Evidence of alveolar macrophage metabolic shift following SBRT-induced lung fibrosis in mice.

BACKGROUND: Radiation-induced pneumopathy is the main dose-limiting factor in cases of chest radiation therapy. Macrophage infiltration is frequently observed in irradiated lung tissues and may participate in lung damage development. Radiation-induced lung fibrosis can be reproduced in rodent models using whole thorax irradiation but suffers from limits concerning the role played by unexposed lung volumes in damage development. METHODS: Here we used an accurate Stereotactic Body Radiation Therapy (SBRT) preclinical model irradiating 4% of the mouse lung. Tissue damage development and macrophages populations were followed by histology, flow cytometry and single cell RNA sequencing. Wild type and CCR2 KO mice in which monocytes recruitment is abrogated, were exposed to single doses of radiations inducing progressive (60 Gy) or rapid (80 Gy) lung fibrosis. RESULTS: Numerous clusters of macrophages were observed around the injured area, during progressive as well as rapid fibrosis. Results indicate that probably CCR2-independent recruitment and/or in situ proliferation may be responsible for macrophage invasion. Alveolar macrophages experience a metabolic shift from fatty acid metabolism to cholesterol biosynthesis, directing them through a possible pro-fibrosing phenotype. Depicted data revealed that the origin and phenotype of macrophages present to the injured area may differ from what has been previously described in preclinical models exposing large lung volumes, representing a potentially interesting trail in the deciphering of radiation-induced lung damage processes. CONCLUSION: Our study brings new possible clues to the understanding of macrophage implication in radiation-induced lung damage, representing an interesting area for exploration in future studies.

Longitudinal transcriptomic analysis reveals persistent enrichment of iron homeostasis and erythrocyte function pathways in severe COVID-19 ARDS.

Introduction: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS. Methods: We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing. Results: We first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 (HBA1, HBA2), hemoglobin subunit beta (HBB), von Willebrand factor C and EGF domains (VWCE), and carbonic anhydrase 1 (CA1), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport. Discussion: These findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution.

Protocol for monitoring fatty acid trafficking from lipid droplets to mitochondria in cultured cells.

Intracellular trafficking of fatty acids (FAs) between organelles is critical for cells to adjust their metabolism in response to stimuli such as exercise, fasting, and cold exposure. Here, we describe a protocol to monitor trafficking of FAs from lipid droplets to mitochondria. We describe the labeling of organelles in cultured C2C12 myoblasts with transfection and dyes. We detail a pulse-chase labeling paradigm using a fluorescent FA analog, live-cell imaging to visualize trafficking of FAs, and steps to quantify FA trafficking. For complete details on the use and execution of this protocol, please refer to Miner et al.1.

Mortality follow-up of Fernald Feed Materials Production Center workers exposed to uranium from 1951 to 1985.

OBJECTIVE: This follow-up study of uranium processing workers at the Fernald Feed Materials Production Center examines the relationship between radiation exposure and cancer and non-cancer mortality among 6403 workers employed for at least 30 days between 1951 and 1985. METHODS: We estimated cumulative, individual, annualised doses to 15 organs/tissues from external, internal and radon exposures. Vital status and cause of death were ascertained in 2017. The analysis employed standardised mortality ratios, Cox proportional hazards and Poisson regression models. Competing risk analysis was conducted for cardiovascular disease (CVD) mortality risk given several assumptions about risk independent of competing outcomes. Emphysema was examined to assess the potential for confounding by smoking. RESULTS: Vital status was confirmed for 98.1% of workers, with 65.1% deceased. All-cause mortality was less than expected in salaried but not hourly workers when compared with the US population. A statistically significant dose response was observed between external (but not total or internal) lung dose and lung cancer mortality (HR at 100 mGy adjusted for internal dose=1.45; 95% CI=1.05 to 2.01). Significantly increased HRs at 100 mGy dose to heart were observed for CVD (1.27; 95% CI=1.07 to 1.50) and ischaemic heart disease (1.30; 95% CI=1.07 to 1.58). CVD risk remained elevated regardless of competing risk assumptions. Both external and internal radiation were associated with emphysema. CONCLUSIONS: Lung cancer was associated with external dose, though positive dose responses for emphysema imply residual confounding by smoking. Novel use of competing risk analysis for CVD demonstrates leveraging retrospective data for future risk prediction.

