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Summary Background INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest. Methods In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316. Findings Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI −30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; −25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI −32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; −20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea. Interpretation In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study. Funding United Therapeutics Corporation.

Background Management of patients with interstitial lung disease (ILD) requires subspecialized, comprehensive, multidisciplinary care. The Pulmonary Fibrosis Foundation established the Care Center Network (CCN) in 2013 with identified criteria to become a designated CCN site. Despite these criteria, the essential components of an ILD clinic remain unknown. Research Questions How are ILD clinics within the CCN structured? What are the essential components of an ILD clinic according to ILD physician experts, patients, and caregivers? Study Design and Methods This study had three components. First, all 68 CCN sites were surveyed to determine the characteristics of their current ILD clinics. Second, an online, three-round modified Delphi survey was conducted between October and December 2019 with 48 ILD experts participating in total. Items for round 1 were generated using expert interviews. During rounds 1 and 2, experts rated the importance of each item on a 5-point Likert scale. The a priori threshold for consensus was more than 75% of experts rating an item as important or very important. In round 3, experts graded items that met consensus and ranked items deemed essential for an ILD clinic. Third, ILD patient and caregiver focus groups were conducted and analyzed for content to determine their perspectives of an ideal ILD clinic. Results Forty items across four categories (members, infrastructure, resources, and multidisciplinary conference) achieved consensus as essential to an ILD clinic. Patient and caregiver focus groups identified three major themes: comprehensive, patient-centered medical care; expanded access to care; and comprehensive support for living and coping with ILD. Interpretation The essential components of an ILD clinic are well-aligned between physician experts and patients. Future research can use these findings to evaluate the impact of these components on patient outcomes and to inform best practices for ILD clinics throughout the world.

Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema. Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management. Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control). Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment (n = 113) or control (n = 59). Mean FEV1 showed statistically significant improvements between the treatment and control groups—between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060–0.141) and 0.099 L (95% BCI, 0.048–0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax. Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Background: INCREASE was a multicenter, randomized, double-blind, placebo-controlled, 16-week study that evaluated the safety and efficacy of inhaled treprostinil in patients with interstitial lung disease and associated pulmonary hypertension (PH-ILD). The study met its primary endpoint of change in peak 6-minute walk distance at Week 16. Methods: Pulmonary function testing and exacerbations of underlying lung disease were conducted as safety assessments. This current analysis assessed the effects of inhaled treprostinil on the forced vital capacity (FVC). Findings: 326 patients were randomized to inhaled treprostinil or placebo. Inhaled treprostinil was associated with placebo-corrected improvements in the FVC of 28·5 mL (95% CI -30·8-87.7, p=0·345) and 44·4 mL (95% CI -25·3-114·1, p=0·211) at Weeks 8 and 16, respectively. The associated percent predicted FVC improvements at Weeks 8 and 16 were 1·79% (95% CI 0·37-3·21, p=0·014) and 1·80% (95% CI 0·20-3·39, p=0·028), respectively. Patients with idiopathic interstitial pneumonia (IIP) demonstrated FVC improvements of 46·5 mL (n=129, 95% CI -32·55-125·5, p=0·247) and 108·2 mL (n=115, 95% CI 15·3-201·1, p=0·023) at Weeks 8 and 16, respectively. Patients with idiopathic pulmonary fibrosis (IPF) demonstrated FVC improvements of 84·5 mL (n=78, 95% CI -20·4-189·5, p=0·113) and 168·5 mL (n=70, 95% CI 40·1-297·0, p=0·011) at Weeks 8 and 16, respectively. Interpretation: In patients with PH-ILD, inhaled treprostinil resulted in improvements in FVC compared to placebo. This difference was most evident in patients with IIP and in particular, IPF. Inhaled treprostinil appears to be a promising therapy for IPF that warrants further prospective clinical study. Trial Registration: The INCREASE study (NCT02630316) is registered with ClinicalTrials.gov. Funding Statement: The INCREASE study was funded by United Therapeutics Corporation. Declaration of Interests: SDN has received research funding and consulting fees from United Therapeutics. He has received consulting fees from Boehringer-Ingelheim, Roche-Genentech and Galapagos. He is also on the speakers bureau for Boehringer-Ingelheim and Roche-Genentech. AW reports grants from United Therapeutics Corporation, during the conduct of the study. SR reports grants from United Therapeutics Corporation, during the conduct of the study; grants and personal fees from United Therapeutics, grants and personal fees from Janssen Pharmaceuticals, personal fees from Altavant Sciences, personal fees from Liquidia Technologies, Inc., personal fees from Insmed, Inc., personal fees from Bayer Pharmaceuticals, outside the submitted work. AC reports grants from United Therapeutics Corporation, during the conduct of the study. SJ reports grants from United Therapeutics Corporation, during the conduct of the study; grants and personal fees from Bayer Pharmaceuticals, grants from Bellerophon Therapeutics, grants and personal fees from Janssen Research and Development, outside the submitted work. HD reports grants from United Therapeutics Corporation during the conduct of the study; grants and personal fees from Actelion Pharmaceuticals, outside the submitted work. DZ reports grants from United Therapeutics Corporation, during the conduct of the study. SS reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees and non-financial support from Bayer Pharmaceuticals, personal fees and non-financial support from United Therapeutics, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees from Liquidia, personal fees from Altavant Sciences, from GSK, grants from ACCP CHEST ILD Research Grant, personal fees from Boehringer Ingelheim, outside the submitted work. CK reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics, personal fees from Actelion, personal fees from Boehringer Ingelheim Pharmaceuticals, personal fees from Genentech, outside the submitted work. LMG reports grants and personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, personal fees from Janssen and Janssen Pharmaceuticals, personal fees from Bayer Pharmaceuticals, outside the submitted work. PS reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. ES reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. LDE reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. AN reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. VFT reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics, outside the submitted work. Ethics Approval Statement: The study protocol was approved by the institutional review board at each participating site. The study was monitored by an independent data and safety monitoring committee and was conducted in accordance with the principles of Good Clinical Practice.

