Effect of Estrogen Receptor Alpha on Cardiopulmonary Adaptation to Chronic Developmental Hypoxia in a Rat Model.

Humans living at high-altitude (HA) have adapted to this environment by increasing pulmonary vascular and alveolar growth. RNA sequencing data from a novel murine model that mimics this phenotypical response to HA suggested estrogen signaling via estrogen receptor alpha (ERα) may be involved in this adaptation. We hypothesized ERα was a key mediator in the cardiopulmonary adaption to chronic hypoxia and sought to delineate the mechanistic role ERα contributes to this process by exposing novel loss-of-function ERα mutant (ERαMut) rats to simulated HA. ERα mutant or wild type (wt) rats were exposed to normoxia or hypoxia starting at conception and continued postnatally until 6 weeks of age. Both wt and ERαMut animals born and raised in hypoxia exhibited lower body mass and higher hematocrits, total alveolar volumes (Va), diffusion capacities of carbon monoxide (DLCO), pulmonary arteriole (PA) wall thickness, and Fulton indices than normoxia animals. Right ventricle adaptation was maintained in the setting of hypoxia. While no major physiologic differences were seen between wt and ERαMut animals at either exposure, ERαMut animals exhibited smaller mean linear intercepts (MLI) and increased PA total and lumen areas. Hypoxia exposure or ERα loss-of-function did not affect lung mRNA abundance of vascular endothelial growth factor, angiopoietin 2 or apelin. Sexual dimorphisms were noted in PA wall thickness and lumen area in ERαMut rats. In summary, in room air-exposed rats and rats with peri- and postnatal hypoxia exposure, ERα loss-of-function was associated with decreased alveolar size (primarily driven by hypoxic animals) and increased PA remodeling.

Lung T1 MRI assessments in children with mild cystic fibrosis lung disease.

RATIONALE: Lung T1 MRI is a potential method to assess cystic fibrosis (CF) lung disease that is safe, quick, and widely available, but there are no data in children with mild CF lung disease. OBJECTIVE: Assess the ability of lung T1 MRI to detect abnormalities in children with mild CF lung disease. METHODS: We performed T1 MRI, multiple breath washout (MBW), chest computed tomography (CT), and spirometry in a cohort of 45 children with mild CF lung disease (6-11 years of age). MAIN RESULTS: Despite mean normal ppFEV1 values, the majority of children with CF in this study exhibited mild lung disease evident in lung clearance index (LCI) measured by MBW, chest CT Brody scores, and percent normal lung perfusion (%NLP) measured by T1 MRI. The %NLP correlated with chest CT Brody scores, as did LCI, but %NLP and LCI did not correlate with each other. Analysis of the Brody subscores showed that %NLP and LCI largely correlated with different Brody subscores. CONCLUSIONS: T1 MRI can detect mild CF lung disease in children and correlates with chest CT findings. The %NLP from T1 MRI and LCI correlate with different chest CT Brody subscores, suggesting they provide complementary information about CF lung disease.

The influence of rurality on melanoma diagnosis in Indiana: A retrospective cohort study.

BACKGROUND: Research from across the United States has shown that rurality is associated with worse melanoma outcomes. In Indiana, nearly a quarter of all residents live in rural counties and an estimated 2180 cases of melanoma will be diagnosed in 2023. AIMS: This study examines how geographical location affects the stage of melanoma diagnosis in Indiana, aiming to identify and address rural health disparities to ultimately ensure equitable care. METHODS AND RESULTS: Demographics and disease characteristics of patients diagnosed with melanoma at Indiana University Health from January 2017 to September 2022 were compared using Students t-tests, Wilcoxon tests, chi-squared or Fisher's exact tests. Patients from rural areas presented with more pathological stage T3 melanomas (15.0% vs. 3.5%, p < 0.001) in contrast to their urban counterparts. Additionally, rural patients presented with fewer clinical stage I melanomas (80.8% vs. 89.3%) and more clinical stage II melanomas (19.2% vs. 8.1%), compared to urban patients, with no stage III (p = 0.028). Concerningly, a significantly higher percentage of the rural group (40.7%) had a personal history of BCC compared to the urban group (22.6%) (p = 0.005) and fewer rural patients (78.0%) compared to urban patients (89.4%) received surgical treatment (p = 0.016). CONCLUSION: Patients from rural counties in Indiana have higher pathological and clinical stage melanoma at diagnosis compared to patients from urban counties. Additionally fewer rural patients receive surgical treatment and may be at higher risk of developing subsequent melanomas.

