Structure and mechanism of human cystine exporter cystinosin.

Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanism and capture the key conformational states of the transport cycle. Our structures, along with functional studies and double electron-electron resonance spectroscopic investigations, reveal the molecular basis for the transporter's conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy.

Facility-Level Variation in Racial Disparities in Anticoagulation for Atrial Fibrillation: The REACH-AF Study.

BACKGROUND: Oral anticoagulation reduces stroke risk for patients with atrial fibrillation (AF). Prior research demonstrates lower anticoagulant prescribing in Black than in White individuals but few studies have examined racial differences in facility-level anticoagulant prescribing for AF. OBJECTIVE: To assess variation in anticoagulant initiation by race within Veterans Health Administration (VA) facilities. DESIGN: Retrospective cohort study. PARTICIPANTS: Black and White patients enrolled in the VA with incident AF from 2020 through 2021. MAIN MEASURES: The primary outcome was rate of any anticoagulant initiation (i.e., warfarin or direct oral anticoagulant [DOAC]) or any DOAC therapy within 90 days of an AF diagnosis, overall and for Black and White patients at each facility. We also estimated the adjusted Black-White risk difference. KEY RESULTS: In 82 VA facilities serving 26,832 Black and White patients, overall unadjusted rates of any anticoagulant therapy ranged from 56.8 to 87.1% across facilities; the corresponding ranges for Black and White patients were 47.6 to 91.3% and 58.2 to 87.1%, respectively. Overall unadjusted rates of DOAC therapy ranged from 55.1 to 85.5% by facility; ranges for Black and White patients were 42.8 to 86.9% and 56.4 to 85.5%, respectively. The adjusted risk difference between Black and White patients ranged from - 29.9 (95% CI, - 54.9 to - 4.8) to 14.2 (95% CI, - 9.1 to 25.0) across facilities for any anticoagulant therapy and from - 28.8 (95% CI, - 58.3 to 0.8) to 15.0 (95% CI, - 8.0 to 38.1) for DOAC therapy. For any anticoagulant therapy there were 3 facilities where prescribing was statistically higher in White than Black patients; for DOAC therapy there were 5 such facilities. CONCLUSIONS: In a national cohort of patients with AF, we observed large facility-level variation and adjusted risk differences in any anticoagulant and DOAC initiation, overall and by race. These findings represent a target for local quality improvement in AF care.

Racial and Ethnic Differences in Health Care Experiences for Veterans Receiving VA Community Care from 2016 to 2021.

BACKGROUND: Prior research documented racial and ethnic disparities in health care experiences within the Veterans Health Administration (VA). Little is known about such differences in VA-funded community care programs, through which a growing number of Veterans receive health care. Community care is available to Veterans when care is not available through the VA, nearby, or in a timely manner. OBJECTIVE: To examine differences in Veterans' experiences with VA-funded community care by race and ethnicity and assess changes in these experiences from 2016 to 2021. DESIGN: Observational analyses of Veterans' ratings of community care experiences by self-reported race and ethnicity. We used linear and logistic regressions to estimate racial and ethnic differences in community care experiences, sequentially adjusting for demographic, health, insurance, and socioeconomic factors. PARTICIPANTS: Respondents to the 2016-2021 VA Survey of Healthcare Experiences of Patients-Community Care Survey. MEASURES: Care ratings in nine domains. KEY RESULTS: The sample of 231,869 respondents included 24,306 Black Veterans (mean [SD] age 56.5 [12.9] years, 77.5% male) and 16,490 Hispanic Veterans (mean [SD] age 54.6 [15.9] years, 85.3% male). In adjusted analyses pooled across study years, Black and Hispanic Veterans reported significantly lower ratings than their White and non-Hispanic counterparts in five of nine domains (overall rating of community providers, scheduling a recent appointment, provider communication, non-appointment access, and billing), with adjusted differences ranging from - 0.04 to - 0.13 standard deviations (SDs) of domain scores. Black and Hispanic Veterans reported higher ratings with eligibility determination and scheduling initial appointments than their White and non-Hispanic counterparts, and Black Veterans reported higher ratings of care coordination, with adjusted differences of 0.05 to 0.21 SDs. Care ratings improved from 2016 to 2021, but differences between racial and ethnic groups persisted. CONCLUSIONS: This study identified small but persistent racial and ethnic differences in Veterans' experiences with VA-funded community care, with Black and Hispanic Veterans reporting lower ratings in five domains and, respectively, higher ratings in three and two domains. Interventions to improve Black and Hispanic Veterans' patient experience could advance equity in VA community care.