Rationale: Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A "molecular diagnosis of UIP" in transbronchial lung biopsy, the Envisia Genomic Classifier, accurately predicted histopathologic UIP.Objectives: We evaluated the combined accuracy of the Envisia Genomic Classifier and local radiology in the detection of UIP pattern.Methods: Ninety-six patients who had diagnostic lung pathology as well as a transbronchial lung biopsy for molecular testing with Envisia Genomic Classifier were included in this analysis. The classifier results were scored against reference pathology. UIP identified on high-resolution computed tomography (HRCT) as documented by features in local radiologists' reports was compared with histopathology.Measurements and Main Results: In 96 patients, the Envisia Classifier achieved a specificity of 92.1% (confidence interval [CI],78.6-98.3%) and a sensitivity of 60.3% (CI, 46.6-73.0%) for histology-proven UIP pattern. Local radiologists identified UIP in 18 of 53 patients with UIP histopathology, with a sensitivity of 34.0% (CI, 21.5-48.3%) and a specificity of 96.9% (CI, 83.8-100%). In conjunction with HRCT patterns of UIP, the Envisia Classifier results identified 24 additional patients with UIP (sensitivity 79.2%; specificity 90.6%).Conclusions: In 96 patients with suspected interstitial lung disease, the Envisia Genomic Classifier identified UIP regardless of HRCT pattern. These results suggest that recognition of a UIP pattern by the Envisia Genomic Classifier combined with HRCT and clinical factors in a multidisciplinary discussion may assist clinicians in making an interstitial lung disease (especially IPF) diagnosis without the need for a surgical lung biopsy.

Objective Patient satisfaction with HIV screening is crucial for sustainable implementation of the Centers for Disease Control and Prevention (CDC) HIV testing recommendations. This investigation assesses patient satisfaction with rapid HIV testing in the emergency department (ED) of an urban tertiary academic medical center. Methods After receiving HIV test results, participants in the Universal Screening for HIV Infection in the Emergency Room (USHER) randomized controlled trial were offered a patient satisfaction survey. Questions concerned overall satisfaction with ED visit, time spent on primary medical problem, time spent on HIV testing, and test provider's ability to answer HIV-related questions. Responses were reported on a 4-point Likert scale, ranging from very dissatisfied to very satisfied (defined as optimal satisfaction). Results Of 4,860 USHER participants, 2,025 completed testing and were offered the survey: 1,616 (79.8%) completed the survey. Overall, 1,478 (91.5%) were very satisfied. Satisfaction was less than optimal for 34.5% (10 of 29) of participants with reactive results and for 7.5% (115 of 1,542) with nonreactive results. The independent factors associated with less than optimal satisfaction were reactive test result, aged 60 years or older, black race, Hispanic/Latino ethnicity, and testing by ED provider instead of HIV counselor. Conclusion Most participants were very satisfied with the ED-based rapid HIV testing program. Identification of independent factors that correlate with patient satisfaction will help guide best practices as EDs implement CDC recommendations. It is critical to better understand whether patients with reactive results were negatively affected by their results or truly had concerns about the testing process.

