Survivorship After Neurocritical Care: A Scoping Review of Outcomes Beyond Physical Status.

Following intensive care unit hospitalization, survivors of acute neurological injury often experience debilitating short-term and long-term impairments. Although the physical/motor impairments experienced by survivors of acute neurological injury have been described extensively, fewer studies have examined cognitive, mental health, health-related quality of life (HRQoL), and employment outcomes. This scoping review describes the publication landscape beyond physical and/or motor sequelae in neurocritical care survivors. Databases were searched for terms related to critical illness, intensive care, and outcomes from January 1970 to March 2022. English-language studies of critically ill adults with a primary neurological diagnosis were included if they reported on at least one outcome of interest: cognition, mental health, HRQoL or employment. Data extraction was performed in duplicate for prespecified variables related to study outcomes. Of 16,036 abstracts screened, 74 citations were identified for inclusion. The studies encompassed seven worldwide regions and eight neurocritical diagnosis categories. Publications reporting outcomes of interest increased from 3 before the year 2000 to 71 after. Follow-up time points included ≤ 1 (n = 15 [20%] citations), 3 (n = 28 [38%]), 6 (n = 28 [38%]), and 12 (n = 21 [28%]) months and 1 to 5 (n = 19 [26%]) and > 5 years (n = 8 [11%]), with 28 (38%) citations evaluating outcomes at multiple time points. Sixty-six assessment tools were used to evaluate the four outcomes of interest: 22 evaluating HRQoL (56 [76%] citations), 21 evaluating cognition (20 [27%] citations), 21 evaluating mental health (18 [24%] citations), and 2 evaluating employment (9 [12%] citations). This scoping review aimed to better understand the literature landscape regarding nonphysical outcomes in survivors of neurocritical care. Although a rising number of publications highlight growing awareness, future efforts are needed to improve study consistency and comparability and characterize outcomes in a disease-specific manner, including outlining of a minimum core outcomes set and associated assessment tools.

Ransomware Cyberattack Associated With Cardiac Arrest Incidence and Outcomes at Untargeted, Adjacent Hospitals.

OBJECTIVES: Healthcare ransomware cyberattacks have been associated with major regional hospital disruptions, but data reporting patient-oriented outcomes in critical conditions such as cardiac arrest (CA) are limited. This study examined the CA incidence and outcomes of untargeted hospitals adjacent to a ransomware-infected healthcare delivery organization (HDO). DESIGN SETTING AND PATIENTS: This cohort study compared the CA incidence and outcomes of two untargeted academic hospitals adjacent to an HDO under a ransomware cyberattack during the pre-attack (April 3-30, 2021), attack (May 1-28, 2021), and post-attack (May 29, 2021-June 25, 2021) phases. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Emergency department and hospital mean daily census, number of CAs, mean daily CA incidence per 1,000 admissions, return of spontaneous circulation, survival to discharge, and survival with favorable neurologic outcome were measured. The study evaluated 78 total CAs: 44 out-of-hospital CAs (OHCAs) and 34 in-hospital CAs. The number of total CAs increased from the pre-attack to attack phase (21 vs. 38; p = 0.03), followed by a decrease in the post-attack phase (38 vs. 19; p = 0.01). The number of total CAs exceeded the cyberattack month forecast (May 2021: 41 observed vs. 27 forecasted cases; 95% CI, 17.0-37.4). OHCA cases also exceeded the forecast (May 2021: 24 observed vs. 12 forecasted cases; 95% CI, 6.0-18.8). Survival with favorable neurologic outcome rates for all CAs decreased, driven by increases in OHCA mortality: survival with favorable neurologic rates for OHCAs decreased from the pre-attack phase to attack phase (40.0% vs. 4.5%; p = 0.02) followed by an increase in the post-attack phase (4.5% vs. 41.2%; p = 0.01). CONCLUSIONS: Untargeted hospitals adjacent to ransomware-infected HDOs may see worse outcomes for patients suffering from OHCA. These findings highlight the critical need for cybersecurity disaster planning and resiliency.

