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The article explains the rationale for appropriate gainsharing in the context of the Medicare and Medicaid reimbursement programs in the U.S. It examines the statutory impediments to hospital gainsharing which includes certain healthcare fraud and abuse laws. It also explores the future role that appropriate hospital gainsharing agreement might have in the U.S. healthcare.

Trypanosomes encode a family of proteins known as Major Surface Metalloproteases (MSPs). We have identified six putative MSPs encoded within the partially sequenced T. congolense genome. Phylogenic analysis indicates that T. congolense MSPs belong to five subfamilies that are conserved among African trypanosome species. Molecular modeling, based on the known structure of Leishmania Major GP63, reveals subfamily-specific structural variations around the putative active site despite conservation of overall structure, suggesting that each MSP subfamily has evolved to recognize distinct substrates. We have cloned and purified a protein encoding the amino-terminal domain of the T. congolense homologue TcoMSP-D (most closely related to Leishmania GP63). We detect TcoMSP-D in the serum of T. congolense-infected mice. Mice immunized with the amino-terminal domain of TcoMSP-D generate a persisting IgG1 antibody response. Surprisingly, a low-dose challenge of immunized mice with T. congolense significantly increases susceptibility to infection, indicating that immunity to TcoMSP-D is a factor affecting virulence. [ABSTRACT FROM AUTHOR]

Background: Progressive pulmonary fibrosis (PFF) is of substantial interest for novel pharmacotherapy discovery, but little is known about clinical trial eligibility criteria. We evaluated eligibility criteria of PPF randomized controlled trials (RCTs), their representativeness in registry patients, and forced vital capacity (FVC) changes and mortality according to trial eligibility., Methods: A systematic search was used to identify completed and in-progress phase II and III PPF RCTs. Common clinical trial eligibility criteria used in ≥60% of previous PPF RCTs were identified. The most common criteria for PPF used in RCTs ("trial-PPF criteria") and the clinical practice guideline definition of PPF ("guideline-PPF criteria") were both applied to patients enrolled in a prospective multicenter Canadian registry. Common trial eligibility criteria were tested for their frequency and association with health outcomes in registry patients who met trial-PPF and guideline-PPF criteria., Results: Ten different definitions of PPF were used in 16 RCTs. At the time of meeting PPF definitions, 50% of 864 patients with trial-PPF and 44% of 408 patients with guideline-PPF met the common trial eligibility criteria. For both definitions, trial-eligible patients had more rapid 1-year FVC decline but better transplant-free survival than trial-ineligible patients. Patients with unclassifiable interstitial lung disease (ILD) had higher proportion of trial exclusion compared to those with connective tissue disease-associated ILD and fibrotic hypersensitivity pneumonitis. Annual FVC decline (trial-PPF: -67 to -21 mL; guideline-PPF: -116 to -41 mL) and 1-year transplant-free survival (trial-PPF: 90.5 to 97.5%; guideline-PPF: 87 to 96.2%) varied in trial-eligible patients across ILD subtypes., Conclusions: Existing RCTs use a variety of definitions for PPF with eligibility criteria that have limited representativeness. FVC decline and transplant-free survival vary according to trial eligibility and ILD subtypes., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: Cough is a key symptom in patients with fibrotic interstitial lung disease (ILD). Objectives: This study evaluated the prevalence, longitudinal change, associations, and prognostic significance of cough severity in patients with fibrotic ILD. Methods: We included consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who completed the 100-mm Cough Severity Visual Analog Scale from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. Baseline cough severity and associations with patient demographics and clinical factors were determined. Relationships between baseline cough severity and health outcomes were evaluated. Measurements and Main Results: Patients with IPF ( n  = 1,061) had higher median baseline cough severity than those with non-IPF fibrotic ILD ( n  = 2,825) (24 vs. 20 mm; P  < 0.001), with worse cough associated with gastroesophageal reflux disease for both cohorts. Worse cough severity was independently associated with worse health-related quality of life at baseline, larger annualized decline in Dl CO , development of disease progression, and reduced transplant-free survival in both IPF and non-IPF fibrotic ILD cohorts. The IPF cohort (2.2 mm; 95% confidence interval, 1.6-2.9 mm) had larger annualized increments in cough severity than the non-IPF fibrotic ILD cohort (1.1 mm; 95% confidence interval, 0.8-1.4 mm; P  = 0.004). There was no difference in worsening cough over time comparing those receiving and not receiving ILD-targeted therapy or with and without lung function decline. Conclusions: Cough is common in patients with IPF and non-IPF fibrotic ILD, with increasing cough severity over time irrespective of ILD-targeted therapy. Patient-reported cough severity has prognostic implications on health-related quality of life, disease progression, and survival in fibrotic ILD.

