Idiopathic pulmonary fibrosis in the United States: time to diagnosis and treatment.

OBJECTIVE: Create a timeline of diagnosis and treatment for IPF in the US. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was performed in collaboration with the OptumLabs Data Warehouse using an administrative claims database of Medicare Fee for Service beneficiaries. Adults 50 and over with IPF were included (2014 to 2019). EXPOSURE: To focus on IPF, the following diagnoses were excluded: post-inflammatory fibrosis, hypersensitivity pneumonitis, rheumatoid arthritis, sarcoidosis, scleroderma, and connective tissue disease. MAIN OUTCOMES AND MEASURES: Data were collected from periods prior, during, and following initial clinical diagnosis of IPF. This included prior respiratory diagnoses, number of respiratory-related hospitalizations, anti-fibrotic and oxygen use, and survival. RESULTS: A total of 44,891 with IPF were identified. The most common diagnoses prior to diagnosis of IPF were upper respiratory infections (47%), acute bronchitis (13%), other respiratory disease (10%), chronic obstructive pulmonary disease and bronchiectasis (7%), and pneumonia (6%). The average time to a diagnosis of IPF was 2.7 years after initial respiratory diagnosis. Half of patients had two or more respiratory-related hospitalizations prior to IPF diagnosis. Also, 37% of patients were prescribed oxygen prior to diagnosis of IPF. These observations suggest delayed diagnosis. We also observed only 10.4% were treated with anti-fibrotics. Overall survival declined each year after diagnosis with median survival of 2.80 years. CONCLUSIONS AND RELEVANCE: Our retrospective cohort demonstrates that IPF is often diagnosed late, usually preceded by other respiratory diagnoses and hospitalizations. Use of available therapies is low and outcomes remain poor.

Evaluation for clinical benefit of metformin in patients with idiopathic pulmonary fibrosis and type 2 diabetes mellitus: a national claims-based cohort analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high morbidity and limited treatment options. Type 2 diabetes mellitus (T2DM) is a common comorbid illness among patients with IPF and is often treated with metformin, the first-line agent in the management of T2DM. There is growing evidence demonstrating metformin's anti-fibrotic properties; however, there is little real-world clinical data regarding its potential effectiveness in IPF. This study aims to evaluate the clinical benefit of metformin in patients with IPF and T2DM. METHODS: This nationwide cohort study used de-identified administrative claims data from OptumLabs® Data Warehouse to identify 3599 adults with IPF and concomitant T2DM between January 1, 2014 and June 30, 2019. Two cohorts were created: a cohort treated with metformin (n = 1377) and a cohort not treated with metformin (n = 2222). A final 1:1 propensity score-matched cohort compared 1100 patients with IPF and T2DM receiving metformin to those with both diagnoses but not receiving metformin; matching accounted for age, sex, race/ethnicity, residence region, year, medications, oxygen use, smoking status, healthcare use, and comorbidities. Outcomes were all-cause mortality (primary) and hospitalizations (secondary). RESULTS: Among 2200 patients with IPF and T2DM included in this matched analysis, metformin therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.36-0.58; p < 0.001) and hospitalizations (HR, 0.82; 95% CI, 0.72-0.93; p = 0.003) compared to patients not receiving metformin. CONCLUSIONS: Among patients with IPF and T2DM, metformin therapy may be associated with improved clinical outcomes. However, further investigation with randomized clinical trials is necessary prior to metformin's broad implementation in the clinical management of IPF.

Cost-effectiveness of the anti-fibrotics for the treatment of idiopathic pulmonary fibrosis in the United States.

