Sex differences in cerebral blood flow among adolescents with bipolar disorder.

BACKGROUND: Abnormalities in cerebral blood flow (CBF) are common in bipolar disorder (BD). Despite known differences in CBF between healthy adolescent males and females, sex differences in CBF among adolescents with BD have never been studied. OBJECTIVE: To examine sex differences in CBF among adolescents with BD versus healthy controls (HC). METHODS: CBF images were acquired using arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) in 123 adolescents (72 BD: 30M, 42F; 51 HC: 22M, 29F) matched for age (13-20 years). Whole brain voxel-wise analysis was performed in a general linear model with sex and diagnosis as fixed factors, sex-diagnosis interaction effect, and age as a covariate. We tested for main effects of sex, diagnosis, and their interaction. Results were thresholded at cluster forming p = 0.0125, with posthoc Bonferroni correction (p = 0.05/4 groups). RESULTS: A main effect of diagnosis (BD > HC) was observed in the superior longitudinal fasciculus (SLF), underlying the left precentral gyrus (F =10.24 (3), p < 0.0001). A main effect of sex (F > M) on CBF was detected in the precuneus/posterior cingulate cortex (PCC), left frontal and occipital poles, left thalamus, left SLF, and right inferior longitudinal fasciculus (ILF). No regions demonstrated a significant sex-by-diagnosis interaction. Exploratory pairwise testing in regions with a main effect of sex revealed greater CBF in females with BD versus HC in the precuneus/PCC (F = 7.1 (3), p < 0.01). CONCLUSION: Greater CBF in female adolescents with BD versus HC in the precuneus/PCC may reflect the role of this region in the neurobiological sex differences of adolescent-onset BD. Larger studies targeting underlying mechanisms, such as mitochondrial dysfunction or oxidative stress, are warranted.

Prescribed fire increases plant-pollinator network robustness to losses of rare native forbs.

Restoration efforts often focus on changing the composition and structure of invaded plant communities, with two implicit assumptions: (1) functional interactions with species of other trophic levels, such as pollinators, will reassemble automatically when native plant diversity is restored and (2) restored communities will be more resilient to future stressors. However, the impact of restoration activities on pollinator richness, plant-pollinator interaction network structure, and network robustness is incompletely understood. Leveraging a restoration chronosequence in Pacific Northwest prairies, we examined the effects of restoration-focused prescribed fire and native forb replanting on floral resources, pollinator visitation, and plant-pollinator network structure. We then simulated the effects of plant species loss/removal scenarios on secondary extinction cascades in the networks. Specifically, we explored three management-relevant plant loss scenarios (removal of an abundant exotic forb, removal of an abundant forb designated a noxious weed, and loss of the rarest native forb) and compared them to control scenarios. Pyrodiversity and proportion of area recently burned increased the abundance and diversity of floral resources, with concomitant increases in pollinator visitation and diversity. Pyrodiversity also decreased network connectance and nestedness, increased modularity, and buffered networks against secondary extinction cascades. Rare forbs contributed disproportionately to network robustness in less restored prairies, while removal of typical "problem" plants like exotic and noxious species had relatively small impacts on network robustness, particularly in prairies with a long history of restoration activities. Restoration actions aimed mainly at improving the diversity and abundance of pollinator-provisioning plants may also produce plant-pollinator networks with increased resilience to plant species losses.

Resting-state functional connectivity indicators of risk and resilience for self-harm in adolescent bipolar disorder.

BACKGROUND: Suicide is the second leading cause of death in all youth and among adults with bipolar disorder (BD). The risk of suicide in BD is among the highest of all psychiatric conditions. Self-harm, including suicide attempts and non-suicidal self-injury, is a leading risk factor for suicide. Neuroimaging studies suggest reward circuits are implicated in both BD and self-harm; however, studies have yet to examine self-harm related resting-state functional connectivity (rsFC) phenotypes within adolescent BD. METHODS: Resting-state fMRI data were analyzed for 141 adolescents, ages 13-20 years, including 38 with BD and lifetime self-harm (BDSH+), 33 with BD and no self-harm (BDSH-), and 70 healthy controls (HC). The dorsolateral prefrontal cortex (dlPFC), orbitofrontal cortex (OFC) and amygdala were examined as regions of interest in seed-to-voxel analyses. A general linear model was used to explore the bivariate correlations for each seed. RESULTS: BDSH- had increased positive rsFC between the left amygdala and left lateral occipital cortex, and between the right dlPFC and right frontal pole, and increased negative rsFC between the left amygdala and left superior frontal gyrus compared to BDSH+ and HC. BDSH+ had increased positive rsFC of the right OFC with the precuneus and left paracingulate gyrus compared to BDSH- and HC. CONCLUSIONS: This study provides preliminary evidence of altered reward-related rsFC in relation to self-harm in adolescents with BD. Between-group differences conveyed a combination of putative risk and resilience connectivity patterns. Future studies are warranted to evaluate changes in rsFC in response to treatment and related changes in self-harm.

Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Self-harm among youth during the first 28 months of the COVID-19 pandemic in Ontario, Canada: a population-based study.

BACKGROUND: Youth have reported worsening mental health during the COVID-19 pandemic. We sought to evaluate rates of pediatric acute care visits for self-harm during the pandemic according to age, sex and mental health service use. METHODS: We conducted a population-based, repeated cross-sectional study using linked health administrative data sets to measure monthly rates of emergency department visits and hospital admissions for self-harm among youth aged 10-17 years between Jan. 1, 2017, and June 30, 2022, in Ontario, Canada. We modelled expected rates of acute care visits for self-harm after the pandemic onset based on prepandemic rates. We reported relative differences between observed and expected monthly rates overall and by age group (10-13 yr and 14-17 yr), sex and mental health service use (new and continuing). RESULTS: In this population of about 1.3 million children and adolescents, rates of acute care visits for self-harm during the pandemic were higher than expected for emergency department visits (0.27/1000 population v. 0.21/1000 population; adjusted rate ratio [RR] 1.29, 95% confidence interval [CI] 1.19-1.39) and hospital admissions (0.74/10 000 population v. 0.43/10 000 population, adjusted RR 1.72, 95% CI 1.46-2.03). This increase was primarily observed among females. Rates of emergency department visits and hospital admissions for self-harm were higher than expected for both those aged 10-13 years and those aged 14-17 years, as well as for both those new to the mental health system and those already engaged in care. INTERPRETATION: Rates of acute care visits for self-harm among children and adolescents were higher than expected during the first 2 and a half years of the COVID-19 pandemic, particularly among females. These findings support the need for accessible and intensive prevention efforts and mental health supports in this population.

Feasibility and Utility of Routine Point-of-Care Gastric Ultrasonography in Patients Undergoing Upper Gastrointestinal Endoscopy Procedures: A Prospective Cohort Study.

OBJECTIVES: Previous studies have indicated that point-of-care ultrasonography (POCUS) of the gastric antrum can predict the adequacy of fasting before surgery and anesthesia. The aim of this study was to evaluate the utility of gastric POCUS in patients undergoing upper gastrointestinal (GI) endoscopy procedures. METHODS: We performed a single-center cohort study in patients undergoing upper GI endoscopy. Consenting patient's gastric antrum was scanned before anesthetic care for endoscopy to determine the cross-sectional area (CSA) and qualitatively determine safe and unsafe contents. Further, an estimate of residual gastric volume was determined using the formula and the nomogram methods. Subsequently, gastric secretions aspirated during endoscopy were quantified and further correlated with nomogram and formula-based assessments. No patient required a change in the primary anesthetic plan except for using rapid sequence induction in those with unsafe contents on POCUS scans. RESULTS: Qualitative ultrasound measurements consistently determined safe and unsafe gastric residual contents in 83 patients enrolled in the study. Unsafe contents were determined by qualitative scans in 4 out of 83 cases (5%) despite adequate fasting status. Quantitatively, only a moderate correlation was demonstrated between measured gastric volumes and nomogram (r = .40, 95% CI: 0.20, 0.57; P = .0002) or formula-based (r = .38, 95% CI: 0.17, 0.55; P = .0004) determinations of residual gastric volumes. CONCLUSION: In daily clinical practice, qualitative POCUS determination of residual gastric content is a feasible and useful technique to identify patients at risk of aspiration before upper GI endoscopy procedures.

Clinical correlates of suicidality and self-injurious behaviour among Canadian adolescents with bipolar disorder.