Utilization and Outcomes of Clinically Indicated Invasive Cardiac Care in Veterans with Acute Coronary Syndrome and Chronic Kidney Disease.

SIGNIFICANCE STATEMENT: Of studies reporting an association of CKD with lower use of invasive cardiac care to treat acute coronary syndrome (ACS), just one accounted for the appropriateness of such care. However, its findings in patients hospitalized nearly 30 years ago may not apply to current practice. In a more recent cohort of 64,695 veterans hospitalized with ACS, CKD was associated with a 32% lower likelihood of receiving invasive care determined to be clinically indicated. Among patients with CKD, not receiving such care was associated with a 1.39-fold higher risk of 6-month mortality. Efforts to elucidate the reasons for this disparity in invasive care in patients with ACS and CKD and implement tailored interventions to enhance its use in this population may offer the potential to improve clinical outcomes. BACKGROUND: Previous studies have shown that patients with CKD are less likely than those without CKD to receive invasive care to treat acute coronary syndrome (ACS). However, few studies have accounted for whether such care was clinically indicated or assessed whether nonuse of such care was associated with adverse health outcomes. METHODS: We conducted a retrospective cohort study of US veterans who were hospitalized at Veterans Affairs Medical Centers from January 2013 through December 2017 and received a discharge diagnosis of ACS. We used multivariable logistic regression to investigate the association of CKD with use of invasive care (coronary angiography, with or without revascularization; coronary artery bypass graft surgery; or both) deemed clinically indicated based on Global Registry of Acute Coronary Events 2.0 risk scores that denoted a 6-month predicted all-cause mortality ≥5%. Using propensity scoring and inverse probability weighting, we examined the association of nonuse of clinically indicated invasive care with 6-month all-cause mortality. RESULTS: Among 34,430 patients with a clinical indication for invasive care, the 18,780 patients with CKD were less likely than the 15,650 without CKD to receive such care (adjusted odds ratio, 0.68; 95% confidence interval, 0.65 to 0.72). Among patients with CKD, nonuse of invasive care was associated with higher risk of 6-month all-cause mortality (absolute risk, 21.5% versus 15.5%; absolute risk difference 6.0%; adjusted risk ratio, 1.39; 95% confidence interval, 1.29 to 1.49). Findings were consistent across multiple sensitivity analyses. CONCLUSIONS: In contemporary practice, veterans with CKD who experience ACS are less likely than those without CKD to receive clinically indicated invasive cardiac care. Nonuse of such care is associated with increased mortality.

Introduction to the special issue on fish bioacoustics: Hearing and sound communicationa).

Fish bioacoustics, or the study of fish hearing, sound production, and acoustic communication, was discussed as early as Aristotle. However, questions about how fishes hear were not really addressed until the early 20th century. Work on fish bioacoustics grew after World War II and considerably in the 21st century since investigators, regulators, and others realized that anthropogenic (human-generated sounds), which had primarily been of interest to workers on marine mammals, was likely to have a major impact on fishes (as well as on aquatic invertebrates). Moreover, passive acoustic monitoring of fishes, recording fish sounds in the field, has blossomed as a noninvasive technique for sampling abundance, distribution, and reproduction of various sonic fishes. The field is vital since fishes and aquatic invertebrates make up a major portion of the protein eaten by a signification portion of humans. To help better understand fish bioacoustics and engage it with issues of anthropogenic sound, this special issue of The Journal of the Acoustical Society of America (JASA) brings together papers that explore the breadth of the topic, from a historical perspective to the latest findings on the impact of anthropogenic sounds on fishes.

