercapnic respiratory failure secondary to COPD exacerbation in conjunction with guideline-recommended therapies, noninvasive ventilation (NIV) has been shown to reduce mortality and endotracheal intubation. Opportunities to increase uptake of NIV continue to exist despite inclusion of this therapy in clinical guidelines. Identifying patients appropriate for NIV, and subsequently providing close monitoring to determine an improvement in clinical condition involves a team consisting of physician, nurse, and respiratory therapist in institutions that successfully implement NIV. We describe to our knowledge the first known evidence-based algorithm speaking to initiation, titration, monitoring, and weaning of NIV in treatment of acute exacerbation of COPD that incorporates the necessary interprofessional collaboration among physicians, nurses, and respiratory therapists caring for these patients., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: N. S. H. serves on the advisory board for Breas, Invent Medical, and Liberate Medical; is a consultant for Caire, Fisher Paykel, Inogen, and Philips Respironics; and is a speaker for Fisher Paykel. None declared (M. J. S. F., C. D. C., A. M. H., K. L. R.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Health-related quality of life (HRQOL) is frequently impaired in pulmonary arterial hypertension. However, little is known about HRQOL in other forms of pulmonary hypertension (PH)., Research Question: Does HRQOL vary across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system?, Study Design and Methods: This cross-sectional study included patients with PH from the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort study. HRQOL was assessed by using emPHasis-10 (e-10), the 36-item Medical Outcomes Study Short Form survey (physical component score [PCS] and mental component score), and the Minnesota Living with Heart Failure Questionnaire. Pearson correlations between HRQOL and demographic, physiologic, and imaging characteristics within each WSPH group were tested. Multivariable linear regressions compared HRQOL across WSPH groups, adjusting for demographic characteristics, disease prevalence, functional class, and hemodynamics. Cox proportional hazards models were used to assess associations between HRQOL and survival across WSPH groups., Results: Among 691 patients with PH, HRQOL correlated with functional class and 6-min walk distance but not hemodynamics. HRQOL was severely depressed across WSPH groups for all measures except the 36-item Medical Outcomes Study Short Form survey mental component score. Compared with Group 1 participants, Group 2 participants had significantly worse HRQOL (e-10 score, 29 vs 24 [P = .001]; PCS, 32.9 ± 8 vs 38.4 ± 10 [P < .0001]; and Minnesota Living with Heart Failure Questionnaire score, 50 vs 38 [P = .003]). Group 3 participants similarly had a worse e-10 score (31 vs 24; P < .0001) and PCS (33.3 ± 9 vs 38.4 ± 10; P < .0001) compared with Group 1 participants, which persisted in multivariable models (P < .05). HRQOL was associated in adjusted models with survival across Groups 1, 2, and 3., Interpretation: HRQOL was depressed in PH and particularly in Groups 2 and 3 despite less severe hemodynamics. HRQOL is associated with functional capacity, but the severity of hemodynamic disease poorly estimates the impact of PH on patients' lives. Further studies are needed to better identify predictors and treatments to improve HRQOL across the spectrum of PH., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: H. M. D. has received grant funding from Bayer Pharmaceuticals, has served on advisory boards for Janssen Pharmaceuticals and has received consulting fees from Janssen Pharmaceuticals. N. S. H. serves on a clinical trial steering committee for Aerovate, advisory board for Gossamer, DSMB for Merch, and consultant for Liquidia and United Therapeutics. R.M. has received an honorarium from the American Academy of Sleep Medicine; funds for service on the American Board of Internal Medicine and as associate editor of the American Journal of Respiratory and Critical Care Medicine; has received National Institutes of Health funding; and has received royalties from UpToDate. A. R. H. has served as a consultant for Bayer, GossamerBio, Janssen, Merck, Tenax, and United Therapeutics. She owns stock in Tenax. P. M. H. has served on a steering committee for Merck and as consultant ARIA-CVS. S. C. M. has served as a consultant for Acceleron, Janssen, Merck, and United Therapeutics. None declared (A. B., A. B. L., E. M. H., M. S. J., J. A. L., M. K. R., S. C. E., E. B. R., R. P. F., F. P. R., G. J. B.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: This study assessed the clinical effects of a ventilatory assist (VA) device in addition to supplemental O 2 (VA+O 2 ) on exercise endurance in subjects with severe to very severe COPD managed with long-term oxygen therapy (LTOT)., Methods: This was a crossover clinical feasibility study of the effects of VA+O 2 in subjects with severe to very severe COPD managed with LTOT ( N = 15). At visit 1, physiologic measures were obtained, and subjects were tested on the cycle ergometer with VA. Peak work rate and flow for continuous supplemental O 2 /VA+O 2 were established. At visit 2, subjects exercised at a constant work rate of 80% peak work rate to maximum endurance after allocation to VA+O 2 or O 2 . Cardiorespiratory variables, work rate, and dyspnea were included to define potential clinical benefits of VA+O 2 . Data were analyzed using a linear mixed model., Results: Fifteen subjects with COPD (mean ± SD, age 67.9 ± 9.0 y, FEV 1 0.89 ± 0.35 observed) completed the study. Exercise duration in minutes was significantly longer with VA+O 2 versus O 2 (least squares mean [standard error], 12.0 [2.0] vs 6.2 [2.0], P = .01). VA+O 2 versus O 2 was also associated with significantly greater isotime improvements in Borg dyspnea scores (3.6 [0.5] vs 5.7 [0.5] , P < .001), S pO 2 (96.9 [0.9] vs 91.4 [0.9] , P < .001), leg fatigue scores (3.8 [0.6] vs 5.2 [0.6] , P = .008), and breathing frequency (22.8 [0.9] vs 25.8 [0.9] breaths/min , P = .01). There were no differences in heart rate., Conclusions: In symptomatic subjects with severe to very severe COPD, VA+O 2 significantly increased exercise time and improved dyspnea, S pO 2 , breathing frequency, and leg fatigue versus O 2 alone., Competing Interests: Ms Hilling discloses a relationship with New Aera. Dr Ameo discloses relationships with New Aera and Inogen. Mr Morishige discloses a relationship with New Aera. Dr Glezer discloses a relationship with Inogen. Dr Hill discloses relationships with New Aera, Inogen, Breas, Caire, Fisher & Paykel, Liberate Medical, Philips Respironics, and Vyaire. The remaining authors have disclosed no conflicts of interest., (Copyright © 2024 by Daedalus Enterprises.)

Pulmonary hypertension (PH) pathogenesis is driven by inflammatory and metabolic derangements as well as glycolytic reprogramming. Induction of both interleukin 6 (IL6) and transglutaminase 2 (TG2) expression participates in human and experimental cardiovascular diseases. However, little is known about the role of TG2 in these pathologic processes. The current study aimed to investigate the molecular interactions between TG2 and IL6 in mediation of tissue remodeling in PH. A lung-specific IL6 over-expressing transgenic mouse strain showed elevated right ventricular (RV) systolic pressure as well as increased wet and dry tissue weights and tissue fibrosis in both lungs and RVs compared to age-matched wild-type littermates. In addition, IL6 over-expression induced the glycolytic and fibrogenic markers, hypoxia-inducible factor 1α, pyruvate kinase M2 (PKM2), and TG2. Consistent with these findings, IL6 induced the expression of both glycolytic and pro-fibrogenic markers in cultured lung fibroblasts. IL6 also induced TG2 activation and the accumulation of TG2 in the extracellular matrix. Pharmacologic inhibition of the glycolytic enzyme, PKM2 significantly attenuated IL6-induced TG2 activity and fibrogenesis. Thus, we conclude that IL6-induced TG2 activity and cardiopulmonary remodeling associated with tissue fibrosis are under regulatory control of the glycolytic enzyme, PKM2., 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 © 2024 Penumatsa, Sharma, Warburton, Singhal, Toksoz, Bhedi, Qi, Preston, Anderlind, Hill and Fanburg.)

