Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-ß0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

Nodal Surgery for Patients ≥ 70 Undergoing Mastectomy for DCIS? Choose Wisely.

BACKGROUND: Routine sentinel lymphadenectomy (SLNB) for early-stage HR+/HER2- breast cancer in women ≥70 is discouraged by Choosing Wisely, but whether SLNB can be routinely omitted in women ≥70 with DCIS undergoing mastectomy is unclear. This study aims to evaluate rates of axillary surgery and nodal positivity (pN+) in this population to determine the impact of axillary surgery on treatment decisions. METHODS: Females ≥70 with DCIS undergoing mastectomy were identified from the National Cancer Database (2012-2020). The rate of upstaging to invasive cancer (≥pT1) or pN+ was assessed. Subset analyses were conducted for ER+ patients. Adjuvant therapies were evaluated among ≥pT1 patients after stratifying by nodal status. RESULTS: Of 9,030 patients, 1,896 (21%) upstaged to ≥pT1. Axillary surgery was performed in 86% of patients, predominantly sentinel lymphadenectomy (SLNB, 65%). Post hoc application of Choosing Wisely criteria demonstrated that 93% of the entire cohort and 97% of ER+ DCIS patients could have avoided axillary surgery. Nodal positivity was 0.3% among those who didn't upstage, and 12% among those upstaging to ≥pT1, with <2% having pN2-3 disease, irrespective of receptor subtype. Node-positive patients had higher adjuvant therapy usage, but there was no recommendation for adjuvant chemotherapy or radiation for 71% and 66% of pN+ patients, respectively. CONCLUSIONS: Axillary surgery can be omitted for most patients ≥70 undergoing mastectomy for ER+ DCIS, aligning with recommendations for invasive cancer, and omission can be considered in those with ER- disease. Future guidelines incorporating preoperative imaging, as in the SOUND trial, may aid in identifying patients benefiting from axillary surgery.

Should Palpable Nodes Be Exclusionary in Patients Who Are Otherwise Candidates for ACOSOG Z0011-Type Trials?

BACKGROUND: Palpable nodes were exclusionary in American College of Surgeons Oncology Group (ACOSOG) Z0011, while SINODAR-ONE excluded those with positive axillary nodes by palpation and ultrasound. To determine whether clinical nodal status should be exclusionary in those fulfilling pathologic criteria for ACOSOG Z0011 and similar trials, this study analyzed the accuracy and implications of clinical nodal positivity. METHODS: Patients ≥ 18 years old with cT1-T2, cN0-cN1, M0 breast cancer were identified in the National Cancer Database between 2004 and 2019. Subset characteristics of cN1 and cN0 were compared with respect to final pathologic nodal status and overall survival (OS). RESULTS: Of 57,823 patients identified, 77.0% were cT1 and 23.0% were cT2. Of the 93.9% of patients who were staged as cN0, 16.7% were pN1; of the remaining 6.1% staged as cN1, 9.6% were found to be pN0. Among cN1/pN0 patients, 14.9% underwent axillary dissection without sentinel node biopsy. There was no difference in adjusted OS for patients staged as cN0 versus cN1 who were found to be pN1 (HR 1.13, 95% CI 0.93-1.37, p = 0.22), a finding that persisted on subset analysis in those with two positive nodes (HR 0.91, 95% CI 0.62-1.33, p = 0.63). CONCLUSIONS: Clinical nodal stage does not affect OS in pN1 patients. Clinical nodal assessment can both overstage patients and result in unnecessary axillary surgery. These data suggest that cN1 patients who are otherwise candidates for a Z0011-like paradigm should still be considered eligible. Their final candidacy should be determined by surgical lymph node pathology and not preoperative clinical status.

The Impact of Early Childhood Life Adversity on Peripubertal Accelerated Epigenetic Aging and Psychopathology.