There is high risk of suicidality in bipolar disorder (BD), particularly in early onset cases. The literature regarding correlates and putative predictors of suicide attempts (SA), non-suicidal self-injury (NSSI) and suicidal ideation (SI) among youth with BD remains sparse. Participants included 197 adolescents with BD, divided into 4 groups: SA (with or without NSSI), NSSI (with or without SI), SI only, and comparison group (CG; no SA/NSSI/SI). Diagnoses, treatment, and suicidality measures were determined via semi-structured interviews, conducted between 2009 and 2017. Univariate analyses were followed by multinomial regression. Overall, 73.6% of participants had history of SA, NSSI, and/or SI. In comparison to CG, SA and NSSI were each associated with BD-II/-NOS (odds ratio [OR] = 15.99, p = 0.002; OR = 16.76, p = 0.003), female sex (OR = 6.89, p = 0.006; OR = 3.76, p = 0.02), and emotion dysregulation (OR = 1.10, p < 0.001; OR = 1.07, p = 0.004). NSSI and SI were each associated with most severe lifetime depression (OR = 1.10, p = 0.01; OR = 1.10, p = 0.01). SA and SI were associated with psychiatric hospitalization (OR = 19.45, p = 0.001; OR = 6.09, p = 0.03). SA was associated with poorer global functioning at most severe episode (OR = 0.88, p = 0.008). NSSI was associated with not living with both natural parents (OR = 0.22, p = 0.009). Study limitations include cross-sectional and retrospective design, stringent cut-offs for SA and NSSI, and recruitment from a tertiary clinical setting. Three quarters of adolescents with BD have had suicidality and/or self-injury. SA and NSSI were most similar to one another, and most different from CG, supporting the broader construct of self-harm. Future research should address the gap in knowledge regarding how sex differences and neurobiology are associated with the observed clinical differences.

Neurostructural differences associated with self-harm in youth bipolar disorder.

BACKGROUND: Youth with bipolar disorder (BD) are at greatly elevated risk for suicide. Self-harm, encompassing all self-injurious behaviors regardless of suicidal intent, is among one of the greatest risk factors for death by suicide. This study aims to extend the sparse literature regarding the neurostructural correlates of self-harm in youth with BD. METHODS: Participants included 156 youth (17.14 ± 1.61 years): 38 BD with lifetime history of self-harm (BDSH+ ), 43 BD without history of self-harm (BDSH- ), and 75 healthy controls (HC). Measures of cortical thickness, surface area (SA), and volume were obtained using 3 T magnetic resonance imaging. Orbitofrontal and ventrolateral prefrontal cortices were examined in region-of-interest (ROI) analyses, complemented by exploratory vertex-wise analyses using a general linear model controlling for age, sex, and intracranial volume. RESULTS: In ROI analyses, there were no between-group differences after correction for multiple comparisons. Vertex-wise analysis revealed three significant clusters in precentral gyrus SA, inferior temporal gyrus SA, and caudal middle frontal gyrus volume. Post-hoc vertex-wise analyses showed BDSH+ had lower cortical SA and volume compared with both BDSH- and HC for all clusters. CONCLUSIONS: Significant vertex-wise findings were observed in frontotemporal regions relevant to BD and self-harm, with smaller neurostructural measures among BDSH+ compared with both BDSH- and HC. Future studies are needed to evaluate the temporal nature of the relationship of these neurostructural differences (i.e., potential risk indicators) to self-harm and to identify mechanisms underlying these findings.

Near-Fatal Self-Harm Among Canadian Adolescents.

OBJECTIVE: To evaluate the clinical features of Canadian adolescents admitted to the intensive care unit (ICU) for medically serious self-harm. METHODS: 2700 Canadian paediatricians were surveyed monthly over two years (January 2017 to December 2018) through the Canadian Paediatric Surveillance Program to ascertain data from eligible cases. RESULTS: Ninety-three cases (73 female; age 15.2 ± 1.5) met the case definition. Four provinces reported the majority of cases: Quebec (n = 27), Ontario (n = 26), Alberta (n = 21), and British Columbia (n = 8). There were 10 deaths, 9 by hanging. Overdose and hanging were the most frequently reported methods of self-harm (74.2% and 19.4%, respectively). Overdose was more common in females (80.8% females vs. 50% males; χ2 = 7.8 (1), p = .005), whereas hanging was more common in males (35% males vs. 15.1% females, χ2 = 3.9 (1), p = .04). More females than males had a past psychiatric diagnosis (79% vs. 58%; χ2 = 4.1 (1), p = .06), a previous suicide attempt (55.9% vs. 29.4%, χ2 = 3.8 (1), p = .05), and prior use of mental health service (69.7% vs. 27.8%, χ2 = 10.4 (1), p = .001). Family conflict was the most commonly identified precipitating factor (43%) of self-harm. CONCLUSIONS: Among Canadian adolescents admitted to the ICU with medically serious self-harm, females demonstrate a higher rate of suicide attempts and prior mental health care engagement, whereas males are more likely to die by suicide. These findings are consistent with data from other adolescent samples, as well as data from working-age and older adults. Therefore, a sex-specific approach to suicide prevention is warranted as part of a national suicide prevention strategy; family conflict may be a specific target for suicide prevention interventions among adolescents.

