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Objective: Insulin resistance and beta-cell dysfunction both are important contributors to the pathogenesis of type 2 diabetes. Exercise training improves insulin sensitivity, but its effects on beta-cell function are less well studied.Research Design and Methods: Sedentary, overweight adults were randomized to control or one of three 8-month exercise programs: 1) low amount/moderate intensity, 2) low amount/vigorous intensity, or 3) high amount/vigorous intensity. Of 387 randomized, 260 completed the study and 237 had complete data. Insulin sensitivity (S(i)), acute insulin response to glucose (AIRg), and the disposition index (DI = S(i) x AIRg) were modeled from an intravenous glucose tolerance test.Results: Compared with control subjects, all three training programs led to increases in DI. However, the moderate-intensity group experienced a significantly larger increase in DI than either of the vigorous-intensity groups and through a different mechanism. The high-amount/vigorous-intensity group improved S(i) and had a compensatory reduction in AIRg, whereas the moderate-intensity group had a similar improvement in S(i) but almost no reduction in AIRg. Importantly, the inactive control group experienced a significant increase in fasting glucose.Conclusions: To the extent that the DI accurately reflects beta-cell function, we observed that both moderate- and vigorous-intensity exercise training improved beta-cell function, albeit through distinct mechanisms. It is not clear which of these mechanisms is preferable for maintenance of metabolic health. While moderate-intensity exercise led to a larger improvement in DI, which may reflect a transition toward a more normal DI, longer-term investigations would be necessary to determine which was more effective at reducing diabetes risk. [ABSTRACT FROM AUTHOR]

Background: Whether sex is an independent prognostic factor in lung cancer survival is the subject of ongoing debate. Both large national registries and single hospital studies have shown conflicting findings. In this study, we explore the impact of sex on lung-cancer-specific survival in an unselected population that is well-characterized with respect to stage and other covariates., Material and Methods: All patients diagnosed with lung cancer at a single hospital serving a whole and defined region in Southern Norway during the 10 years 2007-2016 were included. Follow-up data were available for at least 56 months for all patients. Analyses were adjusted for stage, treatment, performance status, smoking, age, histology, epidermal growth factor receptor/anaplastic lymphoma kinase/immunotherapy treatment and period. Differences in lung-cancer-specific survival by sex were explored using restricted mean survival times (RMST)., Results: Of the 1,261 patients diagnosed with lung cancer, 596 (47%) were females and 665 (53%) males, with mean ages of 68.5 and 69.5 years, respectively. The observed 5-year lung-cancer-specific survival rate was 27.4% (95% CI 23.7, 31.2) in females and 21.4% (95% CI 18.2, 24.8) in males. However, after adjustment for covariates, no significant differences by sex were observed. The 5-year RMST was 0.9 months shorter (95% CI -2.1, 0.31, p = 0.26) in males compared to females., Interpretation: In this cohort, sex was not associated with a difference in lung-cancer-specific survival after adjusting for clinical and biological factors. Imbalance in stage at diagnosis was the main contributor to the observed difference in lung-cancer-specific survival by sex.

Background: COVID-19 has been associated with cardiac troponin T (cTnT) elevations and changes in cardiac structure and function, but the link between cardiac dysfunction and high-sensitive cardiac troponin T (hs-cTnT) in the acute and convalescent phase is unclear., Objective: To assess whether hs-cTnT concentrations are associated with cardiac dysfunction and structural abnormalities after hospitalization for COVID-19, and to evaluate the performance of hs-cTnT to rule out cardiac pathology., Methods: Patients hospitalized with COVID-19 had hs-cTnT measured during the index hospitalization and after 3-and 12 months, when they also underwent an echocardiographic study. A subset also underwent cardiovascular magnetic resonance imaging (CMR) after 6 months. Cardiac abnormalities were defined as left ventricular hypertrophy or dysfunction, right ventricular dysfunction, or CMR late gadolinium., Results: We included 189 patients with hs-cTnT concentrations measured during hospitalization for COVID-19, and after 3-and 12 months: Geometric mean (95%CI) 13 (11-15) ng/L, 7 (6-8) ng/L and 7 (6-8) ng/L, respectively. Cardiac abnormalities after 3 months were present in 45 (30%) and 3 (8%) of patients with hs-cTnT ≥ and < 5 ng/L at 3 months, respectively (negative predictive value 92.3% [95%CI 88.5-96.1%]). The performance was similar in patients with and without dyspnea. Hs-cTnT decreased from hospitalization to 3 months (more pronounced in intensive care unit-treated patients) and remained unchanged from 3 to 12 months, regardless of the presence of cardiac abnormalities., Conclusion: Higher hs-cTnT concentrations in the convalescent phase of COVID-19 are associated with the presence of cardiac pathology and low concentrations (< 5 ng/L) may support in ruling out cardiac pathology following the infection., (© 2024. The Author(s).)

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by damage to the alveolar epithelium, leading to fibrosis and excessive accumulation of extracellular matrix in the interstitium of the lung. In the present study we performed high-resolution proteomic profiling of bronchoalveolar lavage (BAL) from IPF patients and controls, and found that the complement pathway was highly upregulated in IPF. The proteins C5, C6, C7, C8, and C9, all of which are part of the complement end product, TCC, were all upregulated. We also found that TCC levels were increased in plasma among IPF patients compared to controls, after adjustment for age, sex and BMI [mean (SD) 0.62 (0.24) vs. 0.33 (0.10), p  = 0.031]. These findings suggest a role for the complement system in the pathogenesis of IPF., Competing Interests: MTD has received research funding (to his institution) and speaker/consulting fees from Boehringer Ingelheim and Roche, unrelated to the current study. The remaining 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 © 2023 Sikkeland, Ueland, Lund, Durheim and Mollnes.)

Background: For interpretation of pulmonary function tests (PFTs), reference values based on sex, age, height and ethnicity are needed. In Norway, the European Coal and Steel Community (ECSC) reference values remain widely used, in spite of recommendations to implement the more recent Global Lung Function Initiative (GLI) reference values., Objective: To assess the effects of changing from ECSC to GLI reference values for spirometry, DLCO and static lung volumes, using a clinical cohort of adults with a broad range in age and lung function., Methods: PFTs from 577 adults (18-85 years, 45% females) included in recent clinical studies were used to compare ECSC and GLI reference values for FVC, FEV1, DLCO, TLC and RV. Percent predicted and lower limit of normal (LLN) were calculated. Bland-Altman plots were used to assess agreement between GLI and ECSC % predicted values., Results: In both sexes, GLI % predicted values were lower for FVC and FEV1, and higher for DLCO and RV, compared to ECSC. The disagreement was most pronounced in females, with mean (SD) difference 15 (5) percent points (pp) for DLCO and 17 (9) pp for RV (p < 0.001). With GLI, DLCO was below LLN in 23% of the females, with ECSC in 49% of the females., Conclusions: The observed differences between GLI and ECSC reference values are likely to entail significant consequences with respect to criteria for diagnostics and treatment, health care benefits and inclusion in clinical trials. To ensure equity of care, the same reference values should be consistently implemented across centers nationwide., (© 2023. The Author(s).)