Value of preclinical systematic reviews and meta-analyses in pediatric research.

Similar to systematic reviews (SRs) in clinical fields, preclinical SRs address a specific research area, furnishing information on current knowledge, possible gaps, and potential methodological flaws of study design, conduct, and report. One of the main goals of preclinical SRs is to identify aspiring treatment strategies and evaluate if currently available data is solid enough to translate to clinical trials or highlight the gaps, thus justifying the need for new studies. It is imperative to rigorously follow the methodological standards that are widely available. These include registration of the protocol and adherence to guidelines for assessing the risk of bias, study quality, and certainty of evidence. A special consideration should be made for pediatric SRs, clinical and preclinical, due to the unique characteristics of this age group. These include rationale for intervention and comparison of primary and secondary outcomes. Outcomes measured should acknowledge age-related physiological changes and maturational processes of different organ systems. It is crucial to choose the age of the animals appropriately and its possible correspondence for specific pediatric age groups. The findings of well-conducted SRs of preclinical studies have the potential to provide a reliable evidence synthesis to guide the design of future preclinical and clinical studies. IMPACT: This narrative review highlights the importance of rigorous design, conduct and reporting of preclinical primary studies and systematic reviews. A special consideration should be made for pediatric systematic reviews of preclinical studies, due to the unique characteristics of this age group.

Pathogenesis of sleep disordered breathing in the setting of opioid use: A multiple mediation analysis using physiology.

STUDY OBJECTIVES: Opioid medications are commonly used and are known to impact both breathing and sleep, and are linked with adverse health outcomes including death. Clinical data indicate that chronic opioid use causes central sleep apnea, and might also worsen obstructive sleep apnea. The mechanisms by which opioids influence sleep-disordered breathing pathogenesis are not established. METHODS: Patients who underwent clinically-indicated polysomnography confirming sleep-disordered breathing (SDB) (AHI≥5/hr) were included. Each patient using opioids was matched by sex, age, and BMI to three control individuals not using opioids. Physiology known to influence SDB pathogenesis were determined from validated polysomnography-based signal analysis. PSG and physiology paramters of interest were compared between opioid and control individuals, adjusted for covariates. Mediation analysis was used to evaluate the link between opioids, physiology, and polysomnographic metrics. RESULTS: 178 individuals using opioids were matched to 534 controls (median [IQR] age 59 [50,65] years, BMI 33 [29,41] kg/m2, 57% female, daily morphine equivalent 30 [20,80] mg). Compared with controls, opioids were associated with increased central apneas (2.8 vs 1.7 events/hr; p=0.001) and worsened hypoxemia (5 vs 3% sleep with SpO2<88%; p=0.013), with similar overall AHI. Use of opioids was associated with higher loop gain, a lower respiratory rate and higher respiratory rate variability. Higher loop gain and increased respiratory rate variability mediated the effect of opioids on central apnea, but did not mediate the effect on hypoxemia. CONCLUSIONS: Opioids have multi-level effects impacting SDB. Targeting these factors may help mitigate deleterious respiratory consequences of chronic opioid use.

BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension.