AV-101 (imatinib) powder for inhalation, an investigational dry powder inhaled formulation of imatinib designed to target the underlying pathobiology of pulmonary arterial hypertension, was generally well tolerated in healthy adults in a phase 1 single and multiple ascending dose study. I nhaled I m atinib P ulmonary A rterial H ypertension C linical T rial (IMPAHCT; NCT05036135) is a phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging, and confirmatory study. IMPAHCT is designed to identify an optimal AV-101 dose (phase 2b primary endpoint: pulmonary vascular resistance) and assess the efficacy (phase 3 primary endpoint: 6-min walk distance), safety, and tolerability of AV-101 dose levels in subjects with pulmonary arterial hypertension using background therapies. The study has an operationally seamless, adaptive design allowing for continuous recruitment. It includes three parts; subjects enrolled in Part 1 (phase 2b dose-response portion) or Part 2 (phase 3 intermediate portion) will be randomized 1:1:1:1 to 10, 35, 70 mg AV-101, or placebo (twice daily), respectively. Subjects enrolled in Part 3 (phase 3 optimal dose portion) will be randomized 1:1 to the optimal dose of AV-101 and placebo (twice daily), respectively. All study parts include a screening period, a 24-week treatment period, and a 30-day safety follow-up period; the total duration is ∼32 weeks. Participation is possible in only one study part. IMPAHCT has the potential to advance therapies for patients with pulmonary arterial hypertension by assessing the efficacy and safety of a novel investigational drug-device combination (AV-101) using an improved study design that has the potential to save 6-12 months of development time. ClinicalTrials.gov Identifier: NCT05036135., Competing Interests: Hunter Gillies, Benjamin T. Dake, Jonathan Langley, Ralph W. Niven, and Xiaosha Zhang are employees of Aerovate Therapeutics Inc. Murali M. Chakinala received research grants/funding from Acceleron Pharma, Actelion, Gossamer Bio, Medtronic, Respira Therapeutics, and United Therapeutics Corporation; and served as a consultant for Actelion, Altavant Sciences Inc., Express Scripts Holding Company, Liquidia Technologies Inc., PhaseBio Pharmaceuticals, United Therapeutics Corporation, and WebMD LLC (Medscape). Jeremy P. Feldman received honoraria from Acceleron Pharma, Altavant Sciences, Bayer, Gilead Sciences, and United Therapeutics Corporation. Marius M. Hoeper received fees for lectures/consultations from Acceleron, Actelion, AOP Health, Bayer, Ferrer, Gossamer Bio, Janssen, Merck, and Pfizer. Marc Humbert received research grants/funding from Acceleron Pharma, Aerovate Therapeutics Inc., Altavant Sciences Inc., Bayer, Janssen Pharmaceuticals, Merck, Morphogen‐IX Limited, and United Therapeutics Corporation; and received honoraria from Acceleron Pharma, Actelion, Bayer, GSK, Merck, and United Therapeutics Corporation. Vallerie V. McLaughlin received research grants/funding from Aerovate Therapeutics Inc., Altavant Sciences, Gossamer Bio, Janssen Pharmaceuticals, Merck, and SoniVie; and served as a consultant for Aerami Therapeutics, Aerovate Therapeutics Inc., Altavant Sciences, Bayer, Caremark LLC, CorVista, Gossamer Bio, Janssen Pharmaceuticals, Merck, and United Therapeutics Corporation. Stephan Rosenkranz received fees for lectures/consultations from Abbott, Actelion, Acceleron, AstraZeneca, AOP, Bayer, Boehringer Ingelheim, Ferrer, Gossamer, Janssen Pharmaceuticals, MSD, UT, and Vifor; and received institutional research grants from AstraZeneca, Bayer, and Janssen Pharmaceuticals. Nicholas S. Hill served as a consultant for Acceleron/Merck, Aerovate Therapeutics Inc., Altavant Sciences, Gossamer Bio, Insmed, and United Therapeutics Corporation. Zhi‐Cheng Jing declares no conflict of interest., (© 2024 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

A better understanding of the materials' fundamental physical processes is necessary to push hybrid perovskite photovoltaic devices towards their theoretical limits. The role of the perovskite grain boundaries is essential to optimise the system thoroughly. The influence of the perovskite grain size and crystal orientation on physical properties and their resulting photovoltaic performance is examined. We develop a novel, straightforward synthesis approach that yields crystals of a similar size but allows the tuning of their orientation to either the (200) or (002) facet alignment parallel to the substrate by manipulating dimethyl sulfoxide (DMSO) and tetrahydrothiophene-1-oxide (THTO) ratios. This decouples crystal orientation from grain size, allowing the study of charge carrier mobility, found to be improved with larger grain sizes, highlighting the importance of minimising crystal disorder to achieve efficient devices. However, devices incorporating crystals with the (200) facet exhibit an s-shape in the current density-voltage curve when standard scan rates are used, which typically signals an energetic interfacial barrier. Using the drift-diffusion simulations, we attribute this to slower-moving ions (mobility of 0.37 × 10 -10 cm 2 V -1 s -1 ) in combination with a lower density of mobile ions. This counterintuitive result highlights that reducing ion migration does not necessarily minimise hysteresis., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Rationale: It is unclear whether extracorporeal CO 2 removal (ECCO 2 R) can reduce the rate of intubation or the total time on invasive mechanical ventilation (IMV) in adults experiencing an exacerbation of chronic obstructive pulmonary disease (COPD). Objectives: To determine whether ECCO 2 R increases the number of ventilator-free days within the first 5 days postrandomization (VFD-5) in exacerbation of COPD in patients who are either failing noninvasive ventilation (NIV) or who are failing to wean from IMV. Methods: This randomized clinical trial was conducted in 41 U.S. institutions (2018-2022) (ClinicalTrials.gov ID: NCT03255057). Subjects were randomized to receive either standard care with venovenous ECCO 2 R (NIV stratum: n  = 26; IMV stratum: n  = 32) or standard care alone (NIV stratum: n  = 22; IMV stratum: n  = 33). Measurements and Main Results: The trial was stopped early because of slow enrollment and enrolled 113 subjects of the planned sample size of 180. There was no significant difference in the median VFD-5 between the arms controlled by strata ( P  = 0.36). In the NIV stratum, the median VFD-5 for both arms was 5 days (median shift = 0.0; 95% confidence interval [CI]: 0.0-0.0). In the IMV stratum, the median VFD-5 in the standard care and ECCO 2 R arms were 0.25 and 2 days, respectively; median shift = 0.00 (95% confidence interval: 0.00-1.25). In the NIV stratum, all-cause in-hospital mortality was significantly higher in the ECCO 2 R arm (22% vs. 0%, P  = 0.02) with no difference in the IMV stratum (17% vs. 15%, P  = 0.73). Conclusions: In subjects with exacerbation of COPD, the use of ECCO 2 R compared with standard care did not improve VFD-5. Clinical trial registered with www.clinicaltrials.gov (NCT03255057).

Competing Interests: The authors have disclosed no conflicts of interest.

Chemiresitive sensing allows the affordable and facile detection of small molecules such as H 2 O and CO 2 . Herein, we report a novel class of Earth-abundant post transition metal substituted Keggin polyoxometalates (POMs) for chemiresistive sensing applications, with conductivities up to 0.01 S cm -1 under 100% CO 2 and 65% Relative Humidity (RH).