Mild Traumatic Brain Injury in U.S. Military Veterans: Results from the National Health and Resilience in Veterans Study.

OBJECTIVE: This study provides nationally representative data on the prevalence, risk factors, and associated mental health and functional outcomes of mild traumatic brain injury (mTBI) in U.S. military veterans. METHODS: Data (N = 4,069) were analyzed from the National Health and Resilience in Veterans Study (NHRVS). Analyses estimated mTBI prevalence, exposure to different mTBI injuries, and past-week mTBI symptoms (i.e. persistent post-concussive symptoms [PCS]). Comparisons were made between veterans with and without mTBI+PCS on sociodemographic, military, trauma, and psychiatric characteristics. Associations between mTBI+PCS and measures of cognitive, mental, and psychosocial functioning were examined. RESULTS: Overall, 43.7% endorsed a possible mTBI event on the Veterans Affairs' Mild TBI Injury Screening and Evaluation tool, and 10.0% screened positive for mTBI. After combining a self-reported healthcare professional diagnosis of concussion/mTBI/TBI (5.8%) with a positive mTBI screen, the prevalence of mTBI+PCS was 3.0%. Veterans with specific trauma characteristics (e.g. adverse childhood events), military service (e.g. combat), and lifetime psychiatric conditions were more likely to have mTBI+PCS. mTBI+PCS was associated with increased odds of current posttraumatic stress disorder, major depressive disorder, generalized anxiety disorder, and drug use disorder. These veterans also scored significantly lower on cognitive, mental, and psychosocial functioning. CONCLUSIONS: Overall, 3.0% of veterans had mTBI+PCS, suggesting that while mTBI may be prevalent in this population, the majority will likely recover without developing chronic symptoms. Those with mTBI+PCS are at significant risk for comorbid psychiatric diagnoses and poorer psychosocial functioning relative to those without mTBI+PCS, and early targeted identification may assist in prevention of disability and recovery.

Diffuse alveolar hemorrhage in pediatrics: Etiologies and outcomes.

BACKGROUND: Many conditions, including autoimmune disease and idiopathic pulmonary hemosiderosis (IPH), can cause diffuse alveolar hemorrhage (DAH). Little is known about the epidemiology and outcomes in children. OBJECTIVES: This retrospective cohort study sought to describe the etiologies and outcomes of DAH in pediatric patients at a tertiary care center. METHODS: This study involved review of patient records with diagnostic codes or bronchoscopy reports suggestive of pulmonary hemorrhage at a large children's hospital over 11 years (2010-2020). Patients were included if they met criteria for DAH, defined as bilateral pulmonary infiltrates and at least one of the following: (1) hemoptysis, (2) blood visible on bronchoscopic exam without apparent airway source, or (3) DAH noted on biopsy or autopsy. Infants less than 10 days corrected gestational age were excluded. RESULTS: Seventy-one children with DAH were included in the analysis. Cardiovascular disease was the most common etiology. Bleeding diathesis was common, but all patients had other causes of DAH. Patients with IPH were younger than those with autoimmune disease (p < .001). Most (77%) patients required mechanical ventilation, though this was less common among patients with autoimmune disease. Overall mortality was high (37%) but varied based on underlying etiology; mortality was higher in patients with cardiovascular disease (65%) while no deaths were seen in patients with autoimmune disease or IPH (p = .002). Survivors of DAH who performed pulmonary function tests had normal lung function. CONCLUSIONS: DAH frequently causes respiratory failure in children. In our cohort, mortality was highest in patients with cardiovascular disease.

Machine Learning in Electronic Health Records: Identifying High-Risk Obstetric Patients Pre and During Labor.

