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Hypothesis Increased social distancing was associated with a lower incidence of extremely preterm live births (EPLB) during the initial COVID-19 pandemic period. Study design Prospective study at the NICHD Neonatal Research Network sites comparing EPLB (22 0/7 –28 6/7 weeks) and extremely preterm intrapartum stillbirths (EPIS) rates during the pandemic period (March-July, weeks 9–30 of 2020) with the reference period (same weeks in 2018 and 2019), correlating with state-specific social distancing index (SDI). Results EPLB and EPIS percentages did not significantly decrease (1.58–1.45%, p  = 0.07, and 0.08–0.06%, p  = 0.14, respectively). SDI was not significantly correlated with percent change of EPLB (CC = 0.29, 95% CI = −0.12, 0.71) or EPIS (CC = −0.23, 95% CI = −0.65, 0.18). Percent change in mean gestational age was positively correlated with SDI (CC = 0.49, 95% CI = 0.07, 0.91). Conclusions Increased social distancing was not associated with change in incidence of EPLB but was associated with a higher gestational age of extremely preterm births. ClinicalTrials.gov ID Generic Database: NCT00063063.

Background Extremely preterm (EPT) birth has been related to dysregulation of stress responses and behavioral/learning problems at school age. Early adverse experiences can blunt HPA axis reactivity. We hypothesized that an attenuated cortisol awakening response would be associated with developmental and behavioral problems at school age in EPT children. Methods This secondary analysis of a sub-cohort of the SUPPORT study included children born between 24 and 27 weeks, evaluated at 6–7 years with a neurodevelopmental battery and cortisol measures. Differences were tested between EPT and a term-born group. Relationships of cortisol awakening response to test scores were analyzed. Results Cortisol was measured in 110 EPT and 29 term-born 6–7 year olds. Unadjusted WISC-IV and NEPSY-II scores were significantly worse among EPT children only. Conners Parent Rating Scale behavior scores were significantly worse among EPT children. After adjusting for covariates, blunted cortisol awakening responses were found to be associated with poorer scores on memory tests and greater problems with inattention for the EPT group ( p  < 0.05) only. Conclusions Among children born EPT, we identified an association of blunted cortisol awakening response with memory and inattention problems. This may have implications related to stress reactivity and its relationship to learning problems in children born EPT. ClinicalTrials.gov ID Extended Follow-up at School Age for the SUPPORT Neuroimaging and Neurodevelopmental Outcomes (NEURO) Cohort: NCT00233324. Impact In children born EPT, stress reactivity may have a relationship to learning problems. Cortisol awakening response should be a component for follow-up in EPT born children. Components of executive function, such as memory and attention, are related to stress reactivity.

The provision of antenatal corticosteroids to pregnant patients at gestational age (GA) 22 6/7 weeks or less remains controversial and lacks support from randomized clinical trials. To compare rates of survival and survival without major morbidities among infants born at GA 22 0/7 to 23 6/7 weeks after exposure to antenatal steroids at 22 6/7 weeks' gestation or less vs no exposure to antenatal steroids. This cohort study enrolled infants born at GA 22 0/7 to 23 6/7 weeks between January 1, 2016, and December 31, 2019, at centers in the National Institute of Child Health and Human Development Neonatal Research Network. Infants who did not receive intensive care and infants with antenatal steroid exposure after GA 22 6/7 weeks were excluded. Infants were classified as having no, partial, or complete exposure to antenatal steroids. The primary outcome was survival to discharge. The main secondary outcome was survival without major neonatal morbidity. The associations of differential exposures to antenatal steroids with outcomes were evaluated using logistic regression, adjusting for GA, sex, race, maternal education, small for GA status, mode of delivery, multiple birth, prolonged rupture of membranes, year of birth, and Neonatal Research Network center. A total of 431 infants (mean [SD] GA, 22.6 [0.5] weeks; 232 [53.8%] boys) were included, with 110 infants (25.5%) receiving no antenatal steroids, 80 infants (18.6%) receiving partial antenatal steroids, and 241 infants (55.9%) receiving complete antenatal steroids. Seventeen infants were exposed to antenatal steroids at GA 21 weeks. Among infants exposed to complete antenatal steroids, 130 (53.9%) survived to discharge, compared with 30 infants (37.5%) with partial antenatal steroid exposure and 239 infants (35.5%) with no antenatal steroids. Infants born after complete antenatal steroid exposure, compared with those without antenatal steroid exposure, were more likely to survive to discharge (adjusted odds ratio [aOR], 1.95 [95% CI, 1.07-3.56]) and to survive without major morbidity (aOR, 2.74 [95% CI, 1.19-6.30]). In this retrospective cohort study, among infants born between GA 22 0/7 and 23 6/7 weeks who received intensive care, exposure to a complete course of antenatal steroids at GA 22 6/7 weeks or less was independently associated with greater odds of survival and survival without major morbidity. These data suggest that the use of antenatal steroids in patients at GA 22 6/7 weeks or less could be beneficial when active treatment is considered.

