Predicting New-onset Exertional and Resting Hypoxemia in Fibrotic Interstitial Lung Disease.

Rationale: Hypoxemia in fibrotic interstitial lung disease (ILD) indicates disease progression and is of prognostic significance. The onset of hypoxemia signifies disease progression and predicts mortality in fibrotic ILD. Accurately predicting new-onset exertional and resting hypoxemia prompts appropriate patient discussion and timely consideration of home oxygen. Objectives: We derived and externally validated a risk prediction tool for both new-onset exertional and new-onset resting hypoxemia. Methods: This study used ILD registries from Canada for the derivation cohort and from Australia and the United States for the validation cohort. New-onset exertional and resting hypoxemia were defined as nadir oxyhemoglobin saturation < 88% during 6-minute-walk tests, resting oxyhemoglobin saturation < 88%, or the initiation of ambulatory or continuous oxygen. Candidate predictors included patient demographics, ILD subtypes, and pulmonary function. Time-varying Cox regression was used to identify the top-performing prediction model according to Akaike information criterion and clinical usability. Model performance was assessed using Harrell's C-index and goodness-of-fit (GoF) likelihood ratio test. A categorized risk prediction tool was developed. Results: The best-performing prediction model for both new-onset exertional and new-onset resting hypoxemia included age, body mass index, a diagnosis of idiopathic pulmonary fibrosis, and percent predicted forced vital capacity and diffusing capacity of carbon monoxide. The risk prediction tool exhibited good performance for exertional hypoxemia (C-index, 0.70; GoF, P = 0.85) and resting hypoxemia (C-index, 0.77; GoF, P = 0.27) in the derivation cohort, with similar performance in the validation cohort except calibration for resting hypoxemia (GoF, P = 0.001). Conclusions: This clinically applicable risk prediction tool predicted new-onset exertional and resting hypoxemia at 6 months in the derivation cohort and a diverse validation cohort. Suboptimal GoF in the validation cohort likely reflected overestimation of hypoxemia risk and indicated that the model is not flawed because of underestimation of hypoxemia.

Differences in US Regional Healthcare Allocation Guidelines During the COVID-19 Pandemic.

BACKGROUND: Hospitals faced unprecedented scarcity of resources without parallel in modern times during the COVID-19 pandemic. This scarcity led healthcare systems and states to develop or modify scarce resource allocation guidelines that could be implemented during "crisis standards of care" (CSC). CSC describes a significant change in healthcare operations and the level of care provided during a public health emergency. OBJECTIVE: Our study provides a comprehensive examination of the latest CSC guidelines in the western region of the USA, where Alaska and Idaho declared CSC, focusing on ethical issues and health disparities. DESIGN: Mixed-methods survey study of physicians and/or ethicists and review of healthcare system and state allocation guidelines. PARTICIPANTS: Ten physicians and/or ethicists who participated in scarce resource allocation guideline development from seven healthcare systems or three state-appointed committees from the western region of the USA including Alaska, California, Idaho, Oregon, and California. RESULTS: All sites surveyed developed allocation guidelines, but only four (40%) were operationalized either statewide or for specific scarce resources. Most guidelines included comorbidities (70%), and half included adjustments for socioeconomic disadvantage (50%), while only one included specific priority groups (10%). Allocation tiebreakers included the life cycle principle and random number generators. Six guidelines evolved over time, removing restrictions such as age, severity of illness, and comorbidities. Additional palliative care (20%) and ethics (50%) resources were planned by some guidelines. CONCLUSIONS: Allocation guidelines are essential to support clinicians during public health emergencies; however, significant deficits and differences in guidelines were identified that may perpetuate structural inequities and racism. While a universal triage protocol that is equally accepted by all communities is unlikely, the lack of regional agreement on standards with justification and transparency has the potential to erode public trust and perpetuate inequity.

Circulating Plasma Biomarkers of Survival in Antifibrotic-Treated Patients With Idiopathic Pulmonary Fibrosis.