COVID-19 primarily affects the respiratory system. We aimed to evaluate how pulmonary outcomes develop after COVID-19 by assessing participants from the first pandemic wave prospectively 3 and 12 months following hospital discharge. Pulmonary outcomes included self-reported dyspnoea assessed with the modified Medical Research Council dyspnoea scale, 6-min walk distance (6MWD), spirometry, diffusing capacity of the lung for carbon monoxide ( D LCO ), body plethysmography and chest computed tomography (CT). Chest CT was repeated at 12 months in participants with pathological findings at 3 months. The World Health Organization (WHO) ordinal scale for clinical improvement defined disease severity in the acute phase. Of 262 included COVID-19 patients, 245 (94%) and 222 (90%) participants attended the 3- and 12-month follow-up, respectively. Self-reported dyspnoea and 6MWD remained unchanged between the two time points, while D LCO and total lung capacity improved (0.28 mmol·min -1 ·kPa -1 , 95% CI 0.12-0.44, and 0.13 L, 95% CI 0.02-0.24, respectively). The prevalence of fibrotic-like findings on chest CT at 3 and 12 months in those with follow-up chest CT was unaltered. Those with more severe disease had worse dyspnoea, D LCO and total lung capacity values than those with mild disease. There was an overall positive development of pulmonary outcomes from 3 to 12 months after hospital discharge. The discrepancy between the unaltered prevalence of self-reported dyspnoea and the improvement in pulmonary function underscores the complexity of dyspnoea as a prominent factor of long-COVID. The lack of increase in fibrotic-like findings from 3 to 12 months suggests that SARS-CoV-2 does not induce a progressive fibrotic process in the lungs., Competing Interests: Conflict of interest: T.V. Lerum has nothing to disclose. Conflict of interest: C. Meltzer has nothing to disclose. Conflict of interest: J.R. Rodriguez has nothing to disclose. Conflict of interest: T.M. Aaløkken has nothing to disclose. Conflict of interest: E. Brønstad has nothing to disclose. Conflict of interest: B.B. Aarli reports personal fees for lectures and advisory board work from AstraZeneca, personal fees for lectures from GlaxoSmithKline, Novartis, Boehringer Ingelheim and Chiesi Pharma, outside the submitted work. Conflict of interest: K.M. Aarberg-Lund has nothing to disclose. Conflict of interest: M.T. Durheim reports grants to his institution and personal fees from Boehringer Ingelheim and Roche, and personal fees from AstraZeneca, outside the submitted work. Conflict of interest: H. Ashraf reports grants from Boehringer Ingelheim, during the conduct of the study. Conflict of interest: G. Einvik reports grants from Boehringer Ingelheim, during the conduct of the study; and personal fees for consultancy from AstraZeneca AB, outside the submitted work. Conflicts of interest: O.H. Skjønsberg has nothing to disclose. Conflict of interest: K. Stavem reports fees from UCB Pharma and MSD, outside the submitted work., (Copyright ©The authors 2023.)

Objective: To assess the trajectory of symptoms and symptom-defined post-traumatic stress disorder (PTSD) from 1.5 to 12 months after hospitalization for COVID-19 and determine risk factors for persistent symptoms and PTSD., Methods: This was a prospective cohort study of consecutive patients discharged after hospitalization for COVID-19 before 1 June 2020 in six hospitals in Southern Norway. Symptom-defined PTSD was assessed by the post-traumatic stress disorder (PTSD) checklist for DSM-5 (PCL-5) at 1.5, 3 and/or 12 months after hospitalization, using DSM-5 criteria. Changes in PCL-5 symptom score and the prevalence of PTSD were analyzed with multivariable mixed models., Results: In total, 388 patients were discharged alive, and 251 (65%) participated. Respondents had a mean (SD) age of 58.4 (14.2) years, and 142 (57%) were males. The prevalence of symptom-defined PTSD was 14, 8, and 9% at 1.5, 3, and 12 months, respectively. WHO disease severity for COVID-19 was not associated with PCL-5 scores. Female sex, lower age and non-Norwegian origin were associated with higher PCL-5 scores. The odds ratio (OR) (95%CI) for PTSD was 0.32 (0.12 to 0.83, p = 0.019) at 3 months and 0.38 (0.15 to 0.95, p = 0.039) at 12 months compared to 1.5 months. There was no association between PTSD and WHO severity rating., Conclusions: The level of PTSD symptoms decreased from 1.5 to 3 months after hospitalization, but did not decrease further to 12 months, and there was no association between PTSD symptoms and COVID-19 disease severity., (Copyright © 2022 Stavem, Heir, Dammen, Brønstad, Lerum, Durheim, Lund, Aarli and Einvik.)

Background and Objective: Antifibrotic therapy with nintedanib or pirfenidone slows disease progression and reduces mortality in patients with idiopathic pulmonary fibrosis (IPF). However, patients with advanced IPF, as defined by forced vital capacity (FVC) < 50% and/or diffusion capacity for carbon monoxide (DLCO) < 30% of predicted, have not been included in randomized trials, and the outcomes of such patients who initiate treatment are not well understood. We determined lung function, disease progression and mortality outcomes following initiation of antifibrotic therapy in patients with advanced IPF at the time of treatment initiation compared to those with mild-moderate IPF., Methods: We included 502 patients enrolled in IPF registries from four Nordic countries. Linear mixed models were used to assess change in FVC and DLCO over time. Cox proportional hazards models were used to assess transplant-free survival and progression- and transplant-free survival., Results: Of 502 patients, 66 (13%) had advanced IPF. Annual change in FVC was -125 ml (95% CI -163, -87) among patients with mild-moderate IPF, and +28 ml (95% CI -96, +152) among those with advanced IPF. Advanced IPF at treatment initiation was associated with poorer transplant-free survival (hazard ratio [HR] 2.39 [95% CI 1.66, 3.43]) and progression- and transplant-free survival (HR 1.60 [95% CI 1.15, 2.23])., Conclusion: In a broadly representative IPF population, patients with advanced IPF at the initiation of antifibrotic therapy did not have greater lung function decline over time compared with those with mild-moderate IPF, but had substantially higher mortality. Prospective studies are needed to determine the effect of antifibrotic therapy in patients with advanced IPF., (© 2021 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Loss of bone mineral and skeletal muscle mass is common after lung transplantation (LTx), and physical activity (PA) may prevent further deterioration. We aimed to assess the effects of 20-week high-intensity training (HIT) on body composition, bone health, and PA in LTx recipients, 6-60 months after surgery., Methods: In a randomized controlled trial, 51 LTx recipients underwent Dual-energy X-ray absorptiometry (DXA), and PA level and sedentary time were objectively recorded by accelerometers for seven consecutive days. Of these, 39 participants completed the study, including 19 participants in the HIT group and 20 participants in the standard care group., Results: Following the intervention, ANCOVA models revealed a nonsignificant between-group difference for change in lean body mass (LBM) and bone mineral density (BMD) of the lumbar spine of 0.4% (95% CI = -3.2, 1.5) (p = .464) and 1.0% (95% CI=-1.3, 3.4) (p = .373), respectively. Trabecular bone score (TBS) of the lumbar spine (L1-L4), however, increased by 2.2 ± 5.0% in the exercise group and decreased by -1.6 ± 5.9% in the control group, giving a between-group difference of 3.8% (95% CI=0.1, 7.5) (p = .043). There were no between-group differences in PA or sedentary time., Conclusion: High-intensity training after LTx improved TBS significantly, but not PA, LBM or BMD., (© 2021 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Importance: Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis., Objective: To assess the effect of antimicrobial therapy on clinical outcomes., Design, Setting, and Participants: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020)., Interventions: Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group., Main Outcomes and Measures: The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality., Results: Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%)., Conclusions and Relevance: Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease., Trial Registration: ClinicalTrials.gov Identifier: NCT02759120.

