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Background and objective Epidural blood patch (EBP) is a safe and effective treatment for spontaneous intracranial hypotension (SIH), but clinical and procedural variables that predict EBP efficacy remain nebulous. Methods This study is an institutional review board-approved retrospective case series with dichotomized EBP efficacy defined at 3 months. The study included 202 patients receiving 604 EBPs; iatrogenic cerebrospinal fluid leaks were excluded. Results Of the EBPs, 473 (78%) were single-level, 349 (58%) lumbar, 75 (12%) bilevel, and 56 (9%) multilevel (≥3 levels). Higher volume (OR 1.64; p<0.0001), bilevel (3.17, 1.91–5.27; p<0.0001), and multilevel (117.3, 28.04–490.67; p<0.0001) EBP strategies predicted greater efficacy. Only volume (1.64, 1.47–1.87; p<0.0001) remained significant in multivariate analysis. Site-directed patches were more effective than non-targeted patches (8.35, 0.97–72.1; p=0.033). Lower thoracic plus lumbar was the most successful bilevel strategy, lasting for a median of 74 (3–187) days. Conclusions In this large cohort of EBP in SIH, volume, number of spinal levels injected, and site-directed strategies significantly correlated with greater likelihood of first EBP efficacy. Volume and leak site coverage likely explain the increased efficacy with bilevel and multilevel patches. In patients with cryptogenic leak site, and either moderate disability, negative prognostic brain MRI findings for successful EBP, or failed previous lumbar EBP, a low thoracic plus lumbar bilevel EBP strategy is recommended. Multilevel EBP incorporating transforaminal administration and fibrin glue should be considered in patients refractory to bilevel EBP. An algorithmic approach to treating SIH is proposed.

ABSTRACTObjectiveCervical cerclage, when performed in twin gestation, has been reported to be associated with poor outcome. However, the role of first‐trimester history‐indicated cerclage among women with a twin pregnancy and a history of preterm birth has not been evaluated. The aim of this study was to assess pregnancy outcomes among women with a twin pregnancy who underwent first‐trimester history‐indicated cervical cerclage compared with outcomes in those managed expectantly.MethodsThis was a retrospective matched case–control study. The study group comprised all women with a twin pregnancy who had undergone first‐trimester history‐indicated cerclage during the period 2006 to 2017 at Hadassah‐Hebrew University Medical Center. A control group of women with a twin pregnancy who were managed expectantly was established by matching age, history of spontaneous preterm birth (20–36 weeks' gestation) and year of delivery. Pregnancy and delivery characteristics and neonatal outcomes were compared between the two groups.ResultsData from 82 women with a twin gestation were analyzed, of whom 41 underwent first‐trimester history‐indicated cerclage and 41 were matched controls who were managed expectantly. Gestational age at delivery was higher in the cerclage group than in those managed expectantly (median 35 vs 30 weeks; P < 0.0001). Rates of spontaneous preterm birth before 24 weeks (2.4% vs 19.5%; odds ratio (OR), 0.10 (95% CI, 0.01–0.87); P = 0.03), before 28 weeks (12.2% vs 34.1%; OR, 0.27 (95% CI, 0.09–0.84); P = 0.03), before 32 weeks (22.0% vs 56.1%; OR, 0.22 (95% CI, 0.08–0.58); P = 0.003) and before 34 weeks (34.1% vs 82.9%; OR, 0.11 (95% CI, 0.04–0.30); P < 0.0001) were significantly lower in the cerclage group than in the control group. Median birth weight was higher in the cerclage group (2072 g vs 1750 g; P = 0.003), with lower rates of low birth weight (< 2500 g) (65.0% vs 89.4%; P = 0.001) and very low birth weight (< 1500 g) (21.3% vs 37.9%; P = 0.03) than in the group managed expectantly. Rates were also lower in the cerclage group for stillbirth, admission to the neonatal intensive care unit, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, neonatal mortality and composite adverse neonatal outcome.ConclusionsHistory‐indicated cerclage performed in the first trimester, as compared with expectant management, in women with a twin pregnancy had an overall positive effect on pregnancy and neonatal outcomes. These findings suggest the need for adequate randomized trials on cerclage placement in this subset of women. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).