OBJECTIVE: To examine longitudinal associations between early life threat and deprivation on epigenetic age acceleration at ages 9 and 15 years, and to examine associations of age acceleration on later internalizing and externalizing symptoms. METHOD: The study examines a large (n = 2,039) and racially diverse (Black/African American = 44%, Latino = 18%, White = 5%) sample from a national dataset. Epigenetic age acceleration was estimated using the pediatric buccal epigenetic clock. Early life threat and deprivation were measured using composites from the Parent-Child Conflict Tactics Scale and county-level violent and property crime rate data. Internalizing and externalizing symptoms came from parent-reported Child Behavior Checklist. Path analysis models examined associations of threat and deprivation at age 3 years on epigenetic age acceleration at ages 9 and 15. Experiences of threat were further broken down into threat experienced in the home and in the community. RESULTS: Home threat experienced at age 3 years predicted age acceleration at 9 and 15, and community threat experienced at 3 predicted age acceleration at 15, but not at 9. Deprivation was not a significant predictor of accelerated aging. Age acceleration at age 9 predicted externalizing, but not internalizing, symptoms at age 15. Community threat had a direct effect on externalizing. No association emerged with internalizing. CONCLUSION: Findings revealed that threat, not deprivation, was predictive of age acceleration, demonstrating support for this pattern longitudinally, using an epigenetic clock that is accurate in children. The findings provide critical nuance to the examination of threat, and highlight associated risks and possible intervention points for externalizing symptoms.

Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases.

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.

Potential effects of traffic noise on anuran call characteristics in Louisiana, USA during winter.

Urban environments expose wildlife to levels of anthropogenic noise they would not experience in rural areas (e.g., traffic noise), and research suggests that many species adjust their acoustic signals for optimal transmission in urban soundscapes. However, our understanding of anuran (order Anura) responses to noise pollution in urban environments of the southeastern United States is limited, particularly for species that can breed during winter. Our goal was to examine how vocal anuran advertisement call characteristics during winter varied with increasing distance from roadways in bottomland hardwoods of Louisiana, USA. We deployed acoustic recording units at two sites (i.e., rural and urban) perpendicular to Interstate 10 at 200-, 400-, and 600-m intervals (i.e., close, middle, and far) from November 2019 to January 2020. We detected Cajun Chorus Frogs (Pseudacris fouquettei) and Cricket Frogs (Acris spp.) at our rural site, and only detected Cricket Frogs at our urban site. At the rural site, Cajun Chorus Frogs produced longer duration notes at the far location compared to the middle location. At the urban site, Cricket Frogs produced higher dominant frequency calls at the close location compared to the far and middle locations and longer duration notes at the far location compared to the close location. We were unable to account for additional factors in our models (e.g., temperature, noise levels), but our results generally align with previous research. Our study provides baseline data for future research to examine the potential effects of traffic noise on winter advertisement calls in locations with similar environmental conditions and species.

Off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their anti-tumor activity in RAS-driven cancers.

Aberrant activation of RAS-MAPK signaling is common in cancer, and efforts to inhibit pathway components have yielded drugs with promising clinical activities. Unfortunately, treatment-provoked adaptive resistance mechanisms inevitably develop, limiting their therapeutic potential. As a central node essential for receptor tyrosine kinase mediated RAS activation, SHP2 has emerged as an attractive cancer target. Consequently, many SHP2 allosteric inhibitors are now in clinical testing. Here we discovered a previously unrecognized off-target effect associated with SHP2 allosteric inhibitors. We found that these inhibitors accumulate in the lysosome and block autophagic flux in a SHP2-independent manner. We showed that off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their anti-tumor activity. We also demonstrated that SHP2 allosteric inhibitors harboring this off-target activity not only suppress oncogenic RAS signaling but also overcome drug resistance such as MAPK rebound and protective autophagy in response to RAS-MAPK pathway blockage. Finally, we exemplified a therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS driven and drug resistant malignancies such as pancreatic and colorectal cancers. Brief Summary: SHP2 allosteric inhibitors elicit off-target autophagy blockade that can be exploited for improved treatment of RAS-driven and drug-resistant cancers.