BACKGROUND: A number of circulating plasma biomarkers have been shown to predict survival in patients with idiopathic pulmonary fibrosis (IPF), but most were identified before the use of antifibrotic (AF) therapy in this population. Because pirfenidone and nintedanib have been shown to slow IPF progression and may prolong survival, the role of such biomarkers in AF-treated patients is unclear. RESEARCH QUESTION: To determine whether plasma concentration of cancer antigen 125 (CA-125), C-X-C motif chemokine 13 (CXCL13), matrix metalloproteinase 7 (MMP7), surfactant protein D (SP-D), chitinase-3-like protein-1 (YKL-40), vascular cell adhesion protein-1 (VCAM-1), and osteopontin (OPN) is associated with differential transplant-free survival (TFS) in AF-exposed and nonexposed patients with IPF. STUDY DESIGN AND METHODS: A pooled, multicenter, propensity-matched analysis of IPF patients with and without AF exposure was performed. Optimal thresholds for biomarker dichotomization were identified in each group using iterative Cox regression. Longitudinal biomarker change was assessed in a subset of patients using linear mixed regression modeling. A clinical-molecular signature of IPF TFS was then derived and validated in an independent IPF cohort. RESULTS: Three hundred twenty-five patients were assessed, of which 68 AF-exposed and 172 nonexposed patients were included after propensity matching. CA-125, CXCL13, MMP7, YKL-40, and OPN predicted differential TFS in AF-exposed patients but at higher thresholds than in AF-nonexposed individuals. Plasma biomarker level generally increased over time in nonexposed patients but remained unchanged in AF-exposed patients. A clinical-molecular signature predicted decreased TFS in AF-exposed patients (hazard ratio [HR], 5.91; 95% CI, 2.25-15.5; P < .001) and maintained this association in an independent AF-exposed cohort (HR, 3.97; 95% CI, 1.62-9.72; P = .003). INTERPRETATION: Most plasma biomarkers assessed predicted differential TFS in AF-exposed patients with IPF, but at higher thresholds than in nonexposed patients. A clinical-molecular signature of IPF TFS may provide a reliable predictor of outcome risk in AF-treated patients but requires additional research for optimization and validation.

Diagnostic test interpretation and referral delay in patients with interstitial lung disease.

BACKGROUND: Diagnostic delays are common in patients with interstitial lung disease (ILD). A substantial percentage of patients experience a diagnostic delay in the primary care setting, but the factors underpinning this observation remain unclear. In this multi-center investigation, we assessed ILD reporting on diagnostic test interpretation and its association with subsequent pulmonology referral by a primary care physician (PCP). METHODS: A retrospective cohort analysis of patients referred to the ILD programs at UC-Davis and University of Chicago by a PCP within each institution was performed. Computed tomography (CT) of the chest and abdomen and pulmonary function test (PFT) were reviewed to identify the date ILD features were first present and determine the time from diagnostic test to pulmonology referral. The association between ILD reporting on diagnostic test interpretation and pulmonology referral was assessed, as was the association between years of diagnostic delay and changes in fibrotic features on longitudinal chest CT. RESULTS: One hundred and forty-six patients were included in the final analysis. Prior to pulmonology referral, 66% (n = 97) of patients underwent chest CT, 15% (n = 21) underwent PFT and 15% (n = 21) underwent abdominal CT. ILD features were reported on 84, 62 and 33% of chest CT, PFT and abdominal CT interpretations, respectively. ILD reporting was associated with shorter time to pulmonology referral when undergoing chest CT (1.3 vs 15.1 months, respectively; p = 0.02), but not PFT or abdominal CT. ILD reporting was associated with increased likelihood of pulmonology referral within 6 months of diagnostic test when undergoing chest CT (rate ratio 2.17, 95% CI 1.03-4.56; p = 0.04), but not PFT or abdominal CT. Each year of diagnostic delay was associated with a 1.8% increase in percent fibrosis on chest CT. Patients with documented dyspnea had shorter time to chest CT acquisition and pulmonology referral than patients with documented cough and lung crackles. CONCLUSIONS: Determinants of ILD diagnostic delays in the primary care setting include underreporting of ILD features on diagnostic testing and prolonged time to pulmonology referral even when ILD is reported. Interventions to modulate these factors may reduce ILD diagnostic delays in the primary care setting.

Impact of the California Breast Density Law on Screening Breast MR Utilization, Provider Ordering Practices, and Patient Demographics.

PURPOSE: To assess the impact of California's Breast Density Law (BDL) on MRI utilization and clinician ordering practices. MATERIALS AND METHODS: Our institutional review board approved this study that retrospectively compared the ordering pattern for screening breast MRI examinations in the 30-month period before and after the BDL was enacted. Examinations were subcategorized into those with breast density mentioned as an examination indication. Patients were classified into (1) high risk; (2) above average risk, defined but not quantified; and (3) undefined or average risk. χ2 test or Fisher's exact test was used to compare MRI utilization, use of breast density as an indication, patient demographics, and provider characteristics. RESULTS: Screening MRI examinations with breast density as the indication increased from 8.5% (32 of 376) to 21.1% (136 of 646, P < .0001) after BDL. When high-risk patients were excluded, the increase was from 8% to 17.2% (P < .0001). Patient demographics before and after BDL were, by race: white 71.8% versus 71.2%; Asian 6.4% versus 10.5%; black 3.7% versus 3.1%; American Indian 0.3% versus 1.4%; Native Hawaiian or Pacific Islander 1.6% versus 1.7%; by ethnicity: Hispanic or Latino 10.6% versus 7.9%. Before and after BDL, predominantly female providers (81.4% and 77.4%, P = not significant [NS]) and specialists (62.5% and 63.5%, P = NS) ordered the majority of breast MRI examinations compared with males (18.6% and 22.6%, P = NS). CONCLUSION: Screening breast MRI utilization for non-high-risk women more than doubled after the California BDL went into effect. BDL has had an impact on MRI utilization, and its clinical value for changing outcomes deserves further study.