Our goal is to apply artificial intelligence (AI) and statistical analysis to understand the relationship between various factors and outcomes during pregnancy and labor and delivery, in order to personalize birth management and reduce complications for both mothers and newborns. We use a structured electronic health records database with data from approximately 130,000 births to train, test and validate our models. We apply machine learning (ML) methods to predict various obstetrical outcomes before and during labor, with the aim of improving patient care management in the delivery ward. Using a large cohort of data (∼180 million data points), we then demonstrated that ML models can predict successful vaginal delivery, in the general population as well as a sub-cohort of women attempting trial of labor after a cesarean delivery. The real-time dynamic model showed increasing rates of accuracy as the delivery process progressed and more data became available for analysis. Additionally, we developed a cross-facilities application of an AI model that predicts the need for an unplanned cesarean delivery, illuminating the challenges associated with inter-facility variation in reporting practices. Overall, these studies combine novel technologies with currently available data to predict and assist safe deliveries for mothers and babies, both locally and globally.

PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression.

SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.

Do veterans with risky substance use (RSU) use distinct pain treatment modalities?

BACKGROUND AND OBJECTIVES: Risky substance use (RSU) is common among people with chronic pain and is associated with worse pain treatment outcomes. Nonopioid treatment is recommended, but it is unknown whether people with RSU use different or fewer pain treatment modalities. This study describes use of different pain treatments by veterans with and without RSU and those receiving versus not receiving opioid medication. METHODS: Veterans (N = 924) who filed service-connected disability claims related to musculoskeletal conditions and rated their pain four or higher on the Numeric Rating Scale, reported on 25 different pain services in the preceding 90 days. Recent RSU was identified via Alcohol, Smoking, and Substance Involvement Test (ASSIST) cutoffs and/or nail sample toxicology. RESULTS: Overall, RSU was not associated with number of provider-delivered or self-delivered pain modalities. Over-the-counter medications (71%), self-structured exercise (69%), and nonopioid prescription medications (38%) were the most used modalities. Veterans receiving prescribed opioids (8.4%) were more likely to see primary care, receive injections, and attend exercise and/or meditation classes, compared to those without opioid prescriptions. DISCUSSION AND CONCLUSIONS: Opioid and nonopioid pain treatment utilization did not differ based on RSU, and those prescribed opioids were more likely to engage in other nonopioid pain treatments. Regardless of RSU, veterans appear willing to try provider-delivered (58%) and self-delivered (79%) pain treatment. SCIENTIFIC SIGNIFICANCE: In this first-ever evaluation of 25 different pain treatment modalities among veterans with and without RSU, people with RSU did not use less treatment modalities.

Can profiles of behaviors occurring within 48 h of a suicide attempt predict future severity of suicidal thoughts and reattempt?: An examination of hospitalized patients 12 Months post-discharge.

Behavioral warning signs (WS) are near-term changes within individuals, which aid in determining imminent risk for suicide attempts. However, those who attempt suicide differ in their engagement of WS, and it is unclear if these differences relate to future risk of suicidal behavior. Using a sample of 132 adults presenting to a hospital following a suicide attempt, the current study sought to determine if differences in engagement in WS for the index attempt prospectively predicted suicide attempt, frequency of ideation, and intensity of suicide ideation 12 months post discharge. Latent class analyses (LCAs) conducted on 6 behaviors (i.e., alcohol use, nightmares, interpersonal negative life events, suicide communication, risky behavior, low sleep, and high sleep) found a 5-class solution optimally fit the data. One identified class, characterized by engagement in risky behaviors the hours before an attempt differed from other identified classes in terms of risk for future suicidal ideation and behaviors. More specifically, participants in "High Risky Behavior" class had higher rates of 12-month suicide reattempt, significantly more frequent suicide ideation, and significantly worse intensity of suicide ideation during the 12 months following their index attempt compared to participants endorsing typical patterns of WS. These results held when adjusting for various traditional baseline covariates (e.g., depressive symptoms). The current study demonstrates that patterns of behavioral WS may be utilized as their own prognostic indicator of future suicidal ideation and behaviors among high-risk individuals reporting a recent suicide attempt, which can inform post-discharge clinical intervention and prevention efforts.

Enteral nutrition on discharge from intensive care and 30-day unplanned readmission: An exploratory, retrospective study of association.