Development and initial psychometric properties of the Research Complexity Index.

Objective: Research study complexity refers to variables that contribute to the difficulty of a clinical trial or study. This includes variables such as intervention type, design, sample, and data management. High complexity often requires more resources, advanced planning, and specialized expertise to execute studies effectively. However, there are limited instruments that scale study complexity across research designs. The purpose of this study was to develop and establish initial psychometric properties of an instrument that scales research study complexity. Methods: Technical and grammatical principles were followed to produce clear, concise items using language familiar to researchers. Items underwent face, content, and cognitive validity testing through quantitative surveys and qualitative interviews. Content validity indices were calculated, and iterative scale revision was performed. The instrument underwent pilot testing using 2 exemplar protocols, asking participants (n = 31) to score 25 items (e.g., study arms, data collection procedures). Results: The instrument (Research Complexity Index) demonstrated face, content, and cognitive validity. Item mean and standard deviation ranged from 1.0 to 2.75 (Protocol 1) and 1.31 to 2.86 (Protocol 2). Corrected item-total correlations ranged from .030 to .618. Eight elements appear to be under correlated to other elements. Cronbach's alpha was 0.586 (Protocol 1) and 0.764 (Protocol 2). Inter-rater reliability was fair (kappa = 0.338). Conclusion: Initial pilot testing demonstrates face, content, and cognitive validity, moderate internal consistency reliability and fair inter-rater reliability. Further refinement of the instrument may increase reliability thus providing a comprehensive method to assess study complexity and related resource quantification (e.g., staffing requirements).

The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

Although large-scale genetic association studies have proven opportunistic for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.

"If I have a limited amount of time left, this is not how I want to spend it": A qualitative descriptive study of factors influencing daily life participation following a cancer diagnosis.

OBJECTIVE: Following a cancer diagnosis, restricted participation in daily life is common. Restricted participation can be temporary or long lasting. The aim of this study was to characterize how daily life participation is impacted following a cancer diagnosis. METHODS: Eligible individuals included adults (>18 years) with any stage/grade brain, breast, colorectal, or lung cancer in any phase of treatment or post-treatment. Participants completed a semi-structured interview about how their life participation was impacted following their cancer diagnosis. Data were analyzed through team-based thematic analysis. RESULTS: Forty adults, 10 per disease category, participated. Four themes were identified that supported or hindered daily life participation: (1) self-expectations, (2) expectations of others, (3) awareness of mortality, and (4) symptoms and side effects of cancer. Participants discussed how their cancer experience resulted in a reprioritization of what they valued doing in their life. However, many survivors struggled to adapt and described a tension between their need to adapt to their current life circumstances and their contrasting desire to stay connected with their pre-cancer selves through daily life participation. The mental health challenges associated with decreased participation were also outlined by participants. CONCLUSIONS: Cancer survivors' daily life participation is influenced by expectations from themselves and others, awareness of mortality, and disease symptoms/side effects. Future interventions can target these domains to supports survivors' life participation.

Incidence and Risk Factors for New and Recurrent Infarcts in Adults With Sickle Cell Disease.

BACKGROUND: Most adults with sickle cell disease will experience a silent cerebral infarction (SCI) or overt stroke. Identifying patient subgroups with increased stroke incidence is important for future clinical trials focused on stroke prevention. Our 3-center prospective cohort study tested the primary hypothesis that adults with sickle cell disease and SCIs have a greater incidence of new stroke or SCI compared with those without SCI. A secondary aim focused on identifying additional risk factors for progressive infarcts, particularly traditional risk factors for stroke in adults. METHODS AND RESULTS: This observational study included adults with sickle cell disease and no history of stroke. Magnetic resonance imaging scans of the brain completed at baseline and >1 year later were reviewed by 3 radiologists for baseline SCIs and new or progressive infarcts on follow-up magnetic resonance imaging. Stroke risk factors were abstracted from the medical chart. Time-to-event analysis was utilized for progressive infarcts. Median age was 24.1 years; 45.3% of 95 participants had SCIs on baseline magnetic resonance imaging. Progressive infarcts were present in 17 participants (17.9%), and the median follow-up was 2.1 years. Incidence of new infarcts was 11.95 per 100 patient-years (6.17-20.88) versus 3.74 per 100 patient-years (1.21-8.73) in those with versus without prior SCI. Multivariable Cox regression showed that baseline SCI predicts progressive infarcts (hazard ratio, 3.46 [95% CI, 1.05-11.39]; P=0.041); baseline hypertension was also associated with progressive infarcts (hazard ratio, 3.23 [95% CI, 1.16-9.51]; P=0.025). CONCLUSIONS: Selecting individuals with SCIs and hypertension for stroke prevention trials in sickle cell disease may enrich the study population with those at highest risk for infarct recurrence.

