Antenatal corticosteroids are given to pregnant people at risk of preterm birth to reduce newborn morbidity, including respiratory distress syndrome. However, there has been concern surrounding potential adverse effects on subsequent generations. Animal studies have demonstrated endocrine and metabolic changes in those exposed to corticosteroids in utero (F1) and in the second generation (F2). We aimed to assess the effects of parental antenatal corticosteroid exposure on health of the second generation (F2) of Auckland Steroid Trial (AST) participants. In the AST, women (F0) expected to birth between 24 and 36 weeks’ gestation were randomised to betamethasone or placebo. When their children (F1) were 50 years old, they and their children (F2) were followed up with a self-report questionnaire and data linkage. The primary outcome for this analysis was body mass index (BMI) z-score in the F2 generation. Secondary outcomes included respiratory, cardiovascular, neurodevelopmental, mental and general health, and social outcomes. Of the 213 F2 participants, 144 had BMI data available. There was no difference in BMI z-score between participants whose parent was exposed to betamethasone versus placebo (mean (SD) 0.63 (1.45), N = 77 vs 0.41 (1.28), N = 67, adjusted mean difference (95% confidence interval) = 0.16 (-0.37, 0.69)). There was no evidence of a difference in rates of overweight, diabetes, respiratory disease, cardiometabolic risk factors, neurodevelopmental difficulties, mental health difficulties and social outcomes between parental betamethasone versus placebo exposure groups, but confidence intervals were wide. These findings are reassuring regarding the intergenerational safety of antenatal corticosteroids.

Background: Ischemic stroke is a major cause of morbidity and mortality in Canada. Since 2015, mechanical thrombectomy has been the standard of care for eligible large vessel occlusions (LVOs), though anesthetic strategies remain variable. Methods: We conducted a single-center retrospective review of patients undergoing mechanical thrombectomy for anterior circulation LVOs between 2021 and 2023. Patients were categorized by anesthetic strategy (general anesthesia vs. conscious sedation), and outcomes, including time to recanalization, angiographic results (mTICI), and 90-day functional status (mRS), were compared. Statistical analyses included Student’s t-test, Mann-Whitney U-test, and Fisher’s exact test. Results: Among 226 patients, 177 (78%) received general anesthesia and 49 (22%) underwent conscious sedation. Baseline characteristics including sex, age, NIHSS, ASPECTS, collaterals, and laterality were similar between groups. Conscious sedation was associated with a statistically significant shorter time from arrival to the angiography suite to groin puncture (p=0.007), but no differences in time to recanalization (p=0.893), angiographic outcomes (p=0.987), or 90-day functional status (p=0.795) were observed. Conclusions: Conscious sedation led to faster procedural initiation, though no difference in clinical or radiographic outcome was observed. Anesthetic choice should be individualized based on patient and physician factors in acute mechanical thrombectomy.

Background: Inuit children have been observed to have high rates of macrocephaly, which leads to burdensome travel for medical evaluation, often with no pathology identified. Given reports that WHO growth charts may not reflect all populations, we compared head circumference (HC) measurements in a cohort of Inuit children with the WHO charts. Methods: We extracted HC data from a retrospective cohort study where, with Inuit partnership, we reviewed medical records of Inuit children, born between 2010-2013, and residing in Nunavut. We excluded children with preterm birth, documented neurologic/genetic disease, and most congenital anomalies. We compared HC values with the 2007 WHO charts. Results: We analyzed records of 1960 Inuit children (8866 data points). Most data were from ages 0-36 months. At all age points, the cohort had statistically significantly larger HC than WHO medians. At age 12 months, median HC were 1.3 cm and 1.5 cm larger for male and female Inuit children. Using WHO growth curves, macrocephaly was overdiagnosed and microcephaly underdiagnosed. Conclusions: Our results support the observation that Inuit children from Nunavut have larger HCs, and use of the WHO charts may lead to overdiagnosis of macrocephaly and underdiagnosis of microcephaly. Population specific growth curves for Inuit children should be considered.

Background: The combination of PARP inhibitor and immune checkpoint inhibitors have been proposed as a potentially synergistic combinatorial treatment in IDH mutant glioma, targeting dysregulated homologous recombination repair pathways. This study analyzed the cell-free DNA methylome of patients in a phase 2 trial using the PARP inhibitor Olaparib and the PD-1 inhibitor Durvalumab. Methods: Patients with recurrent high-grade IDH-mutant gliomas were enrolled in a phase II open-label study (NCT03991832). Serum was collected at baseline and monthly and cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed. Binomial GLMnet models were developed and model performance was assessed using validation set data. Results: 29 patients were enrolled between 2020–2023. Patients received olaparib 300mg twice daily and durvalumab 1500mg IV every 4 weeks. The overall response rate was 10% via RANO criteria. 144 plasma samples were profiled with cfMeDIP-seq along with 30 healthy controls. The enriched circulating tumour DNA methylome during response periods exhibited a highly specific signature, accurately discriminating response versus failure (AUC 0.98 ± 0.03). Additionally, samples that were taken while on treatment were able to be discriminated from samples off therapy (AUC 0.74 ± 0.11). Conclusions: The cell-free plasma DNA methylome exhibits highly specific signatures that enable accurate prediction of response to therapy.

