Attention and regional gray matter development in very preterm children at age 12 years

Objectives: This study examines the selective, sustained, and executive attention abilities of very preterm (VPT) born children in relation to concurrent structural magnetic resonance imaging (MRI) measures of regional gray matter development at age 12 years. Methods: A regional cohort of 110 VPT (≤32 weeks gestation) and 113 full term (FT) born children were assessed at corrected age 12 years on the Test of Everyday Attention-Children. They also had a structural MRI scan that was subsequently analyzed using voxel-based morphometry to quantify regional between-group differences in cerebral gray matter development, which were then related to attention measures using multivariate methods. Results: VPT children obtained similar selective (p=.85), but poorer sustained (p=.02) and executive attention (p=.01) scores than FT children. VPT children were also characterized by reduced gray matter in the bilateral parietal, temporal, prefrontal and posterior cingulate cortices, bilateral thalami, and left hippocampus; and increased gray matter in the occipital and anterior cingulate cortices (family-wise error-corrected

Child protection and out-of-home placement experiences of preschool children born to mothers enrolled in methadone maintenance treatment during pregnancy

Children born to opiate-dependent women engaged in methadone maintenance treatment are at high risk of child welfare concern. However, few studies have examined the early child protection service (CPS) contacts of this group or the risk factors that place some but not other mother-infant dyads at increased risk of serious concern resulting in the removal of the child from the family home. As part of a prospective longitudinal study based in New Zealand, 73 women enrolled in methadone maintenance treatment during pregnancy and 54 non-methadone maintained comparison mothers were recruited during pregnancy and interviewed close to delivery, 18-months and 4.5-years. At each follow-up evaluation, detailed life history methods were used to describe children's family circumstances and all CPS contacts. By 4.5-years postdelivery, methadone maintained mothers were ten-times more likely to have been investigated by child protection services than comparison mothers (59% v. 6%, p<.001). Of these contacts, almost half (44%) resulted in the removal of the child from the family home compared to no comparison children (p<.001). These children were most frequently placed before age 1, with an average of 1-2 caregiver changes (range: 0-7). In addition to maternal methadone maintenance treatment during pregnancy (p<.001), significant independent predictors of child out-of-home placement included maternal depression (p=.01), maternal history of child custody loss (p=.02), and to some extent, high levels of family socioeconomic adversity (p=.06). Findings highlight the complex psychosocial needs of this high-risk group, as well as the need for careful monitoring and parenting support following hospital discharge.</p

MR diffusion changes in the perimeter of the lateral ventricles demonstrate periventricular injury in post-hemorrhagic hydrocephalus of prematurity

OBJECTIVES: Injury to the preterm lateral ventricular perimeter (LVP), which contains the neural stem cells responsible for brain development, may contribute to the neurological sequelae of intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus of prematurity (PHH). This study utilizes diffusion MRI (dMRI) to characterize the microstructural effects of IVH/PHH on the LVP and segmented frontal-occipital horn perimeters (FOHP). STUDY DESIGN: Prospective study of 56 full-term infants, 72 very preterm infants without brain injury (VPT), 17 VPT infants with high-grade IVH without hydrocephalus (HG-IVH), and 13 VPT infants with PHH who underwent dMRI at term equivalent. LVP and FOHP dMRI measures and ventricular size-dMRI correlations were assessed. RESULTS: In the LVP, PHH had consistently lower FA and higher MD and RD than FT and VPT (p\u3c.050). However, while PHH FA was lower, and PHH RD was higher than their respective HG-IVH measures (p\u3c.050), the MD and AD values did not differ. In the FOHP, PHH infants had lower FA and higher RD than FT and VPT (p\u3c.010), and a lower FA than the HG-IVH group (p\u3c.001). While the magnitude of AD in both the LVP and FOHP were consistently less in the PHH group on pairwise comparisons to the other groups, the differences were not significant (p\u3e.050). Ventricular size correlated negatively with FA, and positively with MD and RD (p\u3c.001) in both the LVP and FOHP. In the PHH group, FA was lower in the FOHP than in the LVP, which was contrary to the observed findings in the healthy infants (p\u3c.001). Nevertheless, there were no regional differences in AD, MD, and RD in the PHH group. CONCLUSION: HG-IVH and PHH results in aberrant LVP/FOHP microstructure, with prominent abnormalities among the PHH group, most notably in the FOHP. Larger ventricular size was associated with greater magnitude of abnormality. LVP/FOHP dMRI measures may provide valuable biomarkers for future studies directed at improving the management and neurological outcomes of IVH/PHH