Menopause and Estrogen Associations With Gut Barrier, Microbial Translocation, and Immune Activation Biomarkers in Women With and Without HIV.

OBJECTIVES: Estrogens may protect the gut barrier and reduce microbial translocation and immune activation, which are prevalent in HIV infection. We investigated relationships of the menopausal transition and estrogens with gut barrier, microbial translocation, and immune activation biomarkers in women with and without HIV. DESIGN: Longitudinal and cross-sectional studies nested in the Women's Interagency HIV Study. METHODS: Intestinal fatty acid binding protein, lipopolysaccharide binding protein, and soluble CD14 (sCD14) levels were measured in serum from 77 women (43 with HIV) before, during, and after the menopausal transition (∼6 measures per woman over ∼13 years). A separate cross-sectional analysis was conducted among 72 postmenopausal women with HIV with these biomarkers and serum estrogens. RESULTS: Women in the longitudinal analysis were a median age of 43 years at baseline. In piecewise, linear, mixed-effects models with cutpoints 2 years before and after the final menstrual period to delineate the menopausal transition, sCD14 levels increased over time during the menopausal transition (Beta [95% CI]: 38 [12 to 64] ng/mL/yr, P = 0.004), followed by a decrease posttransition (-46 [-75 to -18], P = 0.001), with the piecewise model providing a better fit than a linear model (P = 0.0006). In stratified analyses, these results were only apparent in women with HIV. In cross-sectional analyses, among women with HIV, free estradiol inversely correlated with sCD14 levels (r = -0.26, P = 0.03). Lipopolysaccharide binding protein and intestinal fatty acid binding protein levels did not appear related to the menopausal transition and estrogen levels. CONCLUSIONS: Women with HIV may experience heightened innate immune activation during menopause, possibly related to the depletion of estrogens.

Vascular calcification in chronic kidney disease associated with pathogenic variants in ABCC6.

Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10-20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD). Despite the high prevalence of vascular calcification in CKD, no single gene cause has been described. We hypothesized that variants in vascular calcification genes may contribute to disease pathogenesis in CKD, particularly in families who exhibit a predominant vascular calcification phenotype. We developed a list of eight genes that are hypothesized to play a role in vascular calcification due to their involvement in the ectopic calcification pathway: ABCC6, ALPL, ANK1, ENPP1, NT5E, SLC29A1, SLC20A2, and S100A12. With this, we assessed exome data from 77 CKD patients, who remained unsolved following evaluation for all known monogenic causes of CKD. We also analyzed an independent cohort (Ontario Neurodegenerative Disease Research Initiative (ONDRI), n = 520) who were screened for variants in ABCC6 and compared this to a control cohort of healthy adults (n = 52). We identified two CKD families with heterozygous pathogenic variants (R1141X and A667fs) in ABCC6. We identified 10 participants from the ONDRI cohort with heterozygous pathogenic or likely pathogenic variant in ABCC6. Replication in a healthy control cohort did not reveal any variants. Our study provides preliminary data supporting the hypothesis that ABCC6 may play a role in vascular calcification in CKD. By screening CKD patients for genetic causes early in the diagnostic pathway, patients with genetic causes associated with vascular calcification can potentially be preventatively treated with new therapeutics with aims to decrease mortality.