Background: Not all hypercapnic COPD patients benefit from home noninvasive ventilation (NIV), and mechanisms through which NIV improves clinical outcomes remain uncertain. We aimed to identify "responders" to home NIV, denoted by a beneficial effect of NIV on arterial partial pressure of carbon dioxide ( P aCO 2 ), health-related quality of life (HRQoL) and survival, and investigated whether NIV achieves its beneficial effect through an improved P aCO 2 ., Methods: We used individual patient data from previous published trials collated for a systematic review. Linear mixed-effect models were conducted to compare the effect of NIV on P aCO 2 , HRQoL and survival, within subgroups defined by patient and treatment characteristics. Secondly, we conducted a causal mediation analysis to investigate whether the effect of NIV is mediated by a change in P aCO 2 ., Findings: Data of 1142 participants from 16 studies were used. Participants treated with lower pressure support (<14 versus ≥14 cmH 2 O) and with lower adherence (<5 versus ≥5 h·day -1 ) had less improvement in P aCO 2 (mean difference (MD) -0.30 kPa, p<0.001 and -0.29 kPa, p<0.001, respectively) and HRQoL (standardised MD 0.10, p=0.002 and 0.11, p=0.02, respectively), but this effect did not persist to survival. P aCO 2 improved more in patients with severe dyspnoea (MD -0.30, p=0.02), and HRQoL improved only in participants with fewer than three exacerbations (standardised MD 0.52, p=0.03). The results of the mediation analysis showed that the effect on HRQoL is mediated partially (23%) by a change in P aCO 2 ., Interpretation: With greater pressure support and better daily NIV usage, a larger improvement in P aCO 2 and HRQoL is achieved. Importantly, we demonstrated that the beneficial effect of home NIV on HRQoL is only partially mediated through a reduction in diurnal P aCO 2 ., Competing Interests: Conflict of interest: T. Raveling reports a travel grant from Breas Medical. N.S. Hill reports consulting fees from Philips, consulting fees and payments from Fisher & Paykel, and participates in boards of Breas and Philips. C. Casanova reports consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini and Novartis, and participates in boards of AstraZeneca and GlaxoSmithKline. E. Clini reports consulting fees from Chiesi Italia and Novartis, payments from AstraZeneca, Boehringer Ingelheim and GaxoSmithKline, and meeting/travel support from Boehringer Ingelheim and Chiesi. T. Köhnlein reports support from Grifols Deutschland GmbH. P.B. Murphy reports grants and payments from Fisher & Paykel, Resmed, Breas Medical and Philips Respironics, and payments from Chiesi and Genzyme. M.L. Duiverman reports grants from Resmed, Philips, Lowenstein, Vivisol, Sencure and Fisher & Paykel, and payments from Chiesi and Breas Medical. P.J. Wijkstra reports grants from Resmed, and grants and consulting fees from Philips., (Copyright ©The authors 2024.)

Source Citation: Pitre T, Zeraatkar D, Kachkovski GV, et al. Noninvasive oxygenation strategies in adult patients with acute hypoxemic respiratory failure: a systematic review and network meta-analysis. Chest. 2023;164:913-928. 37085046., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J23-0119.

Fescue toxicosis (FT) is produced by an ergot alkaloid (i.e., ergovaline [EV])-producing fungus residing in toxic fescue plants. Associations between EV, decreased weight gain and ruminal volatile fatty acids are unclear. Feces, rumen fluid, and blood were collected from 12 steers that grazed non-toxic (NT) or toxic (E +) fescue for 28 days. The E + group exhibited decreased propionate (P), increased acetate (A), and increased ruminal A:P ratio, with similar trends in feces. Plasma GASP-1 (G-Protein-Coupled-Receptor-Associated-Sorting-Protein), a myostatin inhibitor, decreased (day 14) only in E + steers. Ergovaline was present only in E + ruminal fluid and peaked on day 14. The lower ruminal propionate and higher A:P ratio might contribute to FT while reduced GASP-1 might be a new mechanism linked to E + -related weight gain reduction. Day 14 ergovaline zenith likely reflects ruminal adaptations favoring EV breakdown and its presence only in rumen points to local, rather than systemic effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear., Objectives: The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival., Methods: Pulmonary Vascular Disease Phenomics (National Heart, Lung, and Blood Institute) cohort participants (patients with group 1 PAH, comparators, and healthy control participants) with sleep studies were included. Multimodal RV functional measures were examined in association with AHI and percentage of recording time with oxygen saturation <90% (T90) per 10-unit increment. Linear models, adjusted for demographics, oxygen, diffusing capacity of the lungs for carbon monoxide, pulmonary hypertension medications, assessed AHI and T90, and RV measures. Log-rank test/Cox proportional hazards models adjusted for demographics, oxygen, and positive airway pressure were constructed for transplantation-free survival analyses., Results: Analysis included 186 participants with group 1 PAH with a mean age of 52.6 ± 14.1 years; 71.5% were women, 80.8% were Caucasian, and there were 43 events (transplantation or death). AHI and T90 were associated with decreased RV ejection fraction (on magnetic resonance imaging), by 2.18% (-2.18; 95% CI: -4.00 to -0.36; P = 0.019) and 0.93% (-0.93; 95% CI: -1.47 to -0.40; P < 0.001), respectively. T90 was associated with increased RV systolic pressure (on echocardiography), by 2.52 mm Hg (2.52; 95% CI: 1.61 to 3.43; P < 0.001); increased mean pulmonary artery pressure (on right heart catheterization), by 0.27 mm Hg (0.27; 95% CI: 0.05 to 0.49; P = 0.019); and RV hypertrophy (on electrocardiography), 1.24 mm (1.24; 95% CI: 1.10 to 1.40; P < 0.001). T90, but not AHI, was associated with a 17% increased 5-year risk for transplantation or death (HR: 1.17; 95% CI: 1.07 to 1.28). In non-CTD-associated PAH, T90 was associated with a 21% increased risk for transplantation or death (HR: 1.21; 95% CI: 1.08 to 1.34). In CTD-associated PAH, T90 was associated with RV dysfunction, but not death or transplantation., Conclusions: Sleep-related hypoxia was more strongly associated than AHI with measures of RV dysfunction, death, or transplantation overall and in group 1 non-CTD-associated PAH but only with RV dysfunction in CTD-associated PAH. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887)., Competing Interests: Funding Support and Author Disclosures This study was supported by grants U01 HL125218 (principal investigator, Dr Rosenzweig), U01 HL125205 (principal investigator, Dr Frantz), U01 HL125212 (principal investigator, Dr Hemnes), U01 HL125208 (principal investigator, Dr Rischard), U01 HL125175 (principal investigator, Dr Hassoun), U01 HL125215 (principal investigator, Dr Leopold), and U01 HL125177 (principal investigator, Dr Beck) and the Pulmonary Hypertension Association. Dr Hill is a scientific advisory board member for Aerovate and Insmed; is a consultant for Bellerophon; and is a data and safety monitoring board member for Merck. Dr Finet has served as a clinical practice advisor for Wolters Kluwer Health-Lexicomp (forfeited compensation); and is an Item-Writing Task Force member for the American Board of Internal Medicine. Dr Kwon has received funding from the National Heart, Lung, and Blood Institute (grant 1R01HL170090-01); and has a research agreement with Circle Cardiovascular Imaging. Dr Beck has received support from the Pulmonary Hypertension Association. Dr Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, the France Foundation, IQVIA, Tenax, UpToDate, and United Therapeutics. Dr Hassoun serves on a scientific steering committee for Merck Sharpe & Dohme; and is a scientific adviser for ARIA-CV (unrelated to the present work). Dr Hemnes serves as a consultant for Bayer, United Therapeutics, Janssen, GossamerBio, and Tenax Therapeutics; holds stock in Tenax Therapeutics; and has received grants from the National Institutes of Health, the Cardiovascular Medical Research and Education Fund, and Imara. Dr Horn has conducted research studies with Acceleron/Merck, Cereno, and Insmed. Dr Leopold is a consultant for Abbott Vascular; is a speaker for United Therapeutics; has received research funding from Astellas to her institution; and has received support from the American Heart Association (grant AIM 19AIML34980000; National Heart, Lung, and Blood Institute grant U01 HL125215). Dr Rischard has consulting relationships with Acceleron and United Therapeutics; is a steering committee member for Acceleron; and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Janssen, and Aadi Bioscience. Dr Mehra has received an honorarium from the American Academy of Sleep Medicine; has received funds for service on the American Board of Internal Medicine and as associate editor of the American Journal of Respiratory and Critical Care Medicine; has received National Institutes of Health funding; has received investigator-initiated research funds to her institution from Resmed, Inspire, and Sommetrics; and has received royalties from UpToDate. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2 , which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2 . Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target. NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.