BACKGROUND & AIMS: Individuals who survive critical illness are often malnourished with inadequate oral nutrient intake after leaving the intensive care unit (ICU). Enteral nutrition (EN) improves nutrient intake but there is limited evidence on the impact of maintaining EN after discharge from the ICU. The objective of this exploratory study was to understand the association between EN maintenance after ICU and 30-day unplanned hospital re-admission, to inform on future prospective research into the effects of post-ICU nutrition. METHODS: This was a single-centre, retrospective study of ICU patients, requiring ventilation, who received EN for at least 3 days in ICU and were discharged to the ward. RESULTS: 102 patients met the inclusion criteria; 45 (44.1%) maintained EN and 57 (55.9%) discontinued EN after ICU discharge; there were no significant differences in demographics or clinical measures at ICU admission. Reason for EN discontinuation was documented in 38 (66.7%) patients, with 27 (71%) discontinuing EN due to a routine ward practice of feeding tube removal. Unplanned 30-day hospital re-admission occurred in 17 (16.7%) patients overall, 5 (11.1%) in the EN group and 12 (21.1%) in the non-EN group (crude odds ratio [OR] 0.47, 95% CI 0.15, 1.45, p = 0.188). After adjusting for age, sex, BMI and length of stay, there was a persistent trend to lower re-admission rates in the EN group (OR 0.37, 95% CI 0.09, 1.57, p = 0.176). CONCLUSIONS: EN maintenance after ICU discharge was associated with a trend to lower 30-day unplanned hospital re-admission rates. The clinically relevant reduction of about 50% in unplanned re-admission rates in this exploratory study warrants larger, prospective studies of post-ICU nutrition strategies based on clear discontinuation criteria to optimize nutrition and evaluate patient-centred outcomes.

Cognitive processing therapy (CPT) versus individual drug counseling (IDC) for PTSD for veterans with opioid use disorder maintained on buprenorphine.

BACKGROUND AND OBJECTIVES: There are high rates of comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD). Evidence-based trauma-focused psychotherapies such as Cognitive Processing Therapy (CPT) are a first-line treatment for PTSD. Veterans with OUD are treated primarily in substance use disorder (SUD) clinics where the standard of care is drug counseling; they often do not have access to first-line PTSD treatments. This study tested whether CPT can be conducted safely and effectively in veterans with comorbid OUD treated with buprenorphine. METHODS: This 12-week, 2-site, randomized clinical trial (RCT) included open-label randomization to two groups: (a) CPT versus (b) Individual Drug Counselling (IDC) in veterans with PTSD and comorbid OUD who were maintained on buprenorphine (N = 38). RESULTS: Veterans randomized to either IDC (n = 18) or CPT (n = 20) showed a significant reduction in self-reported PTSD symptoms over time as measured by the PTSD checklist (PCL-5) but there were no treatment group differences; there was some indication that reduction in PTSD symptoms in the CPT group were sustained in contrast to the IDC group. Recruitment was significantly impacted by COVID-19 pandemic, so this study serves as a proof-of-concept pilot study. DISCUSSION AND CONCLUSIONS: Veterans with OUD and PTSD can safely and effectively participate in evidence-based therapy for PTSD; further work should confirm that trauma-focused treatment may be more effective in leading to sustained remission of PTSD symptoms than drug counseling. SCIENTIFIC SIGNIFICANCE: This is the first study to evaluate CPT for PTSD in the context of buprenorphine treatment for OUD.

Maternal hybrid immunity and risk of infant COVID-19 hospitalizations: national case-control study in Israel.

Hybrid immunity, acquired through vaccination followed or preceded by a COVID-19 infection, elicits robust antibody augmentation. We hypothesize that maternal hybrid immunity will provide greater infant protection than other forms of COVID-19 immunity in the first 6 months of life. We conducted a case-control study in Israel, enrolling 661 infants up to 6 months of age, hospitalized with COVID-19 (cases) and 59,460 age-matched non-hospitalized infants (controls) between August 24, 2021, and March 15, 2022. Infants were grouped by maternal immunity status at delivery: Naïve (never vaccinated or tested positive, reference group), Hybrid-immunity (vaccinated and tested positive), Natural-immunity (tested positive before or during the study period), Full-vaccination (two-shot regimen plus 1 booster), and Partial-vaccination (less than full three shot regimen). Applying Cox proportional hazards models to estimate the hazard ratios, which was then converted to percent vaccine effectiveness, and using the Naïve group as the reference, maternal hybrid-immunity provided the highest protection (84% [95% CI 75-90]), followed by full-vaccination (66% [95% CI 56-74]), natural-immunity (56% [95% CI 39-68]), and partial-vaccination (29% [95% CI 15-41]). Maternal hybrid-immunity was associated with a reduced risk of infant hospitalization for Covid-19, as compared to natural-immunity, regardless of exposure timing or sequence. These findings emphasize the benefits of vaccinating previously infected individuals during pregnancy to reduce COVID-19 hospitalizations in early infancy.