BACKGROUND: An imbalance of antiproliferative BMP (bone morphogenetic protein) signaling and proliferative TGF-ß (transforming growth factor-ß) signaling is implicated in the development of pulmonary arterial hypertension (PAH). The posttranslational modification (eg, phosphorylation and ubiquitination) of TGF-ß family receptors, including BMPR2 (bone morphogenetic protein type 2 receptor)/ALK2 (activin receptor-like kinase-2) and TGF-ßR2/R1, and receptor-regulated (R) Smads significantly affects their activity and thus regulates the target cell fate. BRCC3 modifies the activity and stability of its substrate proteins through K63-dependent deubiquitination. By modulating the posttranslational modifications of the BMP/TGF-ß-PPARγ pathway, BRCC3 may play a role in pulmonary vascular remodeling, hence the pathogenesis of PAH. METHODS: Bioinformatic analyses were used to explore the mechanism of BRCC3 deubiquitinates ALK2. Cultured pulmonary artery smooth muscle cells (PASMCs), mouse models, and specimens from patients with idiopathic PAH were used to investigate the rebalance between BMP and TGF-ß signaling in regulating ALK2 phosphorylation and ubiquitination in the context of pulmonary hypertension. RESULTS: BRCC3 was significantly downregulated in PASMCs from patients with PAH and animals with experimental pulmonary hypertension. BRCC3, by de-ubiquitinating ALK2 at Lys-472 and Lys-475, activated receptor-regulated Smad1/5/9 (Smad1/5/9), which resulted in transcriptional activation of BMP-regulated PPARγ, p53, and Id1. Overexpression of BRCC3 also attenuated TGF-ß signaling by downregulating TGF-ß expression and inhibiting phosphorylation of Smad3. Experiments in vitro indicated that overexpression of BRCC3 or the de-ubiquitin-mimetic ALK2-K472/475R attenuated PASMC proliferation and migration and enhanced PASMC apoptosis. In SM22α-BRCC3-Tg mice, pulmonary hypertension was ameliorated because of activation of the ALK2-Smad1/5-PPARγ axis in PASMCs. In contrast, Brcc3-/- mice showed increased susceptibility of experimental pulmonary hypertension because of inhibition of the ALK2-Smad1/5 signaling. CONCLUSIONS: These results suggest a pivotal role of BRCC3 in sustaining pulmonary vascular homeostasis by maintaining the integrity of the BMP signaling (ie, the ALK2-Smad1/5-PPARγ axis) while suppressing TGF-ß signaling in PASMCs. Such rebalance of BMP/TGF-ß pathways is translationally important for PAH alleviation.

A Cross-Sectional Study Evaluating the Association of Brachial Artery Flow Mediated Vasodilation with Physical Activity Measured by Accelerometry in Patients with the Overlap of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Overlap Syndrome (OS), the co-occurrence of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease. Clustering of patients in subgroups with similar pre-clinical manifestations (ie, endothelial dysfunction) may identify relevant therapeutic phenotype categories for patients with OS who are at high risk of CVD. We therefore conducted a cross-sectional pilot study of endothelial function in 7 patients with OS (Forced Expiratory Volume in 1 second/Forced Vital Capacity < 0.7) on continuous positive airway pressure therapy (n = 7) to assess the relationship between FMD and physical activity. We found a strong association between FMD and step counts (rho = 0.77, p = 0.04); and FMD and moderate physical activity (rho = 0.9, p = 0.005). Further, larger studies are needed to confirm that FMD may identify patients with OS at high risk of CVD who benefit from increased physical activity.

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea.

Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

Combining activity and grimace scores reflects perinatal stability in infants <32 weeks gestational age.

BACKGROUND: Over 95% of infants less than 32 weeks gestational age-very preterm infants (VPTI)-require cardiorespiratory support at birth. Clinical condition at birth is assessed by the Apgar score, but the precision and accuracy of activity and grimace has not been evaluated. We hypothesised activity and grimace could predict the level of cardiorespiratory support required for stabilisation. METHODS: Two hundred twenty-nine videos of VPTI resuscitations at Monash Children's Hospital and The Royal Women's Hospital, Melbourne were evaluated, with 78 videos eligible for assessment. Activity and grimace were scored (0, 1, or 2) by seven consultant neonatologists, with inter-rater reliability assessed. Activity and grimace were correlated with the maximum level of cardiorespiratory support required for stabilisation. RESULTS: Kendall's Coefficient of Concordance (W) showed strong interobserver agreement for activity (W = 0.644, p < 0.001) and grimace (W = 0.722, p < 0.001). Neither activity nor grimace independently predicted the level of cardiorespiratory support required. Combining activity and grimace showed non-vigorous infants (combined score <2) received more cardiorespiratory support than vigorous (combined score ≥ 2). CONCLUSION: Scoring of activity and grimace was consistent between clinicians. Independently, activity and grimace did not correlate with perinatal stabilisation. Combined scoring showed non-vigorous infants had greater resuscitation requirements. IMPACT: Our study evaluates the precision and accuracy of activity and grimace to predict perinatal stability, which has not been validated in infants <32 weeks gestational age. We found strong score agreement between assessors, indicating video review is a practical and precise method for grading of activity and grimace. Combined scoring to allow a dichotomous evaluation of infants as non-vigorous or vigorous showed the former group required greater cardiorespiratory support at birth.