McConnell's sign predicts normotensive shock in patients with acute pulmonary embolism.

BACKGROUND: Patients with intermediate-risk pulmonary embolism (PE) and normotensive shock may have worse outcomes. However, diagnosis of normotensive shock requires invasive hemodynamics. Our objective was to assess the predictive value of McConnell's sign in identifying normotensive shock in patients with intermediate-risk PE. METHODS: Patients with intermediate-risk PE who underwent percutaneous mechanical thrombectomy between August 2020 and April 2023 at a large academic public hospital were included in the study. Normotensive shock was defined as systolic blood pressure ≥ 90 mmHg without vasopressor support with pre-procedural invasive measures of cardiac index ≤2.2 L/min/m2 and clinical evidence of hypoperfusion (i.e. elevated lactate, oliguria). The primary outcome was the association between McConnell's sign and normotensive shock. RESULTS: Those with McConnell's sign (29/40, 72.5 %) had higher heart rate (114 vs 99 beats/min, p = 0.008), higher rates of elevated lactate (86 % vs 55 %, p = 0.038), lower cardiac index (1.9 vs 3.1 L/min/m2, p = 0.003), and higher rates of normotensive shock (76 % vs 27 %, p = 0.005). McConnell's sign had a sensitivity of 88 % and specificity of 53 % for identifying intermediate-risk PE patients with normotensive shock. Patients with McConnell's sign had an increased odds (odds ratio 8.38, confidence interval: 1.73-40.53, p = 0.008; area under the curve 0.70, 95 % confidence interval: 0.56-0.85) of normotensive shock. CONCLUSION: This is the first study to suggest that McConnell's sign may identify those in the intermediate-risk group who are at risk for normotensive shock. Larger cohorts are needed to validate our findings.

Bordetella pertussis infection following relaxation of COVID-19 non-pharmaceutical interventions in 2021-2023 in Vancouver metropolitan area, British Columbia, Canada.

BACKGROUND: We recently reported a near disappearance of B. pertussis and a decline in anti-B. pertussis antibodies during the peak implementation of Coronavirus disease 2019 (COVID-19) non-pharmaceutical interventions (NPI) in 2021 in British Columbia (BC), Canada. During 2021-2023, incidence of reported B. pertussis cases remained low in BC at < 1/100,000 population. This study determined how serological evidence of B. pertussis changed after the gradual relaxation of NPI between 2021-2023. METHODS: Randomly selected blood samples from school staff 25-51 years old (n = 65) were collected yearly between 2021-2023 in the Vancouver metropolitan area, BC, Canada, and tested for anti-pertussis toxin (PT) IgG levels. Serological evidence of B. pertussis infection (thereafter "seroconversion") was defined as a quantifiable anti-PT IgG levels in subjects with anti-PT IgG levels below lower limit of quantification in the preceding year or a > 4-fold increase in anti-PT IgG levels between two subsequent years. Samples were also tested for anti-diphtheria toxoid (DT) IgG, and similar seroconversion criteria were applied to exclude seroconversion due to vaccination with tetanus-diphtheria-acellular-pertussis (Tdap). RESULTS: Three subjects met seroconversion criteria for anti-PT IgG between 2021 and 2022 and 9 between 2022 and 2023, yielding a seroconversion rate of 4.6 /100 person-years and 14.9/100 person-years, P = 0.127, respectively. None of the subjects met the criteria for vaccination with Tdap. The geometric mean concentration of anti-PT IgG showed a statistically significant decrease in 2022 compared with 2021, 4.8 IU/mL IU/ml (95 % confidence interval [CI], 3.8-5.9) vs. 6.4 IU/ml (95 % CI, 4.9-8.2; p = 0.001), followed by a statistically significant increase in 2023 compared with 2022 6.5 IU/ml (95 % CI, 4.9-8.5) vs. 4.8 IU/ml (95 % CI, 3.8-5.9; p = 0.0006), respectively. DISCUSSION: Serological evidence of B. pertussis increased between 2022 and 2023 despite low reported cases, which suggests that B. pertussis circulation resumed after relaxing of COVID-19 NPI.