Association of Neighborhood Disadvantage and Anticoagulation for Patients with Atrial Fibrillation in the Veterans Health Administration: the REACH-AF Study.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia, the management of which includes anticoagulation for stroke prevention. Although disparities in anticoagulant prescribing have been well documented for individual socioeconomic factors, less is known about the association of neighborhood-level disadvantage and anticoagulation for AF. OBJECTIVE: To assess the association between neighborhood disadvantage and anticoagulant initiation for patients with incident AF. DESIGN: Retrospective cohort study. PARTICIPANTS: A cohort of patients enrolled in the Veterans Health Administration (VA) with incident AF from January 2014 through December 2020 from the Race, Ethnicity, and Anticoagulant CHoice in Atrial Fibrillation (REACH-AF) Study. MAIN MEASURES: The primary exposure was neighborhood disadvantage quantified using area deprivation index (ADI), classified by quintiles (Q). The outcomes were initiation of any anticoagulant therapy (warfarin or direct oral anticoagulant, DOAC) within 90 days of AF diagnosis and DOAC use among initiators. We used mixed effects logistic regression to assess the association between ADI and anticoagulant therapy, incorporating a fixed effect for treatment site and baseline patient, provider, and facility covariates. KEY RESULTS: Among 161,089 patients, 105,489 (65.5%) initiated any anticoagulant therapy, and 78,903 (74.8%) used DOACs. Any anticoagulant therapy increased 3.2 percentage points (63.0% to 66.2%; p<.001) from Q1 to Q5, whereas DOAC use decreased 8.2 percentage points (79.4% to 71.2%; p<.0001) across quintiles. The adjusted odd ratios of any anticoagulant therapy were non-significantly different for Q2-Q5 than Q1. The adjusted odds of DOAC use decreased progressively from 0.89 (95% CI, 0.84-0.94) in Q2 to 0.77 (95% CI, 0.73-0.83) in Q5 compared to Q1 (p<.0001). CONCLUSIONS: Among Veterans with incident AF, we observed similar initiation of any anticoagulant, though neighborhood deprivation was associated with decreased DOAC use among anticoagulant initiators. Future interventions to improve pharmacoequity in anticoagulant prescribing for AF should consider the role of neighborhood-level determinants of health inequities.

Prevalence and Cost of Care Cascades Following Low-Value Preoperative Electrocardiogram and Chest Radiograph Within the Veterans Health Administration.

BACKGROUND: Low-value care cascades, defined as the receipt of downstream health services potentially related to a low-value service, can result in harm to patients and wasteful healthcare spending, yet have not been characterized within the Veterans Health Administration (VHA). OBJECTIVE: To examine if the receipt of low-value preoperative testing is associated with greater utilization and costs of potentially related downstream health services in Veterans undergoing low or intermediate-risk surgery. DESIGN: Retrospective cohort study using VHA administrative data from fiscal years 2017-2018 comparing Veterans who underwent low-value preoperative electrocardiogram (EKG) or chest radiograph (CXR) with those who did not. PARTICIPANTS: National cohort of Veterans at low risk of cardiopulmonary disease undergoing low- or intermediate-risk surgery. MAIN MEASURES: Difference in rate of receipt and attributed cost of potential cascade services in Veterans who underwent low-value preoperative testing compared to those who did not KEY RESULTS: Among 635,824 Veterans undergoing low-risk procedures, 7.8% underwent preoperative EKG. Veterans who underwent a preoperative EKG experienced an additional 52.4 (95% CI 47.7-57.2) cascade services per 100 Veterans, resulting in $138.28 (95% CI 126.19-150.37) per Veteran in excess costs. Among 739,005 Veterans undergoing low- or intermediate-risk surgery, 3.9% underwent preoperative CXR. These Veterans experienced an additional 61.9 (95% CI 57.8-66.1) cascade services per 100 Veterans, resulting in $152.08 (95% CI $146.66-157.51) per Veteran in excess costs. For both cohorts, care cascades consisted largely of repeat tests, follow-up imaging, and follow-up visits, with low rates invasive services. CONCLUSIONS: Among a national cohort of Veterans undergoing low- or intermediate-risk surgeries, low-value care cascades following two routine low-value preoperative tests are common, resulting in greater unnecessary care and costs beyond the initial low-value service. These findings may guide de-implementation policies within VHA and other integrated healthcare systems that target those services whose downstream effects are most prevalent and costly.

Impact of adherence to procalcitonin antibiotic prescribing guideline recommendations for low procalcitonin levels on antibiotic use.