The long-term pulmonary outcomes of coronavirus disease 2019 (COVID-19) are unknown. We aimed to describe self-reported dyspnoea, quality of life, pulmonary function and chest computed tomography (CT) findings 3 months following hospital admission for COVID-19. We hypothesised outcomes to be inferior for patients admitted to intensive care units (ICUs), compared with non-ICU patients.Discharged COVID-19 patients from six Norwegian hospitals were enrolled consecutively in a prospective cohort study. The current report describes the first 103 participants, including 15 ICU patients. The modified Medical Research Council (mMRC) dyspnoea scale, the EuroQol Group's questionnaire, spirometry, diffusing capacity of the lung for carbon monoxide ( D LCO ), 6-min walk test, pulse oximetry and low-dose CT scan were performed 3 months after discharge.mMRC score was >0 in 54% and >1 in 19% of the participants. The median (25th-75th percentile) forced vital capacity and forced expiratory volume in 1 s were 94% (76-121%) and 92% (84-106%) of predicted, respectively. D LCO was below the lower limit of normal in 24% of participants. Ground-glass opacities (GGO) with >10% distribution in at least one of four pulmonary zones were present in 25% of participants, while 19% had parenchymal bands on chest CT. ICU survivors had similar dyspnoea scores and pulmonary function as non-ICU patients, but higher prevalence of GGO (adjusted OR 4.2, 95% CI 1.1-15.6) and lower performance in usual activities.3 months after admission for COVID-19, one-fourth of the participants had chest CT opacities and reduced diffusing capacity. Admission to ICU was associated with pathological CT findings. This was not reflected in increased dyspnoea or impaired lung function., Competing Interests: Conflict of interest: T.V. Lerum has nothing to disclose. Conflict of interest: T.M. Aaløkken has nothing to disclose. Conflict of interest: E. Brønstad has nothing to disclose. Conflict of interest: B. Aarli reports personal fees for lectures and advisory board work from AstraZeneca, personal fees for lectures from GlaxoSmithKline, Novartis, Boehringer Ingelheim and Chiesi Pharma, outside the submitted work. Conflict of interest: E. Ikdahl has nothing to disclose. Conflict of interest: K.M.A. Lund has nothing to disclose. Conflict of interest: M.T. Durheim reports grants and personal fees from Boehringer Ingelheim, personal fees from Roche and AstraZeneca, outside the submitted work. Conflict of interest: J.R. Rodriguez has nothing to disclose. Conflict of interest: C. Meltzer has nothing to disclose. Conflict of interest: K. Tonby has nothing to disclose. Conflict of interest: K. Stavem has nothing to disclose. Conflict of interest: O.H. Skjønsberg has nothing to disclose. Conflict of interest: H. Ashraf reports grants from Boehringer Ingelheim, during the conduct of the study. Conflict of interest: G. Einvik reports grants from Boehringer Ingelheim, during the conduct of the study; personal fees for consultancy from AstraZeneca AB, outside the submitted work., (Copyright ©ERS 2021.)

Chronic lung allograft dysfunction (CLAD) is a serious complication after lung transplantation (LuTx) and is associated with elevated proportions of neutrophils in bronchoalveolar lavage (BAL). Induced sputum is a less-invasive sampling method than BAL and assesses markers of inflammation on the surfaces of large central airways. We wanted to examine whether % neutrophil levels in induced sputum were elevated prior to CLAD diagnosis among LuTx recipients, and whether sputum markers of inflammation can be used as a tool for predicting the development of CLAD. Induced sputum samples were collected at 1, 3, 6, 12, and 24 months post-LuTx in 36 patients with a history of COPD or pulmonary fibrosis, and of these, 16 developed CLAD either during or after the sputum surveillance period. At 2 years, median (IQR) % neutrophils in induced sputum were significantly higher among patients with CLAD compared with those without CLAD [73 (52-80) % vs 59 (41-76) %, p = .01]. Interestingly, we found a significant increase in the rate of change in % neutrophils beginning at 90 days preceding the diagnosis of CLAD. This suggests using sputum neutrophil percentage as a surveillance modality for monitoring lung allograft function after LuTx., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Common variable immunodeficiency (CVID) is characterized not only by recurrent bacterial infections, but also autoimmune and inflammatory complications including interstitial lung disease (ILD), referred to as granulomatous-lymphocytic interstitial lung disease (GLILD). Some patients with GLILD have waxing and waning radiologic findings, but preserved pulmonary function, while others progress to end-stage respiratory failure. We reviewed 32 patients with radiological features of GLILD from our Norwegian cohort of CVID patients, including four patients with possible monogenic defects. Nineteen had deteriorating lung function over time, and 13 had stable lung function, as determined by pulmonary function testing of forced vital capacity (FVC), and diffusion capacity of carbon monoxide (DLCO). The overall co-existence of other non-infectious complications was high in our cohort, but the prevalence of these was similar in the two groups. Laboratory findings such as immunoglobulin levels and T- and B-cell subpopulations were also similar in the progressive and stable GLILD patients. Thoracic computer tomography (CT) scans were systematically evaluated and scored for radiologic features of GLILD in all pulmonary segments. Pathologic features were seen in all pulmonary segments, with traction bronchiectasis as the most prominent finding. Patients with progressive disease had significantly higher overall score of pathologic features compared to patients with stable disease, most notably traction bronchiectasis and interlobular septal thickening. 18F-2-fluoro-2-deoxy-D-glucose ( 18 F-FDG) positron emission tomography/CT (PET/CT) was performed in 17 (11 with progressive and six with stable clinical disease) of the 32 patients and analyzed by quantitative evaluation. Patients with progressive disease had significantly higher mean standardized uptake value (SUVmean), metabolic lung volume (MLV) and total lung glycolysis (TLG) as compared to patients with stable disease. Nine patients had received treatment with rituximab for GLILD. There was significant improvement in pathologic features on CT-scans after treatment while there was a variable effect on FVC and DLCO., Conclusion: Patients with progressive GLILD as defined by deteriorating pulmonary function had significantly greater pathology on pulmonary CT and FDG-PET CT scans as compared to patients with stable disease, with traction bronchiectasis and interlobular septal thickening as prominent features., 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 © 2021 Fraz, Moe, Revheim, Stavrinou, Durheim, Nordøy, Macpherson, Aukrust, Jørgensen, Aaløkken and Fevang.)