Long-term Renal Preservation and Complication Profile With Ileal Ureter Creation.

OBJECTIVE: To examine long-term ileal ureter replacement results at over 32 years at our institution. Long segment or proximal ureteral strictures pose a challenging reconstructive problem. Ureteroureterostomy, psoas hitch, Boari flap, buccal ureteroplasty, and autotransplantation are common reconstructive techniques. We show that ileal ureter remains a lasting option. METHODS: We performed a retrospective review of patients undergoing open ileal ureter creation from 1989-2021. Patient demographics, operative history, and complications were examined. All patients were followed for changes in renal function. Demographic data were analyzed and Cox proportional hazard models were performed. RESULTS: One hundred and fifty-eight patients were identified with median follow-up time of 40 months. Eighty-one percent had a unilateral ileal ureter creation. Fifty percent were female, median age was 53.3. Twenty-seven percent of patients had radiation-induced strictures. Preoperatively, 56.3% of patients were chronic kidney disease stage 1-2 and 43.7% were stage 3-5. Post-operatively, 54% were stage 1-2 and 46% were stage 3-5. Cox proportional hazard models demonstrated no significant correlation between worsening renal function and stricture cause, bilateral repair, complications, or sex (biologically male or female). Seventy-seven percent had no 30-day complications. Clavien complications included grade 1 (18), grade 2 (4), grade 3 (9), and grade 4 (5). Long-term complications included worsening renal function (3%), incisional hernia (8.2%), and small bowel obstruction (6.9%). Five (3.1%) patients ultimately required dialysis and 5 (3.1%) patients developed metabolic acidosis. CONCLUSION: Ileal ureteral reconstruction is often a last resort for patients with complex ureteral injuries. Clinicians can be reassured by our long-term data that ileal ureteral creation is a safe treatment with good preservation of renal function and low risk of hemodialysis and metabolic acidosis.

Decreased vascular reactivity associated with increased IL-8 in 6-month-old infants of mothers with pre-eclampsia.

BACKGROUND: Offspring born to mothers with pre-eclampsia (Pre-E) suffer higher risks of adult cardiovascular diseases, suggesting that exposure to an antiangiogenic environment in-utero has a lasting impact on the development of endothelial function. The goal of this study is to test the hypothesis that in-utero exposure to Pre-E results in alterations of angiogenic factors/cytokines that negatively impact vascular development during infancy. METHODS: Infants born from mothers with and without Pre-E were recruited and followed up at 6 months. Plasma cytokines, blood pressure, microvessel density, and vascular reactivity were assessed. RESULTS: 6-month-old infants born to mothers with Pre-E had unchanged blood pressure (p = 0.86) and microvessel density (p = 0.57). Vascular reactivity was decreased in infants born to mothers with Pre-E compared to infants born to healthy mothers (p = 0.0345). Interleukin 8 (IL-8) (p = 0.03) and Angiopoeitin-2 (Ang-2) (p = 0.04) were increased in infants born to mothers with Pre-E. We observed that higher IL-8 was associated with lower vascular reactivity (rho = -0.14, p < 0.0001). CONCLUSION: At 6 months of age, infants born to mothers with Pre-E had impaired vascular reactivity and higher IL-8 and Ang-2, but similar blood pressure and microvessel density compared to infants born to non-Pre-E mothers. IMPACT STATEMENT: Changes in cord blood antiangiogenic factors are documented in infants of mothers with pre-eclampsia and may contribute to offspring risks of adult cardiovascular disease. How these factors evolve during early infancy and their correlation with offspring vascular development have not been studied. This study found that 6-month-old infants born to mothers with pre-eclampsia had decreased vascular reactivity, which was correlated with higher IL-8. These findings underscore the lasting impact of maternal pre-eclampsia on offspring vascular development and highlight the need for long-term follow-up in children born to mothers with pre-eclampsia.