Safety of Hepatitis B Vaccines (Monovalent or as Part of Combination) in Preterm Infants: A Systematic Review.

Introduction: The World Health Organization (WHO) recommends vaccination against hepatitis B as soon as possible following birth for all infants, regardless of prematurity. Hepatitis B vaccination at birth is clearly justified, represents a crucial step in the global control of perinatally acquired hepatitis B and there are no safety concerns in infants born at term. However, there is limited information on the safety of the hepatitis B vaccine in preterm infants, whose immune responses and morbidity risk differ from those in infants born at term. Objectives: The objectives of this paper are to systematically review the literature regarding the safety and risk of adverse events following immunisation (AEFIs) associated with the administration of the hepatitis B vaccine (monovalent or as part of a combination vaccine) to preterm infants. Methods: We performed a search for relevant papers published between 1 January 2002 and 30 March 2023 in the Ovid MEDLINE, Ovid Embase, Cochrane Central Register of Controlled Trials and CINAHL Plus databases. Two authors independently reviewed and analysed each article to include in the systematic review. Narrative synthesis is presented. Results: Twenty-one relevant papers were identified and included in this systematic review. The vast majority of data pertained to multi-antigen (combination) vaccine preparations and vaccination episodes from 6 weeks of age onwards. We found no publications investigating the timing of the birth dose of the hepatitis B vaccine, and AEFI reporting was exclusively short-term (hours to days following administration). There was substantial variability in the reported rate of AEFIs between studies, ranging from 0% to 96%. Regardless of frequency, AEFIs were mostly minor and included injection site reactions, temperature instability and self-limiting cardiorespiratory events. Six studies reported serious adverse events (SAEs) such as the requirement for escalation of respiratory support. However, these occurred predominantly in high-risk infant populations and were rare (~1%). Using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, the certainty of evidence was assessed as very low. Conclusions: Despite substantial variability between the relatively small number of published studies in terms of cohort selection, definitions, vaccine preparations and reporting, hepatitis B-containing vaccines (mostly as combination vaccines) appear to be relatively well tolerated in preterm infants from 6 weeks of age. Research focusing on the safety of hepatitis B vaccine in preterm infants specifically within 7 days of birth is lacking, particularly regarding long-term morbidity risk. Further research in this area is required.

Temporal Trends in Severe Brain Injury and Associated Outcomes in Very Preterm Infants.

INTRODUCTION: Severe brain injury (SBI), including severe intraventricular haemorrhage (sIVH) and cystic periventricular leukomalacia, poses significant challenges for preterm infants, yet recent data and trends are limited. METHODS: Analyses were conducted using the Australian and New Zealand Neonatal Network data on preterm infants born <32 weeks' gestation admitted at Monash Children's Hospital, Australia, from January 2014 to April 2021. The occurrence and trends of SBI and sIVH among preterm infants, along with the rates and trends of death and neurodevelopmental impairment (NDI) in SBI infants were assessed. RESULTS: Of 1,609 preterm infants, 6.7% had SBI, and 5.6% exhibited sIVH. A total of 37.6% of infants with SBI did not survive to discharge, with 92% of these deaths occurring following redirection of clinical care. Cerebral palsy was diagnosed in 65.2% of SBI survivors, while 86.4% of SBI survivors experienced NDI. No statistically significant differences were observed in the temporal trends of SBI (adjusted OR [95% CI] 1.08 [0.97-1.20]; p = 0.13) or sIVH (adjusted OR [95% CI] 1.09 [0.97-1.21]; p = 0.11). Similarly, there was no statistically significant difference noted in the temporal trend of the composite outcome, which included death or NDI among infants with SBI (adjusted OR [95% CI] 0.90 [0.53-1.53]; p = 0.71). CONCLUSION: Neither the rates of SBI nor its associated composite outcome of death or NDI improved over time. A notable proportion of preterm infants with SBI faced redirection of care and subsequent mortality, while most survivors exhibited adverse neurodevelopmental challenges. The development of better therapeutic interventions is imperative to improve outcomes for these vulnerable infants.