BACKGROUND: The anti-fibrotic medications nintedanib and pirfenidone were approved in the United States for use in patients with idiopathic pulmonary fibrosis several years ago. While there is a growing body of evidence surrounding their clinical effectiveness, these medications are quite expensive and no prior cost-effectiveness analysis has been performed in the United States. METHODS: A previously published Markov model performed in the United Kingdom was replicated using United States data to project the lifetime costs and health benefits of treating idiopathic pulmonary fibrosis with: (1) symptom management; (2) pirfenidone; or (3) nintedanib. For the cost-effectiveness analysis, strategies were ranked by increasing costs and then checked for dominating treatment strategies. Then an incremental cost-effectiveness ratio was calculated for the dominant therapy. RESULTS: The anti-fibrotic medications were found to cost more than $110,000 per year compared to $12,291 annually for symptom management. While pirfenidone was slightly more expensive than nintedanib and provided the same amount of benefit, neither medication was found to be cost-effective in this U.S.-based analysis, with an average cost of $1.6 million to gain one additional quality-adjusted life year over symptom management. CONCLUSIONS: Though the anti-fibrotics remain the only effective treatment option for patients with idiopathic pulmonary fibrosis and the data surrounding their clinical effectiveness continues to grow, they are not considered cost-effective treatment strategies in the United States due to their high price.

Outcomes for hospitalized patients with idiopathic pulmonary fibrosis treated with antifibrotic medications.

BACKGROUND: Idiopathic Pulmonary Fibrosis is a chronic, progressive interstitial lung disease for which there is no cure. However, lung function decline, hospitalizations, and mortality may be reduced with the use of the antifibrotic medications, nintedanib and pirfenidone. Historical outcomes for hospitalized patients with Idiopathic Pulmonary Fibrosis are grim; however there is a paucity of data since the approval of nintedanib and pirfenidone for treatment. In this study, we aimed to determine the effect of nintedanib and pirfenidone on mortality following respiratory-related hospitalizations, intensive care unit (ICU) admission, and mechanical ventilation. METHODS: Using a large U.S. insurance database, we created a one-to-one propensity score matched cohort of patients with idiopathic pulmonary fibrosis treated and untreated with an antifibrotic who underwent respiratory-related hospitalization between January 1, 2015 and December 31, 2018. Mortality was evaluated at 30 days and end of follow-up (up to 2 years). Subgroup analyses were performed for all patients receiving treatment in an ICU and those receiving invasive and non-invasive mechanical ventilation during the index hospitalization. RESULTS: Antifibrotics were not observed to effect utilization of mechanical ventilation or ICU treatment during the index admission or effect mortality at 30-days. If patients survived hospitalization, mortality was reduced in the treated cohort compared to the untreated cohort when followed up to two years (20.1% vs 47.8%). CONCLUSIONS: Treatment with antifibrotic medications does not appear to directly improve 30-day mortality during or after respiratory-related hospitalizations. Post-hospital discharge, however, ongoing antifibrotic treatment was associated with improved long-term survival.

Clinical Effectiveness of Antifibrotic Medications for Idiopathic Pulmonary Fibrosis.

Rationale: Since their approval, there has been no real-world or randomized trial evidence evaluating the effect of the antifibrotic medications pirfenidone and nintedanib on clinically important outcomes such as mortality and hospitalizations. Objectives: To evaluate the clinical effectiveness of the antifibrotic medications pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis. Methods: Using a large U.S. insurance database, we identified 8,098 patients with idiopathic pulmonary fibrosis between October 1, 2014 and March 1, 2018. A one-to-one propensity score-matched cohort was created to compare patients treated with antifibrotic medications (n = 1,255) with those not on treatment (n = 1,255). The primary outcome was all-cause mortality. The secondary outcome was acute hospitalizations. Subgroup analyses were performed to evaluate mortality differences by drug. Measurements and Main Results: The use of antifibrotic medications was associated with a decreased risk of all-cause mortality (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.62-0.98; P value = 0.034). However, this association was present only through the first 2 years of treatment. There was also a decrease in acute hospitalizations in the treated cohort (HR, 0.70; 95% CI, 0.61-0.80; P value <0.001). There was no significant difference in all-cause mortality between patients receiving pirfenidone and those on nintedanib (HR, 1.14; 95% CI, 0.79-1.65; P = 0.471). Conclusions: Among patients with idiopathic pulmonary fibrosis, antifibrotic agents may be associated with a lower risk of all-cause mortality and hospitalization compared with no treatment. Future research should test the hypothesis that these treatments reduce early, but not long-term, mortality as demonstrated in our study.