Unpacking the relationship between shared decision-making and decisional quality, decision to screen, and screening completion in lung cancer screening.

OBJECTIVES: Lung cancer screening is a complex and individualized decision. To understand how best to support patients in this decision, we must understand how shared decision-making is associated with both decisional and behavioral outcomes. METHODS: Observational cohort study combining patient survey data with electronic health record data of lung screening-eligible patients who recently engaged in a shared decision-making discussion about screening with a primary care clinician. RESULTS: Using multivariable analysis (n = 529), factors associated with higher lung cancer screening decisional quality include higher knowledge (OR = 1.33, p < .0001), lower perceived benefits (OR = 0.90, p = .0004), higher perceived barriers (OR = 1.07, p < .0001), higher self-efficacy (OR = 1.13, p < .0001), and higher levels of perceiving the discussion was shared (OR = 1.04, p < .0001). Factors associated with the patient's decision to screen include older age (OR = 1.12, p = .0050) and higher self-efficacy (OR = 1.11, p = .0407). Factors associated with screening completion included older age (OR = 1.05, p = .0050), higher knowledge (OR = 1.24, p = .0045), and higher self-efficacy (OR = 1.12, p = .0003). CONCLUSIONS: Shared decision-making in lung cancer screening is a dyadic process between patient and clinician. As we continue to strive for high-quality patient-centered care, patient decision quality may be enhanced by targeting key factors such as high-quality knowledge, self-efficacy, and fostering a shared discussion to support patient engagement in lung cancer screening decisions.

Cardiac injury in children with COVID-19.

BACKGROUND: There is little known about the spectrum of cardiac injury in acute COVID-19 infection in children. METHODS: A single-centre, retrospective chart analysis was performed. The protocol was deemed IRB exempt. All patients under the age of 21 years admitted from 20 March, 2020 to 22 June, 2021 for acute symptomatic COVID-19 infection or clinical suspicion of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 were included. Past medical history, lab findings, echocardiogram and electrocardiogram/telemetry findings, and clinical outcomes were reviewed. RESULTS: Sixty-six patients with MIS-C and 178 with acute COVID-19 were reviewed. Patients with MIS-C had more cardiac testing than those with acute COVID-19. Inflammatory markers were more likely elevated, and function was more likely abnormal on echocardiogram in those with MIS-C with testing performed. Among patients with MIS-C, 17% had evidence of coronary dilation versus 0% in the acute COVID-19 group. One (0.6%) patient with acute COVID-19 had clinically significant electrocardiogram or telemetry findings, and this was in the setting of prior arrhythmias and CHD. Four (6%) patients with MIS-C had clinically significant findings on electrocardiogram or telemetry. Among patients with acute COVID-19, extracorporeal membrane oxygenation support was required in 0.6% of patients with acute COVID-19, and there was a 2.8% mortality. There were no deaths in the setting of MIS-C. CONCLUSIONS: Patients with acute COVID-19 and clinical suspicion of cardiac injury had a lower incidence of abnormal laboratory findings, ventricular dysfunction, or significant arrhythmia than those with MIS-C.

Clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis.

BACKGROUND AND AIMS: Little is known about the clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis (mAH) as compared to severe alcohol-associated hepatitis (sAH). Therefore, we aimed to describe the clinical characteristics and risk factors associated with mortality in hospitalized mAH patients. METHODS: Patients hospitalized with alcohol-associated hepatitis (AH) from 1 January 2010 to 31 December 2020 at a large US healthcare system [11 hospitals, one liver transplant centre] were retrospectively analysed for outcomes. Primary outcome was 90-day mortality. AH and mAH were defined according to NIAAA Alcoholic Hepatitis Consortia and Model for End-stage Liver Disease Score ≤ 20 respectively. Multivariable Cox regression analysis was performed to identify independent risk factors associated with 90-day mortality. RESULTS: 1504 AH patients were hospitalized during the study period, of whom 39% (n = 590) had mAH. Compared to sAH patients, mAH patients were older (50 vs. 48 years, p < 0.001) and less likely to have underlying cirrhosis (74% vs. 83%, p < 0.001). There were no differences between the two groups for median alcohol intake g/day (mAH 140.0 vs. sAH 112.0, p = 0.071). The cumulative proportion surviving at 90 days was 88% in mAH versus 62% in sAH (p < 0.001). On multivariable analysis, older age [HR 1.03 (95% CI 1.00-1.06), p = 0.020], corticosteroid use [HR 1.80 (95% CI 1.06-3.06), p = 0.030] and acute kidney injury (AKI) [HR 2.43 (95% CI 1.33-4.47), p = 0.004] were independently associated with 90-day mortality. CONCLUSIONS: mAH carries a 12% mortality rate at 90 days. Age, AKI and corticosteroid use were associated with an increased risk for 90-day mortality. Avoidance of corticosteroids and strategies to reduce the risk of AKI could improve outcomes in mAH patients.