BACKGROUND: The Procalcitonin Antibiotic Consensus Trial (ProACT) found provision of a procalcitonin antibiotic prescribing guideline to hospital-based clinicians did not reduce antibiotic use. Possible reasons include clinician reluctance to follow the guideline, with an observed 64.8% adherence rate. In this study we sought to determine the threshold adherence rate for reduction in antibiotic use, and to explore opportunities to increase adherence. METHODS: This study is a retrospective analysis of ProACT data. ProACT randomized 1656 patients presenting to 14 U.S. hospitals with suspected lower respiratory tract infection to usual care or provision of procalcitonin assay results and an antibiotic prescribing guideline to the treating clinicians. We simulated varying adherence to guideline recommendations for low procalcitonin levels and determined which threshold adherence rate could have resulted in rejection of the null hypothesis of no difference between groups at alpha = 0.05. We also performed sensitivity analyses within specific clinical settings and grouped patients initially prescribed antibiotics despite low procalcitonin into low, medium, and high risk of illness severity or bacterial infection. RESULTS: Our primary outcome was number of antibiotic-days by day 30 using an intention-to-treat approach and a null hypothesis of no difference in antibiotic use. We determined that an 84% adherence rate in the hospital setting (emergency department and inpatient) for low procalcitonin could have allowed rejection of the null hypothesis (3.7 vs 4.3 antibiotic-days, p = 0.048). The threshold adherence rate was 76% for continued guideline adherence after discharge. Even 100% adherence in the emergency department alone failed to reduce antibiotic-days. Of the 218 patients prescribed antibiotics in the emergency department despite low procalcitonin, 153 (70.2%) were categorized as low or medium risk. CONCLUSIONS: High adherence in the hospital setting to a procalcitonin antibiotic prescribing guideline is necessary to reduce antibiotic use in suspected lower respiratory tract infection. Continued guideline adherence after discharge and withholding of antibiotics in low and medium risk patients with low procalcitonin may offer impactful potential opportunities for antibiotic reduction. Trial registration Procalcitonin Antibiotic Consensus Trial (ProACT), ClinicalTrials.gov Identifier: NCT02130986. First posted May 6, 2014.

Human TRPML1 channel structures in open and closed conformations.

Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily. The opening of TRPML1 is associated with distinct dilations of its lower gate together with a slight structural movement of pore helix 1. Our work reveals the regulatory mechanism of TRPML channels, facilitates better understanding of TRP channel activation, and provides insights into the molecular basis of mucolipidosis type IV pathogenesis.

A Structural Overview of TRPML1 and the TRPML Family.

This chapter explores the existing structural and functional studies on the endo-lysosomal channel TRPML1 and its analogs TRPML2, TRPML3. These channels represent the mucolipin subfamily of the TRP channel superfamily comprising important roles in sensory physiology, ion homeostasis, and signal transduction. Since 2016, numerous structures have been determined for all three members using either cryo-EM or X-ray crystallography. These studies along with recent functional analysis have considerably strengthened our knowledge on TRPML channels and its related endo-lysosomal function. This chapter, together with relevant reports in other chapters from this handbook, provides an informative and detailed tool to study the endo-lysosomal cation channels.

Sound production and mechanism in the cryptic cusk-eel Parophidion vassali.

This study investigates the sounds and the anatomy of the sound-producing organ in the male and female sand-dwelling cusk-eel Parophidion vassali. Although both sexes have similar external phenotype, they can be distinguished by their sonic apparatus and sounds. As in many Ophioidei, Parophidion vassali presents a panel of highly derived characters. Fish possess three pairs of sonic muscles, and males have mineralized swimbladder caps on which inserts the ventral sonic muscle, a neural arch that pivots, a stretchable swimbladder fenestra, an osseous swimbladder plate and a rounded pressure-release membrane in the caudal swimbladder. Females, however, do not possess anterior swimbladder caps, a swimbladder fenestra and the caudal rounded membrane. Males possess the unusual ability to produce sounds starting with a set of low amplitude pulses followed by a second set with higher amplitudes clearly dividing each sound unit into two parts. Females do not vary their sound amplitude in this way: they produce shorter sounds and pulse periods but with a higher peak frequency. Morphology and sound features support the sound-producing mechanism is based on a rebound system (i.e. quick backward snap of the anterior swimbladder). Based on features of the sounds from tank recordings, we have putatively identified the sound of male Parophidion vassali at sea. As these species are ecologically cryptic, we hope this work will allow assessment and clarify the distribution of their populations.

Association Between Neighborhood-Level Poverty and Incident Atrial Fibrillation: a Retrospective Cohort Study.