Background: While expected need for intensive care after lung transplantation (LTx) does not normally affect organ allocation, it would be useful to estimate whether intensive care capacity is limited. The aim of this study was to assess factors available before LTx to identify predictors of prolonged intensive care unit (ICU) length of stay (LOS) after LTx., Methods: All bilateral LTx recipients excluding re-transplantation and multi-organ transplantation at Oslo University Hospital from 2000 to 2013 were included (n = 277). Predictive factors for ICU LOS were identified using pre- and perioperative variables., Results: Univariate analyses showed that recipients with pulmonary arterial hypertension, young age, female gender, low body height, low pretransplant actual total lung capacity (aTLC), and recipients who received an oversized donor lung were at risk for long ICU LOS. Patients with emphysema had lower risk of long ICU LOS. In multivariate analyses, a lower aTLC (p < .001) and a higher mean pulmonary artery pressure (mPAP) (p = .004) predicted prolonged ICU LOS., Conclusions: We found that small recipient lung volume and high mPAP were predictors for prolonged ICU LOS. Our observations may be useful in planning use of resources in LTx, particularly in times of limited intensive care resources., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hospitalizations are common in patients with idiopathic pulmonary fibrosis (IPF) and are associated with high mortality. We used data from the Premier Healthcare Database to determine in-hospital mortality rates and the factors associated with in-hospital mortality in patients with IPF in the era of approved antifibrotic drugs.The Premier Healthcare Database is a detailed and broadly representative database of hospital admissions and discharges in the US. Patients with IPF who were hospitalized between 1 January 2015 and 28 February 2018 were identified using a diagnostic algorithm comprising International Classification of Diseases -9 and International Classification of Diseases -10 diagnostic codes and billing data. Associations between patient-, hospital- and treatment-related factors and a composite outcome of death during the index visit, lung transplant during the index visit but >1 day after admission, or death during a readmission within 90 days of the index visit were analyzed using logistic regression.The cohort comprised 9667 hospitalized patients with IPF. In total, 1414 patients (14.6%) met the composite outcome: 1036 (10.7%) died during the index visit, 371 (3.8%) died during a readmission within 90 days; 7 (0.1%) underwent lung transplant >1 day after admission. Factors significantly associated with a higher risk of the composite outcome included mechanical ventilation (odds ratio 6.41 [95% CI: 5.24, 7.84]), admission to the intensive care unit (1.73 [1.49, 2.00]), attendance by a critical care physician (2.12 [1.33, 3.38]), older age (1.20 [1.12, 1.28] per 10-year increase), and use of intravenous steroids (1.16 [1.00, 1.34]), intravenous antibiotics (1.49 [1.22, 1.83]) and opioids (3.41 [2.95, 3.93]). Factors significantly associated with a lower risk of the composite outcome included female sex (0.70 [0.61, 0.80]), comorbid chronic obstructive pulmonary disease (0.69 [0.60, 0.78]), attendance by a family medicine physician (0.67 [0.48, 0.94]) or internal medicine physician (0.59 [0.46, 0.75]), and use of oral steroids (0.62 [0.51, 0.77]), statins (0.76 [0.67, 0.87]) and proton pump inhibitors (0.80 [0.70, 0.92]).In conclusion, patients with IPF are at risk of mortality during a hospital stay or readmission within 90 days, particularly those who receive mechanical ventilation.

Background: Peak oxygen uptake (VO 2peak ) remains low after lung transplantation (LTx). We evaluated the effect of high-intensity interval training (HIIT) on VO 2peak , muscular strength, health-related quality of life (HRQOL), pulmonary function, and physical function after LTx., Methods: In this randomized controlled trial, 54 participants were enrolled from 6 to 60 months after LTx. The HIIT group (n = 25) followed a supervised HIIT program, consisting of endurance and strength trainings 3 times a week for 20 weeks. The control group (n = 29) received usual care. The primary outcome was a change in VO 2peak measured by cardiopulmonary exercise testing. The secondary outcomes were changes in 1-repetition maximum (1RM) for arm press and leg press, HRQOL (36-Item Short-Form Health Survey [SF-36]), pulmonary function (forced expiratory volume in 1 sec, diffusing capacity of the lungs for carbon monoxide), and physical function (1RM in handgrip, 15-sec stair run, and 30-sec chair stand)., Results: A total of 46 participants completed the study, including 23 of 25 in the intervention group. For the primary outcome, the intention-to-treat analysis revealed a non-significant between-group difference for change in VO 2peak of 0.7 ml/(kg.min) (95% CI = ‒0.3, 1.8) (p = 0.17). The between-group differences for 1RM arm press and leg press and mental aspect of SF-36 were 4.9 kg (95% CI = ‒0.1, 9.9) (p = 0.05), 11.6 kg (95% CI = 0.1, 23.0) (p < 0.05), and 5.7 kg (95% CI = 0.9, 10.4) (p = 0.02), respectively. There were no between-group differences in pulmonary function or physical function. When excluding participants with an attendance of <70% (n = 16), the between-group difference for VO 2peak was 1.2 ml/(kg.min) (95% CI = 0.1, 2.4) (p = 0.032)., Conclusions: HIIT improved muscular strength and HRQOL but did not improve VO 2peak more than usual care after LTx. However, with acceptable adherence, HIIT appears to have beneficial effects on VO 2peak ., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) are fibrotic ILDs with divergent disease populations. Little is known about health-related quality of life (HRQL) in SSc-ILD relative to IPF., Methods: We used the Kings Brief Interstitial Lung Disease Questionnaire (K-BILD) to compare HRQL in a cross-sectional study of 57 patients with IPF and 29 patients with SSc-ILD. Analysis of covariance was used to adjust for age, gender and lung function., Results: The unadjusted mean K-BILD score was 63.1 (95% CI 57.1 to 69.1) among patients with SSc-ILD, as compared with 54.7 (51.8-57.5) among those with IPF (p=0.005). However, this difference in HRQL was attenuated after adjustment for age, gender and lung function. In a multivariable model, only forced vital capacity was associated with K-BILD scores. K-BILD scores were correlated with both forced vital capacity and with other relevant HRQL measures, regardless of ILD diagnosis., Discussion: Patients with SSc-ILD may have better ILD-specific quality of life than patients with IPF, but this difference appears to be driven primarily by better lung function. These results underscore the impact of lung function on HRQL in fibrotic ILD and the utility of K-BILD to assess HRQL in SSc-ILD., Competing Interests: Competing interests: MTD reports research funding from Boehringer Ingelheim Norway KS, unrelated to the current study, lecture and consulting fees from Boehringer Ingelheim, Roche and AstraZeneca, unrelated to the current study, having participated in advisory boards for Boehringer Ingelheim and Roche, and that an immediate family member is a full-time employee of Boehringer Ingelheim who was not involved in this study. A-MH-V reports research funding and/or consulting fees or other remuneration from Actelion, Boehringer Ingelheim, Bayer, Roche, MSD and GlaxoSmithKline. TE reports receiving lecture fees from Boehringer Ingelheim and having participated in advisory boards for GlaxoSmithKline and Boehringer Ingelheim. A-OH and OEJ are full-time employees of Boehringer Ingelheim Norway KS. MBL and GB have no competing interests to report. SB reports research funding to his institution for the use of K-BILD in other studies, but not for the current study. TMJ reports receiving lecture fees from Boehringer Ingelheim and Roche. TS reports lecture fees from Boehringer Ingelheim and Roche., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120.