Background: Latinas are at a higher risk than Caucasians for both type 1 and type 2 diabetes (DM), as well as DM-associated reproductive health (RH) complications. Healthcare providers (HCPs) should deliver culturally-sensitive care to enhance the care relationship between Latinos and HCPs and to improve patient outcomes. This study explored an expert panel’s cultural understanding, experiences, barriers, and facilitators regarding RH and preconception counseling (PC) for adolescent Latinas with DM and their families. Methods: This study used open-ended questions with a focus group of 8 HCPs from the mid-Atlantic, Southwest, and Northwest regions of the United States in a teleconference format. Two researchers transcribed and reviewed the transcript for accuracy. Using content analysis, four members of the team identified themes. All researchers discussed themes and a 100% consensus was reached. For confirmation, a coding protocol was created based on the emerging themes. Results: Five themes related to cultural understanding and experiences were identified: 1) issues of identity; 2) acculturation; 3) stigma; 4) ambivalence toward birth control, RH education, and PC; and 5) cultural sensitivity vs. best practice. Four barriers were identified: 1) language; 2) religion; 3) access to healthcare, and 4) discomfort with discussion. Ten facilitators were identified: 1) the importance of support and support networks; 2) promoting trust among HCPs, daughters, and families; 3) assessing emotional development; 4) empowerment; 5) emphasizing safety; 6) communicating in patients’ preferred language; 7) discussing RH-related topics and PC using cultural sensitivity; 8) importance of being ready/temporality/planning for the future; 9) the importance of family-centered care; and 10) variation in educational tailoring and dissemination/ care delivery. Conclusions: Findings support the need for culturally sensitive and developmentally appropriate PC programs to empower adolescent Latinas with DM.

ObjectiveTo estimate the prevalence of undiagnosed HIV, the prevalence of diagnosed HIV, and proportion of HIV that is undiagnosed in populations with similar demographics as the Universal Screening for HIV in the Emergency Room (USHER) Trial and the Brigham and Women's Hospital (BWH) Emergency Department (ED) in Boston, MA. We also sought to estimate these quantities within demographic and risk behavior subgroups.MethodWe used data from the USHER Trial, which was a randomized clinical trial of HIV screening conducted in the BWH ED. Since eligible participants were HIV-free at time of enrollment, we were able to calculate the prevalence of undiagnosed HIV. We used data from the Massachusetts Department of Public Health (MA/DPH) to estimate the prevalence of diagnosed HIV since the MA/DPH records the number of persons within MA who are HIV-positive. We calculated the proportion of HIV that is undiagnosed using these estimates of the prevalence of undiagnosed and diagnosed HIV. Estimates were stratified by age, sex, race/ethnicity, history of testing, and risk behaviors.ResultsThe overall expected prevalence of diagnosed HIV in a population similar to those presenting to the BWH ED was 0.71% (95% CI: 0.63%, 0.78%). The prevalence of undiagnosed HIV was estimated at 0.22% (95% CI: 0.10%, 0.42%) and resultant overall prevalence was 0.93%. The proportion of HIV-infection that is undiagnosed in this ED-based setting was estimated to be 23.7% (95% CI: 11.6%, 34.9%) of total HIV-infections.ConclusionsDespite different methodology, our estimate of the proportion of HIV that is undiagnosed in an ED-setting was similar to previous estimates based on national surveillance data. Universal routine testing programs in EDs should use these data to help plan their yield of HIV detection.

Background Oral rapid HIV testing has been reported to have a lower sensitivity and specificity than rapid HIV testing with whole-blood and has been associated with clusters of false positive results. Patient preference for oral rapid HIV testing compared to more invasive whole-blood fingerstick may influence the acceptance of rapid HIV testing.