Use and acceptance of long lasting insecticidal net screens for dengue prevention in Acapulco, Guerrero, Mexico.

BACKGROUND: Dengue, recognized by the WHO as the most important mosquito-borne viral disease in the world, is a growing problem. Currently, the only effective way of preventing dengue is vector control. Standard methods have shown limited effect, and there have been calls to develop new integrated vector management approaches. One novel tool, protecting houses with long lasting insecticidal screens on doors and windows, is being trialled in a cluster randomised controlled trial by a joint UADY/WHO TDR/IDRC study in various districts of Acapulco, Mexico, with exceptionally high levels of crime and insecurity.This study investigated the community's perspectives of long lasting insecticidal screens on doors and windows in homes and in schools, in order to ascertain their acceptability, to identify challenges to further implementation and opportunities for future improvements. METHODS: This was a sequential mixed-methods study. The quantitative arm contained a satisfaction survey administered to 288 houses that had received the intervention examining their perspectives of both the intervention and dengue prevention in general. The qualitative arm consisted of Focus Group Discussions (FGDs) with those who had accepted the intervention and key informant interviews with: schoolteachers to discuss the use of the screens in schools, program staff, and community members who had refused the intervention. RESULTS: Overall satisfaction and acceptance of the screens was very high, with only some operational and technical complaints relating to screen fragility and the installation process. However, the wider social context of urban violence and insecurity was a major barrier to screen acceptance. Lack of information dissemination and community collaboration were identified as project weaknesses. CONCLUSIONS: The screens are widely accepted by the population, but the project implementation could be improved by reassuring the community of its legitimacy in the context of insecurity. More community engagement and better information sharing structures are needed.The screens could be a major new dengue prevention tool suitable for widespread use, if further research supports their entomological and epidemiological effectiveness and their acceptability in different social and environmental contexts. Further research is needed looking at the impact of insecurity of dengue prevention programmes.

Unlocking the genetic diversity and population structure of the newly introduced two-row spring European HerItage Barley collecTion (ExHIBiT).

In the last century, breeding programs have traditionally favoured yield-related traits, grown under high-input conditions, resulting in a loss of genetic diversity and an increased susceptibility to stresses in crops. Thus, exploiting understudied genetic resources, that potentially harbour tolerance genes, is vital for sustainable agriculture. Northern European barley germplasm has been relatively understudied despite its key role within the malting industry. The European Heritage Barley collection (ExHIBiT) was assembled to explore the genetic diversity in European barley focusing on Northern European accessions and further address environmental pressures. ExHIBiT consists of 363 spring-barley accessions, focusing on two-row type. The collection consists of landraces (~14%), old cultivars (~18%), elite cultivars (~67%) and accessions with unknown breeding history (~1%), with 70% of the collection from Northern Europe. The population structure of the ExHIBiT collection was subdivided into three main clusters primarily based on the accession's year of release using 26,585 informative SNPs based on 50k iSelect single nucleotide polymorphism (SNP) array data. Power analysis established a representative core collection of 230 genotypically and phenotypically diverse accessions. The effectiveness of this core collection for conducting statistical and association analysis was explored by undertaking genome-wide association studies (GWAS) using 24,876 SNPs for nine phenotypic traits, four of which were associated with SNPs. Genomic regions overlapping with previously characterised flowering genes (HvZTLb) were identified, demonstrating the utility of the ExHIBiT core collection for locating genetic regions that determine important traits. Overall, the ExHIBiT core collection represents the high level of untapped diversity within Northern European barley, providing a powerful resource for researchers and breeders to address future climate scenarios.