Objectives: Interstitial lung disease (ILD) in CTDs has highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality, and immunosuppression response., Methods: Patients with CTD-ILD had high-resolution chest CT (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern [usual interstitial pneumonia (UIP); non-specific interstitial pneumonia (NSIP); organizing pneumonia (OP); fibrotic hypersensitivity pneumonitis (fHP); and other]. Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed-effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment., Results: Among 645 CTD-ILD patients, the most frequent CTDs were SSc (n = 215), RA (n = 127), and inflammatory myopathies (n = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with the case for patients with UIP, FVC decline was slower in patients with NSIP (by 1.1%/year, 95% CI 0.2, 1.9) or OP (by 3.5%/year, 95% CI 2.0, 4.9), and mortality was lower in patients with NSIP [hazard ratio (HR) 0.65, 95% CI 0.45, 0.93] or OP (HR 0.18, 95% CI 0.05, 0.57), but higher in fHP (HR 1.58, 95% CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95% CI 1.4, 2.8), with no change for UIP or fHP., Conclusion: Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Previous studies have shown the importance of frailty in patients with fibrotic interstitial lung disease (ILD)., Research Question: Is the Clinical Frailty Scale (CFS) a valid tool to improve risk stratification in patients with fibrotic ILD?, Study Design and Methods: Patients with fibrotic ILD were included from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. The CFS was assessed using available information from initial ILD clinic visits. Patients were stratified into fit (CFS score 1-3), vulnerable (CFS score 4), and frail (CFS score 5-9) subgroups. Cox proportional hazards and logistic regression models with mixed effects were used to estimate time to death or lung transplantation. A derivation and validation cohort was used to establish prognostic performance. Trajectories of functional tests were compared using joint models., Results: Of the 1,587 patients with fibrotic ILD, 858 (54%) were fit, 400 (25%) were vulnerable, and 329 (21%) were frail. Frailty was a risk factor for early mortality (hazard ratio, 5.58; 95% CI, 3.64-5.76, P < .001) in the entire cohort, in individual ILD diagnoses, and after adjustment for potential confounders. Adding frailty to established risk prediction parameters improved the prognostic performance in derivation and validation cohorts. Patients in the frail subgroup had larger annual declines in FVC % predicted than patients in the fit subgroup (-2.32; 95% CI, -3.39 to -1.17 vs -1.55; 95% CI, -2.04 to -1.15, respectively; P = .02)., Interpretation: The simple and practical CFS is associated with pulmonary and physical function decline in patients with fibrotic ILD and provides additional prognostic accuracy in clinical practice., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: BAL cellular analysis is often recommended during the initial diagnostic evaluation of fibrotic interstitial lung disease (ILD). Despite recommendation for its use, between-center heterogeneity exists and supportive data concerning the clinical utility and correlation of BAL findings with radiologic features or patterns remain sparse., Research Question: In patients with fibrotic ILD, are BAL findings associated with radiologic features, patterns, and clinical diagnoses?, Study Design and Methods: Patients with fibrotic ILD who underwent BAL for diagnostic evaluation and who were enrolled in the prospective Canadian Registry for Pulmonary Fibrosis were re-reviewed in a standardized multidisciplinary discussion (MDD). BAL was categorized according to guideline-recommended thresholds, and using thresholds of lymphocytosis > 20% and neutrophils > 4.5%. High-resolution