Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes. METHODS: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete. FINDINGS: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo. INTERPRETATION: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults. FUNDING: National Institutes of Health and the US Department of Veterans Affairs.

Early Neurodevelopmental Assessments for Predicting Long-Term Outcomes in Infants at High Risk of Cerebral Palsy.

Importance: Studies suggest that early neurodevelopmental assessments are beneficial for identifying cerebral palsy, yet their effectiveness in practical scenarios and their ability to detect cognitive impairment are limited. Objective: To assess the effectiveness of early neurodevelopmental assessments in identifying cerebral palsy and cognitive and other neurodevelopmental impairments, including their severity, within a multidisciplinary clinic. Design, Setting, and Participants: This diagnostic study was conducted at Monash Children's Hospital, Melbourne, Australia. Participants were extremely preterm infants born at less than 28 weeks' gestation or extremely low birth weight infants less than 1000 g and term encephalopathic infants who received therapeutic hypothermia, attending the early neurodevelopmental clinic between January 2019 and July 2021. Data were analyzed from December 2023 to January 2024. Exposures: Early cerebral palsy or high risk of cerebral palsy, the absence of fidgety movements, and Hammersmith Infant Neurological Examination (HINE) scores at corrected age (CA) 3 to 4 months. Early cerebral palsy or high risk of cerebral palsy diagnosis was based on absent fidgety movements, a low HINE score (<57), and medical neurological examination. Main Outcome and Measures: The outcomes of interest were cerebral palsy, cognitive and neurodevelopmental impairments and their severity, diagnosed at 24 to 36 months' CA. Results: A total of 116 infants (median [IQR] gestational age, 27 [25-29] weeks; 65 [56%] male) were included. Diagnosis of early cerebral palsy or high risk of cerebral palsy demonstrated a sensitivity of 92% (95% CI, 63%-99%) and specificity of 84% (95% CI, 76%-90%) for predicting cerebral palsy and 100% (95% CI, 59%-100%) sensitivity and 80% (95% CI, 72%-87%) specificity for predicting moderate to severe cerebral palsy. Additionally, the accuracy of diagnosis of early cerebral palsy or high risk of cerebral palsy was 85% (95% CI, 77%-91%) for predicting cerebral palsy and 81% (95% CI, 73%-88%) for predicting moderate to severe cerebral palsy. Similarly, the absence of fidgety movements had an 81% (95% CI, 73%-88%) accuracy in predicting cerebral palsy, and HINE scores exhibited good discriminatory power with an area under the curve of 0.88 (95% CI, 0.79-0.97) for cerebral palsy prediction. However, for cognitive impairment, the predictive accuracy was 44% (95% CI, 35%-54%) for an early cerebral palsy or high risk of cerebral palsy diagnosis and 45% (95% CI, 36%-55%) for the absence of fidgety movements. Similarly, HINE scores showed poor discriminatory power for predicting cognitive impairment, with an area under the curve of 0.62 (95% CI, 0.51-0.73). Conclusions and Relevance: In this diagnostic study of infants at high risk for cerebral palsy or other cognitive or neurodevelopmental impairment, early neurodevelopmental assessments at 3 to 4 months' CA reliably predicted cerebral palsy and its severity at 24 to 36 months' CA, signifying its crucial role in facilitating early intervention. However, for cognitive impairment, longer-term assessments are necessary for accurate identification.

Mechanical Interactions Between the Upper Airway and the Lungs that Affect the Propensity to Obstructive Sleep Apnea in Health and Chronic Lung Disease.

Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive narrowing and collapse of the upper airways during sleep. It is caused by multiple anatomic and nonanatomic factors but end-expiratory lung volume (EELV) is an important factor as increased EELV can stabilize the upper airway via caudal traction forces. EELV is impacted by changes in sleep stages, body position, weight, and chronic lung diseases, and this article reviews the mechanical interactions between the lungs and upper airway that affect the propensity to OSA. In doing so, it highlights the need for additional research in this area.

Association Between Sleep Apnea Treatment and Health Care Resource Use in Patients With Atrial Fibrillation.