Treatment of Sleep Apnea and Reduction in Blood Pressure: The Role of Heart Rate Response and Hypoxic Burden.

BACKGROUND: Obstructive sleep apnea is associated with increased blood pressure (BP). Obstructive sleep apnea treatment reduces BP with substantial variability, not explained by the apnea-hypopnea index, partly due to inadequate characterization of obstructive sleep apnea's physiological consequences, such as oxygen desaturation, cardiac autonomic response, and suboptimal treatment efficacy. We sought to examine whether a high baseline heart rate response (ΔHR), a marker of high cardiovascular risk in obstructive sleep apnea, predicts a larger reduction in post-treatment systolic BP (SBP). Furthermore, we aimed to assess the extent to which a reduction in SBP is explained by a treatment-related reduction in hypoxic burden (HB). METHODS: ΔHR and HB were measured from pretreatment and posttreatment polygraphy, followed by a 24-hour BP assessment in 168 participants treated with continuous positive airway pressure or nocturnal supplemental oxygen from the HeartBEAT study (Heart Biomarker Evaluation in Apnea Treatment). Multiple linear regression models assessed whether high versus mid (reference) ΔHR predicted a larger reduction in SBP (primary outcome) and whether there was an association between treatment-related reductions in SBP and HB. RESULTS: A high versus mid ΔHR predicted improvement in SBP (adjusted estimate, 5.8 [95% CI, 1.0-10.5] mm Hg). Independently, a greater treatment-related reduction in HB was significantly associated with larger reductions in SBP (4.2 [95% CI, 0.9-7.5] mm Hg per 2 SD treatment-related reduction in HB). Participants with substantial versus minimal treatment-related reductions in HB had a 6.5 (95% CI, 2.5-10.4) mm Hg drop in SBP. CONCLUSIONS: A high ΔHR predicted a more favorable BP response to therapy. Furthermore, the magnitude of the reduction in BP was partly explained by a greater reduction in HB.

Phenotype of early-onset fetal growth restriction in sheep.

Introduction: Fetal growth restriction (FGR) is a common pregnancy complication, caused by placental insufficiency, with serious adverse consequences for development in utero and postnatal wellbeing. There are no antenatal treatments to improve growth or organ development in FGR, and animal models are essential to mimic the physiological adaptations in FGR and to assess potential interventions. This study aimed to identify the temporal nature of reduced developmental trajectory in fetuses with FGR, and to examine the effects of common factors that may mediate differential growth such as glucocorticoid treatment. We hypothesised that the trajectory of growth would be adversely impacted by FGR. Methods: FGR was induced via surgical placental insufficiency in fetal sheep (89 days gestation/0.6 gestation; n=135) and compared to age-matched controls over the last third of gestation and into neonatal life (n=153). Results: Body weight of FGR fetuses/lambs was significantly reduced compared to controls (p<0.0001) from 127 days of gestation (term is 148 days), with increased brain:body weight ratio (p<0.0001) indicative of brain sparing. All biometric measures of body size were reduced in the FGR group with the exception of biparietal (head) diameter. The trajectory of body growth in the last trimester of sheep pregnancy was significantly reduced in the FGR group compared to controls, and stillbirth rate increased with longer gestation. Discussion: This work provides a well characterised FGR animal model that mimics the known physiological adaptations in human pregnancy and can be used to determine the efficacy of potential interventions.

Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial.