Background: This update summarizes key changes made to the protocol for the Frequency of Screening and Spontaneous Breathing Trial (SBT) Technique Trial-North American Weaning Collaborative (FAST-NAWC) trial since the publication of the original protocol. This multicenter, factorial design randomized controlled trial with concealed allocation, will compare the effect of both screening frequency (once vs. at least twice daily) to identify candidates to undergo a SBT and SBT technique [pressure support + positive end-expiratory pressure vs. T-piece] on the time to successful extubation (primary outcome) in 760 critically ill adults who are invasively ventilated for at least 24 h in 20 North American intensive care units., Methods/design: Protocols for the pilot, factorial design trial and the full trial were previously published in J Clin Trials ( https://doi.org/10.4172/2167-0870.1000284 ) and Trials (https://doi: 10.1186/s13063-019-3641-8). As planned, participants enrolled in the FAST pilot trial will be included in the report of the full FAST-NAWC trial. In response to the onset of the coronavirus disease of 2019 (COVID-19) pandemic when approximately two thirds of enrollment was complete, we revised the protocol and consent form to include critically ill invasively ventilated patients with COVID-19. We also refined the statistical analysis plan (SAP) to reflect inclusion and reporting of participants with and without COVID-19. This update summarizes the changes made and their rationale and provides a refined SAP for the FAST-NAWC trial. These changes have been finalized before completion of trial follow-up and the commencement of data analysis., Trial Registration: Clinical Trials.gov NCT02399267., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Source Citation: Romanet C, Wormser J, Fels A, et al. Effectiveness of exercise training on the dyspnoea of individuals with long COVID: a randomised controlled multicentre trial. Ann Phys Rehabil Med. 2023;66:101765. 37271020., Competing Interests: Disclosures: The commentator has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J23-0073.

Background: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition., Methods: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (≈11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO 2peak )>15 mL/(kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance., Results: A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (area under the curve, 0.87; P =0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (log-rank P =0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64-0.88]; P =0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise., Conclusions: RVFnRec defined by RV end-diastolic volume therapeutic decrease of -15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise., Competing Interests: Disclosures Dr Rischard has consulting relationships with Bayer and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Merck, and Janssen. Dr Naeije reports relationships including consultancies, speakers fees, and membership of advisory boards with AOP Orphan Pharmaceuticals, Johnson & Johnson, Lung Biotechnology Corporation, and United Therapeutics. Dr Garcia is Chief Executive Officer and founder of Aqualung Therapeutics Corporation. Dr Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, France Foundation, IQVIA, Tenax, UpToDate, and United Therapeutics. Dr Hassoun has served as consultant for Merck. Dr Hemnes has consulting relationships with Janssen, Merck, Gossamer, Bio, United Therapeutics, Bayer, Tenax. She owns stock in Tenax therapeutics and she has received research support from National Heart, Lung, and Blood Institute and Cardiovascular Medical Research and Education Fund. Dr Hill is the chair for an Aerovate steering committee. He is a consultant for Bellerophon and Liquidia and Merck. Dr Horn has consulting relationships with Biotronik and AADI biosciences. She serves on the DSMB for SoniVie and V-waves Ltd. She receives research support from Merck and Cereno. Dr Leopold Abbott has served as a consultant for Aria. She has research support from Astellas Pharma and United Therapeutics. Dr Rosenzweig has received consulting fees from Acceleron for a scientific advisory board meeting; and her institution receives grant support from Bayer, United Therapeutics, Janssen, and SonVie. Dr Tang served as consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, WhiteSwell, Kiniksa, Boston Scientific, and CardiaTec Biosciences and has received honorarium from Springer Nature and American Board of Internal Medicine. The other authors report no conflicts.

The prevalence of acute vasodilator response (AVR) to inhaled nitric oxide (iNO) during right heart catheterization (RHC) is 12% in idiopathic pulmonary arterial hypertension (IPAH). AVR, however, is reportedly lower in other disease-associated pulmonary arterial hypertension (PAH), such as connective tissue disease (CTD). The prevalence of AVR in patients on PAH therapy (prevalent cases) is unknown. We sought to determine AVR prevalence in Group 1 PH in the PVDOMICS cohort of incident and prevalent patients undergoing RHC. AVR was measured in response to 100% O 2 and O 2 plus iNO, with positivity defined as (1) decrease in mean pulmonary artery pressure (mPAP) by ≥10 mmHg to a value ≤40 mmHg, with no change or an increase in cardiac output (definition 1); or (2) decrease in mPAP by ≥12% and pulmonary vascular resistance by ≥30% (definition 2). AVR rates and cumulative survival were compared between incident and prevalent patients. In 338 mainly prevalent (86%) patients, positive AVR to O 2 -only was <2%, and 5.1% to 16.9%, based on definition 1 and 2 criteria, respectively; following O 2  + iNO. IPAH AVR prevalence (4.1%-18.7%) was similar to prior reports. AVR positivity was 7.7% to 15.4% in mostly CTD-PAH prevalent cases, and 2.6% to 11.8% in other PAH groups. Survival was 89% in AVR responders versus 77% in nonresponders from PAH diagnosis, and 91% versus 86% from PVDOMICS enrollment (log-rank test p  = 0.04 and p  = 0.05, respectively). In conclusion, AVR in IPAH patients is similar to prior studies. AVR in non-IPAH patients was higher than previously reported. The relationship between PAH therapy, AVR response, and survival warrants further investigation., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Despite record-breaking devices, interfaces in perovskite solar cells are still poorly understood, inhibiting further progress. Their mixed ionic-electronic nature results in compositional variations at the interfaces, depending on the history of externally applied biases. This makes it difficult to measure the band energy alignment of charge extraction layers accurately. As a result, the field often resorts to a trial-and-error process to optimize these interfaces. Current approaches are typically carried out in a vacuum and on incomplete cells, hence values may not reflect those found in working devices. To address this, a pulsed measurement technique characterizing the electrostatic potential energy drop across the perovskite layer in a functioning device is developed. This method reconstructs the current-voltage (JV) curve for a range of stabilization biases, holding the ion distribution "static" during subsequent rapid voltage pulses. Two different regimes are observed: at low biases, the reconstructed JV curve is "s-shaped", whereas, at high biases, typical diode-shaped curves are returned. Using drift-diffusion simulations, it is demonstrated that the intersection of the two regimes reflects the band offsets at the interfaces. This approach effectively allows measurements of interfacial energy level alignment in a complete device under illumination and without the need for expensive vacuum equipment., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Aims: Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear., Methods and Results: Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide., Conclusion: The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes., Competing Interests: Conflict of interest P.M. has received consultancy fees from AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, Daiichi Sankyo, Novartis, Novo Nordisk, and Vifor Pharma. B.A.B. receives research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics, has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer-Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations, and is named inventor (US Patent no. 10307179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. A.R.H. has served as a consultant for GossamerBio, Tenax Therapeutics, United Therapeutics, Merck, and Janssen. She is a stock holder in Tenax Therapeutics. W.H.W.T. is a consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, Kiniksa, WhiteSwell, Boston Scientific, and CardiaTec Biosciences and has received honorarium from Springer Nature and American Board of Internal Medicine. All other authors reported no relevant relationships to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Fescue toxicosis is caused by grazing ergot alkaloid-producing endophyte ( Epichloë coenophiala )-infected tall fescue (E+). Summer grazing of E+ leads to decreased productivity, associated impaired thermoregulation, and altered behavior. The goal of this study was to determine the role of E+ grazing-climate interaction on animal behavior and thermoregulation during late fall. Eighteen Angus steers were placed on nontoxic (NT), toxic (E+) and endophyte-free (E-) fescue pastures for 28 days. Physiological parameters, such as rectal temperature (RT), respiration rate (RR), ear and ankle surface temperature (ET, AT), and body weights, were measured. Skin surface temperature (SST) and animal activity were recorded continuously with temperature and behavioral activity sensors, respectively. Environmental conditions were collected using paddocks-placed data loggers. Across the trial, steers on E+ gained about 60% less weight than the other two groups. E+ steers also had higher RT than E- and NT, and lower SST than NT post-pasture placement. Importantly, animals grazing E+ spent more time lying, less time standing, and took more steps. These data suggest that late fall E+ grazing impairs core and surface temperature regulation and increases non-productive lying time, which may be partly responsible for the observed decreased weight gains.