Critical Care Staffing in Pandemics and Disasters: A Consensus Report From a Subcommittee of the Task Force for Mass Critical Care - Systems Strategies to Sustain the Health Care Workforce.

BACKGROUND: The COVID-19 pandemic has led to unprecedented mental health disturbances, burnout, and moral distress among health care workers, affecting their ability to care for themselves and their patients. RESEARCH QUESTION: In health care workers, what are key systemic factors and interventions impacting mental health and burnout? STUDY DESIGN AND METHODS: The Workforce Sustainment subcommittee of the Task Force for Mass Critical Care (TFMCC) utilized a consensus development process, incorporating evidence from literature review with expert opinion through a modified Delphi approach to determine factors affecting mental health, burnout, and moral distress in health care workers, to propose necessary actions to help prevent these issues and enhance workforce resilience, sustainment, and retention. RESULTS: Consolidation of evidence gathered from literature review and expert opinion resulted in 197 total statements that were synthesized into 14 major suggestions. These suggestions were organized into three categories: (1) mental health and well-being for staff in medical settings; (2) system-level support and leadership; and (3) research priorities and gaps. Suggestions include both general and specific occupational interventions to support health care worker basic physical needs, lower psychological distress, reduce moral distress and burnout, and foster mental health and resilience. INTERPRETATION: The Workforce Sustainment subcommittee of the TFMCC offers evidence-informed operational strategies to assist health care workers and hospitals plan, prevent, and treat the factors affecting health care worker mental health, burnout, and moral distress to improve resilience and retention following the COVID-19 pandemic.

Association of outpatient use of renin-angiotensin-aldosterone system blockers on outcomes of acute respiratory illness during the COVID-19 pandemic: a cohort study.

OBJECTIVES: Evaluate the associations between patients taking ACE inhibitors and angiotensin receptor blockers (ARBs) and their clinical outcomes after an acute viral respiratory illness (AVRI) due to COVID-19. DESIGN: Retrospective cohort. SETTING: The USA; 2017-2018 influenza season, 2018-2019 influenza season, and 2019-2020 influenza/COVID-19 season. PARTICIPANTS: People with hypertension (HTN) taking an ACEi, ARB or other HTN medications, and experiencing AVRI. MAIN OUTCOME MEASURES: Change in hospital admission, intensive care unit (ICU) or coronary care unit (CCU), acute respiratory distress (ARD), ARD syndrome (ARDS) and all-cause mortality, comparing COVID-19 to pre-COVID-19 influenza seasons. RESULTS: The cohort included 1 059 474 episodes of AVRI (653 797 filled an ACEi or ARB, and 405 677 other HTN medications). 58.6% were women and 72.9% with age ≥65. The ACEi/ARB cohort saw a larger increase in risk in the COVID-19 influenza season than the other HTN medication cohort for four out of five outcomes, with an additional 1.5 percentage point (pp) increase in risk of an inpatient stay (95% CI 1.2 to 1.9 pp) and of ICU/CCU use (95% CI 0.3 to 2.7 pp) as well as a 0.7 pp (0.1 to 1.2 pp) additional increase in risk of ARD and 0.9 pp (0.4 to 1.3 pp) additional increase in risk of ARDS. There was no statistically significant difference in the absolute risk of death (-0.2 pp, 95% CI -0.4 to 0.1 pp). However, the relative risk of death in 2019/2020 versus 2017/2018 for the ACEi/ARB group was larger (1.40 (1.36 to 1.44)) than for the other HTN medication cohort (1.24 (1.21 to 1.28)). CONCLUSIONS: People with AVRI using ACEi/ARBs for HTN had a greater increase in poor outcomes during the COVID-19 pandemic than those using other medications to treat HTN. The small absolute magnitude of the differences likely does not support changes in clinical practice.

