First-trimester or second-trimester screening, or both, for Down's syndrome

BACKGROUND: It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters.METHODS: Women with singleton pregnancies underwent first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin at 10 weeks 3 days through 13 weeks 6 days of gestation) and second-trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation). We compared the results of stepwise sequential screening (risk results provided after each test), fully integrated screening (single risk result provided), and serum integrated screening (identical to fully integrated screening, but without nuchal translucency).RESULTS: First-trimester screening was performed in 38,167 patients; 117 had a fetus with Down's syndrome. At a 5 percent false positive rate, the rates of detection of Down's syndrome were as follows: with first-trimester combined screening, 87 percent, 85 percent, and 82 percent for measurements performed at 11, 12, and 13 weeks, respectively; with second-trimester quadruple screening, 81 percent; with stepwise sequential screening, 95 percent; with serum integrated screening, 88 percent; and with fully integrated screening with first-trimester measurements performed at 11 weeks, 96 percent. Paired comparisons found significant differences between the tests, except for the comparison between serum integrated screening and combined screening.CONCLUSIONS: First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down's syndrome, with low false positive rates

Prenatal ultrasound staging system for placenta accreta spectrum disorders.

OBJECTIVES: To develop a prenatal ultrasound staging system for placenta accreta spectrum (PAS) disorders in women with placenta previa and to evaluate its association with surgical outcome, placental invasion and the clinical staging system for PAS disorders proposed by the International Federation of Gynecology and Obstetrics (FIGO). METHODS: This was a secondary retrospective analysis of prospectively collected data from women with placenta previa. We classified women according to the following staging system for PAS disorders, based upon the presence of ultrasound signs of PAS in women with placenta previa: PAS0, placenta previa with no ultrasound signs of invasion or with placental lacunae but no evidence of abnormal uterus-bladder interface; PAS1, presence of at least two of placental lacunae, loss of the clear zone or bladder wall interruption; PAS2, PAS1 plus uterovescical hypervascularity; PAS3, PAS1 or PAS2 plus evidence of increased vascularity in the inferior part of the lower uterine segment potentially extending into the parametrial region. We explored whether this ultrasound staging system correlates with surgical outcome (estimated blood loss (EBL, mL), units of packed red blood cells (PRBC), fresh frozen plasma (FFP) and platelets (PLT) transfused, operation time (min), surgical complications defined as the occurrence of any damage to the bladder, ureters or bowel, length of hospital stay (days) and admission to intensive care unit (ICU)) and depth of placental invasion. The correlation between the present ultrasound staging system and the clinical grading system proposed by FIGO was assessed. Prenatal and surgical management were not based on the proposed prenatal ultrasound staging system. Linear and multiple regression models were used. RESULTS: Two-hundred and fifty-nine women were included in the analysis. Mean EBL was 516 ± 151 mL in women with PAS0, 609 ± 146 mL in those with PAS1, 950 ± 190 mL in those with PAS2 and 1323 ± 533 mL in those with PAS3, and increased significantly with increasing severity of PAS ultrasound stage. Mean units of PRBC transfused were 0.05 ± 0.21 in PAS0, 0.10 ± 0.45 in PAS1, 1.19 ± 1.11 in PAS2 and 4.48 ± 2.06 in PAS3, and increased significantly with PAS stage. Similarly, there was a progressive increase in the mean units of FFP transfused from PAS1 to PAS3 (0.0 ± 0.0 in PAS1, 0.25 ± 1.0 in PAS2 and 3.63 ± 2.67 in PAS3). Women presenting with PAS3 on ultrasound had significantly more units of PLT transfused (2.37 ± 2.40) compared with those with PAS0 (0.03 ± 0.18), PAS1 (0.0 ± 0.0) or PAS2 (0.0 ± 0.0). Mean operation time was longer in women with PAS3 (184 ± 32 min) compared with those with PAS1 (153 ± 38 min) or PAS2 (161 ± 28 min). Similarly, women with PAS3 had longer hospital stay (7.4 ± 2.1 days) compared with those with PAS0 (3.4 ± 0.6 days), PAS1 (6.4 ± 1.3 days) or PAS2 (5.9 ± 0.8 days). On linear regression analysis, after adjusting for all potential confounders, higher PAS stage was associated independently with a significant increase in EBL (314 (95% CI, 230-399) mL per one-stage increase; P < 0.001), units of PRBC transfused (1.74 (95% CI, 1.33-2.15) per one-stage increase; P < 0.001), units of FFP transfused (1.19 (95% CI, 0.61-1.77) per one-stage increase; P < 0.001), units of PLT transfused (1.03 (95% CI, 0.59-1.47) per one-stage increase; P < 0.001), operation time (38.8 (95% CI, 31.6-46.1) min per one-stage increase; P < 0.001) and length of hospital stay (0.83 (95% CI, 0.46-1.27) days per one-stage increase; P < 0.001). On logistic regression analysis, increased severity of PAS was associated independently with surgical complications (odds ratio, 3.14 (95% CI, 1.36-7.25); P = 0.007), while only PAS3 was associated with admission to the ICU (P < 0.001). All women with PAS0 on ultrasound were classified as having Grade-1 PAS disorder according to the FIGO grading system. Conversely, of the women presenting with PAS1 on ultrasound, 64.1% (95% CI, 48.4-77.3%) were classified as having Grade-3, while 35.9% (95% CI, 22.7-51.6%) were classified as having Grade-4 PAS disorder, according to the FIGO grading system. All women with PAS2 were categorized as having Grade-5 and all those with PAS3 as having Grade-6 PAS disorder according to the FIGO system. CONCLUSION: Ultrasound staging of PAS disorders is feasible and correlates with surgical outcome, depth of invasion and the FIGO clinical grading system. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd

Integration of first-trimester assessment in the ultrasound staging of placenta accreta spectrum disorders.

OBJECTIVE: To explore the role of early first trimester ultrasound at 5-7 postmenstrual weeks of gestation in predicting sonographic staging of placenta accreta spectrum (PAS) and to elucidate whether integrating first trimester assessment with ultrasound staging of PAS can predict surgical outcome in women at risk for PAS. METHODS: Secondary analysis of prospectively collected data of women who had at least one previous caesarean delivery (CD) or uterine surgery and placenta previa for whom early (5-7 weeks of gestation) ultrasound images could be retrieved. The relationship between gestational sac position and prior CD scar was assessed using classifications by Cali et al. (cross-over COS), Kaelin Agten et al. ("on the scar" vs "in the niche" implantation) and Timor-Tritsch et al. ("above the line" vs "below the line" implantation) by two different examiners blinded to the final diagnosis and clinical outcome. Primary aim of the study was to explore the strength of association and predictive accuracy of first trimester ultrasound in predicting PAS stage. Secondary aim was to elucidate whether integration of first trimester ultrasound with PAS staging can predict surgical outcome. Logistic regression and area under the curve analyses were used to analyse the data. RESULTS: One hundred and eighty-seven women were included. Of these ,79.6% (95% CI 67.1-88.2) had COS1, 94.4% (95% CI 84.9-98.1) "in the niche" and 92.6% (95% CI 82.4-97.1) "below the line" implantation confirmed to be affected by PAS3 in the third trimester of pregnancy. On multivariate logistic regression analysis, COS1 (OR: 7.9 (95% CI 4.0-15.5; p<0.001), "in the niche" (OR: 29.1, 95% CI 8.1-104; p<0.001) and "below the line" (OR: 38.1, 95% CI 12.1-121; p<0.001) implantations, however, neither parity (p= 0.4), nor the number of prior CDs (p= 0.5) were independently associated with PAS3. When translating these figures in a diagnostic model, either COS1 (AUC: 0.94, 95% CI 0.91-0.97), or implantation "in the niche" (AUC: 0.92, 95% CI 0.89-0.96) or "below the line" (AUC: 0.92, 95% CI 0.88-0.96) had a high predictive accuracy for PAS3. Adverse surgical outcome was more common in women with COS1 (p<0.001), implantation "in the niche" (p<0.001) and "below the line" (p<0.001) then those without them.) On multivariate logistic regression analysis, ultrasound diagnosis of PAS3 (OR: 4.3, 95% CI 2.1-17.3), COS1 (OR: 7.9, 95% CI 4.0-15.5; p<0.001), "in the niche" (OR: 29.1, 95% CI 8.1-104; p<0.001) and "below the line" (OR: 7.9, 95% CI 4.0-15.5; p<0.001) implantations were independently associated with adverse surgical outcome. When combining the three imaging methods, we identified, an area we call "high-risk-for-PAS Triangle" which may enable an easy visual perception and application of the three methods to prognosticate the risk for CSP and PAS, although it requires validation in further large prospective studies. CONCLUSION: Early first trimester sonographic assessment of pregnancies after CDs can reliably predict ultrasound staging of possible PAS. Integrating first with second and third trimester ultrasound can stratify surgical risk of women affected by PAS. This article is protected by copyright. All rights reserved

