Sex Difference in Cigarette-Smoking Status and Its Association with Brain Volumes Using Large-Scale Community-Representative Data.

BACKGROUND: Cigarette smoking is believed to accelerate age-related neurodegeneration. Despite significant sex differences in both smoking behaviors and brain structures, the active literature is equivocal in parsing out a sex difference in smoking-associated brain structural changes. OBJECTIVE: The current study examined subcortical and lateral ventricle gray matter (GM) volume differences among smokers, active, past, and never-smokers, stratified by sex. METHODS: The current study data included 1959 Dallas Heart Study (DHS) participants with valid brain imaging data. Stratified by gender, multiple-group comparisons of three cigarette-smoking groups were conducted to test whether there is any cigarette-smoking group differences in GM volumes of the selected regions of interest (ROIs). RESULTS: The largest subcortical GM volumetric loss and enlargement of the lateral ventricle were observed among past smokers for both females and males. However, these observed group differences in GM volumetric changes were statistically significant only among males after adjusting for age and intracranial volumes. CONCLUSIONS: The study findings suggest a sex difference in lifetime-smoking-associated GM volumetric changes, even after controlling for aging and intracranial volumes.

Development of guidelines for school staff on supporting students who self-harm: a Delphi study.

OBJECTIVE: Self-harm is a major public health issue that significantly impacts communities, making early intervention and prevention paramount in addressing this public health issue. This study aimed to develop evidence-based, culturally responsive, safe, and practical guidelines to assist school staff in effectively supporting students who self-harm. METHODS: This Delphi study comprised of a five-step process, oversighted by a Ropu Matanga Maori (Maori clinical and cultural governance group), and drawing on the expertise and knowledge gained from existing literature, interviews with stakeholders, and two panels of experts (youth and stakeholders). The Ropu Matanga Maori ensured accountability to the principles of Te Tiriti o Waitangi (Treaty of Waitangi) and kept Maori processes central to the research aims. The panels completed two rounds of questionnaires, rating their endorsement of each statement. Statements rated as important or essential by 80% or more of both panels and Maori participants were included in the final guidelines. The Ropu Matanga Maori reviewed any remaining statements to determine inclusion. RESULTS: Following the five-step process, 305 statements were included in the guidelines. These statements provided guiding actions that endorsed communication, collaborative responsibility, and wellbeing and a student-centred approach. CONCLUSION: The guidelines provide guidance to all school staff that is culturally responsive and safe, consensus-based, and evidence-based. It is informed by the voices and experiences of young people and those who support them.

A comparison of prolonged exposure therapy, pharmacotherapy, and their combination for PTSD: What works best and for whom; study protocol for a randomized trial.

BACKGROUND: Several efficacious psychological and pharmacological treatments for posttraumatic stress disorder (PTSD) are available; however, the comparative effectiveness of these treatments represents a major gap in the literature. The proposed study will compare the effectiveness of two leading PTSD treatments - Prolonged Exposure (PE) therapy and pharmacotherapy with paroxetine or venlafaxine extended release - as well as the combination of PE and medication. METHODS: In a randomized clinical trial, veterans with PTSD (N = 450) recruited across six Veterans Affairs Medical Centers will complete assessments at baseline, mid-treatment (Week 7), post-treatment (Week 14), and follow-up (Weeks 27 and 40). The primary outcome will be change in (both clinician-rated and self-reported) PTSD severity. Depression symptoms, quality of life, and functioning will also be measured and examined as secondary outcomes. Baseline demographic and clinical data will be used to develop "personalized advantage indices" (PAIs), with the goal of identifying who is most likely to benefit from which treatment. CONCLUSIONS: This planned trial will yield findings to directly inform clinical practice guidelines for PTSD, by providing comparative effectiveness data to support recommendations about what can be considered the "first-line" treatment option(s) for PTSD. Further, findings from this trial have the potential to guide treatment planning for individual patients, through implementation of PAIs developed from study data, in service of "personalized medicine." TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04961190.

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.

BACKGROUND: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia. METHODS: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months. RESULTS: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome. CONCLUSIONS: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).

Genetic Analysis of Patients With Sickle Cell Anemia and Stroke Before 4 Years of Age Suggest an Important Role for Apoliprotein E.

BACKGROUND: Ischemic stroke is a devastating complication affecting children with sickle cell anemia. Genetic factors are likely to be important in determining the risk of stroke but are poorly defined. METHODS: We have studied a cohort of 19 children who had an overt ischemic stroke before 4 years of age. We predicted genetic determinants of stroke would be more prominent in this group. We performed whole exome sequencing on this cohort and applied 2 hypotheses to our variant filtering. First, we looked for strong, potentially mono- or oligogenic variants for ischemic stroke, and second, we considered that more common polygenic variants will be enriched in our cohort. Candidate variants emerging from both strategies were validated in a cohort of 283 patients with sickle cell anemia and known pediatric cerebrovascular outcomes. We used principal component analysis in this cohort to control for relatedness and population substructure. RESULTS: Our primary finding was that the Apoliprotein E genotypes ε2/ε4 and ε4/ ε4, defined by the interplay of rs7412 and rs429358, were associated with increased stroke risk, with an odds ratio of 4.35 ([95% CI, 1.85-10.0] P=0.0011) for ischemic stroke in the validation cohort. We also found that rs2297518 in NOS (NO synthase) 2 (odds ratio, 2.25 [95% CI, 1.21-4.19]; P=0.014) and rs2230123 in signal transducer and activator of transcription (odds ratio, 2.60 [95% CI, 1.30-5.20]; P=0.009) both had increased odds ratios for ischemic stroke, although these two variants were below the threshold for statistical significance after correction for multiple testing. CONCLUSIONS: These data identify new loci for future functional investigations into cerebrovascular disease in sickle cell anemia. Based on African population reference allele frequencies, the Apoliprotein E genotypes would be present in about 10% of children with sickle cell anemia and represent a genetic risk factor that is potentially modifiable by both dietary and pharmaceutical manipulation of its dyslipidemic effects.