Emergency department visits for self-harm in adolescents after release of the Netflix series '13 Reasons Why'.

OBJECTIVE: To determine whether the release of the first season of the Netflix series '13 Reasons Why' was associated with changes in emergency department presentations for self-harm. METHODS: Healthcare utilization databases were used to identify emergency department and outpatient presentations according to age and sex for residents of Ontario, Canada. Data from 2007 to 2018 were used in autoregressive integrated moving average models for time series forecasting with a pre-specified hypothesis that rates of emergency department presentations for self-harm would increase in the 3-month period following the release of 13 Reasons Why (1 April 2017 to 30 June 2017). Chi-square and t tests were used to identify demographic and health service use differences between those presenting to emergency department with self-harm during this epoch compared to a control period (1 April 2016 to 30 June 2016). RESULTS: There was a significant estimated excess of 75 self-harm-related emergency department visits (+6.4%) in the 3 months after 13 Reasons Why above what was predicted by the autoregressive integrated moving average model (standard error = 32.4; p = 0.02); adolescents aged 10-19 years had 60 excess visits (standard error = 30.7; p = 0.048), whereas adults demonstrated no significant change. Sex-stratified analyses demonstrated that these findings were largely driven by significant increases in females. There were no differences in demographic or health service use characteristics between those who presented to emergency department with self-harm in April to June 2017 vs April to June 2016. CONCLUSIONS: This study demonstrated a significant increase in self-harm emergency department visits associated with the release of 13 Reasons Why. It adds to previously published mortality, survey and helpline data collectively demonstrating negative mental health outcomes associated with 13 Reasons Why.

Videoconference microscopy is a reliable alternative to conventional microscopy in the evaluation of Barrett's esophagus: Zooming into a new era.

Telepathology, practicing pathology from a distance, allows experts to review cases without the need to transfer glass slides. Due to significant intra- and inter-observer variabilities in the histological evaluation of Barrett's esophagus (BE), current guidelines recommend expert consultation in cases of dysplasia. We aimed to determine whether telepathology using microscope videoconferencing can be reliably used for evaluation of BE. Biopsies from 62 patients with endoscopic findings of salmon colored mucosa extending ≥1 cm proximal to the gastroesophageal junction were randomly selected to represent benign esophagus, non-dysplastic BE, low-grade dysplasia, high-grade dysplasia, and adenocarcinoma. Three gastrointestinal-trained pathologists reviewed the cases via videoconference microscopy followed by conventional microscopy. Intra-observer and pairwise inter-observer agreements between the conventional microscopy and videoconference methodologies were calculated for each of the three pathologists using Fleiss-Cohen weighted kappa (K) analysis. The intra-observer agreement for each pathologist's assessment of videoconference microscopy and glass slide readings showed very good reliability (K = 0.94, 95% confidence interval = 0.89-0.99; 0.88, 95% confidence interval = 0.79-0.98; 0.93, 95% confidence interval = 0.90-0.97). Mean pairwise inter-observer agreement was 0.90 for videoconference and 0.91 for conventional microscopy. Diagnosis and grading of BE using videoconference microscopy show similar reliability as conventional microscopy. Based on our findings, we propose that videoconferencing pathology is a valid instrument for evaluating BE.

Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress.