Background: Low cardiorespiratory fitness and inactivity are common after lung transplantation (LTx). The causes of exercise intolerance are incompletely understood., Objectives: The aim of this study was to objectively assess cardiorespiratory fitness and physical activity, evaluate causes of exercise intolerance, and explore clinical factors associated with cardiorespiratory fitness after bilateral LTx (BLTx)., Materials and Methods: Peak oxygen uptake (V∙O2peak) and exercise-limiting factors were evaluated by a treadmill cardiopulmonary exercise test (CPET) 6-60 months after BLTx. Physical activity was measured with accelerometers, and results were compared with Norwegian normative data and the World Health Organization's (WHO) recommendations for physical activity., Results: In 54 included BLTx recipients (mean age 50 ± 15 years, 50% females), V∙O2peak (mL × kg-1 × min-1) was 21.8 ± 7.7 for men and 22.4 ± 6.2 for women, corresponding to 57 ± 17 and 70 ± 12% of predicted, respectively. Three patients (6%) met criteria for normal V∙O2peak. Deconditioning limited V∙O2peak in 22 patients (41%), while ventilatory limitation and abnormal gas exchange were observed in 14 (26%) and 20 (37%) patients, respectively (some had more than 1 finding). Forty-three patients (86%) did not meet the WHO physical activity recommendations. There was a moderate correlation between V∙O2peak and physical activity (r = 0.642, p < 0.01). Body mass index, physical activity, forced expiratory volume after 1 second, sex, and hemoglobin together accounted for 73% of the variability in V∙O2peak., Conclusions: Low cardiorespiratory fitness was observed in the majority of BLTx recipients. Both deconditioning and cardiopulmonary limitations were common findings. Nearly 90% were classified as being inactive according to physical activity recommendations. CPET appears to identify a deconditioned subgroup of BLTx recipients for whom exercise training may be especially beneficial., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Purpose: In patients with idiopathic pulmonary fibrosis (IPF), hospitalizations are associated with high mortality. We sought to determine in-hospital mortality rates and factors associated with in-hospital mortality in patients with IPF., Methods: Patients with IPF were identified from the Premier Healthcare Database, a representative administrative dataset that includes > 20% of hospital discharges in the US, using an algorithm based on diagnostic codes and billing data. We used logistic regression to analyze associations between patient-, hospital-, and treatment-related characteristics and a composite primary outcome of death during the index visit, lung transplant during the index visit and > 1 day after admission, or death during a readmission within 90 days., Results: The cohort comprised 6665 patients with IPF hospitalized between October 2011 and October 2014. A total of 963 (14.4%) met the primary outcome. Factors significantly associated with a higher risk of the primary outcome included mechanical ventilation [odds ratio 4.65 (95% CI 3.73, 5.80)], admission to the intensive care unit [1.83 (1.52, 2.21)], treatment with opioids (3.06 [2.57, 3.65]), and a diagnosis of pneumonia [1.44 (1.21, 1.71)]. Factors significantly associated with a lower risk included concurrent chronic obstructive pulmonary disease [0.65 (0.55, 0.77)] and female sex [0.67 (0.57, 0.79)]., Conclusions: Patients with IPF, particularly those receiving mechanical ventilation or intensive care, are at substantial risk of death or lung transplant during hospitalization or death during a readmission within 90 days.

Background: Pulmonary fibrosis (PF) is the most common disease indication for lung transplantation. Our recent work implicated an excess of rare genetic variants in the telomere-related genes TERT, RTEL1, and PARN in PF disease risk. The impact of such variants on posttransplant outcomes is uncertain. The objective of this study was to determine if patients with these PF-associated variants have altered rates of posttransplant acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival., Methods: The study cohort consisted of 262 PF lung transplant recipients previously genetically characterized by whole exome sequencing. Thirty-one patients (11.8%) had variants in TERT, RTEL1, or PARN, whereas 231 (88.2%) did not. Multivariate Cox proportional hazards models adjusted for relevant clinical variables were used to assess the outcomes of death and CLAD. The AR burden was quantified and compared over the first posttransplant year., Results: Patients with PF with disease-associated variants in TERT, RTEL1, or PARN had a significantly higher risk of death (adjusted hazard ratio [HR], 1.82; 95% CI, 1.07-3.08; P = .03) and CLAD (adjusted HR, 2.88; 95% CI, 1.42-5.87; P = .004) than patients without these variants. There was no difference in AR burden or rates of grade 3 primary graft dysfunction between the two groups., Conclusions: Rare variants in the telomere-related genes TERT, RTEL1, or PARN are associated with poor posttransplant outcomes among PF lung transplant recipients. Further research is needed to understand the biological mechanisms by which telomere-related variants increase the risk for death and CLAD., (Published by Elsevier Inc.)

Background: Organs from older donors are increasingly used in lung transplantation, and studies have demonstrated that this could be safe in selected recipients. However, which recipient groups that have the largest benefit of older organs are unclear. This multicenter study reviews all bilateral lung transplantations (BLTx) from donors 55 years or older stratified by recipient diagnosis and compares outcomes with transplantations from younger donors., Methods: All BLTx recipients (excluding retransplantation) at 5 Scandiatransplant centers between 2000 and 2013 were included (n = 913). Recipients were stratified to diagnosis groups including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and "other." Intensive care unit (ICU) length of stay (LOS) and survival were assessed., Results: Overall, there was no difference in survival among patients transplanted from donors 55 years or older compared with younger donors. However, in CF recipients, donor age 55 years or older was associated with inferior survival (P = 0.014), and this remained significant in a multivariate model (hazard ratio, 5.0; 95% confidence interval, 1.8-14.1; P = 0.002). There was no significant effect of donor age on survival in recipients with COPD, ILD, or in the "other" group in multivariate models. Utilization of older donors was associated with increased ICU LOS for recipients with CF and ILD, but not in the COPD or "other" group., Conclusions: The BLTx recipients with CF had inferior survival and longer ICU LOS when receiving organs from donors 55 years or older. Recipients with COPD, ILD, or in the "other" group did not have inferior survival in multivariate models.