BACKGROUND: Atrial fibrillation (AF) is a leading cause of cardiovascular morbidity and mortality. While neighborhood-level factors, such as poverty, have been related to prevalence of AF risk factors, the association between neighborhood poverty and incident AF has been limited. OBJECTIVE: Using a large cohort from a health system serving the greater Chicago area, we sought to determine the association between neighborhood-level poverty and incident AF. DESIGN: Retrospective cohort study. PARTICIPANTS: Adults, aged 30 to 80 years, without baseline cardiovascular disease from January 1, 2005, to December 31, 2018. MAIN MEASURES: We geocoded and matched residential addresses of all eligible patients to census-level poverty estimates from the American Community Survey. Neighborhood-level poverty (low, intermediate, and high) was defined as the proportion of residents in the census tract living below the federal poverty threshold. We used generalized linear mixed effects models with a logit link function to examine the association between neighborhood poverty and incident AF, adjusting for patient demographic and clinical AF risk factors. KEY RESULTS: Among 28,858 in the cohort, patients in the high poverty group were more often non-Hispanic Black or Hispanic and had higher rates of AF risk factors. Over 5 years of follow-up, 971 (3.4%) patients developed incident AF. Of these, 502 (51.7%) were in the low poverty, 327 (33.7%) in the intermediate poverty, and 142 (14.6%) in the high poverty group. The adjusted odds ratio (aOR) of AF was higher for the intermediate poverty compared with that for the low poverty group (aOR 1.23 [95% CI 1.01-1.48]). The point estimate for the aOR of AF incidence was similar, but not statistically significant, for the high poverty compared with the low poverty group (aOR 1.25 [95% CI 0.98-1.59]). CONCLUSION: In adults without baseline cardiovascular disease managed in a large, integrated health system, intermediate neighborhood poverty was significantly associated with incident AF. Understanding neighborhood-level drivers of AF disparities will help achieve equitable care.

Vocal repertoire and sound characteristics in the variegated cardinalfish, Fowleria variegata (Pisces: Apogonidae).

The variegated cardinalfish Fowleria variegata produces grunt and hoot calls during agonistic and courtship interactions. Both sounds are tonal and occur as single and multiunit calls. Grunts are of short duration with variable frequency spectra. Hoots are longer, have a higher fundamental frequency, and a more developed harmonic structure. Agonistic grunt calls and short hoot calls (1-2 hoots) are produced during chases and when striking an individual or a mirror. Grunts are produced primarily in male-female and mirror-image encounters, and short hoot calls are produced primarily in male-male interactions. During the reproductive period, long hoot calls (three and four hoots) are the main sound type in a mix-sexed tank and at Dongsha Atoll. These are likely produced by males because isolated females are silent, and isolated males emit long hoot calls. Courtship interactions are mostly silent, and males are silent after capturing eggs for oral brooding. Tank sounds peak at dusk to early evening with a smaller peak at noon, although there are dusk and dawn peaks at Dongsha Atoll. Tank sounds exhibit a semilunar rhythm with peaks at the new and full moon. Other cardinalfish species from the atoll produce grunts but not hoot calls.

Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection.

BACKGROUND: The effect of procalcitonin-guided use of antibiotics on treatment for suspected lower respiratory tract infection is unclear. METHODS: In 14 U.S. hospitals with high adherence to quality measures for the treatment of pneumonia, we provided guidance for clinicians about national clinical practice recommendations for the treatment of lower respiratory tract infections and the interpretation of procalcitonin assays. We then randomly assigned patients who presented to the emergency department with a suspected lower respiratory tract infection and for whom the treating physician was uncertain whether antibiotic therapy was indicated to one of two groups: the procalcitonin group, in which the treating clinicians were provided with real-time initial (and serial, if the patient was hospitalized) procalcitonin assay results and an antibiotic use guideline with graded recommendations based on four tiers of procalcitonin levels, or the usual-care group. We hypothesized that within 30 days after enrollment the total antibiotic-days would be lower - and the percentage of patients with adverse outcomes would not be more than 4.5 percentage points higher - in the procalcitonin group than in the usual-care group. RESULTS: A total of 1656 patients were included in the final analysis cohort (826 randomly assigned to the procalcitonin group and 830 to the usual-care group), of whom 782 (47.2%) were hospitalized and 984 (59.4%) received antibiotics within 30 days. The treating clinician received procalcitonin assay results for 792 of 826 patients (95.9%) in the procalcitonin group (median time from sample collection to assay result, 77 minutes) and for 18 of 830 patients (2.2%) in the usual-care group. In both groups, the procalcitonin-level tier was associated with the decision to prescribe antibiotics in the emergency department. There was no significant difference between the procalcitonin group and the usual-care group in antibiotic-days (mean, 4.2 and 4.3 days, respectively; difference, -0.05 day; 95% confidence interval [CI], -0.6 to 0.5; P=0.87) or the proportion of patients with adverse outcomes (11.7% [96 patients] and 13.1% [109 patients]; difference, -1.5 percentage points; 95% CI, -4.6 to 1.7; P<0.001 for noninferiority) within 30 days. CONCLUSIONS: The provision of procalcitonin assay results, along with instructions on their interpretation, to emergency department and hospital-based clinicians did not result in less use of antibiotics than did usual care among patients with suspected lower respiratory tract infection. (Funded by the National Institute of General Medical Sciences; ProACT ClinicalTrials.gov number, NCT02130986 .).