CT (HRCT) scans were scored (anonymized to clinical data) for specific features and percentage lung involvement. Radiologists classified HRCT scans according to guideline-defined patterns for idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis; then, MDD diagnoses were assigned, considering all available data., Results: Bronchoscopy with cellular analysis was performed in 209 of 1,593 patients (13%). Lymphocyte % was weakly negatively correlated with total fibrosis % (r = -0.16, P = .023) but not statistically significantly correlated with ground glass opacity % (r = 0.01, P = .94). A mixed BAL pattern was the most frequent in all radiologic patterns (range, 45%-69%), with a minority classifiable according to BAL guidelines. BAL lymphocytosis appeared with similar frequency across HRCT patterns of fibrotic hypersensitivity pneumonitis (21%) and usual interstitial pneumonia (18%). Only 5% of patients with MDD-based fibrotic hypersensitivity pneumonitis had a guideline-defined isolated lymphocytosis > 15%., Interpretation: BAL cellular analyses did not significantly correlate with radiologic features, guideline patterns, or MDD-based diagnoses. Ground glass opacities are often interpreted to represent pulmonary inflammation, but were not associated with BAL lymphocytosis in this cohort., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: A visual analog scale (VAS) is a simple and easily administered tool for measuring the impact of disease; however, little is known about the use of a dyspnea VAS in interstitial lung disease (ILD). Objectives: To validate the use of a dyspnea VAS in a large and heterogeneous cohort of patients with fibrotic ILD, including its minimal clinically important difference (MCID), responsiveness to change, and prognostic significance. Methods: Patients with fibrotic ILD were identified from a large prospective registry. The validity of a 100-mm dyspnea VAS was assessed by testing its correlation in change score with other measures of ILD severity, including the University of California San Diego Shortness of Breath Questionnaire, the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain, the European Quality of Life VAS, forced vital capacity, and diffusing capacity of the lung for carbon monoxide. The responsiveness of the dyspnea VAS was qualitatively confirmed on the basis of there being an observable difference in the change in dyspnea VAS across tertiles of change in anchor variables. The MCID in dyspnea VAS was calculated using both anchor (linear regression) and distribution (one-half standard deviation) approaches, with anchors including the above variables that had a correlation with dyspnea VAS (| r | ≥ 0.30). The association of dyspnea VAS with time to death or transplant was determined. Results: The cohort included 826 patients with fibrotic ILD, including 127 patients with follow-up measurements at 6 months. The mean baseline dyspnea VAS was 53 ± 24 mm. Dyspnea VAS change scores were moderately correlated with the University of California San Diego Shortness of Breath Questionnaire (| r | = 0.55) and the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain (| r | = 0.44) and weakly correlated with the European Quality of Life VAS (| r | = 0.19), forced vital capacity percent predicted (| r | = 0.21), and diffusing capacity of the lung for carbon monoxide percent predicted (| r | = 0.05). The MCID was 2.7 to 4.5 using the more reliable anchor-based methods and 12.0 based on distribution-based methods. Dyspnea VAS was associated with time to death or transplant in unadjusted models and after adjustment for age and sex (hazard ratios, 1.16 and 1.15, respectively; P  < 0.05 for both). Conclusions: This study provides support for the use of the dyspnea VAS in patients with fibrotic ILD, with an estimated anchor-based MCID of 5 mm.