Background: Oral imatinib has been shown to be effective, but poorly tolerated, in patients with advanced pulmonary arterial hypertension (PAH). To maintain efficacy while improving tolerability, AV-101, a dry powder inhaled formulation of imatinib, was developed to deliver imatinib directly to the lungs., Methods: This phase 1, placebo-controlled, randomised single ascending dose (SAD) and multiple ascending dose (MAD) study evaluated the safety/tolerability and pharmacokinetics of AV-101 in healthy adults. The SAD study included five AV-101 cohorts (1 mg, 3 mg, 10 mg, 30 mg, 90 mg) and placebo, and a single-dose oral imatinib 400-mg cohort. The MAD study included three AV-101 cohorts (10 mg, 30 mg, 90 mg) and placebo; dosing occurred twice daily for 7 days., Results: 82 participants (SAD n=48, MAD n=34) were enrolled. For the SAD study, peak plasma concentrations of imatinib occurred within 3 h of dosing with lower systemic exposure compared to oral imatinib (p<0.001). For the MAD study, systemic exposure of imatinib was higher after multiple doses of AV-101 compared to a single dose, but steady-state plasma concentrations were lower for the highest AV-101 cohort (90 mg) compared to simulated steady-state oral imatinib at day 7 (p=0.0002). Across AV-101 MAD dose cohorts, the most common treatment-emergent adverse events were cough (n=7, 27%) and headache (n=4, 15%)., Conclusions: AV-101 was well tolerated in healthy adults, and targeted doses of AV-101 significantly reduced the systemic exposure of imatinib compared with oral imatinib. An ongoing phase 2b/phase 3 study (IMPAHCT; clinicaltrials.gov identifier NCT05036135) will evaluate the safety/tolerability and clinical benefit of AV-101 for PAH., Competing Interests: Conflict of interest: H. Gillies, R. Niven and B. Dake are employees of Aerovate Therapeutics, Inc. M.M. Chakinala received research grants/funding from Acceleron Pharma, Actelion, Eiger Biopharmaceuticals, Gossamer Bio, Medtronic and United Therapeutics Corporation; served as a consultant for Actelion, Altavant Sciences, Inc., Express Scripts Holding Company, Liquidia Technologies, Inc., PhaseBio Pharmaceuticals, United Therapeutics Corporation and WebMD LLC (Medscape). J.P. Feldman received honoraria from Acceleron Pharma, Altavant Sciences, Bayer, Gilead Sciences and United Therapeutics Corporation. M. Humbert received research grants/funding from Acceleron Pharma, Aerovate Therapeutics, Inc., Altavant Sciences, Inc., Bayer, Janssen Pharmaceuticals, Merck, Morphogen-IX Limited and United Therapeutics Corporation; and received honoraria from Acceleron Pharma, Actelion, Bayer, GlaxoSmithKline, Merck and United Therapeutics Corporation. M. Kankam is an employee of Altasciences Kansas, Inc.; and received research grants/funding from Actelion, Acurx, Biogen, BioXcel, DynPort Vaccine Company, Grifols, Jazz Pharmaceuticals, Novo Nordisk, Novus, Pfizer, Urovant Sciences, ViroDefense, and the US Food and Drug Administration/National Institutes of Health. N.S. Hill, M.M. Hoeper and V.V. McLaughlin have no disclosures to declare., (Copyright ©The authors 2023.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is believed to involve both vascular obstruction and vasoconstriction; hence, pulmonary vasodilators such as riociguat may be beneficial. Acute vasoreactivity testing (AVT) is seldom performed routinely in CTEPH patients, so there is limited understanding of the frequency and significance of an acute vasodilator response. Systematic vasodilator testing with oxygen (O 2 ) and oxygen plus inhaled nitric oxide (O 2  + iNO) was performed as part of the Pulmonary Vascular Disease Omics (PVDOMICS) NHLBI project, providing an opportunity to examine AVT responses in CTEPH. Patients with CTEPH enrolled in PVDOMICS ( n  = 49, 40 with prevalent CTEPH [82%]) underwent right heart catheterization including AVT with O 2 and O 2  + iNO. Hemodynamics were obtained at baseline and with each challenge. Fourteen of 49 patients (29%) had >20% drop in pulmonary vascular resistance (PVR) with O 2 . With O 2  + iNO, 30/49 (61%) had >20% drop in PVR, 20% had >20% drop in mean pulmonary artery pressure (mPAP) and PVR, and 8% had >10 mmHg decline in mPAP to mPAP < 40 with normal cardiac output. Patients on riociguat had less response to O 2  + iNO than patients on phosphodiesterase-5 inhibitors. Our findings shed light on the significant variability in vascular tone that is present in CTEPH, confirming that CTEPH represents a combination of mechanical obstruction and vasoconstriction that appears similar to that observed with Group 1 PAH. Additional study regarding whether results of acute vasodilator testing predict response to therapy and relate to prognosis is warranted., Competing Interests: Anna R. Hemnes has served as a consultant for Bayer, United Therapeutics, Janssen, GossamerBio, and Tenax Therapeutics; holds stock in Tenax Therapeutics; and has received grants from the National Institutes of Health, CMREF, and Imara. Erika B. Rosenzweig has received consulting fees from Acceleron for a scientific advisory board meeting; and her institution receives grant support from Bayer, United Therapeutics, Janssen, and SonVie. Robert P. Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, France Foundation, IQVIA, Tenax Therapeutics, UpToDate, and United Therapeutics. Paul M. Hassoun has served as scientific advisor for Merck Sharp & Dohme, an activity unrelated to the current work. Nicholas S. Hill has received research grants for Acceleron, Aerovate. Altavant, Gossamer. Liquidia, Merck, and United Therapeutics; and has served on advisory boards for Acceleron, Aerovate, Altavant, Gossamer, and Liquidia. Actelion Sciences, and Tenax Therapeutics; and has U.S. Patent#9,605,047, Patent pending PCT/US2019/059890, Patent application 2021/133937. Stephen C. Mathai has served as a consultant for Acceleron, Actelion Sciences, Bayer, and United Therapeutics.  Margaret M. Park has served on the Speakers Bureau of Lantheus Medical Imaging (Definity contrast). Franz P. Rischard has consulting relationships with Acceleron and United Therapeutics; is on a Steering Committee for Acceleron; and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Janssen, and AADI. Evelyn M. Horn has served on the Data and Safety Monitoring Board of AADi Biosciences and SoniVie; has served on the Clinical Events Committee for V‐wave; and has served as a consultant for Biotronik. The remaining authors declare no conflicts of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: In the midst of the COVID-19 pandemic, noninvasive respiratory support (NRS) therapies such as high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) were central to respiratory care. The extent to which these treatments increase the generation and dispersion of infectious respiratory aerosols is not fully understood. The objective of this study was to characterize SARS-CoV-2 aerosol dispersion from subjects with COVID-19 undergoing NRS therapy., Methods: Several different aerosol sampling devices were used to collect air samples in the vicinity of 31 subjects with COVID-19, most of whom were receiving NRS therapy, primarily HFNC. Aerosols were collected onto filters and analyzed for the presence of SARS-CoV-2 RNA. Additional measurements were collected in an aerosol chamber with healthy adult subjects using respiratory therapy devices under controlled and reproducible conditions., Results: Fifty aerosol samples were collected from subjects receiving HFNC or NIV therapy, whereas 6 samples were collected from subjects not receiving NRS. Only 4 of the 56 aerosol samples were positive for SARS-CoV-2 RNA, and all positive samples were collected using a high air flow scavenger mask collection device placed in close proximity to the subject. The chamber measurements with healthy subjects did not show any significant increase in aerosol dispersion caused by the respiratory therapy devices compared to baseline., Conclusions: Our findings demonstrate very limited detection of SARS-CoV-2-containing aerosols in the vicinity of subjects with COVID-19 receiving NRS therapies in the clinical setting. These results, combined with controlled chamber measurements showing that HFNC and NIV device usage was not associated with increased aerosol dispersion, suggest that NRS therapies do not result in increased dispersal of aerosols in the clinical setting., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Background: During diagnostic bronchoscopies, conscious sedation improves patient tolerance, but it can contribute to hypercapnia and hypoxia by various mechanisms including depression of ventilatory drive. This prospective study was undertaken to determine the frequency of respiratory events and associated oxygen desaturations during bronchoscopy with conscious sedation., Patients and Methods: The Nox-T3 monitoring system was placed before starting the bronchoscopy and remained in place for 30 minutes following the procedure. The primary endpoint was the occurrence of obstructive and central apneic events during bronchoscopy under conscious sedation., Results: Obstructive events (apnea and hypopnea) occurred in 100% of patients (n=31), and central apneas occurred in 58% of patients (n=18) during the procedure with a median of 9 and 2 events per patient, respectively. During recovery, a significant proportion of patients had detectable obstructive (86%) and central (36%) events. Higher body mass index was associated with oxygen desaturation to <90% and with the need for escalation of care. Furthermore, a conscious sedation regimen that included propofol was significantly associated with central apneic events., Conclusion: Respiratory events are common during and immediately postprocedure after conscious sedation for bronchoscopy. Most events are obstructive, and the use of propofol predisposes to central apneas during the procedure. Both types of events are associated with a higher body mass index. Oxygen desaturation to <90% triggers escalation of care. A further prospective study will be required to determine the clinical significance of these apneic events and whether alleviating these events will improve the safety and outcomes of bronchoscopic procedures performed under conscious sedation., Competing Interests: Disclosure: There is no conflict of interest or other disclosures., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification., Objectives: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort., Methods: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death., Results: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH., Conclusions: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887)., Competing Interests: Funding Support and Author Disclosures The study received grants U01 HL125218 (Principal Investigator: Dr Rosenzweig), U01 HL125205 (Principal Investigator: Dr Frantz), U01 HL125212 (Principal Investigator: Dr Hemnes), U01 HL125208 (Principal Investigator: Dr Rischard), U01 HL125175 (Principal Investigator: Dr Hassoun), U01 HL125215 (Principal Investigator: Dr Leopold), and U01 HL125177 (Principal Investigator: Dr Beck) and was supported by the Pulmonary Hypertension Association. Dr Hemnes has served as a consultant for Bayer, United Therapeutics, Janssen, GossamerBio, and Tenax Therapeutics; holds stock in Tenax Therapeutics; and has received grants from the National Institutes of Health, CMREF, and Imara. Dr Leopold is supported by the National Institutes of Health grant U01 125215 and the American Heart Association 19AIML34980000; receives salary support from the Massachusetts Medical Society; has received research funding (to her institution) from Astellas; has served as a consultant for Abbott Vascular and United Therapeutics; and has served as a site principal investigator for a study sponsored by Aria CV. Dr Abidov is supported by research grants from Astellas Pharma, Boehringer Ingelheim, and Kiniksa outside of the submitted work. Dr Rosenzweig has received consulting fees from Acceleron for a scientific advisory board meeting; and her institution receives grant support from Bayer, United Therapeutics, Janssen, and SonVie. Dr Borlaug has received research grants from National Institutes of Health/NHLBI, AstraZeneca, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and has received consulting fees from Actelion, Amgen, Aria, Axon Therapies, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. Dr Dubrock has received consulting fees from Janssen Pharmaceuticals; and has served on advisory boards for Janssen Pharmaceuticals and United Therapeutics. Dr Finet is a consultant to Wolters Kluwer Health, Clinical Drug Information Ad Honorem. Dr Frantz has consulting, steering committee, and advisory board relationships with Altavant Sciences, Bayer, Gossamer Bio, Janssen, Shouti, France Foundation, IQVIA, Tenax, UpToDate, and United Therapeutics. Dr Garcia is CEO and founder of Aqualing Therapeutics. Dr Hassoun has served as scientific advisor for Merck Sharp & Dohme, an activity unrelated to the current work. Dr Highland has grants/contracts with Acceleron Pharmaceuticals, Actelion Pharmaceuticals (Janssen), Bayer Healthcare, Boehringer Ingelheim, Eiger Pharmaceuticals, Eli Lilly, Gossamer Bio, United Therapeutics, and Viela Bio (Horizon); has served as a consultant and/or member of a steering or advisory committee with Acceleron Pharmaceuticals, Actelion Pharmaceuticals (Janssen), Boehringer Ingelheim, Forsee, Genentech, Gossamer Bio, and United Therapeutics; and has served on the Speakers Bureau for Actelion Pharmaceuticals (Janssen), Bayer Healthcare, Boehringer Ingelheim, and United Therapeutics. Dr Hill has received research grants for Acceleron, Aerovate. Altavant, Gossamer. Liquidia, Merck, and United Therapeutics; and has served on advisory boards for Acceleron, Aerovate, Altavant, Gossamer, and Liquidia. Dr Maron has relationships with Deerfield Corporation, Actelion Sciences, and Tenax Therapeutics; and has U.S. Patent #9,605,047, Patent pending PCT/US2019/059890, Patent application 2021/133937. Dr Mathai has served as a consultant for Acceleron, Actelion, Bayer, and United Therapeutics. Dr Mehra is supported by National Institutes of Health grants U01HL125177 and UH3HL140144 and the American Heart Association AHA 18SFRN34170013; has received royalties from Up to Date; has received compensation from the American Board of Internal Medicine; and has received an honorarium from the American Academy of Sleep Medicine. M.M. Park has served on the Speakers Bureau of Lantheus Medical Imaging (Definity contrast). Dr Rischard has consulting relationships with Acceleron and United Therapeutics; is on a Steering Committee for Acceleron; and receives research support from Ismed, United Therapeutics, Bayer, Acceleron, Janssen, and AADI. Dr Thomas has served as a consultant for GE, Abbott, egnite, EchoIQ, and Caption Health; as well as spouse employment for Caption Health. Dr Horn has served on the Data and Safety Monitoring Board of AADi Biosciences and SoniVie; has served on the Clinical Events Committee for V-wave; and has served as a consultant for Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The INSPIRE trial was a Phase 3, open-label, multicenter trial (LTI-301) that enrolled patients with pulmonary arterial hypertension (PAH) ≥ 18 years of age who transitioned to Yutrepia from nebulized treprostinil (Transition) or added Yutrepia to prostacyclin naïve patients on ≤2 nonprostacyclin oral therapies. The objectives of the trial were to evaluate the safety and tolerability of Yutrepia (dry-powder formulation of treprostinil) in patients with PAH. The primary safety measures were the incidence of adverse events (AEs) and serious AEs. Exploratory efficacy measures were also assessed during the trial. Transition patients initiated Yutrepia at a dose comparable to their nebulized treprostinil dose while prostacyclin naïve patients received 26.5-mcg QID; up-titration in 26.5-mcg increments was permitted for both groups. A total of 121 patients were enrolled, of which 29 patients discontinued from the trial, with the most common reason being AEs. Eighty percent of the Transition group and 96% of the prostacyclin naïve group titrated to a dose ≥79.5 mcg QID at Day 360, respectively, with one patient achieving a dose of 212-mcg QID. The most common AEs were cough, headache, upper respiratory tract infection, dyspnea, dizziness, throat irritation, diarrhea, chest discomfort, fatigue, and nasopharyngitis. Most of these events were considered treatment-related though mild to moderate in severity and expected for prostacyclin therapy administered by inhalation. In an evaluation of exploratory efficacy measures, patients remained stable or improved over the 1 year of treatment. Yutrepia was found to be a convenient, safe, and well-tolerated inhaled prostacyclin treatment option for PAH patients., Competing Interests: N. S. H.: Liquidia and Aerovate, consulting fees; Altavant, lectures, presentations, speakers bureaus, manuscript writing, and/or educational events; Liquidia, expert testimony; Liquidia, support for attending meetings and/or travel; Merck and United Therapeutics, data safety monitoring board or advisory board. J. P. F.: Liquidia, advisory board. S. S.: ACCP CHEST and United Therapeutics, research grants; Liquidia, steering committee; Gossamer Bio, United Therapeutics, and Bayer, advisor; Bayer, United Therapeutics, and Johnson & Johnson, speaker; Johnson & Johnson, planned patent; Bayer, advisory board; GSK, endpoint adjudication committee. R. L. B.: Bayer, Abbot, United Therapeutics, Abbott, Gossamer Bio, and Acceleron, consulting fees; Society of Heart and Lung Transplantation and the Pulmonary Vascular Disease Institute, leadership and/or fiduciary role. I. R. P.: Janssen, United Therapeutics, PhaseBio, and Tenax, research grants and/or contracts; Altavant, Janssen, United Therapeutics, and Liquidia, consulting fees; Medscape and Med on the Go, lectures, presentations, speakers bureaus, manuscript writing and/or educational events; Bayer, expert testimony; Altavant, Janssen, United Therapeutics, and Liquidia, data safety monitoring or advisory board; ISHLT, leadership or fiduciary role. D. B.: Acceleron, Arena/United Therapeutics, Altavant, Actelion/Janssen/Johnson & Johnson, Ikaria, Reata, Complexa Liquidia, and Merck, research grants; Acceleron, Altavant, Bayer, Merck, and Liquidia, consulting fees; Practice Point Communications, lectures, presentations, speakers bureaus, manuscript writing and/or educational events; Bayer, expert testimony; United Therapeutics, data safety or advisory board; USPHSR (United States Pulmonary Hypertension Scientific Registry), leadership or fiduciary role; Johnson & Johnson, stock or stock options. R. P. F.: NHLBI, research grant; Up to Date, royalties or licenses; Janssen, Liquidia, Shouti, Altavant, Gossamer Bio, Bayer, and Tenax, consulting fees; United Therapeutics, France Foundation, and Janssen, lectures, presentations, speakers bureaus, manuscript writing and/or educational events; Janssen and Liquidia, data safety or advisory board; Tenax, stock or stock options. S. P.: Liquidia, employee, stock or stock options. A. G.: Liquidia, employee, attending meetings and/or travel patents, and stock or stock options. T. M. B.: Bayer, research grant; Liquidia and Bayer, steering committee and consulting fees; NHLBI and MESA, data safety and/or advisory board., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Many key insights into actin regulation have been derived through examining how microbial pathogens intercept the actin cytoskeleton during infection. Mycobacterium marinum, a close relative of the human pathogen Mycobacterium tuberculosis, polymerizes host actin at the bacterial surface to drive intracellular movement and cell-to-cell spread during infection. However, the mycobacterial factor that commandeers actin polymerization has remained elusive. Here, we report the identification and characterization of the M. marinum actin-based motility factor designated mycobacterial intracellular rockets A (MirA), which is a member of the glycine-rich PE&#95;PGRS protein family. MirA contains an amphipathic helix to anchor into the mycobacterial outer membrane and, surprisingly, also the surface of host lipid droplet organelles. MirA directly binds to and activates the host protein N-WASP to stimulate actin polymerization through the Arp2/3 complex, directing both bacterial and lipid droplet actin-based motility. MirA is dissimilar to known N-WASP activating ligands and may represent a new class of microbial and host actin regulator. Additionally, the MirA-N-WASP interaction represents a model to understand how the enigmatic PE&#95;PGRS proteins contribute to mycobacterial pathogenesis., (© 2022. The Author(s).)