A comparison of how four countries use health IT to support care for people with chronic conditions.

Countries around the globe are investing in health information and communications technologies (ICTs) as critical tools for improving care for chronically ill patients. We profiled four high-income nations with varied health ICT strategies--Australia, Canada, Denmark, and the United States--to describe their use of ICTs to improve chronic care. Our goal was to identify common challenges and opportunities for cross-national learning. We found four key themes. First, although all four countries have a national strategy for health ICT adoption, strategies are implemented and adapted to chronic care needs regionally, which creates the challenge of spreading successful efforts across regions. Second, each country struggles with how to ensure that clinical information follows patients seamlessly between care settings. Third, although each nation is pursuing telehealth solutions as a component of chronic care, the telehealth initiatives are usually stand-alone efforts that are not well integrated into other ICT solutions, such as electronic health records. Finally, countries have made progress in improving patients' access to their clinical data but have not fully succeeded in engaging patients to apply the data to improve care. These common themes suggest that although the four nations have different health care systems and ICT strategies, all of them face a similar set of challenges, creating an opportunity for cross-national learning.

Challenges in Reducing Readmissions: Lessons from Leadership and Frontline Personnel at Eight Minority-Serving Hospitals.

BACKGROUND: Hospitals that serve minority patients have higher readmission rates than other hospitals and, as a result, receive higher penalties under the federal government's Hospital Readmissions Reduction Program. A study was conducted to determine how minority-serving hospitals are responding to federal readmissions policy and whether they face specific challenges as they work to reduce readmissions. METHODS: In-depth case studies were created for eight minority-serving hospitals, selected to reflect a range of geographies and sizes. Semistructured interviews with hospital leaders and frontline personnel focused on knowledge of readmission rates and prioritization of readmission reduction, strategies to reduce readmissions, barriers to reducing readmissions, and opinions about federal readmissions policy. RESULTS: Each hospital had only a general awareness of its performance on readmissions metrics but placed a high priority on reducing readmissions, largely spurred by federal readmissions policy. Respondents reported that socioeconomics, rather than race alone, was a key factor in readmissions reduction. The hospitals followed a similar progression in strategies to reduce readmissions-moving from working on the discharge process to creating customized approaches to transitional care to, finally, focusing more on building community supports and resources. Salient barriers to reducing readmission rates included scarce resources, the variety of patient needs, limited ability to influence care in the community, and a misalignment of financial incentives. CONCLUSIONS: Among eight hospitals serving a high proportion of minority patients, the findings uncovered the importance of addressing issues specific to the patient population and community and reaching outside the walls of the hospital to implement programs that improve outpatient access and management.

Small interfering RNAs that deplete the cellular translation factor eIF4H impede mRNA degradation by the virion host shutoff protein of herpes simplex virus.

The herpes simplex virus (HSV) virion host shutoff (Vhs) protein is an endoribonuclease that accelerates decay of many host and viral mRNAs. Purified Vhs does not distinguish mRNAs from nonmessenger RNAs and cuts target RNAs at many sites, yet within infected cells it is targeted to mRNAs and cleaves those mRNAs at preferred sites including, for some, regions of translation initiation. This targeting may result in part from Vhs binding to the translation initiation factor eIF4H; in particular, several mutations in Vhs that abrogate its binding to eIF4H also abolish its mRNA-degradative activity, even though the mutant proteins retain endonuclease activity. To further investigate the role of eIF4H in Vhs activity, HeLa cells were depleted of eIF4H or other proteins by transfection with small interfering RNAs (siRNAs) 48 h prior to infection or mock infection in the presence of actinomycin D. Cellular mRNA levels were then assayed 5 h after infection. In cells transfected with an siRNA for the housekeeping enzyme glyceraldehyde-3-phosphate dehydrogenase, wild-type HSV infection reduced beta-actin mRNA levels to between 20 and 30% of those in mock-infected cells, indicative of a normal Vhs activity. In contrast, in cells transfected with any of three eIF4H siRNAs, beta-actin mRNA levels were indistinguishable in infected and mock-infected cells, suggesting that eIF4H depletion impeded Vhs-mediated degradation. Depletion of the related factor eIF4B did not affect Vhs activity. The data suggest that eIF4H binding is required for Vhs-induced degradation of many mRNAs, perhaps by targeting Vhs to mRNAs and to preferred sites within mRNAs.