Severe hepatic encephalopathy with mechanical ventilation may inform waitlist priority in acute liver failure: A UNOS database analysis.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) awaiting liver transplantation (LT) may develop multiorgan failure, but organ failure does not impact waitlist prioritization. The aim of this study was to examine the impact of organ failure on waitlist mortality risk and post LT outcomes in patients with ALF. METHODS: We studied adults waitlisted for ALF in the United Network for Organ Sharing (UNOS) database (2002-2019). Organ failures were defined using a previously described Chronic Liver Failure modified sequential organ failure score assessment adapted to UNOS data. Regression analyses of the primary endpoints, 30-day waitlist mortality (Competing risk), and post-LT mortality (Cox-proportional hazards), were performed. Latent class analysis (LCA) was used to determine the organ failures most closely associated with 30-day waitlist mortality. RESULTS: About 3212 adults with ALF were waitlisted, for hepatotoxicity (41%), viral (12%) and unspecified (36%) etiologies. The median number of organ failures was three (interquartile range 1-3). Having ≥3 organ failures (vs. ≤2) was associated with a sub hazard ratio (HR) of 2.7 (95%CI 2.2-3.4)) and a HR of 1.5 (95%CI 1.1-2.5)) for waitlist and post-LT mortality, respectively. LCA identified neurologic and respiratory failure as most impactful on 30-day waitlist mortality. The odds ratios for both organ failures (vs. neither) were higher for mortality 4.5 (95% CI 3.4-5.9) and lower for delisting for spontaneous survival .5 (95%CI .4-.7) and LT .6 (95%CI .5-.7). CONCLUSION: Cumulative organ failure, especially neurologic and respiratory failure, significantly impacts waitlist and post-LT mortality in patients with ALF and may inform risk-prioritized allocation of organs.

Proteomic Analyses of Plasma From Patients With Fracture-Related Infection Reveals Systemic Activation of the Complement and Coagulation Cascades.

OBJECTIVES: The objective of this study was to compare plasma proteomes of patients with confirmed fracture-related infections (FRIs) matched to noninfected controls using liquid chromatography-mass spectrometry. DESIGN: This was a prospective case-control study. SETTING: The study was conducted at a single, academic, Level 1 trauma center. PATIENT SELECTION CRITERIA: Patients meeting confirmatory FRI criteria were matched to controls without infection based on fracture region, age, and time after surgery from June 2019 to January 2022. Tandem mass tag liquid chromatography-mass spectrometry analysis of patient plasma samples was performed. OUTCOME MEASURES AND COMPARISONS: Protein abundance ratios in plasma for patients with FRI compared with those for matched controls without infection were calculated. RESULTS: Twenty-seven patients meeting confirmatory FRI criteria were matched to 27 controls. Abundance ratios for more than 1000 proteins were measured in the 54 plasma samples. Seventy-three proteins were found to be increased or decreased in patients with FRI compared with those in matched controls (unadjusted t test P < 0.05). Thirty-two of these proteins were found in all 54 patient samples and underwent subsequent principal component analysis to reduce the dimensionality of the large proteomics dataset. A 3-component principal component analysis accounted for 45.7% of the variation in the dataset and had 88.9% specificity for the diagnosis of FRI. STRING protein-protein interaction network analysis of these 3 PCs revealed activation of the complement and coagulation cascades through the Reactome pathway database (false discovery rates <0.05). CONCLUSIONS: Proteomic analyses of plasma from patients with FRI demonstrate systemic activation of the complement and coagulation cascades. Further investigation along these lines may help to better understand the systemic response to FRI and improve diagnostic strategies using proteomics. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Early Results of Orthopaedic Trauma and Anemia: Conservative Versus Liberal Transfusion Strategy.