Rho kinase (ROCK) is implicated in the development of pulmonary arterial hypertension (PAH) in which abnormal pulmonary vascular smooth muscle (VSM) contractility and remodeling lead to right heart failure. Pharmacologic ROCK inhibitors block experimental pulmonary hypertension (PH) development in rodents but can have off-target effects and do not distinguish between the two ROCK forms, ROCK1 and ROCK2, encoded by separate genes. An earlier study using gene knock out (KO) in mice indicated that VSM ROCK2 is required for experimental PH development, but the role of ROCK1 is not well understood. Here we investigated the in vivo role of ROCK1 in PH development by generating a VSM-targeted homozygous ROCK1 gene KO mouse strain. Adult control mice exposed to Sugen5416 (Su)/hypoxia treatment to induce PH had significantly increased right ventricular systolic pressures (RVSP) and RV hypertrophy versus normoxic controls. In contrast, Su/hypoxia-exposed VSM ROCK1 KO mice did not exhibit significant RVSP elevation, and RV hypertrophy was blunted. Su/hypoxia-induced pulmonary small vessel muscularization was similarly elevated in both control and VSM ROCK1 KO animals. siRNA-mediated ROCK1 knock-down (KD) in human PAH pulmonary arterial SM cells (PASMC) did not affect cell growth. However, ROCK1 KD led to reduced AKT and MYPT1 signaling in serotonin-treated PAH PASMC. The findings suggest that like VSM ROCK2, VSM ROCK1 actively contributes to PH development, but in distinction acts via nonproliferative pathways to promote hypoxemia, and thus may be a distinct therapeutic target in PH., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 ( strongly disagree ) to +5 ( strongly agree ) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus-based recommendations may be helpful to clinicians and beneficial for patients when evidence-based guidance is unavailable., Competing Interests: Franck F. Rahaghi reports consultation, research, and speakership honoraria from Bayer and Janssen, consultation and speakership from United Therapeutics, and consultation fees from Acceleron. Vijay P. Balasubramanian reports a research grant from United Therapeutics and serves on a speakers bureau for Bayer. Robert C. Bourge reports research grant support to my institution from United Therapeutics and Bayer, and service on a Scientific Advisory Board at United Therapeutics. Murali M. Chakinala reports grants or contracts from Actelion/Janssen, Bayer, Medtronic, NIH, Reata, Liquidia, Phase Bio, Complexa, United Therapeutics, Altavant, Trio Health Analytics, Reata, Acceleron, Arena, and Gossamer; consulting fees from Altavant, Vaderis Therapeutics, Aerovate, Reata, VWave, and Arena; honoraria from Bayer, Gilead, Simply Speaking, WebMD, and United Therapeutics; support for attending meetings and/or travel from Actelion/Janssen, United Therapeutics, Bayer, Acceleron, Reata, and Gilead; participation on a Data Safety Monitoring Board or Advisory Board for Actelion/Janssen, Express Scripts, Phase Bio, Altavant, Gossamer, United Therapeutics, Bayer, Acceleron, and Liquidia; and leadership or a fiduciary role in the Pulmonary Hypertension Association and the Cure HHT Global Research and Medical Advisory Board. Michael S. Eggert reports research contracts with United Therapeutics (BREEZE and ADVANCE Outcomes), Acceleron, and Actelion. Jean M. Elwing reports grants from Actelion, Acceleron, Reata, United Therapeutics, Liquidia, Phase Bio, Complexa, Gossamer Bio, Bayer, Arena, Eiger, Akros, Bellerophon, and Lung LLC and consulting fees from United Therapeutics, Acceleron, Liquidia, Altavant, Bayer, Gossamer Bio, Actelion, Bayer. Jeremy Feldman reports consulting and giving talks for Bayer, United Therapeutics, and Jansen. Christopher King reports personal fees from Actelion, personal fees from Genentech, United Therapeutics, and Boehringer Ingelheim; has served on advisory boards for and is on the Speakers’ Bureau of Actelion, Boehringer‐Ingelheim Pharmaceuticals, and United Therapeutics. James R. Klinger reports that his institution receives research funding from United Technologies, service on a Steering Committee and a Clinical Outcomes Committee for Bayer, and a leadership role in the Pulmonary Hypertension Association. Stephen C. Mathai reports personal fees from United Therapeutics; participation on a data safety monitoring board or advisory board from United Therapeutics, Actelion, and Bayer, and leadership or a fiduciary role in the PCORI Rare Disease Advisory Panel and the World Symposium on Pulmonary Hypertension. John Wesley McConnell reports consulting fees from Actelion, Bayer, Gossamer, Altavant, and Liquidia; honoraria from Actelion, Bayer, Simply Speaking, Impact PH, and Reata, and participation on a data safety monitoring board or advisory board for Actelion, Liquidia, Gossamer, and Altavant. Harold I. Palevsky reports honoraria for serving on scientific advisory boards for Acceleron, Actelion/Janssen, PhaseBio and United Therapeutics, and serving on a DSMB for United Therapeutics. Ricardo Restrepo‐Jaramillo reports serving on speaker's bureau for United Therapeutics, Bayer, and Actelion. Zeenat Safdar reports serving on a speakers bureau, consultation and advisory boards for Actelion, United Therapeutics, Boehringer Ingelheim, Bayer, and Roche. Jeffrey S. Sager reports personal fees from Bayer pharmaceuticals, grants and personal fees from United Therapeutics, grants and personal fees from Janssen (J and J), and grants from Reata outside the submitted work. Namita Sood reports a speaking fee from Bayer. Roxana Sulica reports research grants from Bayer, United Therapeutics, Complexa, and Reata, and serves on advisory boards for Actelion, Bayer, United Therapeutics, and Reata. R. James White reports research grants from United Therapeutics, Reata, Bayer, Merck, and Janssen and consulting fees from Merck and Bayer. Nicholas S. Hill reports honoraria from Axon Research for this study; grants to his institution from Actelion, Bayer, Gilead, and United Therapeutics; consulting fees from United Therapeutics; and participation in Data Safety Monitoring Boards for United Therapeutics and Pfizer. All authors had access to the Delphi questionnaire analysis and data and participated in the review, revision, and approval of the content of the manuscript for submission. Charles D. Burger reports no disclosures or conflicts of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Bovine fescue toxicosis (FT) is caused by grazing ergot alkaloid-producing endophyte (Epichloë coenophiala)-infected tall fescue. Endophyte's effects on the animal's microbiota and metabolism were investigated recently, but its effects in planta or on the plant-animal interactions have not been considered. We examined multi-compartment microbiota-metabolome perturbations using multi-'omics (16S and ITS2 sequencing, plus untargeted metabolomics) in Angus steers grazing non-toxic (Max-Q) or toxic (E+) tall fescue for 28 days and in E+ plants. E+ altered the plant/animal microbiota, decreasing most ruminal fungi, with mixed effects on rumen bacteria and fecal microbiota. Metabolic perturbations occurred in all matrices, with some plant-animal overlap (e.g., Vitamin B6 metabolism). Integrative interactomics revealed unique E+ network constituents. Only E+ had ruminal solids OTUs within the network and fecal fungal OTUs in E+ had unique taxa (e.g., Anaeromyces). Three E+-unique urinary metabolites that could be potential biomarkers of FT and targeted therapeutically were identified., (© 2022. The Author(s).)