Neonatal motor functional connectivity and motor outcomes at age two years in very preterm children with and without high-grade brain injury

Preterm-born children have high rates of motor impairments, but mechanisms for early identification remain limited. We hypothesized that neonatal motor system functional connectivity (FC) would relate to motor outcomes at age two years; currently, this relationship is not yet well-described in very preterm (VPT; born \u3c32 weeks\u27 gestation) infants with and without brain injury. We recruited 107 VPT infants - including 55 with brain injury (grade III-IV intraventricular hemorrhage, cystic periventricular leukomalacia, post-hemorrhagic hydrocephalus) - and collected FC data at/near term-equivalent age (35-45 weeks postmenstrual age). Correlation coefficients were used to calculate the FC between bilateral motor and visual cortices and thalami. At two years corrected-age, motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development, 3rd edition. Multiple imputation was used to estimate missing data, and regression models related FC measures to motor outcomes. Within the brain-injured group only, interhemispheric motor cortex FC was positively related to gross motor outcomes. Thalamocortical and visual FC were not related to motor scores. This suggests neonatal alterations in motor system FC may provide prognostic information about impairments in children with brain injury

Association of prenatal exposure to early-life adversity with neonatal brain volumes at birth

Importance: Exposure to early-life adversity alters the structural development of key brain regions underlying neurodevelopmental impairments. The association between prenatal exposure to adversity and brain structure at birth remains poorly understood. Objective: To examine whether prenatal exposure to maternal social disadvantage and psychosocial stress is associated with neonatal global and regional brain volumes and cortical folding. Design, Setting, and Participants: This prospective, longitudinal cohort study included 399 mother-infant dyads of sociodemographically diverse mothers recruited in the first or early second trimester of pregnancy and their infants, who underwent brain magnetic resonance imaging in the first weeks of life. Mothers were recruited from local obstetric clinics in St Louis, Missouri from September 1, 2017, to February 28, 2020. Exposures: Maternal social disadvantage and psychosocial stress in pregnancy. Main Outcomes and Measures: Confirmatory factor analyses were used to create latent constructs of maternal social disadvantage (income-to-needs ratio, Area Deprivation Index, Healthy Eating Index, educational level, and insurance status) and psychosocial stress (Perceived Stress Scale, Edinburgh Postnatal Depression Scale, Everyday Discrimination Scale, and Stress and Adversity Inventory). Neonatal cortical and subcortical gray matter, white matter, cerebellum, hippocampus, and amygdala volumes were generated using semiautomated, age-specific, segmentation pipelines. Results: A total of 280 mothers (mean [SD] age, 29.1 [5.3] years; 170 [60.7%] Black or African American, 100 [35.7%] White, and 10 [3.6%] other race or ethnicity) and their healthy, term-born infants (149 [53.2%] male; mean [SD] infant gestational age, 38.6 [1.0] weeks) were included in the analysis. After covariate adjustment and multiple comparisons correction, greater social disadvantage was associated with reduced cortical gray matter (unstandardized β = -2.0; 95% CI, -3.5 to -0.5; P = .01), subcortical gray matter (unstandardized β = -0.4; 95% CI, -0.7 to -0.2; P = .003), and white matter (unstandardized β = -5.5; 95% CI, -7.8 to -3.3; P \u3c .001) volumes and cortical folding (unstandardized β = -0.03; 95% CI, -0.04 to -0.01; P \u3c .001). Psychosocial stress showed no association with brain metrics. Although social disadvantage accounted for an additional 2.3% of the variance of the left hippocampus (unstandardized β = -0.03; 95% CI, -0.05 to -0.01), 2.3% of the right hippocampus (unstandardized β = -0.03; 95% CI, -0.05 to -0.01), 3.1% of the left amygdala (unstandardized β = -0.02; 95% CI, -0.03 to -0.01), and 2.9% of the right amygdala (unstandardized β = -0.02; 95% CI, -0.03 to -0.01), no regional effects were found after accounting for total brain volume. Conclusions and Relevance: In this baseline assessment of an ongoing cohort study, prenatal social disadvantage was associated with global reductions in brain volumes and cortical folding at birth. No regional specificity for the hippocampus or amygdala was detected. Results highlight that associations between poverty and brain development begin in utero and are evident early in life. These findings emphasize that preventive interventions that support fetal brain development should address parental socioeconomic hardships