Importance Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. Objective To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. Design, Setting, and Participants This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Interventions Near-infrared spectroscopy monitoring of Csat and Msat. Main Outcomes and Measures Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower–hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher–hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs −0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41;P = .03). Conclusions and Relevance In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. Trial Registration ClinicalTrials.gov Identifier:NCT01702805

Abstract Medications are critical for managing acutely ill infants in neonatal intensive care unit (NICU). Tailoring therapies to individual differences in response and dose requirements might help improve outcomes. However, tools for optimizing pharmacotherapy remain limited. In this retrospective study, we explored the potential utility of pharmacogenetics for commonly prescribed NICU medications. All patients admitted to our local NICU March-December, 2022 were eligible for inclusion in the study. In infants who received at least three doses of one or more medications, we extracted DNA from residual EDTA blood collected for routine clinical care according to IRB-approved study protocols. Demographic, pharmacy, and clinical information was recorded retrospectively. Targeted pharmacogenetics testing was performed with a custom TaqMan OpenArray and a QuantStudio 12K Flex (ThermoFisher Scientific) with DNA normalized to 50 ng/mL. Results were analyzed using Genotyper Software version 1.3 and allele calls were made based on the combination of variants detected and consensus nomenclature. For drugs administered to at least 30 NICU patients, pharmacogenes were evaluated for variant allele frequency and potential clinical relevance. Of the 132 patients enrolled, 81 were male. Average length of stay was 47 days. Of the 64 different medications prescribed to at least one infant, for 15 of them are described clinical annotations with specific pharmacogenes by the PharmGKB and/or Clinical Pharmacogenetics Implementation Consortium. Of those 15 medications, three were administered at least three times to at least 30 infants: caffeine (n=102), morphine (n=56), and lorazepam (n=31). The associated pharmacogenes were CYP1A2 (caffeine); CYP3A4, OPRM1, COMT, ABCB1 (morphine); and UGT2B15 (lorazepam). Relevant to the rate of clearance of caffeine, rs2069514 (CYP1A2) was heterozygous in 18% of patients, and homozygous in 5%. Relevant to the rate of clearance of morphine, CYP3A4*22 was heterozygous in 5%. The common variants associated with response to morphine, c.472G>A (COMT) and c.118A>G (OPRM1) were heterozygous in 43% and 26%, and were homozygous in 22% and 8%, respectively. The transporter variant ABCB1*2 was heterozygous in 6% and homozygous in 11%. Relevant to the rate of clearance of lorazepam, UGT2B15*2 (rs1902023) was heterozygous in 45%, and homozygous in 31%. Correlation of pharmacogenetic results to specific clinical phenotypes is currently in progress. Pharmacogenetic variants relevant to commonly prescribed medications in the NICU are prevalent. Further clinical correlation of pharmacogenetic results may help inform selection and dosing of medications for critically ill NICU infants. This research may also facilitate detection and definition of new drug-gene associations unique to this patient population.

Forest soils are difficult to sample quantitatively because of obstruction by rocks and coarse roots. Collecting quantitative soil cores with a motorized diamond-tipped cylindrical bit can provide much faster access to deep soil samples than digging quantitative soil pits. However, the grinding of rock and soil during coring could elevate exchangeable cation concentrations relative to samples collected manually. We compared soils collected by rotary coring to those collected from quantitative pits at four sites in the United States with differing soil types: Alfisols in California (CA), Mollisols in Nevada (NV), Inceptisols in New York (NY), and Spodosols in New Hampshire (NH). Estimates of soil mass were 34% higher from cores than pits at the NY site (p < 0.0001). Estimates of rock mass were lower in cores than pits by 60% at the NH site (p < 0.0001), by 36% at the NY site (p < 0.0001), and by 55% at the CA site (p = 0.002). Exchangeable K was significantly elevated in cores relative to pits at all four sites by 32 to 1700%, and Ca, Mg, and Na showed elevated concentrations at one or more sites. We tested whether the inner portion of the core was comparable to samples from pits, but found that the rotary action of the corer mixed soils throughout the core bit at the two sites we tested. Coring does have the advantage that more samples can be collected for the same effort, compared to pits. Some degree of inaccuracy might be acceptable in a tradeoff for greater precision in the site-level mean, for example in studies aimed at detecting change in soil nutrients over time.

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele ( P =0.0001), which was consistent across the two sample sets ( P =0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model ( P =0.001). This result was consistent across the two datasets ( P =0.017 and 0.019). The dominant model yielded modest evidence for association ( P <0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic–pituitary–adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.