Early hybrid cardiac rehabilitation in congenital heart disease: the QUALIREHAB trial.

BACKGROUND AND AIMS: Cardiopulmonary fitness in congenital heart disease (CHD) decreases faster than in the general population resulting in impaired health-related quality of life (HRQoL). As the standard of care seems insufficient to encourage and maintain fitness, an early hybrid cardiac rehabilitation programme could improve HRQoL in CHD. METHODS: The QUALIREHAB multicentre, randomized, controlled trial evaluated and implemented a 12-week centre- and home-based hybrid cardiac rehabilitation programme, including multidisciplinary care and physical activity sessions. Adolescent and young adult CHD patients with impaired cardiopulmonary fitness were randomly assigned to either the intervention (i.e. cardiac rehabilitation) or the standard of care. The primary outcome was the change in HRQoL from baseline to 12-month follow-up in an intention-to-treat analysis. The secondary outcomes were the change in cardiovascular parameters, cardiopulmonary fitness, and mental health. RESULTS: The expected number of 142 patients was enroled in the study (mean age 17.4 ± 3.4 years, 52% female). Patients assigned to the intervention had a significant positive change in HRQoL total score [mean difference 3.8; 95% confidence interval (CI) 0.2; 7.3; P = .038; effect size 0.34], body mass index [mean difference -0.7 kg/m2 (95% CI -1.3; -0.1); P = .022; effect size 0.41], level of physical activity [mean difference 2.5 (95% CI 0.1; 5); P = .044; effect size 0.39], and disease knowledge [mean difference 2.7 (95% CI 0.8; 4.6); P = .007; effect size 0.51]. The per-protocol analysis confirmed these results with a higher magnitude of differences. Acceptability, safety, and short-time effect of the intervention were good to excellent. CONCLUSIONS: This early hybrid cardiac rehabilitation programme improved HRQoL, body mass index, physical activity, and disease knowledge, in youth with CHD, opening up the possibility for the QUALIREHAB programme to be rolled out to the adult population of CHD and non-congenital cardiac disease.

Giving Voice to Women with Substance Use Disorder: Findings from Expressive Writing About Trauma.

Background: Trauma exposure is a risk factor for substance use disorders (SUD) among women. This study explores written content from an expressive writing (EW) intervention conducted within a residential SUD program to examine themes across trauma experiences and characterize their deep insight into such experiences. Materials and Methods: This qualitative study is a secondary data analysis of written content of the first writing session from women (n = 44) randomized to an EW condition while in residential SUD treatment. Results: Nearly all participants (72.7% African American; mean age 37.3 years) reported a significant trauma event (93.2%) with an average of 3.7 types of trauma events (54.4% had a current posttraumatic stress disorder diagnosis). Four primary themes emerged: (1) trauma across the lifespan; (2) loss of safety; (3) altered self-concept; and (4) desire to move on. Most participants identified interpersonal trauma, especially at an early age, as well as parental neglect and physical and/or sexual violence. These themes indicate a pattern of interpersonal betrayal and paint a picture of trauma and the subsequent "rippling effect" such that the physical, mental, and emotional consequences were often as impactful as the event itself. However, there was also a desire to move on and gain a sense of normalcy. Conclusions: Findings highlight the importance of the written word and addressing underlying trauma in addiction treatment to facilitate healing and the woman's desire to move on.

Impact of Fontan Fenestration on Adverse Cardiovascular Outcomes: A Multicentre Study.