Background and Objective: Establishing an accurate and timely diagnosis of idiopathic pulmonary fibrosis (IPF) is essential for appropriate management and prognostication. In some cases, surgical lung biopsy (SLB) is performed but carries non-negligible risk. The objective of this retrospective study was to determine if SLB is associated with accelerated lung function decline in patients with IPF using the Canadian Registry for Pulmonary Fibrosis., Methods: Linear mixed models and Cox proportional hazards regression models were used to compare decline in forced vital capacity (FVC)%, diffusion capacity of the lung (DLCO%) and risk of death or lung transplantation between SLB and non-SLB patients. Adjustments were made for baseline age, sex, smoking history, antifibrotic use, and lung function. A similar analysis compared lung function changes 12 months pre- and post-SLB., Results: A total of 81 SLB patients and 468 non-SLB patients were included. In the SLB group, the post-biopsy annual FVC% decline was 2.0% (±0.8) in unadjusted, and 2.1% (±0.8) in adjusted models. There was no difference in FVC% decline, DLCO% decline, or time to death or lung transplantation between the two groups, in adjusted or unadjusted models (all p-values >0.07). In the pre-post SLB group, no differences were identified in FVC% decline in unadjusted or adjusted models (p = 0.07 for both)., Conclusion: No association between SLB and lung function decline or risk of death or lung transplantation was identified in this multi-centre study of patients with IPF., (© 2024 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Patients with fibrotic hypersensitivity pneumonitis (fHP) are frequently treated with immunosuppression to slow lung function decline; however, the impact of this treatment has not been studied across different types of antigen exposure., Research Question: In patients with fHP, do disease outcomes and response to treatment vary by antigen type?, Study Design and Methods: A multicenter interstitial lung disease database (Canadian Registry for Pulmonary Fibrosis) was used to identify patients with fHP. The causative antigen was categorized as avian, mold, unknown, or other. Treatment was defined as mycophenolate ≥ 1,000 mg/d or azathioprine ≥ 75 mg/d for ≥ 30 days. Statistical analysis included t tests, χ 2 tests, and one-way analysis of variance. Unadjusted and adjusted competing risks and Cox proportional hazards models were used to assess survival., Results: A total of 344 patients were identified with the following causative antigens: avian (n = 93; 27%), mold (n = 88; 26%), other (n = 15; 4%), and unknown (n = 148; 43%). Patient characteristics and lung function were similar among antigen groups with a mean FVC % predicted of 75 ± 20. The percent of patients treated with immunosuppression was similar between antigens with 58% of patients treated. There was no change in lung function or symptom scores with the initiation of immunosuppression in the full cohort. Immunosuppression was not associated with a change in survival for patients with avian or mold antigen (avian: hazard ratio, 0.41; 95% CI, 0.11-1.59; P = .20; mold: hazard ratio, 1.13; 95% CI, 0.26-4.97; P = .88). For patients with unknown causative antigen, survival was worse when treated with immunosuppression (hazard ratio, 2.65; 95% CI, 1.01-6.92; P = .047)., Interpretation: Response to immunosuppression varies by antigen type in patients with fHP. Additional studies are needed to test the role of immunosuppression in fHP, and particularly in those with an unknown antigen., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. W. W. reports personal fees from Boehringer Ingelheim and Astra Zeneca, outside the submitted work. V. M. reports personal fees from Boehringer Ingelheim Canada, Hoffman-La Roche Ltd, and Astra Zeneca; and reports grants from the University of Saskatchewan, Royal University Hospital Foundation, Boehringer Ingelheim, Astra Zeneca, and Hoffman-La Roche. D.