Medication Treatment of Active Opioid Use Disorder in Veterans With Cirrhosis.

INTRODUCTION: Although opioid use disorder (OUD) is common in patients with cirrhosis, it is unclear how medication treatment for OUD (MOUD) is used in this population. We aimed to assess the factors associated with MOUD and mortality in a cohort of Veterans with cirrhosis and OUD. METHODS: Within the Veterans Health Administration Corporate Data Warehouse, we developed a cohort of Veterans with cirrhosis and active OUD, using 2 outpatient or 1 inpatient International Classification of Diseases, ninth revision codes from 2011 to 2015 to define each condition. We assessed MOUD initiation with methadone or buprenorphine over the 180 days following the first OUD International Classification of Diseases, ninth revision code in the study period. We fit multivariable regression models to assess the association of sociodemographic and clinical factors with receiving MOUD and the associations between MOUD and subsequent clinical outcomes, including new hepatic decompensation and mortality. RESULTS: Among 5,600 Veterans meeting criteria for active OUD and cirrhosis, 722 (13%) were prescribed MOUD over 180 days of follow-up. In multivariable modeling, MOUD was significantly, positively associated with age (adjusted odds ratio [AOR] per year: 1.04, 95% confidence interval (CI): 1.01-1.07), hepatitis C virus (AOR = 2.15, 95% CI = 1.37-3.35), and other substance use disorders (AOR = 1.47, 95% CI = 1.05-2.04) negatively associated with alcohol use disorder (AOR = 0.70, 95% CI = 0.52-0.95), opioid prescription (AOR = 0.51, 95% CI = 0.38-0.70), and schizophrenia (AOR = 0.59, 95% CI = 0.37-0.95). MOUD was not significantly associated with mortality (adjusted hazards ratio = 1.20, 95% CI = 0.95-1.52) or new hepatic decompensation (OR = 0.57, CI = 0.30-1.09). DISCUSSION: Few Veterans with active OUD and cirrhosis received MOUD, and those with alcohol use disorder, schizophrenia, and previous prescriptions for opioids were least likely to receive these effective therapies.

Impact of Alcohol Use Disorder Treatment on Clinical Outcomes Among Patients With Cirrhosis.

BACKGROUND AND AIMS: Despite the significant medical and economic consequences of coexisting alcohol use disorder (AUD) in patients with cirrhosis, little is known about AUD treatment patterns and their impact on clinical outcomes in this population. We aimed to characterize the use of and outcomes associated with AUD treatment in patients with cirrhosis. APPROACH AND RESULTS: This retrospective cohort study included Veterans with cirrhosis who received Veterans Health Administration care and had an index diagnosis of AUD between 2011 and 2015. We assessed the baseline factors associated with AUD treatment (pharmacotherapy or behavioral therapy) and clinical outcomes for 180 days following the first AUD diagnosis code within the study time frame. Among 93,612 Veterans with cirrhosis, we identified 35,682 with AUD, after excluding 2,671 who had prior diagnoses of AUD and recent treatment. Over 180 days following the index diagnosis of AUD, 5,088 (14%) received AUD treatment, including 4,461 (12%) who received behavioral therapy alone, 159 (0.4%) who received pharmacotherapy alone, and 468 (1%) who received both behavioral therapy and pharmacotherapy. In adjusted analyses, behavioral and/or pharmacotherapy-based AUD treatment was associated with a significant reduction in incident hepatic decompensation (6.5% vs. 11.6%, adjusted odds ratio [AOR], 0.63; 95% confidence interval [CI], 0.52, 0.76), a nonsignificant decrease in short-term all-cause mortality (2.6% vs. 3.9%, AOR, 0.79; 95% CI, 0.57, 1.08), and a significant decrease in long-term all-cause mortality (51% vs. 58%, AOR, 0.87; 95% CI, 0.80, 0.96). CONCLUSIONS: Most Veterans with cirrhosis and coexisting AUD did not receive behavioral therapy or pharmacotherapy treatment for AUD over a 6-month follow-up. The reductions in hepatic decompensation and mortality suggest that future studies should focus on delivering evidence-based AUD treatments to patients with coexisting AUD and cirrhosis.