Objective: Chronic obstructive pulmonary disease (COPD) is associated with the development of atrial fibrillation (AF), and may complicate treatment of AF. We examined the association between COPD and symptoms, quality of life (QoL), treatment and outcomes among patients with AF., Methods: We compared patients with and without a diagnosis of COPD in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, a prospective registry that enrolled outpatients with AF not secondary to reversible causes, from both academic and community settings., Results: Among 9749 patients with AF, 1605 (16%) had COPD. Relative to patients without COPD, those with COPD were more likely to be older, current/former smokers (73% vs 43%), have heart failure (54% vs 29%) and coronary artery disease (49% vs 34%). Oral anticoagulant and beta blocker use were similar, whereas digoxin use was more common among patients with COPD. Symptom burden was generally higher, and QoL worse, among patients with COPD (median Atrial Fibrillation Effect on QualiTy-of-Life score 76 vs 83). Patients with COPD had higher risk of all-cause mortality (adjusted HR 1.52 (95% CI 1.32 to 1.74)), cardiovascular mortality (adjusted HR 1.51 (95% CI 1.24 to 1.84)) and cardiovascular hospitalisation (adjusted HR 1.15 (95% CI 1.05 to 1.26)). Patients with COPD also had higher risk of major bleeding events (adjusted HR 1.25 (95% CI 1.05 to 1.50)). There did not appear to be associations between COPD and AF progression, ischaemic events or new-onset heart failure., Conclusions: Among patients with AF, COPD is associated with higher symptom burden, worse QoL, and worse cardiovascular and bleeding outcomes. These associations were not fully explained by cardiovascular risk factors, AF treatment or smoking history., Clinical Registration Number: NCT01165710., Competing Interests: Competing interests: LAA reports personal fees from Novartis and from Janssen during the conduct of the study, grants from PCORI, grants from American Heart Association, grants from NIH and personal fees from Boston Scientific, outside the submitted work. PSC reports consulting fees from Optum Rx and from American Heart Association, and grants from NIH. JVF reports personal fees from American College of Cardiology and from the National Cardiovascular Data Registry, personal fees from Janssen Pharmaceuticals, and grants from NHLBI, outside the submitted work. GCF reports personal fees from Janssen and personal fees from Medtronic, outside the submitted work. ASG reports that he has received a research grant through his institution from iRhythm Technologies. EMH reports personal fees from Advisory Boards: Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Medtronic, Pfizer and Portola; personal fees from honoraria for symposia: Bristol Myers Squibb, Boehringer Ingelheim, DOASENSE and Pfizer, outside the submitted work. KWM reports grants from Afferent, grants from Amgen, grants and personal fees from AstraZeneca, from Daiichi, grants from Ferring, grants from Google (Verily), grants and personal fees from Johnson & Johnson, grants from Medtronic, grants and personal fees from Merck, grants and personal fees from Novartis, grants from Sanofi, grants from St. Jude, personal fees from Ablynx, personal fees from BAROnova, from Bio2Medical, personal fees from Boehringer Ingelheim, personal fees from Bristol Myers Squibb, personal fees from Cardiometabolic Health Congress, personal fees from Cubist, personal fees from Eli Lilly, personal fees from Elsevier, personal fees from Epson, personal fees from Glaxo Smith Kline, personal fees from Mt. Sinai, personal fees from Myokardia, personal fees from Oculeve, personal fees from Portola, personal fees from Radiomeer, personal fees from Springer Publishing, personal fees from The Medicines Company, personal fees from Theravance, personal fees from UCSF, personal fees from Vindico, personal fees from WebMD, outside the submitted work. SDP reports grants from Janssen Pharmaceuticals, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Pfizer, grants from Food and Drug Administration, during the conduct of the study; grants and personal fees from Boston Scientific, personal fees from Medtronic, grants from Gilead, outside the submitted work. JAR reports grants from Janssen, during the conduct of the study; grants from Medtronic, personal fees from Portola, personal fees from Boehringer Ingelheim, outside the submitted work. DES reports personal fees from Johnson & Johnson, during the conduct of the study; grants from Bristol-Myers Squibb, grants from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Boehringer Ingelheim, personal fees from CVS Health, personal fees from Johnson & Johnson, personal fees from Merck, personal fees from Pfizer, personal fees from Medtronic, outside the submitted work. EDP reports grants and personal fees from Janssen Pharmaceuticals, outside the submitted work. JPP reports grants to his institution from ARCA Biopharma, Boston Scientific, Gilead Sciences, Janssen Pharmaceuticals, St. Jude Medical, and ResMed; consultancy fees from Amgen, Spectranetics, Medtronic, Allergan, Janssen Pharmaceuticals., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Surgical lung biopsy contributes to establishing a specific diagnosis among many patients with interstitial lung disease (ILD). The risks of death and respiratory failure associated with elective thoracoscopic surgical lung biopsy, and patient characteristics associated with these outcomes, are not well understood., Methods: This is a retrospective cohort study of patients who underwent elective thoracoscopic lung biopsy for ILD between 2008 and 2014, according to The Society of Thoracic Surgeons database. The study determined the incidence of operative mortality and of postoperative respiratory failure. Multivariable models were used to identify risk factors for these adverse outcomes., Results: Among 3,085 patients, 46 (1.5%) died before hospital discharge or within 30 days of thoracoscopic lung biopsy. Postoperative respiratory failure occurred in 90 (2.9%) patients. Significant risk factors for operative mortality among patients with ILD included a diagnosis of pulmonary hypertension, preoperative corticosteroid treatment, and low diffusion capacity., Conclusions: Elective thoracoscopic lung biopsy among patients with ILD is associated with a low risk of operative mortality and postoperative respiratory failure. Attention to the presence of pulmonary hypertension, preoperative corticosteroid treatment, and diffusion capacity may help inform risk stratification for thoracoscopic lung biopsy among patients with ILD., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology., Objectives: The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis., Methods: We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis., Measurements and Main Results: We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10 -7 ) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10 -22 )., Conclusions: We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.

Background: Impaired psychological function is common among lung transplant candidates and may affect clinical outcomes following transplantation. Although numerous studies have examined the relationship between pretransplant depression, quality of life (QoL), and post-transplant outcomes, few have examined the relationship between depression and QoL shortly following transplantation and subsequent clinical outcomes. We therefore examined the association between depression, QoL, and short-term mortality in a consecutive series of lung transplant recipients., Methods: Depression (Patient Health Questionnaire-9; Hospital Anxiety and Depression Scale; Centers for Epidemiologic Studies Depression Scale) and QoL (UCSD Shortness of Breath Questionnaire; Pulmonary Quality of Life Scale) were assessed prior to transplantation (median 0.9 months [IQR=1.6]) and again approximately 2 weeks following transplantation (median=0.5 months [IQR=0.5]), in a series of 66 patients transplanted between March 2013 and April 2014. The association between psychiatric diagnoses from participants' comprehensive pretransplant assessment and mortality also was examined. Cox proportional hazards models were used to examine the association between depression, QoL, and mortality., Results: During a median follow-up of 2.8 years (range 0.4-3.3), 21 patients died (32%). Greater depressive symptoms assessed shortly after transplant were associated with subsequent mortality (HR=2.17 [1.01, 4.67], P=.048), and this relationship persisted after controlling for primary graft dysfunction, duration of transplant hospitalization, and gender. In contrast, neither pretransplant depression, history of depression, nor QoL was associated with mortality., Conclusions: Greater post-transplant depressive symptoms are independently associated with mortality among lung transplant recipients., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Rationale: Lung transplantation is an accepted and increasingly employed treatment for advanced lung diseases, but the anticipated survival benefit of lung transplantation is poorly understood., Objectives: To determine whether and for which patients lung transplantation confers a survival benefit in the modern era of U.S. lung allocation., Methods: Data on 13,040 adults listed for lung transplantation between May 2005 and September 2011 were obtained from the United Network for Organ Sharing. A structural nested accelerated failure time model was used to model the survival benefit of lung transplantation over time. The effects of patient, donor, and transplant center characteristics on the relative survival benefit of transplantation were examined., Measurements and Main Results: Overall, 73.8% of transplant recipients were predicted to achieve a 2-year survival benefit with lung transplantation. The survival benefit of transplantation varied by native disease group (P = 0.062), with 2-year expected benefit in 39.2 and 98.9% of transplants occurring in those with obstructive lung disease and cystic fibrosis, respectively, and by lung allocation score at the time of transplantation (P < 0.001), with net 2-year benefit in only 6.8% of transplants occurring for lung allocation score less than 32.5 and in 99.9% of transplants for lung allocation score exceeding 40., Conclusions: A majority of adults undergoing transplantation experience a survival benefit, with the greatest potential benefit in those with higher lung allocation scores or restrictive native lung disease or cystic fibrosis. These results provide novel information to assess the expected benefit of lung transplantation at an individual level and to enhance lung allocation policy.