INTRODUCTION: The purpose of this study was to determine whether it is safe to use a conservative packed red blood cell transfusion hemoglobin threshold (5.5 g/dL) compared with a liberal transfusion threshold (7.0 g/dL) for asymptomatic patients with musculoskeletal-injured trauma out of the initial resuscitative period. METHODS: This was a multicenter, prospective, nonblinded, randomized study done at three level 1 trauma centers. One hundred patients were enrolled. One patient was inappropriately enrolled, withdrawn from the study, and excluded from analysis leaving 99 patients (49 liberal and 50 conservative) with 30-day follow-up. After initial resuscitation, patients were enrolled and randomized to either a liberal or a conservative transfusion strategy. This strategy was followed throughout the index hospitalization. The primary outcome of the study was infection. Superficial infection was defined as clinical diagnosis of cellulitis or other superficial infection treated with oral antibiotics only. Deep infection was defined as clinical diagnosis of fracture-related infection requiring IV antibiotics and/or surgical débridement. RESULTS: Ninety-nine patients were successfully followed for 30 days with 100% follow-up during this time. Seven infections (14%) occurred in the liberal group and none in the conservative group ( P < 0.01). Five deep infections (10%) occurred in the liberal group and none in the conservative group ( P = 0.03). Three superficial infections (6%) occurred in the liberal and none in the conservative group, which was not a significant difference ( P = 0.1). No difference was observed in length of stay between groups. DISCUSSION: Transfusing young healthy asymptomatic patients with orthopaedic trauma for hemoglobin <7.0 g/dL increases the risk of infection. No increased risk of anemia-related complications was identified with a conservative transfusion threshold of 5.5 g/dL. DATA AVAILABILITY AND TRIAL REGISTRATION NUMBERS: Data are available on request. IRB protocol number is 1402557771. This study was registered with Clinicaltrials.gov identifier NCT02972593. LEVEL OF EVIDENCE: Level 2, unblinded prospective randomized multicenter study.

Orthopaedic Trauma and Anemia: Conservative versus Liberal Transfusion Strategy: A Prospective Randomized Study.

OBJECTIVES: To determine whether it is safe to use a conservative packed red blood cell transfusion hemoglobin (Hgb) threshold (5.5 g/dL) compared with a liberal transfusion threshold (7.0 g/dL) for asymptomatic musculoskeletal injured trauma patients who are no longer in the initial resuscitative period. METHODS: Design: Prospective, randomized, multicenter trial. SETTING: Three level 1 trauma centers. PATIENT SELECTION CRITERIA: Patients aged 18-50 with an associated musculoskeletal injury with Hgb less than 9 g/dL or expected drop below 9 g/dL with planned surgery who were stable and no longer being actively resuscitated were randomized once their Hgb dropped below 7 g/dL to a conservative transfusion threshold of 5.5 g/dL versus a liberal threshold of 7.0 g/dL. OUTCOME MEASURES AND COMPARISONS: Postoperative infection, other post-operative complications and Musculoskeletal Functional Assessment scores obtained at baseline, 6 months, and 1 year were compared for liberal and conservative transfusion thresholds. RESULTS: Sixty-five patients completed 1 year follow-up. There was a significant association between a liberal transfusion strategy and higher rate of infection (P = 0.01), with no difference in functional outcomes at 6 months or 1 year. This study was adequately powered at 92% to detect a difference in superficial infection (7% for liberal group, 0% for conservative, P < 0.01) but underpowered to detect a difference for deep infection (14% for liberal group, 6% for conservative group, P = 0.2). CONCLUSIONS: A conservative transfusion threshold of 5.5 g/dL in an asymptomatic young trauma patient with associated musculoskeletal injuries leads to a lower infection rate without an increase in adverse outcomes and no difference in functional outcomes at 6 months or 1 year. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Plating Versus Intramedullary Nailing of OTA/AO 43C1 and C2 Intra-articular Distal Tibia Fractures: A Propensity Score and Multivariate Analysis.