We investigated and modeled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukemia (ALL). We used gene expression profiling, cytokine/chemokine quantification, flow cytometry, and a variety of imaging techniques to show that MSCs, directly isolated from the primary bone marrow specimens of patients with ALL, frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, primary human MSCs and the MSC cell line HS27a both were activated de novo, when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) and daunorubicin (DNR), a phenomenon blocked by the antioxidant N-acetyl cysteine. Chemotherapy-activated HS27a cells were functionally evaluated in a coculture model with ALL targets. Activated MSCs prevented therapy-induced apoptosis and death in ALL targets, via mitochondrial transfer through tunneling nanotubes (TNTs). Reduction of mitochondrial transfer by selective mitochondrial depletion or interference with TNT formation by microtubule inhibitors, such as vincristine (VCR), prevented the "rescue" function of activated MSCs. Corticosteroids, also a mainstay of ALL therapy, prevented the activation of MSCs. We also demonstrated that AraC (but not VCR) induced activation of MSCs, mitochondrial transfer, and mitochondrial mass increase in a murine NSG model of disseminated SEM cell-derived ALL, wherein CD19+ cells closely associated with nestin+ MSCs after AraC, but not in the other conditions. Our data propose a readily clinically exploitable mechanism for improving treatment of ALL, in which traditional ROS-inducing chemotherapies are often ineffective at eradicating residual disease, despite efficiently killing the bulk population.

Clinical and neuroimaging correlates of cardiorespiratory fitness in adolescents with bipolar disorder.

INTRODUCTION: Cardiovascular disease (CVD) is exceedingly prevalent, and occurs prematurely in individuals with bipolar disorder (BD). Cardiorespiratory fitness (CRF), arguably the most important modifiable CVD risk factor, is also associated with brain structure and function. There is a gap in knowledge regarding CRF in BD, particularly in relation to brain structure. METHODS: Adolescents with BD (n = 54) and healthy controls (HC; n = 53) completed semi-structured diagnostic interviews, self-report questionnaires, and 20 minutes of cardiorespiratory exercise at 60-80% of estimated maximum heart rate (HR) on a bicycle ergometer. Average power (watts/kg) within this HR range served as a previously validated proxy for CRF. Brain magnetic resonance imaging (MRI) structural analysis was done using FreeSurfer. Analyses controlled for age and sex. RESULTS: CRF was significantly lower in BD vs HC (0.91 ± 0.32 vs 1.01 ± 0.30, p = 0.03, F = 4.66, df=1, η2 =0.04). Within BD, greater depression symptoms were associated with lower CRF (P = .02), and greater physical activity (PA) was associated with greater CRF (P < .001). In multivariable analyses, there were significant main effects of diagnosis (HC>BD; P = .03) and sex (M > F; P < .001) on power. Significant predictors of power within BD included male sex (P = .02) and PA (P = .002) but not depression symptoms (P = .29). Significant diagnosis by CRF interaction effects was found in frontal, parietal, and occipital cortical regions. CONCLUSION: CRF was reduced among adolescents with BD, particularly women, related in part to depression symptoms and inactivity and was differentially associated with regional brain structure. Studies seeking to improve CRF as a means of reducing psychiatric symptoms of BD are warranted.

Intraspecific trait variability shapes leaf trait response to altered fire regimes.

BACKGROUND AND AIMS: Understanding impacts of altered disturbance regimes on community structure and function is a key goal for community ecology. Functional traits link species composition to ecosystem functioning. Changes in the distribution of functional traits at community scales in response to disturbance can be driven not only by shifts in species composition, but also by shifts in intraspecific trait values. Understanding the relative importance of these two processes has important implications for predicting community responses to altered disturbance regimes. METHODS: We experimentally manipulated fire return intervals in replicated blocks of a fire-adapted, longleaf pine (Pinus palustris) ecosystem in North Carolina, USA and measured specific leaf area (SLA), leaf dry matter content (LDMC) and compositional responses along a lowland to upland gradient over a 4 year period. Plots were burned between zero and four times. Using a trait-based approach, we simulate hypothetical scenarios which allow species presence, abundance or trait values to vary over time and compare these with observed traits to understand the relative contributions of each of these three processes to observed trait patterns at the study site. We addressed the following questions. (1) How do changes in the fire regime affect community composition, structure and community-level trait responses? (2) Are these effects consistent across a gradient of fire intensity? (3) What are the relative contributions of species turnover, changes in abundance and changes in intraspecific trait values to observed changes in community-weighted mean (CWM) traits in response to altered fire regime? KEY RESULTS: We found strong evidence that altered fire return interval impacted understorey plant communities. The number of fires a plot experienced significantly affected the magnitude of its compositional change and shifted the ecotone boundary separating shrub-dominated lowland areas from grass-dominated upland areas, with suppression sites (0 burns) experiencing an upland shift and annual burn sites a lowland shift. We found significant effects of burn regimes on the CWM of SLA, and that observed shifts in both SLA and LDMC were driven primarily by intraspecific changes in trait values. CONCLUSIONS: In a fire-adapted ecosystem, increased fire frequency altered community composition and structure of the ecosystem through changes in the position of the shrub line. We also found that plant traits responded directionally to increased fire frequency, with SLA decreasing in response to fire frequency across the environmental gradient. For both SLA and LDMC, nearly all of the observed changes in CWM traits were driven by intraspecific variation.