Prenatal exposure to maternal social disadvantage and psychosocial stress and neonatal white matter connectivity at birth

Early life adversity (social disadvantage and psychosocial stressors) is associated with altered microstructure in fronto-limbic pathways important for socioemotional development. Understanding when these associations begin to emerge may inform the timing and design of preventative interventions. In this longitudinal study, 399 mothers were oversampled for low income and completed social background measures during pregnancy. Measures were analyzed with structural equation analysis resulting in two latent factors: social disadvantage (education, insurance status, income-to-needs ratio [INR], neighborhood deprivation, and nutrition) and psychosocial stress (depression, stress, life events, and racial discrimination). At birth, 289 healthy term-born neonates underwent a diffusion MRI (dMRI) scan. Mean diffusivity (MD) and fractional anisotropy (FA) were measured for the dorsal and inferior cingulum bundle (CB), uncinate, and fornix using probabilistic tractography in FSL. Social disadvantage and psychosocial stress were fitted to dMRI parameters using regression models adjusted for infant postmenstrual age at scan and sex. Social disadvantage, but not psychosocial stress, was independently associated with lower MD in the bilateral inferior CB and left uncinate, right fornix, and lower MD and higher FA in the right dorsal CB. Results persisted after accounting for maternal medical morbidities and prenatal drug exposure. In moderation analysis, psychosocial stress was associated with lower MD in the left inferior CB among the lower-to-higher socioeconomic status (SES) (INR ≥ 200%) group, but not the extremely low SES (INR \u3c 200%) group. Increasing access to social welfare programs that reduce the burden of social disadvantage and related psychosocial stressors may be an important target to protect fetal brain development in fronto-limbic pathways

Trial by Dutch Laboratories for Evaluation of Non-Invasive Prenatal Testing.:Part II - Women's Perspectives

Contains fulltext : 171863.pdf (publisher's version ) (Open Access)OBJECTIVE: To evaluate preferences and decision-making among high-risk pregnant women offered a choice between Non-Invasive Prenatal Testing (NIPT), invasive testing or no further testing. METHODS: Nationwide implementation study (TRIDENT) offering NIPT as contingent screening test for women at increased risk for fetal aneuploidy based on first-trimester combined testing (>1:200) or medical history. A questionnaire was completed after counseling assessing knowledge, attitudes and participation following the Multidimensional Measure of Informed Choice. RESULTS: A total of 1091/1253 (87%) women completed the questionnaire. Of these, 1053 (96.5%) underwent NIPT, 37 (3.4%) invasive testing and 1 (0.1%) declined testing. 91.7% preferred NIPT because of test safety. Overall, 77.9% made an informed choice, 89.8% had sufficient knowledge and 90.5% had positive attitudes towards NIPT. Women with intermediate (odds ratio (OR) = 3.51[1.70-7.22], p < 0.001) or high educational level (OR = 4.36[2.22-8.54], p < 0.001) and women with adequate health literacy (OR = 2.60[1.36-4.95], p = 0.004) were more likely to make an informed choice. Informed choice was associated with less decisional conflict and less anxiety (p < 0.001). Intention to terminate the pregnancy for Down syndrome was higher among women undergoing invasive testing (86.5%) compared to those undergoing NIPT (58.4%) (p < 0.001). CONCLUSIONS: The majority of women had sufficient knowledge and made an informed choice. Continuous attention for counseling is required, especially for low-educated and less health-literate women. (c) 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Enhanced future changes in wet and dry extremes over Africa at convection-permitting scale

African society is particularly vulnerable to climate change. The representation of convection in climate models has so far restricted our ability to accurately simulate African weather extremes, limiting climate change predictions. Here we show results from climate change experiments with a convection-permitting (4.5 km grid-spacing) model, for the first time over an Africa-wide domain (CP4A). The model realistically captures hourly rainfall characteristics, unlike coarser resolution models. CP4A shows greater future increases in extreme 3-hourly precipitation compared to a convection-parameterised 25 km model (R25). CP4A also shows future increases in dry spell length during the wet season over western and central Africa, weaker or not apparent in R25. These differences relate to the more realistic representation of convection in CP4A, and its response to increasing atmospheric moisture and stability. We conclude that, with the more accurate representation of convection, projected changes in both wet and dry extremes over Africa may be more severe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570