-C. M. reports consultancy and speaking fees from Boehringer Ingelheim. B. Z. reports speaking fees from Boehringer Ingelheim and Abbvie. D. A. is supported by the Fonds de Recherche du Quebec en Santé, reports personal fees and grants from Boehringer Ingelheim, reports personal fees from Hoffmann-La Roche, and reports grants from the Canadian Institute for Health Research. K. A. J. reports grants from Boehringer Ingelheim, Pulmonary Fibrosis Society of Calgary, and University of Calgary School of Medicine; and reports personal fees from Boehringer Ingelheim, Roche, Three Lakes Foundation, Pliant Therapeutics, Theravance, and Blade Therapeutics. M. K. reports grants from the Canadian Institute for Health Research, Roche, Boehringer Ingelheim, Pieris, and Prometic; and reports personal fees from Boehringer Ingelheim, Roche, European Respiratory Journal, Belerophon, United Therapeutics, Nitto Denko, MitoImmune, Pieris, Abbvie, DevPro Biopharma, Horizon, Algernon, and CSL Behring. H. M. reports grants from Boehringer Ingelheim and Gilead. J. M. reports personal fees from Boehringer Ingelheim and Roche. C. J. R. reports grants from Boehringer Ingelheim; and reports personal fees from Astra Zeneca, Boehringer Ingelheim, Roche, Pliant Therapeutics, Cipla, and Veracyte. None declared (M. L. M., G. F., J. H. F., N. K., B. M., E. F.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Fibrotic interstitial lung disease (ILD) is frequently associated with abnormal oxygenation; however, little is known about the accuracy of oxygen saturation by pulse oximetry (SpO 2 ) compared with arterial blood gas (ABG) saturation (SaO 2 ), the factors that influence the partial pressure of carbon dioxide (PaCO 2 ) and the impact of PaCO 2 on outcomes in patients with fibrotic ILD., Study Design and Methods: Patients with fibrotic ILD enrolled in a large prospective registry with a room air ABG were included. Prespecified analyses included testing the correlation between SaO 2 and SpO 2 , the difference between SaO 2 and SpO 2 , the association of baseline characteristics with both the difference between SaO 2 and SpO 2 and the PaCO 2 , the association of baseline characteristics with acid-base category, and the association of PaCO 2 and acid-base category with time to death or transplant., Results: A total of 532 patients with fibrotic ILD were included. Mean resting SaO 2 was 92±4% and SpO 2 was 95±3%. Mean PaCO 2 was 38±6 mmHg, with 135 patients having PaCO 2 <35 mmHg and 62 having PaCO 2 >45 mmHg. Correlation between SaO 2 and SpO 2 was mild to moderate (r=0.39), with SpO 2 on average 3.0% higher than SaO 2 . No baseline characteristics were associated with the difference in SaO 2 and SpO 2 . Variables associated with either elevated or abnormal (elevated or low) PaCO 2 included higher smoking pack-years and lower baseline forced vital capacity (FVC). Lower baseline lung function was associated with an increased risk of chronic respiratory acidosis. PaCO 2 and acid-base status were not associated with time to death or transplant., Interpretation: SaO 2 and SpO 2 are weakly-to-moderately correlated in fibrotic ILD, with limited ability to accurately predict this difference. Abnormal PaCO 2 was associated with baseline FVC but was not associated with outcomes., Competing Interests: Competing interests: MAD reports no conflicts of interest relevant to this manuscript. KD reports no conflicts of interest relevant to this manuscript. DA reports grants and personal fees from Boehringer Ingelheim, grants from Canadian Institute for Health Research and from Fonds de Recherche du Quebec en Santé. CD reports no conflicts of interest relevant to this manuscript. JHF reports personal fees from AstraZeneca and Boehringer Ingelheim. KJ reports grants from Boehringer Ingelheim, Pulmonary Fibrosis Society of Calgary, University of Calgary School of Medicine; personal fees from Boehringer Ingelheim, Roche, Three Lakes Foundation, Pliant Therapeutics, Theravance, Blade Therapeutics. MK reports grants from Canadian Institute for Health Research, Roche, Boehringer Ingelheim, Pieris, Prometic; personal fees from Boehringer Ingelheim, Roche, European Respiratory Journal, Belerophon, United Therapeutics, Nitto Denko, MitoImmune, Pieris, AbbVie, DevPro Biopharma, Horizon, Algernon, CSL Behring. SDL reports consulting/personal fees and moderator honoraria from Boehringer-Ingelheim, honoraria from Hoffman-La Roche Ltd, grants from AstraZeneca and the University of Saskatchewan. HM reports grants from Boehringer Ingelheim and Gilead. VM reports grants from Boehringer Ingelheim, AstraZeneca, and Roche; personal fees from Boehringer Ingelheim and Roche. BM reports no conflicts of interest relevant to this manuscript. JM reports personal fees from Boehringer Ingelheim and Roche. D-CM reports personal fees from Boehringer Ingelheim. CJR reports grants from Boehringer Ingelheim; personal fees from AstraZeneca, Boehringer Ingelheim, Roche, Pliant Therapeutics, Cipla, Veracyte., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)