OBJECTIVE: To compare rates of reduction loss, nonunion, and infection in intra-articular distal tibia fractures (IADTF) treated with limited open reduction internal fixation and intramedullary nailing (IMN) as compared to open reduction internal fixation with plate and screws (plate fixation [PF]). DESIGN: Retrospective review. SETTING: Level-I academic trauma center. PATIENT SELECTION CRITERIA: Patients age ≥ 18 with OTA/AO 43C1 and C2 IADTF treated with IMN or PF between 2013-2021. OUTCOME MEASURES AND COMPARISONS: Loss of reduction, surgical site infection (SSI), nonunion, and patient-reported outcomes (PROs) were compared for IMN versus PF treatments. RESULTS: One hundred ten patients met the inclusion criteria (IMN 33 and PF 77). There was no loss of reduction found. Seventeen nonunions (15% overall; IMN 4/33 and PF 13/77) and 13 SSIs (12% overall; IMN 2/33 and PF11/77) were identified. Despite several risk factors being identified for nonunion and SSI in bivariate analysis, only open fracture remained significant as a risk factor for both nonunion (odds ratio 0.09 for closed fracture, 95% confidence interval, 0.02-0.56, P = 0.009) and SSI (odds ratio 0.07 for closed fracture, 95% confidence interval, 0.06-0.26, P = 0.012) in the multivariate model. Propensity scoring based on presurgical variables was significantly different between patients who received IMN versus PF ( P = 0.03); however, logistic regression incorporating the propensity score revealed no significant association with nonunion and SSI. Adjusting for the propensity score, there remained no association comparing IMN versus PF with nonunion and SSI ( P = 0.54 and P = 0.17, respectively). There was also no difference in PROs between IMN and PF (physical function: P = 0.25 and pain interference: P = 0.21). CONCLUSIONS: Overall nonunion and SSI prevalence was 15% and 12%, respectively, in operatively treated OTA/AO 43C1 and C2 IADTF. An open fracture was a significant risk factor for nonunion and SSI. Metaphyseal fixation through IMN or PF did not affect loss of reduction, nonunion, SSI, or PROs. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Assessment and management of anxiety and depression in a pediatric high-risk asthma clinic.

OBJECTIVE: The aims of this study were to determine the prevalence of positive mental health (MH) screens in a pediatric high-risk asthma (HRA) clinic population, and to determine the success rate of engagement in MH services before and after adding a clinical psychologist to our multidisciplinary clinic. HYPOTHESIS: We hypothesized that the HRA population would have a higher prevalence of anxiety/depression symptoms than that previously reported for the general pediatric asthma population. We anticipated that the presence of an embedded psychologist in HRA clinic would facilitate successful connection to MH services. METHODS: Pediatric patients in the HRA clinic were prospectively screened for anxiety and depression using validated screening instruments. Positive scores were referred for MH services. Time to MH service engagement was recorded before and after the addition of a clinical psychologist. RESULTS: A total of 186 patients were screened; 60% had a positive MH screen. Female sex was associated with higher median scores on both screening tools and higher likelihood of engagement in MH services. After addition of a clinical psychologist, new engagement in MH services increased (20% vs. 80%, p < 0.0001), and median time to engagement decreased (14.5 vs. 0.0 months, p = 0.003). CONCLUSION: There is a high prevalence of anxiety and depression in this pediatric HRA population. Success of engagement in MH services improved after a clinical psychologist joined our multidisciplinary team, suggesting access to care as a primary barrier to engagement.

Patterns of Opioid Prescriptions in the Veterans Health Administration for Patients With Chronic Low-Back Pain After the Onset of the COVID-19 Pandemic: A Retrospective Cohort Analysis.