Adoption of the Antifibrotic Medications Pirfenidone and Nintedanib for Patients with Idiopathic Pulmonary Fibrosis.

Rationale: In October 2014, the antifibrotic medications pirfenidone and nintedanib became the first medications approved by the U.S. Food and Drug Administration for use in patients with idiopathic pulmonary fibrosis (IPF). Since approval, there has been no nonregistry analysis of the real-world adoption of these medications in everyday clinical practice. Objectives: To evaluate the adoption, persistence, and out-of-pocket (OOP) costs of pirfenidone and nintedanib since their approval in the United States in 2014. Methods: A retrospective cohort analysis was performed by identifying privately insured and Medicare Advantage beneficiaries with IPF. We then split the patients into three cohorts: those who were untreated and those who filled a prescription for either pirfenidone or nintedanib between October 1, 2014, and July 31, 2019. The primary outcome was adoption of the medications. Secondary outcomes included medication persistence and prescription drug costs. Results: A total of 10,996 patients with IPF were identified in the data set. A minority of patients (26.4%) with IPF identified in the cohort had started either medication since approval in 2014, with the adoption of both medications being comparable at around 13.2%. Those receiving the medications were younger (72 vs. 73.9 yr; P < 0.0001) and healthier (3.9 vs. 4.9 comorbidities; P < 0.0001) than those not receiving treatment. Men were significantly more likely to receive treatment than woman (30.0% vs. 21.9%; P < 0.0001). Among treated patients, 42.8% discontinued the medications during the study period. Patients' OOP expenses per month were high for both drugs (mean, $397.51 for nintedanib; mean, $394.49 for pirfenidone). Conclusions: The adoption of both the antifibrotic medications in the United States in everyday practice has been low since approval and may be associated with the high OOP cost.

Association of outpatient ACE inhibitors and angiotensin receptor blockers and outcomes of acute respiratory illness: a retrospective cohort study.

OBJECTIVES: Evaluate associations between ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) and clinical outcomes in acute viral respiratory illness (AVRI). DESIGN: Retrospective cohort analysis of claims data. SETTING: The USA; 2018-2019 influenza season. PARTICIPANTS: Main cohort: people with hypertension (HTN) taking an ACEi, ARB or other HTN medications, and experiencing AVRI. Falsification cohort: parallel cohort receiving elective knee or hip replacement. MAIN OUTCOME MEASURES: Main cohort: hospital admission, intensive care unit, acute respiratory distress (ARD), ARD syndrome and all-cause mortality. Falsification cohort: complications after surgery and all-cause mortality. RESULTS: The main cohort included 236 843 episodes of AVRI contributed by 202 629 unique individuals. Most episodes were in women (58.9%), 81.4% in people with Medicare Advantage and 40.3% in people aged 75+ years. Odds of mortality were lower in the ACEi (0.78 (0.74 to 0.83)) and ARB (0.64 (0.61 to 0.68)) cohorts compared with other HTN medications. On all other outcomes, people taking ARBs (but not ACEis) had a >10% reduction in odds of inpatient stays compared with other HTN medications.In the falsification analysis (N=103 353), both ACEis (0.89 (0.80 to 0.98)) and ARBs (0.82 (0.74 to 0.91)) were associated with decreased odds of complications compared with other HTN medications; ARBs (0.64 (0.47 to 0.87)) but not ACEis (0.79 (0.60 to 1.05)) were associated with lower odds of death compared with other HTN medications. CONCLUSIONS: Outpatient use of ARBs was associated with better outcomes with AVRI compared with other medications for HTN. ACEis were associated with reduced risk of death, but with minimal or no reduction in risk of other complications. A falsification analysis conducted to provide context on the possible causal implications of these findings did not provide a clear answer. Further analysis using observational data will benefit from additional approaches to assess causal relationships between these drugs and outcomes in AVRI.

Human immunodeficiency virus type 1 Vpr: oligomerization is an essential feature for its incorporation into virus particles.

