Efficacy of Antenatal Corticosteroid Treatment on Neurodevelopmental Outcome according to Head Circumference at Birth

BACKGROUND: There are concerns about the efficacy of antenatal corticosteroid treatment (ACT) in the growth-restricted fetus. OBJECTIVE: To evaluate the effect of ACT on neurodevelopmental outcome at 2 years of corrected age according to the z score of birth head circumference (ZS HC) in a large prospective cohort of preterm infants. METHODS: This study was conducted as a population-based, prospective, multicenter study, including 4,965 infants born between 24 and 33 weeks\u27 gestation and whose status regarding ACT and the measurement of head circumference at birth were available. They were evaluated at 2 years of corrected age to assess neurological outcome. Three approaches were considered to estimate the effect of ACT on neurodevelopment: (i) logistic regression with adjustment on propensity score, (ii) weighted logistic regression using the inverse probability of treatment weighting method, and (iii) 1:1 matching of gestational age, ZS HC, and propensity score between treated and nontreated infants. RESULTS: ACT was documented in 60% of infants. Three groups of infants were considered according to their ZS HC: between -3 and -1 standard deviation (SD), -1 and +1 SD, and +1 and +3 SD, respectively. ACT was associated with a significant improvement of neurodevelopmental outcome only for infants with an ZS HC of between +1 and +3 SD (adjusted OR 1.72; 95% CI 1.06-2.79). Moreover, ORs estimated in the -3 to -1 and +1 to +3 categories were significantly different. CONCLUSION: We found beneficial effects of ACT on neurodevelopmental outcomes at 2 years of corrected age only in preterm infants with a ZS HC >1 SD

Variation at the NFATC2 Locus Increases the Risk of Thiazolidinedione-Induced Edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Study

Objective: Thiazolidinediones are used to treat type 2 diabetes. Their use has been associated with peripheral edema and congestive heart failure - outcomes that may have a genetic etiology. Research Design and Methods: We genotyped 4,197 participants of the multiethnic DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) trial with a 50k single nucleotide polymorphisms (SNP) array, which captures ∼2000 cardiovascular, inflammatory, and metabolic genes. We tested 32,088 SNPs for an association with edema among Europeans who received rosiglitazone (n = 965). Results: One SNP, rs6123045, in NFATC2 was significantly associated with edema (odds ratio 1.89 [95% CI 1.47-2.42]; P = 5.32 × 10-7, corrected P = 0.017). Homozygous individuals had the highest edema rate (hazard ratio 2.89, P = 4.22 × 10-4) when compared with individuals homozygous for the protective allele, with heterozygous individuals having an intermediate risk. The interaction between the SNP and rosiglitazone for edema was significant (P = 7.68 × 10-3). Six SNPs in NFATC2 were significant in both Europeans and Latin Americans (P < 0.05). Conclusions: Genetic variation at the NFATC2 locus contributes to edema among individuals who receive rosiglitazone

Chemical Proteomics-Based Analysis of Off-target Binding Profiles for Rosiglitazone and Pioglitazone: Clues for Assessing Potential for Cardiotoxicity

Drugs exert desired and undesired effects based on their binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target—in this case, PPARγ. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with these drugs. Our results suggest that glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity

Supplementary Material for: Efficacy of Antenatal Corticosteroid Treatment on Neurodevelopmental Outcome according to Head Circumference at Birth

<p><b><i>Background:</i></b> There are concerns about the efficacy of antenatal corticosteroid treatment (ACT) in the growth-restricted fetus. <b><i>Objective:</i></b> To evaluate the effect of ACT on neurodevelopmental outcome at 2 years of corrected age according to the <i>z</i> score of birth head circumference (ZS HC) in a large prospective cohort of preterm infants. <b><i>Methods:</i></b> This study was conducted as a population-based, prospective, multicenter study, including 4,965 infants born between 24 and 33 weeks' gestation and whose status regarding ACT and the measurement of head circumference at birth were available. They were evaluated at 2 years of corrected age to assess neurological outcome. Three approaches were considered to estimate the effect of ACT on neurodevelopment: (i) logistic regression with adjustment on propensity score, (ii) weighted logistic regression using the inverse probability of treatment weighting method, and (iii) 1:1 matching of gestational age, ZS HC, and propensity score between treated and nontreated infants. <b><i>Results:</i></b> ACT was documented in 60% of infants. Three groups of infants were considered according to their ZS HC: between -3 and -1 standard deviation (SD), -1 and +1 SD, and +1 and +3 SD, respectively. ACT was associated with a significant improvement of neurodevelopmental outcome only for infants with an ZS HC of between +1 and +3 SD (adjusted OR 1.72; 95% CI 1.06-2.79). Moreover, ORs estimated in the -3 to -1 and +1 to +3 categories were significantly different. <b><i>Conclusion:</i></b> We found beneficial effects of ACT on neurodevelopmental outcomes at 2 years of corrected age only in preterm infants with a ZS HC >1 SD.</p

Quantum disordered state in the J(1)-J(2) square-lattice antiferromagnet Sr2Cu(Te0.95W0.05)O-6

The B-site ordered double perovskites Sr2Cu(Te1-xWx)O6 provide an excellent arena for investigating exotic phases expected for the J1-J2 square-lattice Heisenberg antiferromagnet. Here, combining magnetic susceptibility and specific-heat measurements with electron spin resonance (ESR) and muon spin rotation/relaxation (μSR) techniques, we explore a spin-liquid-like state in the vicinity of the Néel critical end point (x=0.05-0.1). The specific heat and the ESR and muon relaxation rates give evidence for an energy hierarchy of low-energy excitations, reminiscent of randomness-induced singlet states. In addition, the weak transverse μSR data show a fraction of frozen magnetic moments in the random-singlet background. The origin of a random-singlet-like state near the phase boundary is discussed in terms of concomitant exchange randomness and local strain generated by the W6+-for-Te6+ substitution. © 2021 American Physical Society.1