The COVID-19 pandemic led to severe disruptions in health care and a relaxation of rules surrounding opioid prescribing-changes which led to concerns about increased reliance on opioids for chronic pain and a resurgence of opioid-related harms. Although some studies found that opioid prescriptions increased in the first 6 months of the pandemic, we know little about the longer-term effects of the pandemic on opioid prescriptions. Further, despite the prevalence of pain in veterans, we know little about patterns of opioid prescriptions in the Veterans Health Administration (VA) associated with the pandemic. Using a retrospective cohort of VA patients with chronic low-back pain, we examined the proportion of patients with an opioid prescription and mean morphine milligram equivalents over a 3-year period-1 year prior to and 2 years after the pandemic's onset. Analyses revealed that both measures fell during the entire observation period. The largest decrease in the odds of filling an opioid prescription occurred in the first quarter of the pandemic, but this downward trend continued throughout the observation period, albeit at a slower pace. Clinically meaningful differences in opioid prescriptions and dose over time did not emerge based on patient race or rurality; however, differences emerged between female and male veterans, with decreases in opioid prescriptions slowing more markedly for women after the pandemic onset. These findings suggest that the pandemic was not associated with short- or long-term increases in opioid prescriptions or doses in the VA. PERSPECTIVE: This article examines opioid prescribing over a 3-year period-1 year prior to and 2 years after the onset of the COVID-19 pandemic-for VA patients with chronic low-back pain. Results indicate that, despite disruptions to health care, opioid prescriptions and doses decreased over the entire observation period.

Incidence, clinical characteristics, and risk factors associated with recurrent alcohol-associated hepatitis.

BACKGROUND: Alcohol relapse occurs frequently in alcohol-associated hepatitis (AH) survivors, but data on the frequency and course of recurrent alcohol-associated hepatitis (rAH) are sparse. We investigated the incidence, risk factors, and outcomes of rAH. METHODS: Hospitalized patients with AH from 2010 to 2020 at a large health care system were followed until death/liver transplant, last follow-up, or end of study (December 31, 2021). AH was defined by NIAAA Alcoholic Hepatitis Consortium criteria; rAH was defined a priori as a discrete AH episode >6 months from index AH hospitalization with interim >50% improvement or normalization of total bilirubin. Multivariable competing risk analysis was performed to identify factors associated with rAH. Landmark Kaplan-Meier analysis was performed to compare survival between patients who did versus those who did not develop rAH. RESULTS: Of 1504 hospitalized patients with AH, 1317 (87.6%) survived and were analyzed. During a 3055 person-year follow-up, 116 (8.8%) developed rAH at an annual incidence rate of 3.8% (95% CI: 2.8-4.8). On multivariable competing risk analysis, marital status [sub-HR 0.54 (95% CI: 0.34, 0.92), p=0.01] and medications for alcohol use disorder [sub-HR 0.56 (95% CI: 0.34, 0.91), p=0.02] were associated with a lower risk for rAH. On landmark Kaplan-Meier analysis, the cumulative proportion surviving at 1 year (75% vs. 90%) and 3 years (50% vs. 78%) was significantly lower in patients who developed rAH compared to those who did not develop rAH (log-rank p<0.001). CONCLUSIONS: rAH develops in ~1 in 10 AH survivors and is associated with lower long-term survival. Medications for alcohol use disorder lower the risk for rAH and, therefore, could be a key preventative strategy to improve outcomes.

Nasal airway inflammatory responses and pathogen detection in infants with cystic fibrosis.

BACKGROUND: Detecting airway inflammation non-invasively in infants with cystic fibrosis (CF) is difficult. We hypothesized that markers of inflammation in CF [IL-1ß, IL-6, IL-8, IL-10, IL-17A, neutrophil elastase (NE) and tumor necrosis factor (TNF-α)] could be measured in infants with CF from nasal fluid and would be elevated during viral infections or clinician-defined pulmonary exacerbations (PEx). METHODS: We collected nasal fluid, nasal swabs, and hair samples from 34 infants with CF during monthly clinic visits, sick visits, and hospitalizations. Nasal fluid was isolated and analyzed for cytokines. Respiratory viral detection on nasal swabs was performed using the Luminex NxTAG® Respiratory Pathogen Panel. Hair samples were analyzed for nicotine concentration by reverse-phase high-performance liquid chromatography. We compared nasal cytokine concentrations between the presence and absence of detected respiratory viruses, PEx, and smoke exposure. RESULTS: A total of 246 samples were analyzed. Compared to measurements in the absence of respiratory viruses, mean concentrations of IL-6, IL-8, TNF-α, and NE were significantly increased while IL-17A was significantly decreased in infants positive for respiratory viruses. IL-17A was significantly decreased and NE increased in those with a PEx. IL-8 and NE were significantly increased in infants with enteric pathogen positivity on airway cultures, but not P. aeruginosa or S. aureus. Compared to those with no smoke exposure, there were significantly higher levels of IL-6, IL-10, and NE in infants with detectable levels of nicotine. CONCLUSIONS: Noninvasive collection of nasal fluid may identify inflammation in infants with CF during changing clinical or environmental exposures.