Elevated lipids are associated with reduced regional brain structure in youth with bipolar disorder.

OBJECTIVE: Abnormal blood lipid levels are common in bipolar disorder (BD) and correlate with mood symptoms and neurocognition. However, studies have not examined the lipid-brain structure association in BD or youth. METHODS: This study examined low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), triglycerides, and total cholesterol (TC) levels in relation to brain structure utilizing T1-weighted images, among participants ages 13-20 with BD (n = 55) and healthy controls (HC; n = 47). General linear models investigated group differences in the association of lipids with anterior cingulate cortex (ACC), hippocampus, and inferior parietal lobe structure, controlling for age, sex, body mass index, and intracranial volume. For significant associations, post hoc within-group analyses were undertaken. Exploratory vertex-wise analyses further investigated group differences in the lipid-brain structure association. RESULTS: There were significant group differences in the association of LDL-C (ß = -0.29 p = 0.001), and TC (ß = -0.21 p = 0.016), with hippocampal volume, and triglycerides with ACC volume (ß = -0.25 p = 0.01) and area (ß = -0.26 p = 0.004). Elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC. Post hoc analyses revealed that elevated LDL-C (ß = -0.27 p = 0.007) and reduced HDL-C (ß = 0.24 p = 0.01) were associated with smaller hippocampal volume in the BD group. Exclusion of BD second-generation antipsychotic users did not alter these results. Vertex-wise analyses further showed that elevated lipids were associated with smaller brain structure to a significantly greater extent in BD vs HC, across the cortex. CONCLUSION: Elevated lipids are associated with smaller brain structure in BD. Research evaluating lipid-brain structure associations prospectively and whether lipid optimization has salutary effects on brain structure is necessary.

Type 1 Interferon Responses Underlie Tumor-Selective Replication of Oncolytic Measles Virus.

The mechanism of tumor-selective replication of oncolytic measles virus (MV) is poorly understood. Using a stepwise model of cellular transformation, in which oncogenic hits were additively expressed in human bone marrow-derived mesenchymal stromal cells, we show that MV-induced oncolysis increased progressively with transformation. The type 1 interferon (IFN) response to MV infection was significantly reduced and delayed, in accordance with the level of transformation. Consistently, we observed delayed and reduced signal transducer and activator of transcription (STAT1) phosphorylation in the fully transformed cells. Pre-treatment with IFNß restored resistance to MV-mediated oncolysis. Gene expression profiling to identify the genetic correlates of susceptibility to MV oncolysis revealed a dampened basal level of immune-related genes in the fully transformed cells compared to their normal counterparts. IFN-induced transmembrane protein 1 (IFITM1) was the foremost basally downregulated immune gene. Stable IFITM1 overexpression in MV-susceptible cells resulted in a 50% increase in cell viability and a significant reduction in viral replication at 24 h after MV infection. Overall, our data indicate that the basal reduction in functions of the type 1 IFN pathway is a major contributor to the oncolytic selectivity of MV. In particular, we have identified IFITM1 as a restriction factor for oncolytic MV, acting at early stages of infection.

Clinical correlates of socioeconomic status in adolescent bipolar disorder.