BACKGROUND: Obstructive sleep apnea (OSA) contributes to the generation, recurrence, and perpetuation of atrial fibrillation, and it is associated with worse outcomes. Little is known about the economic impact of OSA therapy in atrial fibrillation. This retrospective cohort study assessed the impact of positive airway pressure (PAP) therapy adherence on health care resource use and costs in patients with OSA and atrial fibrillation. METHODS AND RESULTS: Insurance claims data for ≥1 year before sleep testing and 2 years after device setup were linked with objective PAP therapy use data. PAP adherence was defined from an extension of the US Medicare 90-day definition. Inverse probability of treatment weighting was used to create covariate-balanced PAP adherence groups to mitigate confounding. Of 5867 patients (32% women; mean age, 62.7 years), 41% were adherent, 38% were intermediate, and 21% were nonadherent. Mean±SD number of all-cause emergency department visits (0.61±1.21 versus 0.77±1.55 [P=0.023] versus 0.95±1.90 [P<0.001]), all-cause hospitalizations (0.19±0.69 versus 0.24±0.72 [P=0.002] versus 0.34±1.16 [P<0.001]), and cardiac-related hospitalizations (0.06±0.26 versus 0.09±0.41 [P=0.023] versus 0.10±0.44 [P=0.004]) were significantly lower in adherent versus intermediate and nonadherent patients, as were all-cause inpatient costs ($2200±$8054 versus $3274±$12 065 [P=0.002] versus $4483±$16 499 [P<0.001]). All-cause emergency department costs were significantly lower in adherent and intermediate versus nonadherent patients ($499±$1229 and $563±$1292 versus $691±$1652 [P<0.001 and P=0.002], respectively). CONCLUSIONS: These data suggest clinical and economic benefits of PAP therapy in patients with concomitant OSA and atrial fibrillation. This supports the value of diagnosing and managing OSA and highlights the need for strategies to enhance PAP adherence in this population.

The Temporal Relationship between Blood-Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia.

Blood-brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia-ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). At 6, 12, 24, and 72 h (h) post-HI, brains were collected to assess neuropathology and BBB dysfunction. A significant breakdown of the BBB was observed in the HI injury group compared to the sham group from 6 h in the cortex and hippocampus (p < 0.001), including a significant increase in albumin extravasation (p < 0.0033) and decrease in basal lamina integrity and tight-junction proteins. There was a decrease in resting microglia (p < 0.0001) transitioning to an intermediate state from as early as 6 h post-HI, with the intermediate microglia peaking at 12 h (p < 0.0001), which significantly correlated to the peak of microbleeds. Neonatal HI insult leads to significant brain injury over the first 72 h that is mediated by BBB disruption within 6 h and a transitioning state of the resident microglia. Key BBB events coincide with the appearance of the intermediate microglial state and this relationship warrants further research and may be a key target for therapeutic intervention.

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.

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.

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.

Potential Therapeutic Targets in Obesity, Sleep Apnea, Diabetes, and Fatty Liver Disease.

Obesity and metabolic syndrome affect the majority of the US population. Patients with obesity are at increased risk of developing type 2 diabetes (T2DM), obstructive sleep apnea (OSA), and metabolic dysfunction-associated steatotic liver disease (MASLD), each of which carry the risk of further complications if left untreated and lead to adverse outcomes. The rising prevalence of obesity and its comorbidities has led to increased mortality, decreased quality of life, and rising healthcare expenditures. This phenomenon has resulted in the intensive investigation of exciting therapies for obesity over the past decade, including more treatments that are still in the pipeline. In our present report, we aim to solidify the relationships among obesity, T2DM, OSA, and MASLD through a comprehensive review of current research. We also provide an overview of the surgical and pharmacologic treatment classes that target these relationships, namely bariatric surgery, the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptor agonists.

Electrographic monitoring for seizure detection in the neonatal unit: current status and future direction.