Background: The complex interaction between pulmonary function, cardiac function and adverse cardiovascular events has only been partially described. We sought to describe the association between pulmonary function with left heart structure and function, all-cause mortality and incident cardiovascular hospitalization., Methods: This study is a retrospective analysis of patients evaluated in a single tertiary care medical center. We used multivariable linear regression analyses to examine the relationship between FVC and FEV1 with left ventricular ejection fraction (LVEF), left ventricular internal dimension in systole and diastole (LVIDS, LVIDD) and left atrial diameter, adjusting for baseline characteristics, right ventricular function and lung hyperinflation. We also used Cox proportional hazards models to examine the relationship between FVC and FEV1 with all-cause mortality and cardiac hospitalization., Results: A total of 1807 patients were included in this analysis with a median age of 61 years and 50% were female. Decreased FVC and FEV1 were both associated with decreased LVEF. In individuals with FVC less than 2.75 L, decreased FVC was associated with increased all-cause mortality after adjusting for left and right heart echocardiographic variables (hazard ratio [HR] 0.49, 95% CI 0.29, 0.82, respectively). Decreased FVC was associated with increased cardiac hospitalization after adjusting for left heart size (HR 0.80, 95% CI 0.67, 0.96), even in patients with normal LVEF (HR 0.75, 95% CI 0.57, 0.97)., Conclusion: In a tertiary care center reduced pulmonary function was associated with adverse cardiovascular events, a relationship that is not fully explained by left heart remodeling or right heart dysfunction., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterised by progressive loss of lung function. Its clinical course is variable but ultimately fatal. There is a need for a multicentre patient registry incorporating longitudinal clinical data and biological samples to improve understanding of the natural history of IPF and contemporary practice patterns., Methods/design: The Idiopathic Pulmonary Fibrosis-PRospective Outcomes (IPF-PRO) registry is a national IPF registry in the USA. This registry will enrol approximately 300 patients with newly diagnosed IPF over 2 years at approximately 14 tertiary pulmonary care sites. Participants will be followed for 3-5 years and will receive usual care, as defined by their physician. Clinical data from the year prior to diagnosis will be collected from medical record review on enrolment. Subsequently, data on diagnostic evaluations, pulmonary function tests, physical examinations, laboratory data and clinical events will be collected at routine clinical visits and via a call centre. Participants will complete patient-reported outcome questionnaires at enrolment and then at approximately 6-month intervals. Blood samples for cellular, genetic and transcriptomic analyses will be collected at the same intervals., Results: The first results from the IPF-PRO registry will be presented in 2015., Conclusions: The IPF-PRO registry will improve understanding of the natural history of IPF, its impact on patients and current practice in the diagnosis and care of patients with IPF. The registry will establish a repository of biological samples from a well-characterised patient population for future research., Clinical Trial Number: NCT01915511.

Background: Comorbid chronic obstructive pulmonary disease (COPD) is associated with poor outcomes among patients with cardiovascular disease. The risks of stroke and mortality associated with COPD among patients with atrial fibrillation are not well understood., Methods: We analyzed patients from ARISTOTLE, a randomized trial of 18,201 patients with atrial fibrillation comparing the effects of apixaban versus warfarin on the risk of stroke or systemic embolism. Using Cox proportional hazards models, we assessed the associations between comorbid COPD and risk of stroke or systemic embolism and of mortality, adjusting for treatment allocation, smoking history and other risk factors., Results: COPD was present in 1950 (10.8%) of 18,134 patients with data on pulmonary disease history. After multivariable adjustment, COPD was not associated with risk of stroke or systemic embolism (adjusted HR 0.85 [95% CI 0.60, 1.21], p=0.356). However, COPD was associated with a higher risk of all-cause mortality (adjusted HR 1.60 [95% CI 1.36, 1.88], p<0.001) and both cardiovascular and non-cardiovascular mortality. The benefit of apixaban over warfarin on stroke or systemic embolism was consistent among patients with and without COPD (HR 0.92 [95% CI 0.52, 1.63] versus 0.78 [95% CI 0.65, 0.95], interaction p=0.617)., Conclusions: COPD was independently associated with increased risk of cardiovascular and non-cardiovascular mortality among patients with atrial fibrillation, but was not associated with risk of stroke or systemic embolism. The effect of apixaban on stroke or systemic embolism in COPD patients was consistent with its effect in the overall trial population., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Rationale: Older patients are at high risk of death and rehospitalization after hospitalizations for acute exacerbations of chronic obstructive pulmonary disease (AE-COPD). Emergency department visits comprise a substantial portion of acute care encounters in this patient population. The risks of mortality and repeat acute care encounters, including both hospital readmission and repeat emergency department visits, after AE-COPD among older adults are not well understood., Objectives: To examine early and long-term rates of death and repeat acute care encounters after hospitalization or emergency department visit for AE-COPD in Medicare fee-for-service beneficiaries and to identify patient characteristics, including medical comorbid conditions, associated with these outcomes., Methods: A retrospective analysis was conducted using a nationally representative 5% sample of Medicare fee-for-service claims data from the U.S. Centers for Medicare and Medicaid Services to identify Medicare beneficiaries 65 years or older who had an acute care episode for an AE-COPD between January 1, 2006, and December 31, 2010 (n = 52,741). Outcomes of interest were all-cause mortality, repeat acute care encounters for any cause, and repeat acute care encounters for AE-COPD at 30 days, 1 year, and 3 years., Measurements and Main Results: Acute care encounters, including hospitalizations and emergency department visits for AE-COPD, were associated with substantial subsequent mortality risk, with 4.6, 24.4, and 48.2% dying by 30 days, 1 year, and 3 years, respectively. The risk of repeat hospitalization or emergency department visit was similarly high, with 1 in 4 patients having a repeat acute care encounter within 30 days of discharge, increasing to 9 in 10 in the next 3 years. Several comorbid conditions and other patient factors, including heart failure, malnutrition, dual eligibility for Medicare and Medicaid, and prior supplemental oxygen use, were independently associated with increased risk of repeat acute care encounter., Conclusions: Repeat hospitalizations and emergency department visits and death are common in older fee-for-service Medicare beneficiaries seen in acute care for AE-COPD. Our results suggest that addressing important comorbid conditions, such as heart failure or malnutrition, and targeting resources to oxygen-dependent or dual Medicare- and Medicaid-eligible patients may help modify these outcomes.