Racial/Ethnic Differences in 30-Day Mortality for Heart Failure and Pneumonia in the Veterans Health Administration Using Claims-based, Clinical, and Social Risk-adjustment Variables.

BACKGROUND: Prior studies have identified lower mortality in Black Veterans compared with White Veterans after hospitalization for common medical conditions, but these studies adjusted for comorbid conditions identified in administrative claims. OBJECTIVES: The objectives of this study were to compare mortality for non-Hispanic White (hereafter, "White"), non-Hispanic Black (hereafter, "Black"), and Hispanic Veterans hospitalized for heart failure (HF) and pneumonia and determine whether observed mortality differences varied according to whether claims-based comorbid conditions and/or clinical variables were included in risk-adjustment models. RESEARCH DESIGN: This was an observational study. SUBJECTS: The study cohort included 143,520 admissions for HF and 127,782 admissions for pneumonia for Veterans hospitalized in 132 Veterans Health Administration (VA) Medical Centers between January 2009 and September 2015. MEASURES: The primary independent variable was racial/ethnic group (ie, Black, Hispanic, and non-Hispanic White), and the outcome was all-cause mortality 30 days following admission. To compare mortality by race/ethnicity, we used logistic regression models that included different combinations of claims-based, clinical, and sociodemographic variables. For each model, we estimated the average marginal effect (AME) for Black and Hispanic Veterans relative to White Veterans. RESULTS: Among the 143,520 (127,782) hospitalizations for HF (pneumonia), the average patient age was 71.6 (70.9) years and 98.4% (97.1%) were male. The unadjusted 30-day mortality rates for HF (pneumonia) were 7.2% (11.0%) for White, 4.1% (10.4%) for Black and 8.4% (16.9%) for Hispanic Veterans. Relative to White Veterans, when only claims-based variables were used for risk adjustment, the AME (95% confidence interval) for the HF [pneumonia] cohort was -2.17 (-2.45, -1.89) [0.08 (-0.41, 0.58)] for Black Veterans and 1.32 (0.49, 2.15) [4.51 (3.65, 5.38)] for Hispanic Veterans. When clinical variables were incorporated in addition to claims-based ones, the AME, relative to White Veterans, for the HF [pneumonia] cohort was -1.57 (-1.88, -1.27) [-0.83 (-1.31, -0.36)] for Black Veterans and 1.50 (0.71, 2.30) [3.30 (2.49, 4.11)] for Hispanic Veterans. CONCLUSIONS: Compared with White Veterans, Black Veterans had lower mortality, and Hispanic Veterans had higher mortality for HF and pneumonia. The inclusion of clinical variables into risk-adjustment models impacted the magnitude of racial/ethnic differences in mortality following hospitalization. Future studies examining racial/ethnic disparities should consider including clinical variables for risk adjustment.

National Media Coverage of the Veterans Affairs Waitlist Scandal: Effects on Veterans' Distrust of the VA Health Care System.

BACKGROUND: On April 23, 2014, US media outlets broadcast reports of excessive wait times and "secret" waitlists at some Veterans Affairs (VA) hospitals, precipitating legislation to increase Veterans' access to private sector health care. OBJECTIVE: The aims were to assess changes in Veterans' distrust in the VA health care system before and after the media coverage and explore sex and racial/ethnic differences in the temporal patterns. METHODS: Veterans completed semistructured interviews on health care satisfaction from June 2013 to January 2015, including a validated scale of health system distrust (range: 1-5). We used linear splines with knots at 90-day intervals to assess changes in distrust before and after April 23, 2014 ("day 0") in linear mixed models. To explore sex and racial/ethnic differences in temporal patterns, we stratified models by sex and tested for interactions of race/ethnicity with time. RESULTS: For women (n=600), distrust scores (mean=2.09) increased by 0.45 in days 0-90 (P<0.01), then decreased by 0.45 in days 90-180 (P<0.01). Among men (n=575), distrust scores (mean=2.05) increased by 0.18 in days 0-90 (P=0.059). Distrust levels were significantly higher for Black versus White women (time adjusted mean difference=0.21) and for Black and Hispanic versus White men (differences=0.26 and 0.18). However, the temporal patterns did not vary by race/ethnicity for women or men (interaction P=0.85 and 0.21, respectively). CONCLUSIONS: Health system distrust increased in women following media coverage of VA access problems and was higher in Black/Hispanic versus White Veterans at all time periods. Such perceptions could influence Veteran decisions to seek health care in the community rather than VA.