Background: This study brings a human-centered design (HCD) perspective to understanding the patient experience when using noninvasive ventilation (NIV) with the goal of creating better strategies to improve NIV comfort and tolerance., Methods: Using an HCD motivational approach, we created a semi-structured interview to uncover the patients' journey while being treated with NIV. We interviewed 16 patients with chronic obstructive pulmonary disease (COPD) treated with NIV while hospitalized. Patients' experiences were captured in a stepwise narrative creating a journey map as a framework describing the overall experience and highlighting the key processes, tensions, and flows. We broke the journey into phases, steps, emotions, and themes to get a clear picture of the overall experience levers for patients., Results: The following themes promoted NIV tolerance: trust in the providers, the favorable impression of the facility and staff, understanding why the mask was needed, how NIV works and how long it will be needed, immediate relief of the threatening suffocating sensation, familiarity with similar treatments, use of meditation and mindfulness, and the realization that treatment was useful. The following themes deterred NIV tolerance: physical and psychological discomfort with the mask, impaired control, feeling of loss of control, and being misinformed., Conclusions: Understanding the reality of patients with COPD treated with NIV will help refine strategies that can improve their experience and tolerance with NIV. Future research should test ideas with the best potential and generate prototypes and design iterations to be tested with patients., (JCOPDF © 2022.)