Functional Refinement in the Projection from Ventral Cochlear Nucleus to Lateral Superior Olive Precedes Hearing Onset in Rat

Principal neurons of the lateral superior olive (LSO) compute the interaural intensity differences necessary for localizing high-frequency sounds. To perform this computation, the LSO requires precisely tuned, converging excitatory and inhibitory inputs that are driven by the two ears and that are matched for stimulus frequency. In rodents, the inhibitory inputs, which arise from the medial nucleus of the trapezoid body (MNTB), undergo extensive functional refinement during the first postnatal week. Similar functional refinement of the ascending excitatory pathway, which arises in the anteroventral cochlear nucleus (AVCN), has been assumed but has not been well studied. Using whole-cell voltage clamp in acute brainstem slices of neonatal rats, we examined developmental changes in input strength and pre- and post-synaptic properties of the VCN-LSO pathway. A key question was whether functional refinement in one of the two major input pathways might precede and then guide refinement in the opposite pathway. We find that elimination and strengthening of VCN inputs to the LSO occurs over a similar period to that seen for the ascending inhibitory (MNTB-LSO) pathway. During this period, the fractional contribution provided by NMDA receptors (NMDARs) declines while the contribution from AMPA receptors (AMPARs) increases. In the NMDAR-mediated response, GluN2B-containing NMDARs predominate in the first postnatal week and decline sharply thereafter. Finally, the progressive decrease in paired-pulse depression between birth and hearing onset allows these synapses to follow progressively higher frequencies. Our data are consistent with a model in which the excitatory and inhibitory projections to LSO are functionally refined in parallel during the first postnatal week, and they further suggest that GluN2B-containing NMDARs may mediate early refinement in the VCN-LSO pathway

First-trimester cesarean scar pregnancy: a comparative analysis of treatment options from the international registry

Background: A cesarean scar pregnancy is an iatrogenic consequence of a previous cesarean delivery. The gestational sac implants into a niche created by the incision of the previous cesarean delivery, and this carries a substantial risk for major maternal complications. The aim of this study was to report, analyze, and compare the effectiveness and safety of different treatments options for cesarean scar pregnancies managed in the first trimester through a registry. Objective: This study aimed to evaluated the ultrasound findings, disease behavior, and management of first-trimester cesarean scar pregnancies. Study design: We created an international registry of cesarean scar pregnancy cases to study the ultrasound findings, disease behavior, and management of cesarean scar pregnancies. The Cesarean Scar Pregnancy Registry collects anonymized ultrasound and clinical data of individual patients with a cesarean scar pregnancy on a secure, digital information platform. Cases were uploaded by 31 participating centers across 19 countries. In this study, we only included live and failing cesarean scar pregnancies (with or without a positive fetal heart beat) that received active treatment (medical or surgical) before 12+6 weeks' gestation to evaluate the effectiveness and safety of the different management options. Patients managed expectantly were not included in this study and will be reported separately. Treatment was classified as successful if it led to a complete resolution of the pregnancy without the need for any additional medical interventions. Results: Between August 29, 2018, and February 28, 2023, we recorded 460 patients with cesarean scar pregnancies (281 live, 179 failing cesarean scar pregnancy) who fulfilled the inclusion criteria and were registered. A total of 270 of 460 (58.7%) patients were managed surgically, 123 of 460 (26.7%) patients underwent medical management, 46 of 460 (10%) patients underwent balloon management, and 21 of 460 (4.6%) patients received other, less frequently used treatment options. Suction evacuation was very effective with a success rate of 202 of 221 (91.5%; 95% confidence interval, 87.8-95.2), whereas systemic methotrexate was least effective with only 38 of 64 (59.4%; 95% confidence interval, 48.4-70.4) patients not requiring additional treatment. Overall, surgical treatment of cesarean scar pregnancies was successful in 236 of 258 (91.5%, 95% confidence interval, 88.4-94.5) patients and complications were observed in 24 of 258 patients (9.3%; 95% confidence interval, 6.6-11.9). Conclusion: A cesarean scar pregnancy can be managed effectively in the first trimester of pregnancy in more than 90% of cases with either suction evacuation, balloon treatment, or surgical excision. The effectiveness of all treatment options decreases with advancing gestational age, and cesarean scar pregnancies should be treated as early as possible after confirmation of the diagnosis. Local medical treatment with potassium chloride or methotrexate is less efficient and has higher rates of complications than the other treatment options. Systemic methotrexate has a substantial risk of failing and a higher complication rate and should not be recommended as first-line treatment