An Interrupted Time-series Evaluation of the Association Between State Laws Mandating Prescriber Use of Prescription Drug Monitoring Programs and Discontinuation of Chronic Opioid Therapy in US Veterans.

BACKGROUND: Most states have recently passed laws requiring prescribers to use prescription drug monitoring programs (PDMPs) before prescribing opioid medications. The impact of these mandates on discontinuing chronic opioid therapy among Veterans managed in the Veterans Health Administration (VA) is unknown. We assess the association between the earliest of these laws and discontinuation of chronic opioid therapy in Veterans receiving VA health care. METHODS: We conducted a comparative interrupted time-series study in the 5 states mandating PDMP use before August 2013 (Ohio, West Virginia, Kentucky, New Mexico, and Tennessee), adjusting for trends in the 17 neighboring control states without such mandates. We modeled 25 months of prescribing for each state centered on the month the mandate became effective. We included Veterans prescribed long-term outpatient opioid therapy (305 of the preceding 365 d). Our outcomes were discontinuation of chronic opioid therapy (primary outcome) and the average daily quantity of opioids per Veteran over the following 6 months (secondary outcome). RESULTS: We included 250 monthly cohorts with 225,665 unique Veterans and 3.4 million Veteran-months. Baseline discontinuation rates before the PDMP mandates were 0.4%-2.7% per month. Kentucky saw a discontinuation increase of 1 absolute percentage point following its PDMP mandate which decreased over time. The other 4 states had no significant association between their mandates and change in opioid discontinuation. There was no evidence of decreasing opioid quantities following PDMP mandates. CONCLUSION: We did not find consistent evidence that state laws mandating provider PDMP use were associated with the discontinuation of chronic opioid therapy within the VA for the time period studied.

Racial/Ethnic Differences in the Medical Treatment of Opioid Use Disorders Within the VA Healthcare System Following Non-Fatal Opioid Overdose.

BACKGROUND: After non-fatal opioid overdoses, opioid prescribing patterns are often unchanged and the use of medications for opioid use disorder (MOUDs) remains low. Whether such prescribing differs by race/ethnicity remains unknown. OBJECTIVE: To assess the association of race/ethnicity with the prescribing of opioids and MOUDs after a non-fatal opioid overdose. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients prescribed ≥ 1 opioid from July 1, 2010, to September 30, 2015, with a non-fatal opioid overdose in the Veterans Health Administration (VA). MAIN MEASURES: Primary outcomes were the proportion of patients prescribed: (1) any opioid during the 30 days before and after overdose and (2) MOUDs within 30 days after overdose by race and ethnicity. We conducted difference-in-difference analyses using multivariable regression to assess whether the change in opioid prescribing from before to after overdose differed by race/ethnicity. We also used multivariable regression to test whether MOUD prescribing after overdose differed by race/ethnicity. KEY RESULTS: Among 16,210 patients with a non-fatal opioid overdose (81.2% were white, 14.3% black, and 4.5% Hispanic), 10,745 (66.3%) patients received an opioid prescription (67.1% white, 61.7% black, and 65.9% Hispanic; p < 0.01) before overdose. After overdose, the frequency of receiving opioids was reduced by 18.3, 16.4, and 20.6 percentage points in whites, blacks, and Hispanics, respectively, with no significant difference-in-difference in opioid prescribing by race/ethnicity (p = 0.23). After overdose, 526 (3.2%) patients received MOUDs (2.9% white, 4.6% black, and 5.5% Hispanic; p < 0.01). Blacks (adjusted OR (aOR) 1.6; 95% CI 1.2, 1.9) and Hispanics (aOR 1.8; 95% CI 1.2, 2.6) had significantly larger odds of receiving MOUDs than white patients. CONCLUSIONS: In a national cohort of patients with non-fatal opioid overdose in VA, there were no racial/ethnic differences in changes in opioid prescribing after overdose. Although blacks and Hispanics were more likely than white patients to receive MOUDs in the 30 days after overdose, less than 4% of all groups received such therapy.