Neonatal neurocritical intensive care is dedicated to safeguarding the newborn brain by prioritising clinical practices that promote early identification, diagnosis and treatment of brain injuries. The most common newborn neurological emergency is neonatal seizures, which may also be the initial clinical indication of neurological disease. A high seizure burden in the newborn period independently contributes to increased mortality and morbidity. The majority of seizures in newborns are subclinical (without clinical presentation), and hence identification may be difficult. Neuromonitoring techniques most frequently used to monitor brain wave activity include conventional electroencephalography (cEEG) or amplitude-integrated EEG (aEEG). cEEG with video is the gold standard for diagnosing and treating seizures. Many neonatal units do not have access to cEEG, and frequently those that do, have little access to real-time interpretation of monitoring. IMPACT: EEG monitoring is of no benefit to an infant without expert interpretation. Whilst EEG is a reliable cot-side tool and of diagnostic and prognostic use, both conventional EEG and amplitude-integrated EEG have strengths and limitations, including sensitivity to seizure activity and ease of interpretation. Automated seizure detection requires a sensitive and specific algorithm that can interpret EEG in real-time and identify seizures, including their intensity and duration.

The Effect of Obesity on Sleep Apnea Pathogenesis Differs in Women vs Men: Multiple Mediation Analyses in the Retrospective SNOOzzzE Cohort.

BACKGROUND AND OBJECTIVE: There are multiple mechanisms underlying obstructive sleep apnea (OSA) development. However, how classic OSA risk factors such as body mass index (BMI) and sex portend to OSA development have not been fully described. Thus, we sought to evaluate how obesity leads to OSA, and assess how these mechanisms differ between men and women. Methods The San Diego Multi-Outcome OSA Endophenotype (SNOOzzzE) cohort includes 3,319 consecutive adults who underwent a clinical in-laboratory polysomnography at the UCSD sleep clinic between 1/2017-12/2019. Using routine polysomnography signals, we determined OSA endotypes. We then performed mediation analyses stratified by sex to determine how BMI influenced apnea hypopnea index (AHI) using OSA endotypic traits as mediators. Results We included 2,146 patients of whom 919 (43%) were women and 1,227 (57%) were obese. BMI was significantly associated with AHI in both women and men. In men, the effect of BMI on AHI was partially mediated by a reduction in upper airway stiffness (31% of total effect, TE), by a reduction in circulatory delay (16%TE), and by an increase in arousal threshold (7%TE). In women, the effect of BMI on AHI was partially mediated by a reduction in circulatory delay (22%TE). Discussion BMI-related OSA pathogenesis differs by sex. An increase in upper airway collapsibility (in men) is consistent with prior studies. A reduction in circulatory delay may lead to shorter and thus more events per hour (i.e., higher AHI), while the association between a higher arousal threshold and higher AHI may reflect reverse causation.

Rest-activity rhythm disruption and metabolic health in schizophrenia: a cross-sectional actigraphy study of community-dwelling people living with schizophrenia and non-psychiatric comparison participants.

STUDY OBJECTIVES: People living with schizophrenia (PLWS) have increased physical comorbidities and premature mortality which may be linked to dysregulated rest-activity rhythms (RARs). This study aimed to compare RARs between PLWS and non-psychiatric comparison participants (NCs); examine the relationships of RARs with age, sleep, metabolic and physical health outcomes; and, among PLWS, relationships of RARs with illness-related factors. METHODS: The study sample included 26 PLWS and 36 NCs, assessed with wrist-worn actigraphy to compute RAR variables and general sleep variables. Participants completed assessments for clinical symptoms, physical health, sleep quality, medication use, and assays for fasting glycosylated hemoglobin (HbA1c) levels. We examined group differences in RAR and sleep variables, relationships of RAR variables with metabolic and physical health measures, and, among PLWS, relationships between RAR variables and illness-related measures. RESULTS: PLWS had significantly shorter active periods, lower relative amplitude, and lower mean activity during their most active 10 hours compared to the NCs (Cohen's d=.79, .58, and .62; respectively). PLWS had poorer sleep quality, greater mean percent sleep, less wake after sleep onset, and higher total sleep time (TST) variability compared to NCs. PLWS had higher rates of antidepressant, anxiolytic, and antipsychotic medication use compared to NCs, which may have impacted sleep quality and objective sleep measures. Across both groups, more fragmented and variable RARs were associated with higher HbA1c levels (ηp2=0.10) and worse physical health (ηp2=0.21). Among PLWS, RARs were correlated with TST (rs=.789, p<0.01) and percent sleep (rs=.509, p<0.05), but not with age, sleep quality, or other illness-related factors. CONCLUSIONS: RARs provide unique information about sleep and activity for PLWS and have the potential for targeted interventions to improve metabolic health and mortality.

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.

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.

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.

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.

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.

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.