Background: There is strong evidence that noninvasive ventilation (NIV) improves the outcomes of patients hospitalized with severe COPD exacerbation, and NIV is recommended as the first-line therapy for these patients. Yet, several studies have demonstrated substantial variation in NIV use across hospitals, leading to preventable morbidity and mortality. In addition, prior studies suggested that efforts to increase NIV use in COPD need to account for the complex and interdisciplinary nature of NIV delivery and the need for team coordination. Therefore, our initial project aimed to compare two educational strategies: online education (OLE) and interprofessional education (IPE), which targets complex team-based care in NIV delivery. Due to the impact of the COVID-19 pandemic on recruitment and planned intervention, we had made several changes in the study design, statistical analysis, and implementation strategies delivery as outlined in the methods., Methods: We originally proposed a two-arm, pragmatic, cluster, randomized hybrid implementation-effectiveness trial comparing two education strategies to improve NIV uptake in patients with severe COPD exacerbation in 20 hospitals with a low baseline rate of NIV use. Due to logistical constrains and slow recruitment, we changed the study design to an opened cohort stepped-wedge design with three steps which will allow the institutions to enroll when they are ready to participate. Only the IPE strategy will be implemented, and the education will be provided in an online virtual format. Our primary outcome will be the hospital-level risk-standardized NIV proportion for the period post-IPE training, along with the change in rate from the period prior to training. Aim 1 will compare the change over time of NIV use among patients with COPD in the step-wedged design. Aim 2 will explore the mediators' role (respiratory therapist autonomy and team functionality) on the relationship between the implementation strategies and effectiveness. Finally, in Aim 3, through interviews with providers, we will assess the acceptability and feasibility of the educational training., Conclusion: The changes in study design will result in several limitation. Most importantly, the hospitals in the three cohorts are not randomized as they enroll based on their readiness. Second, the delivery of the IPE is virtual, and it is not known if remote education is conducive to team building. However, this study will be among the first to test the impact of IPE in the inpatient setting carefully and may generalize to other interventions directed to seriously ill patients., Trial Registration: ClinicalTrials.gov NCT04206735 . Registered on December 20, 2019., (© 2021. The Author(s).)

This document summarizes the work of the COPD Technical Expert Panel working group. For patients with COPD, the most pressing current coverage barriers identified were onerous diagnostic requirements focused on oxygenation (rather than ventilation) and difficulty obtaining bilevel devices with backup rate capabilities. Because of these difficulties, many patients with COPD were instead sometimes prescribed home mechanical ventilators. Critical evidence supports changes to current policies, including randomized controlled trial evidence suggesting a mortality benefit from bilevel positive airway pressure with backup rate and updated clinical practice guidelines from the American Thoracic Society as well as the European Respiratory Society. To achieve optimal access to noninvasive ventilation for patients with COPD, we make the following key recommendations: (1) removal of the need for overnight oximetry testing; (2) the ability to initiate therapy using bilevel devices with backup rate capability; and (3) increased duration of time to meet adherence criteria (ie, a second 90-day trial period) in those patients actively engaged in their care. Clear guidelines based on medical necessity are also included for patients who require initiation of or switch to a home mechanical ventilator. Adoption of these proposed recommendations would result in the right device, for the right type of patient with COPD, at the right time. Finally, we emphasize the need for adequate clinical support during initiation and maintenance of home noninvasive ventilation in such patients., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Tall fescue ( Lolium arundinaceum (Schreb.) S.J. Darbyshire) often forms a symbiotic relationship with fungal endophytes ( Epichloë coenophiala ), which provides increased plant performance and greater tolerance to environmental stress compared to endophyte-free tall fescue. Whether this enhanced performance of tall fescue exclusively results from the grass-fungus symbiosis, or this symbiosis additionally results in the recruitment of soil microbes in the rhizosphere that in turn promote plant growth, remain a question. We investigated the soil bacterial and fungal community composition in iron-rich soil in the southeastern USA, and possible community shifts in soil microbial populations based on endophyte infection in tall fescue by analyzing the 16s rRNA gene and ITS specific region. Our data revealed that plant-available phosphorus (P) was significantly ( p < 0.05) influenced by endophyte infection in tall fescue. While the prominent soil bacterial phyla were similar, a clear fungal community shift was observed between endophyte-infected (E+) and endophyte-free (E-) tall fescue soil at the phylum level. Moreover, compared to E- soil, E+ soil showed a greater fungal diversity at the genus level. Our results, thus, indicate a possible three-way interaction between tall fescue, fungal endophyte, and soil fungal communities resulting in improved tall fescue performance.