Code status orders in hospitalized patients with COVID-19.

Background: The COVID-19 pandemic created complex challenges regarding the timing and appropriateness of do-not-attempt cardiopulmonary resuscitation (DNACPR) and/or Do Not Intubate (DNI) code status orders. This paper sought to determine differences in utilization of DNACPR and/or DNI orders during different time periods of the COVID-19 pandemic, including prevalence, predictors, timing, and outcomes associated with having a documented DNACPR and/or DNI order in hospitalized patients with COVID-19. Methods: A cohort study of hospitalized patients with COVID-19 at two hospitals located in the Midwest. DNACPR code status orders including, DNI orders, demographics, labs, COVID-19 treatments, clinical interventions during hospitalization, and outcome measures including mortality, discharge disposition, and hospice utilization were collected. Patients were divided into two time periods (early and late) by timing of hospitalization during the first wave of the pandemic (March-October 2020). Results: Among 1375 hospitalized patients with COVID-19, 19% (n = 258) of all patients had a documented DNACPR and/or DNI order. In multivariable analysis, age (older) p =< 0.01, OR 1.12 and hospitalization early in the pandemic p = 0.01, OR 2.08, were associated with having a DNACPR order. Median day from DNACPR order to death varied between cohorts p => 0.01 (early cohort 5 days versus late cohort 2 days). In-hospital mortality did not differ between cohorts among patients with DNACPR orders, p = 0.80. Conclusions: There was a higher prevalence of DNACPR and/or DNI orders and these orders were written earlier in the hospital course for patients hospitalized early in the pandemic versus later despite similarities in clinical characteristics and medical interventions. Changes in clinical care between cohorts may be due to fear of resource shortages and changes in knowledge about COVID-19.

Findings from a Peer-Facilitated, Social Isolation Intervention in the Veterans Health Administration Healthcare System: A Mixed-Methods, Pilot Feasibility Study.

BACKGROUND: Social isolation is a global public health threat. Veterans are particularly at risk for social isolation due to high rates of comorbid physical and mental health problems. Yet, effective interventions are limited. OBJECTIVES: Our primary objective was to assess the feasibility and acceptability of CONNECTED, a novel, transdiagnostic intervention to reduce social isolation that includes individual and group components and is delivered by peers via telehealth. Secondary objectives were to identify appropriate outcome measures and explore preliminary intervention effects. METHODS: This was a two-phase study. In Phase 1, to evaluate study feasibility, we surveyed 200 veterans to assess prevalence of social isolation and their interest in social connectedness interventions. In Phase 2, we employed a mixed-methods, pre-post study design in which we piloted CONNECTED with 19 veterans through 2 successive cohorts to further assess feasibility, to evaluate acceptability, and to explore preliminary effectiveness. Quantitative analyses involved descriptive and bivariate analyses as well as multivariate modeling. Qualitative interviews were analyzed using thematic analysis. RESULTS: For Phase 1, 39% of veterans surveyed were socially isolated. Participants who were ≤ 55 years old, caregivers, and those who experienced unmet social needs were more likely to report social isolation. Over 61% expressed interest in VA programs to reduce social isolation. For Phase 2, the pilot intervention, recruitment rate was 88% and the enrollment rate was 86%. Retention rates for the two cohorts were 80% and 50%, respectively, and satisfaction rates among intervention completers were 100%. Results also showed statistically significant improvements in social isolation (+ 5.91, SD = 4.99; p = .0028), social support (+ 0.74, SD = 1.09; p = .03), anxiety (-3.92, SD = 3.73; p = .003), and depression (-3.83, SD = 3.13; p = .001). Results for the other measures were not statistically significant. CONCLUSION: CONNECTED is a feasible and acceptable intervention and is likely to be an effective tool to intervene on social isolation among veterans.