Background: Nipocalimab is a human IgG1 monoclonal antibody targeting FcRn that selectively reduces IgG levels without impacting antigen presentation, T- and B-cell functions. This study describes the effect of nipocalimab on vaccine response. Methods: Open-label, parallel, interventional study randomized participants 1:1 to receive intravenous 30mg/kg nipocalimab at Week0 and 15mg/kg at Week2 and Week4 (active) or no drug (control). On Day 3, participants received Tdap and PPSV®23 vaccinations and were followed through Wk16. Results: Twenty-nine participants completed the study and are included (active, n=15; control, n=14). Participants with a positive anti-tetanus IgG response was comparable between groups at Wk2 and Wk16, but lower at Wk4 (nipocalimab 3/15 [20%] vs control 7/14 [50%]; P=0.089). All maintained anti-tetanus IgG above the protective threshold (0.16IU/mL) through Wk16. While anti-pneumococcal-capsular-polysaccharide (PCP) IgG levels were lower during nipocalimab treatment, the percent increase from baseline at Wk2 and Wk16 was comparable between groups. Post-vaccination, anti-PCP IgG remained above 50mg/L and showed a 2-fold increase from baseline throughout the study in both groups. Nipocalimab co-administration with vaccines was safe and well-tolerated. Conclusions: These findings suggest that nipocalimab does not impact the development of an adequate IgG response to T-cell–dependent/independent vaccines and that nipocalimab-treated patients can follow recommended vaccination schedules.

Depression, a leading cause of global disability, arises from a multifaceted combination of genetic and environmental components. This study explores the relationship between major depressive disorder (MDD) polygenic scores (PGS), characteristics and symptoms of depression, and community-shared socioeconomic factors derived from postal code data in a cohort of 12,646 individuals from the Australian Genetics of Depression Study (AGDS). Our findings reveal that people living in areas with relatively higher socioeconomic advantages and education/occupation scores are more likely to report experiencing fewer depressive symptoms during their worst depressive period, as well as fewer number of lifetime episodes. Additionally, participants who reported depression onset later in life tend to currently reside in wealthier areas. Interestingly, no significant interaction between genetic and socioeconomic factors was observed, suggesting their independent contribution to depression outcomes. This research underscores the importance of integrating socioeconomic factors into psychiatric evaluation and care, and points to the critical role of public policy in addressing mental health disparities driven by socioeconomic factors. Future research should aim to further elucidate the causal relationships within these associations and explore the potential for integrated genetic and socioeconomic approaches in mental health interventions.

Multicenter clinical trials are essential for evaluating interventions but often face significant challenges in study design, site coordination, participant recruitment, and regulatory compliance. To address these issues, the National Institutes of Health’s National Center for Advancing Translational Sciences established the Trial Innovation Network (TIN). The TIN offers a scientific consultation process, providing access to clinical trial and disease experts who provide input and recommendations throughout the trial’s duration, at no cost to investigators. This approach aims to improve trial design, accelerate implementation, foster interdisciplinary teamwork, and spur innovations that enhance multicenter trial quality and efficiency. The TIN leverages resources of the Clinical and Translational Science Awards (CTSA) program, complementing local capabilities at the investigator’s institution. The Initial Consultation process focuses on the study’s scientific premise, design, site development, recruitment and retention strategies, funding feasibility, and other support areas. As of 6/1/2024, the TIN has provided 431 Initial Consultations to increase efficiency and accelerate trial implementation by delivering customized support and tailored recommendations. Across a range of clinical trials, the TIN has developed standardized, streamlined, and adaptable processes. We describe these processes, provide operational metrics, and include a set of lessons learned for consideration by other trial support and innovation networks.

Following the recent report of strongyloidiasis caused by Strongyloides fuelleborni within a semi-captive colony of baboons in a UK safari park, we investigated the genetic relationships of this isolate with other Strongyloides isolates across the world. Whole-genome sequencing data were generated with later phylogenetic analysis of mitochondrial (mt) cytochrome oxidase subunit 1 (cox1) and nuclear ribosomal 18S sequences against 300 published Strongyloides reference genotypes. The putative African origin of the UK S. fuelleborni was confirmed and full-length mt genome sequences were assembled to facilitate a more detailed phylogenetic analysis of 14 mt coding regions against all available Strongyloides species. Our analyses demonstrated that the UK isolate represented a novel African lineage not previously described. Additional complete mt genomes were assembled for several individual UK safari park worms to reveal a slightly altered mt genome gene arrangement, allowing clear separation from Asian S. fuelleborni. Furthermore, these UK worms possessed expanded intergenic regions of unknown function that increase their mt genome size to approximately 24 kilobases (kb) as compared with some 16 kb for Asian S. fuelleborni; this may have arisen from unique populational founder and genetic drift effects set within the peculiar mixed species baboon and drill ancestry of this semi-captive primate colony. A maximum likelihood phylogeny constructed from 14 mt coding regions also supported an evolutionary distinction between Asian and African S. fuelleborni.

While adapting to future sea-level rise (SLR) and its hazards and impacts is a multidisciplinary challenge, the interaction of scientists across different research fields, and with practitioners, is limited. To stimulate collaboration and develop a common research agenda, a workshop held in June 2024 gathered 22 scientists and policymakers working in the Netherlands. Participants discussed the interacting uncertainties across three different research fields: sea-level projections, hazards and impacts, and adaptation. Here, we present our view on the most important uncertainties within each field and the feasibility of managing and reducing those uncertainties. We find that enhanced collaboration is urgently needed to prioritize uncertainty reductions, manage expectations and increase the relevance of science to adaptation planning. Furthermore, we argue that in the coming decades, significant uncertainties will remain or newly arise in each research field and that rapidly accelerating SLR will remain a possibility. Therefore, we recommend investigating the extent to which early warning systems can help policymakers as a tool to make timely decisions under remaining uncertainties, in both the Netherlands and other coastal areas. Crucially, this will require viewing SLR, its hazards and impacts, and adaptation as a whole.