Associations between the social environment and early childhood developmental outcomes of Puerto Rican children with prenatal Zika virus exposure: a cross-sectional study.

BACKGROUND: Prenatal exposure to the Zika virus can lead to microcephaly and adverse developmental outcomes, even in children without evident birth defects. The social environment plays a crucial role in infant health and developmental trajectories, especially during periods of heightened brain plasticity. The study aimed to assess socioenvironmental factors as predictors of developmental outcomes of 36-month-old children exposed to Zika virus prenatally. STUDY DESIGN: This cross-sectional study included 53 mothers and 55 children enrolled in the Pediatric Outcomes of Prenatal Zika Exposure cohort study in Puerto Rico. The study performs follow-up developmental assessments of children born to mothers with confirmed and probable Zika virus infection during pregnancy. Mothers completed socioenvironmental questionnaires (e.g., Perceived Neighborhood Scale and US Household Food Insecurity Survey). Children's developmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development: Third Edition, the Ages and Stages Questionnaires: Third Edition, the Ages and Stages Questionnaire-Socioemotional: Second Edition, and the Child Adjustment and Parent Efficacy Scale. RESULTS: Linear regression models, adjusting for a child's sex and age and maternal education, revealed that early life exposure to food insecurity and maternal pregnancy stressors were significantly associated with poorer developmental outcomes in Zika virus-exposed children at 36 months of age. Maternal resilience representation of adaptive ability was associated with the preservation of adequate developmental outcomes in children. CONCLUSIONS: Pregnancy and early childhood are critical life periods for ensuring optimal brain development in children. While the mechanisms in the interaction of children with their environment are complex, the risk and protective factors identified in the study are modifiable through public policy and preventive initiatives. Implementation of comprehensive strategies that improve access to social support programs, educational and nutritional interventions, and mental health services during pregnancy and early childhood can enhance the developmental potential of vulnerable children.

Comparison of artificial intelligence large language model chatbots in answering frequently asked questions in anaesthesia.

Background: Patients are increasingly using artificial intelligence (AI) chatbots to seek answers to medical queries. Methods: Ten frequently asked questions in anaesthesia were posed to three AI chatbots: ChatGPT4 (OpenAI), Bard (Google), and Bing Chat (Microsoft). Each chatbot's answers were evaluated in a randomised, blinded order by five residency programme directors from 15 medical institutions in the USA. Three medical content quality categories (accuracy, comprehensiveness, safety) and three communication quality categories (understandability, empathy/respect, and ethics) were scored between 1 and 5 (1 representing worst, 5 representing best). Results: ChatGPT4 and Bard outperformed Bing Chat (median [inter-quartile range] scores: 4 [3-4], 4 [3-4], and 3 [2-4], respectively; P<0.001 with all metrics combined). All AI chatbots performed poorly in accuracy (score of ≥4 by 58%, 48%, and 36% of experts for ChatGPT4, Bard, and Bing Chat, respectively), comprehensiveness (score ≥4 by 42%, 30%, and 12% of experts for ChatGPT4, Bard, and Bing Chat, respectively), and safety (score ≥4 by 50%, 40%, and 28% of experts for ChatGPT4, Bard, and Bing Chat, respectively). Notably, answers from ChatGPT4, Bard, and Bing Chat differed statistically in comprehensiveness (ChatGPT4, 3 [2-4] vs Bing Chat, 2 [2-3], P<0.001; and Bard 3 [2-4] vs Bing Chat, 2 [2-3], P=0.002). All large language model chatbots performed well with no statistical difference for understandability (P=0.24), empathy (P=0.032), and ethics (P=0.465). Conclusions: In answering anaesthesia patient frequently asked questions, the chatbots perform well on communication metrics but are suboptimal for medical content metrics. Overall, ChatGPT4 and Bard were comparable to each other, both outperforming Bing Chat.