HIV-1 Vpr, a nonstructural viral protein associated with virus particles, has a positive role in the efficient transport of PIC into the nucleus of non-dividing target cells and enhances virus replication in primary T cells. Vpr is a 96 amino acid protein and the structure by NMR shows three helical domains. Vpr has been shown to exist as dimers and higher order oligomers. Considering the multifunctional nature of Vpr, the contribution of distinct helical domains to the dimer/oligomer structure of Vpr and the relevance of this feature to its functions are not clear. To address this, we have utilized molecular modeling approaches to identify putative models of oligomerization. The predicted interface residues were subjected to site-directed mutagenesis and evaluated their role in intermolecular interaction and virion incorporation. The interaction between Vpr molecules was monitored by Bimolecular Fluorescence complementation (BiFC) method. The results show that Vpr forms oligomers in live cells and residues in helical domains play critical roles in oligomerization. Interestingly, Vpr molecules defective in oligomerization also fail to incorporate into the virus particles. Based on the data, we suggest that oligomerization of Vpr is essential for virion incorporation property and may also have a role in the events associated with virus infection.

Miles to Go Before We Sleep. Reforming the Pulmonary and Critical Care Milestones to Improve Trainee Assessment.

The Accreditation Council for Graduate Medical Education (ACGME) Milestones are a systematic assessment framework for medical trainees within the six core competencies of practice. Their use by internal medicine subspecialties, including semiannual reports to the ACGME, was mandated beginning in 2014. The Milestones, which were based on specific, observable behaviors, improved upon the prior subjective, global comparisons of each fellow with an "average" fellow in his or her field and served the goals of competency-based medical education. However, the original set of Milestones has proven challenging to apply and interpret. Part of the challenge stems from the use of identical Milestones across all medicine subspecialties, which led to unclear relevance of the patient care and medical knowledge domains to the practice of pulmonary and critical care. This also precluded their use for individualized feedback or development of a learning plan for fellows. In addition, verbose behavioral descriptors, which were designed to provide specificity, ultimately led to rater fatigue among assessors and clinical competency committees. Therefore, the ACGME convened committees for each of the medical subspecialties to revise the original Milestones in an effort to improve subspecialty relevance, minimize educational jargon, and simplify the current iteration. New patient care and medical knowledge Milestones were created to be subspecialty specific and improve utility. The remaining four Milestones were developed as a common set of shorter Milestones, harmonized across specialties. For pulmonary, critical care, and combined fellowship programs, the resulting Milestones 2.0 aims to simplify the use, implementation, and interpretation of this framework for program directors, trainees, and society.

Lessons learned from an under-reported mumps epidemic among Rohingya refugees in Cox's Bazar District, Bangladesh.

BACKGROUND: In 2018, a large mumps epidemic coincided with an outbreak of diphtheria in refugee camps established in Bangladesh for the Rohingya people. These refugees did not receive a mumps-containing vaccine. METHODS: Cases of mumps were reported to the WHO's Early Warning, Alert and Response System (EWARS) during the Rohingya refugee crisis. The authors present amalgamated epidemiological data of a major, previously under-reported, mumps epidemic. RESULTS: In total, 19 215 mumps cases across a total of 218 facilities were reported to EWARS during 2018. The attack rate was 2.1% of the whole population. Of these cases, 7687 (40%) were in children aged <5 y. Mumps was more commonly seen among males than females. CONCLUSION: Detailed reporting of outbreaks of all vaccine-preventable diseases is essential to ensure appropriate vaccination decisions can be made in future humanitarian crises.

How Should Clinicians Navigate Decision Making for Unrepresented Patients?

Caring for patients who lack decision-making capacity is common in health care and presents numerous practical and ethical challenges. Unrepresented patients are vulnerable in part because they do not have anyone to help articulate their values and preferences, and they cannot do so themselves. This commentary suggests a deliberative approach to responding to these patients' needs.