BACKGROUND: Weight reduction is a standard recommendation for obstructive sleep apnea (OSA) treatment in people with obesity or overweight; however, weight loss can be challenging to achieve and maintain without bariatric surgery. Currently, no approved anti-obesity medication has demonstrated effectiveness in OSA management. This study is evaluating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA in people with obesity. METHODS: SURMOUNT-OSA, a randomized, placebo -controlled, 52-week phase 3 trial, is investigating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA (apnea hypopnea- index ≥15 events/h) in participants with obesity (body mass index ≥30 kg/m2) and an established OSA diagnosis. SURMOUNT-OSA is made of 2 intervention-specific appendices (ISAs): ISA-1 includes participants with no current OSA treatment, and ISA-2 includes participants using positive airway pressure therapy. Overall, 469 participants have been randomized 1:1 to receive tirzepatide or placebo across the master protocol (ISA-1, n = 234; ISA-2, n = 235). All participants are also receiving lifestyle intervention for weight reduction. RESULTS: The primary endpoint for the individual ISAs is the difference in apnea hypopnea- index response, as measured by polysomnography, between tirzepatide and placebo arms at week 52. Secondary endpoints include sleep apnea-specific hypoxic burden, functional outcomes, and cardiometabolic biomarkers. The trial employs digital wearables, including home sleep testing to capture time to improvement and accelerometry for daily physical activity assessment, to evaluate exploratory outcomes. CONCLUSION: SURMOUNT-OSA brings a novel design to investigate if tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting the underlying etiology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05412004.

The effect of SARS-COV-2 variant on non-respiratory features and mortality among vaccinated and non-fully vaccinated patients.

OBJECTIVE: To determine the effect of SARS-CoV-2 variants on non-respiratory features of COVID-19 in vaccinated and not fully vaccinated patients using a University of California database. METHODS: A longitudinal retrospective review of medical records (n = 63,454) from 1/1/2020-4/26/2022 using the UCCORDS database was performed to compare non-respiratory features, vaccination status, and mortality between variants. Chi-square tests were used to study the relationship between categorical variables using a contingency matrix. RESULTS: Fever was the most common feature across all variants. Fever was significantly higher in not fully vaccinated during the Delta and Omicron waves (p = 0.001; p = 0.001). Cardiac features were statistically higher in not fully vaccinated during Omicron; tachycardia was only a feature of not fully vaccinated during Delta and Omicron; diabetes and GI reflux were features of all variants regardless of vaccine status. Odds of death were significantly increased among those not fully vaccinated in the Delta and Omicron variants (Delta OR: 1.64, p = 0.052; Omicron OR: 1.96, p < 0.01). Vaccination was associated with a decrease in the frequency of non-respiratory features. CONCLUSIONS: Risk of non-respiratory features of COVID-19 is statistically higher in those not fully vaccinated across all variants. Risk of death and correlation with vaccination status varied.

Mandibular Jaw Movement Automated Analysis for Oral Appliance Monitoring in Obstructive Sleep Apnea: A Prospective Cohort Study.

RATIONALE: Oral appliances are second-line treatments options after continuous positive airway pressure for obstructive sleep apnea (OSA) management. However, the need for oral appliance titration limits their use due to monitoring challenges to assess the treatment effect. OBJECTIVES: To assess the validity of mandibular jaw movements (MJM) automated analysis compared to polysomnography/polygraphy (PSG/PG) in evaluating the effect of oral appliance treatment and the effectiveness of MJM monitoring for oral appliance titration at home in OSA patients. METHODS: This observational, prospective study included 135 OSA patients eligible for oral appliance therapy. The primary outcome was the apnea-hypopnea index (AHI), measured through in-laboratory PSG/PG and MJM-based technology. . Additionally, MJM monitoring at-home was conducted at regular intervals during the titration process. The agreement between PSG/PG and MJM automated analysis was evaluated using Bland-Altman analysis. Change in AHI during the home-based oral appliance titration process was evaluated using GLMM and GEE models. RESULTS: The automated MJM analysis demonstrated strong agreement with PG in assessing AHI during MAD treatment, with a median bias of 0.24/h (limits of agreement: -11.2 to 12.8/h). The improvement of AHI from baseline in response to oral appliance treatment was consistent across 3 evaluation conditions : in-lab PG (-59.6%; 59.8 to -59.5), in-lab MJM (-59.2%; -65.2 to -52.2) and at-home MJM analysis (-59.7% ; -67.4 to -50). CONCLUSIONS: Incorporating MJM automated analysis into the oral appliance titration process has the potential to optimize oral appliance therapy outcomes for OSA.