BACKGROUND: Fenestrating a Fontan baffle has been associated with improved perioperative outcomes in patients with univentricular hearts. However, longer-term potential adverse effects remain debated. We sought to assess the impact of a fenestrated Fontan baffle on adverse cardiovascular events including all-cause mortality, cardiac transplantation, atrial arrhythmias, and thromboemboli. METHODS: A multicentre North American retrospective cohort study was conducted on patients with total cavopulmonary connection Fontan baffle, with and without fenestration. All components of the composite outcome were independently adjudicated. Potential static and time-varying confounders were taken into consideration, along with competing risks. RESULTS: A total of 407 patients were followed for 10.4 (7.1-14.4) years; 70.0% had fenestration of their Fontan baffle. The fenestration spontaneously closed or was deliberately sealed in 79.9% of patients a median of 2.0 years after Fontan completion. In multivariable analysis in which a persistent fenestration was modelled as a time-dependent variable, an open fenestration did not confer a higher risk of the composite outcome (hazard ratio, 1.18; 95% confidence interval, 0.71-1.97; P = 0.521). In secondary analyses, an open fenestration was not significantly associated with components of the primary outcome: that is, mortality or transplantation, atrial arrhythmias, or thromboemboli. However, sensitivity analyses to assess the possible range of error resulting from imprecise dates for spontaneous fenestration closures could not rule out significant associations between an open fenestration and atrial arrhythmias or thromboemboli. CONCLUSIONS: In this multicentre study, no significant association was identified between an open fenestration in the Fontan baffle and major adverse cardiovascular events.

Written exposure therapy for veterans with co-occurring substance use disorders and PTSD: Study design of a randomized clinical trial.

There are high rates of posttraumatic stress disorder (PTSD) among treatment-seeking veterans with substance use disorders (SUD). While addiction programs traditionally do not address PTSD, there is evidence that trauma treatments for individuals with this comorbidity have improved PTSD and SUD outcomes. Written exposure therapy (WET), a five-session evidence-based psychotherapy (EBP) for PTSD, has high patient satisfaction, and lower dropout compared to other EBPs for PTSD. WET may be ideally suited for clinical settings that may not have the trauma expertise found in PTSD specialty clinics, given it requires less training time, treatment sessions, preparation time, and therapist involvement than existing EBPs, and no homework assignments. This paper describes the design, methodology, and protocol of a randomized clinical trial to evaluate whether treatment as usual (TAU) plus WET (n = 51) is superior to TAU plus a neutral topic writing condition (n = 51) on both PTSD and addiction outcomes for veterans in SUD treatment. The primary hypothesis is that participants assigned to TAU+WET, compared to those in TAU+ neutral topic writing, will report reduced symptoms of PTSD. The secondary hypothesis is that veterans receiving WET will have greater decreases in number of days of substance use compared to TAU+ neutral topic controls at follow-up. Assessments will take place at baseline, post-treatment, 8-week, and 12-week follow-up. Exploratory aims will examine the association between heart rate variability and treatment outcomes. If results prove promising, they will support WET as an effective brief, easy to disseminate, adjunct to current SUD treatment for veterans with comorbid PTSD. Trial registration: ClinicalTrials.gov ID NCT05327504.

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size.

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to lipogenesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the endoplasmic reticulum (ER) lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs after a fatty acid pulse, which contain more unsaturated triglyceride after fatty acid pulse-chase. This LD size phenotype was rescued by chimeric APOE that targets only LDs. Like APOE depletion, APOE4-expressing astrocytes form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 causes aberrant LD composition and morphology. Our study contributes to accumulating evidence that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation, which could contribute to Alzheimer's disease risk.

Orientation-invariant autoencoders learn robust representations for shape profiling of cells and organelles.

Cell and organelle shape are driven by diverse genetic and environmental factors and thus accurate quantification of cellular morphology is essential to experimental cell biology. Autoencoders are a popular tool for unsupervised biological image analysis because they learn a low-dimensional representation that maps images to feature vectors to generate a semantically meaningful embedding space of morphological variation. The learned feature vectors can also be used for clustering, dimensionality reduction, outlier detection, and supervised learning problems. Shape properties do not change with orientation, and thus we argue that representation learning methods should encode this orientation invariance. We show that conventional autoencoders are sensitive to orientation, which can lead to suboptimal performance on downstream tasks. To address this, we develop O2-variational autoencoder (O2-VAE), an unsupervised method that learns robust, orientation-invariant representations. We use O2-VAE to discover morphology subgroups in segmented cells and mitochondria, detect outlier cells, and rapidly characterise cellular shape and texture in large datasets, including in a newly generated synthetic benchmark.