BACKGROUND: Lower socioeconomic status (SES) is associated with symptomatic severity, comorbidity, and functional impairment in adults with bipolar disorder (BD). Little is known about clinical correlates of SES in adolescents with BD. METHODS: Participants included 195 adolescents, 13-20 years old, with BD type I, II or not otherwise specified (NOS). Diagnoses were determined by standardized semi-structured interviews. Based on the Hollingshead scale, participants were divided into "low" (SES 1-3) and the "high" (SES 4-5) SES groups. Demographic and clinical correlates of SES were evaluated in univariate analyses; significant variables were evaluated in a logistic regression model. RESULTS: Compared to participants in the high SES group (n = 150), participants in the low SES group (n = 45) were significantly younger, less likely to be of Caucasian race and living with natural parents. In the logistic regression model, controlling for age and race, the low SES group had higher risk of police contact or arrest (OR = 2.41, 95% CI:1.14-5.11, p = 0.022), less treatment with stimulants(OR = 0.20 95% CI: 0.06-0.67, p = 0.009), and more post-traumatic stress disorder (PTSD) (OR = 4.08, 95% CI:1.33-12.46, p = 0.014) compared to the high SES group. In sensitivity analyses that further controlled for intact family, the finding of higher rates of police contact or arrest was no longer significant. LIMITATIONS: Cross-sectional design; higher-skewed SES sample. CONCLUSIONS: Lower SES in adolescent BD is associated with higher legal risk, increased PTSD, and under-treatment of attention-deficit/hyperactivity disorder (ADHD). Future studies are needed to evaluate the inter-relationships of these correlates, using prospective designs that can evaluate the direction of these associations. Further studies incorporating neurobiological markers are also needed to explore mechanisms underlying SES-related differences in BD.

Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia.

Somatic mutations within noncoding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines in addition to 3.7% of pediatric (6 of 160) and 5.5% of adult (9 of 163) T-ALL patient samples. The majority of indels harbor putative de novo MYB, ETS1, or RUNX1 consensus binding sites. Analysis of 5'-capped RNA transcripts in mutant cell lines identified the usage of an intermediate promoter site, with consequential monoallelic LMO2 overexpression. CRISPR/Cas9-mediated disruption of the mutant allele in PF-382 cells markedly downregulated LMO2 expression, establishing clear causality between the mutation and oncogene dysregulation. Furthermore, the spectrum of CRISPR/Cas9-derived mutations provides important insights into the interconnected contributions of functional transcription factor binding. Finally, these mutations occur in the same intron as retroviral integration sites in gene therapy-induced T-ALL, suggesting that such events occur at preferential sites in the noncoding genome.

Somatic variants of potential clinical significance in the tumors of BRCA phenocopies.

BACKGROUND: BRCA phenocopies are individuals with the same phenotype (i.e. cancer consistent with Hereditary Breast and Ovarian Cancer syndrome = HBOC) as their affected relatives, but not the same genotype as assessed by blood germline testing (i.e. they do not carry a germline BRCA1 or BRCA2 mutation). There is some evidence of increased risk for HBOC-related cancers in relatives of germline variant carriers even though they themselves test negative for the familial variant (BRCA non-carriers). At this time, BRCA phenocopies are recommended to undergo the same cancer surveillance as individuals in the general population. This raises the question of whether the increased cancer risk in BRCA non-carriers is due to alterations (germline, somatic or epigenetic) in other cancer-associated genes which were not analyzed during BRCA analysis. METHODS: To assess the nature and potential clinical significance of somatic variants in BRCA phenocopy tumors, DNA from BRCA non-carrier tumor tissue was analyzed using next generation sequencing of 572 cancer genes. Tumor diagnoses of the 11 subjects included breast, ovarian, endometrial and primary peritoneal carcinoma. Variants were called using FreeBayes genetic variant detector. Variants were annotated for effect on protein sequence, predicted function, and frequency in different populations from the 1000 genomes project, and presence in variant databases COSMIC and ClinVar using Annovar. RESULTS: None of the familial BRCA1/2 mutations were found in the tumor samples tested. The most frequently occurring somatic gene variants were ROS1(6/11 cases) and NUP98 (5/11 cases). BRCA2 somatic variants were found in 2/6 BRCA1 phenocopies, but 0/5 BRCA2 phenocopies. Variants of uncertain significance were found in other DNA repair genes (ERCC1, ERCC3, ERCC4, FANCD2, PALB2), one mismatch repair gene (PMS2), a DNA demethylation enzyme (TET2), and two histone modifiers (EZH2, SUZ12). CONCLUSIONS: Although limited by a small sample size, these results support a role of selected somatic variants and epigenetic mechanisms in the development of tumors in BRCA phenocopies.