Functional EPAS1/HIF2A missense variant is associated with hematocrit in Andean highlanders.

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.

Pulmonary primary oxysterol and bile acid synthesis as a predictor of outcomes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH.

Developing a novel mobile application for cognitive behavioral therapy for insomnia for people with schizophrenia: integration of wearable and environmental sleep sensors.

BACKGROUND: People with serious mental illnesses (SMIs) have three-fold higher rates of comorbid insomnia than the general population, which has downstream effects on cognitive, mental, and physical health. Cognitive Behavioral Therapy for Insomnia (CBT-i) is a safe and effective first-line treatment for insomnia, though the therapy's effectiveness relies on completing nightly sleep diaries which can be challenging for some people with SMI and comorbid cognitive deficits. Supportive technologies such as mobile applications and sleep sensors may aid with completing sleep diaries. However, commercially available CBT-i apps are not designed for individuals with cognitive deficits. To aid with this challenge, we have developed an integrated mobile application, named "Sleep Catcher," that will automatically incorporate data from a wearable fitness tracker and a bed sensor to track nightly sleep duration, overnight awakenings, bed-times, and wake-times to generate nightly sleep diaries for CBT-i. METHODS: The application development process will be described-writing algorithms to generating useful data, creating a clinician web portal to oversee patients and the mobile application, and integrating sleep data from device platforms and user input. RESULTS: The mobile and web applications were developed using Flutter, IBM Code Engine, and IBM Cloudant database. The mobile application was developed with a user-centered approach and incremental changes informed by a series of beta tests. Special user-interface features were considered to address the challenges of developing a simple and effective mobile application targeting people with SMI. CONCLUSION: There is strong potential for synergy between engineering and mental health expertise to develop technologies for specific clinical populations. Digital health technologies allow for the development of multi-disciplinary solutions to existing health disparities in vulnerable populations, particularly in people with SMI.

Impact of a deep learning sepsis prediction model on quality of care and survival.

Sepsis remains a major cause of mortality and morbidity worldwide. Algorithms that assist with the early recognition of sepsis may improve outcomes, but relatively few studies have examined their impact on real-world patient outcomes. Our objective was to assess the impact of a deep-learning model (COMPOSER) for the early prediction of sepsis on patient outcomes. We completed a before-and-after quasi-experimental study at two distinct Emergency Departments (EDs) within the UC San Diego Health System. We included 6217 adult septic patients from 1/1/2021 through 4/30/2023. The exposure tested was a nurse-facing Best Practice Advisory (BPA) triggered by COMPOSER. In-hospital mortality, sepsis bundle compliance, 72-h change in sequential organ failure assessment (SOFA) score following sepsis onset, ICU-free days, and the number of ICU encounters were evaluated in the pre-intervention period (705 days) and the post-intervention period (145 days). The causal impact analysis was performed using a Bayesian structural time-series approach with confounder adjustments to assess the significance of the exposure at the 95% confidence level. The deployment of COMPOSER was significantly associated with a 1.9% absolute reduction (17% relative decrease) in in-hospital sepsis mortality (95% CI, 0.3%-3.5%), a 5.0% absolute increase (10% relative increase) in sepsis bundle compliance (95% CI, 2.4%-8.0%), and a 4% (95% CI, 1.1%-7.1%) reduction in 72-h SOFA change after sepsis onset in causal inference analysis. This study suggests that the deployment of COMPOSER for early prediction of sepsis was associated with a significant reduction in mortality and a significant increase in sepsis bundle compliance.