Background: Mortality is an impractical primary endpoint for clinical trials in patients with idiopathic pulmonary fibrosis who have mild-to-moderate physiological impairment because event rates are low. Change in forced vital capacity (FVC) is widely accepted as a surrogate for mortality and is the most common primary endpoint in clinical trials for this disorder. Use of hospital admission as a predictor for mortality, independent of FVC decline, has not been well defined. We aimed to ascertain the independent and combined association of hospital admission and at least a 10% decrease in FVC with all-cause mortality., Methods: We did a pooled cohort study of 517 patients with idiopathic pulmonary fibrosis from three IPFnet multicentre randomised controlled trials. We compared the incidence of non-elective hospital admission and a 10% or greater reduction in FVC across strata of baseline physiological impairment. We used Cox proportional-hazards models to assess the risk of all-cause mortality associated with these surrogate events, occurring up to a predefined landmark timepoint. The three studies are registered at ClinicalTrials.gov, numbers NCT00650091, NCT00517933, and NCT00957242., Findings: Seven patients died before the landmark timepoint. Of the 510 patients remaining, 38 (7%) were admitted to hospital up to the predefined timepoint and 58 (11%) had a categorical decrease in FVC of at least 10%. Most patients admitted to hospital did not have a 10% or greater decrease in FVC (30 vs eight). Both surrogate events were associated with subsequent time to death from any cause (hazard ratio [HR] for admission 4·05, 95% CI 1·36-12·11 vs HR for 10% or greater decline in FVC 4·68, 1·83-11·99). When causes of hospital admission were considered, only respiratory events were associated with mortality (5·97, 1·81-19·74)., Interpretation: Hospital admission might be an appropriate component of a clinically meaningful composite endpoint that improves the feasibility of clinical trials in idiopathic pulmonary fibrosis. Further studies are needed to refine the most appropriate definition of hospital admission for future trials., Funding: US National Heart, Lung, and Blood Institute (NHLBI), and The Cowlin Family Fund at the Chicago Community Trust., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Rationale: The 2011 combined Global Initiative for Chronic Obstructive Lung Disease (GOLD) assessment incorporates symptoms, exacerbation history, and spirometry in discriminating risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD). Six-minute-walk distance (6MWD) and accelerometry also have been used to assess disease severity in COPD. The association between these measures and the risks of hospitalization and mortality in the context of GOLD 2011 is unknown., Objectives: To describe changes in exercise tolerance and physical activity over time in patients with COPD and to test the hypothesis that lower baseline 6MWD or accelerometry step count is associated with increased risk of COPD-related hospitalization or all-cause mortality, independent of GOLD 2011 group., Methods: Physical function and medical outcomes were prospectively assessed in 326 patients with moderate to severe COPD in INSPIRE-II, a randomized controlled trial of a coping skills training intervention. Cox models were used to determine if GOLD 2011 group, 6MWD, or accelerometry steps were associated with risk of COPD-related hospitalization or all-cause mortality., Measurements and Main Results: Physical function declined over time in GOLD group D but remained stable in groups A, B, and C. GOLD classification was associated with time to death or first COPD-related hospitalization. Baseline 6MWD was more strongly associated with time to death or first COPD-related hospitalization (hazard ratio, 0.50 [95% confidence interval, 0.34, 0.73] per 150 m, P=0.0003) than GOLD 2011 classification. A similar relationship was observed for accelerometry steps (hazard ratio, 0.80 [95% confidence interval, 0.70, 0.92] per 1,000 steps, P=0.002)., Conclusions: Exercise tolerance and daily physical activity are important predictors of hospitalization and mortality in COPD, independent of GOLD 2011 classification. Physical function may represent a modifiable risk factor that warrants increased attention as a target for interventions to improve clinically meaningful outcomes in COPD.

Background: Delirium is relatively common after lung transplantation, although its prevalence and prognostic significance have not been systematically studied. The purpose of the present study was to examine pretransplant predictors of delirium and the short-term impact of delirium on clinical outcomes among lung transplant recipients., Methods: Participants underwent pretransplant cognitive testing using the Repeatable Battery for the Assessment of Neuropsychological Status and the Trail Making Test. After transplant, delirium was assessed using the Confusion Assessment Method until discharge., Results: Sixty-three patients were transplanted between March and November 2013, of which 23 (37%) developed delirium. Among transplanted patients, 48 patients completed pretransplant cognitive testing. Better pretransplant cognitive function was associated with lower risk of delirium (odds ratio, 0.69 [95% confidence interval 0.48, 0.99], P = .043); and demographic and clinical features including native disease (P = .236), the Charlson comorbidity index (P = .581), and the lung allocation score (P = .871) were unrelated to risk of delirium, although there was a trend for women to experience delirium less frequently (P = .071). The presence (P = .006) and duration (P = .027) of delirium were both associated with longer hospital stays., Conclusion: Delirium occurs in more than one-third of patients after lung transplantation. Delirium was associated with poorer pretransplant cognitive functioning and longer hospital stays, after accounting for other medical and demographic factors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Endurance exercise (EE) leads to beneficial alterations in skeletal muscle lipid metabolism in overweight and obese individuals; however, the mechanisms of these improvements are poorly understood. The primary goal of the current investigation was to test the hypothesis that long-term EE training (6 mo) leads to alterations in the mRNA abundance of key lipid metabolism enzymes in skeletal muscle of overweight and obese middle-aged women and men. A secondary aim of this study was to investigate the hypothesis that exercise-mediated adaptations in mRNA levels differ between women and men. The mRNA abundance of representative lipogenic and lipolytic genes from major lipid metabolism pathways, as well as representative lipogenic and lipolytic transcription factors, were determined by real-time PCR from skeletal muscle biopsies collected before and approximately 24 h after the final bout of 6 mo of EE. Six months of EE led to increases in muscle lipoprotein lipase, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, carnitine palmitoyltransferase-1 beta, diacylglycerol acyltransferase-1, and acid ceramidase mRNA in women, but not men. In contrast, in men, EE led to reductions in the mRNA content of the lipogenic factors sterol regulatory element binding protein-1c and serine palmitoyl transferase. These data suggest that EE-mediated alterations in the abundance of the lipid metabolism genes studied here are fundamentally different between overweight and obese middle-aged women and men. Future studies should determine whether these adaptations in mRNA levels translate into changes in protein function.

Small LDL and HDL particle size are characteristic of a proatherogenic lipoprotein profile. Aerobic exercise increases these particle sizes. Although visceral adipose tissue (VAT) has been strongly linked with dyslipidemia, the importance of intermuscular adipose tissue (IMAT) to dyslipidemia and exercise responses is less well understood. We measured exercise-associated changes in thigh IMAT and VAT and examined their relationships with changes in LDL and HDL particle size. Sedentary, dyslipidemic, overweight subjects (n = 73) completed 8-9 mo of aerobic training. Linear regression models were used to compare the power of IMAT change and VAT change to predict lipoprotein size changes. In men alone (n = 40), IMAT change correlated inversely with both HDL size change (r = -0.42, P = 0.007) and LDL size change (r = -0.52, P < 0.001). That is, reduction of IMAT was associated with a shift toward larger, less atherogenic lipoprotein particles. No significant correlations were observed in women. After adding VAT change to the model, IMAT change was the only significant predictor of either HDL size change (P = 0.034 for IMAT vs. 0.162 for VAT) or LDL size change (P = 0.004 for IMAT vs. 0.189 for VAT) in men. In conclusion, in overweight dyslipidemic men, exercise-associated change in thigh IMAT was inversely correlated with both HDL and LDL size change and was more predictive of these lipoprotein changes than was change in VAT. Reducing IMAT through aerobic exercise may be functionally related to some improvements in atherogenic dyslipidemia in men.