Developmental Splicing Deregulation in Leukodystrophies Related to EIF2B Mutations

Leukodystrophies (LD) are rare inherited disorders that primarily affect the white matter (WM) of the central nervous system. The large heterogeneity of LD results from the diversity of the genetically determined defects that interfere with glial cells functions. Astrocytes have been identified as the primary target of LD with cystic myelin breakdown including those related to mutations in the ubiquitous translation initiation factor eIF2B. EIF2B is involved in global protein synthesis and its regulation under normal and stress conditions. Little is known about how eIF2B mutations have a major effect on WM. We performed a transcriptomic analysis using fibroblasts of 10 eIF2B-mutated patients with a severe phenotype and 10 age matched patients with other types of LD in comparison to control fibroblasts. ANOVA was used to identify genes that were statistically significantly differentially expressed at basal state and after ER-stress. The pattern of differentially expressed genes between basal state and ER-stress did not differ significantly among each of the three conditions. However, 70 genes were specifically differentially expressed in eIF2B-mutated fibroblasts whatever the stress conditions tested compared to controls, 96% being under-expressed. Most of these genes were involved in mRNA regulation and mitochondrial metabolism. The 13 most representative genes, including genes belonging to the Heterogeneous Nuclear Ribonucleoprotein (HNRNP) family, described as regulators of splicing events and stability of mRNA, were dysregulated during the development of eIF2B-mutated brains. HNRNPH1, F and C mRNA were over-expressed in foetus but under-expressed in children and adult brains. The abnormal regulation of HNRNP expression in the brain of eIF2B-mutated patients was concomitant with splicing dysregulation of the main genes involved in glial maturation such as PLP1 for oligodendrocytes and GFAP in astrocytes. These findings demonstrate a developmental deregulation of splicing events in glial cells that is related to abnormal production of HNRNP, in eIF2B-mutated brains

ATP signalling in epilepsy

This paper focuses on a role for ATP neurotransmission and gliotransmission in the pathophysiology of epileptic seizures. ATP along with gap junctions propagates the glial calcium wave, which is an extraneuronal signalling pathway in the central nervous system. Recently astrocyte intercellular calcium waves have been shown to underlie seizures, and conventional antiepileptic drugs have been shown to attenuate these calcium waves. Blocking ATP-mediated gliotransmission, therefore, represents a potential target for antiepileptic drugs. Furthermore, while knowledge of an antiepileptic role for adenosine is not new, a recent study showed that adenosine accumulates from the hydrolysis of accumulated ATP released by astrocytes and is believed to inhibit distant synapses by acting on adenosine receptors. Such a mechanism is consistent with a surround-inhibitory mechanism whose failure would predispose to seizures. Other potential roles for ATP signalling in the initiation and spread of epileptiform discharges may involve synaptic plasticity and coordination of synaptic networks. We conclude by making speculations about future developments

First-Trimester or Second-Trimester Screening, or Both, for Down's Syndrome

BACKGROUND It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters. METHODS Women with singleton pregnancies underwent first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin at 10 weeks 3 days through 13 weeks 6 days of gestation) and second-trimester quadruple screening (measurement ofalpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation). We compared the results of stepwise sequential screening (risk results provided after each test), fully integrated screening (single risk result provided), and serum integrated screening (identical to fully integrated screening, but without nuchal translucency). RESULTS First-trimester screening was performed in 38,167 patients; 117 had a fetus with Down's syndrome. At a 5 percent false positive rate, the rates of detection of Down's syndrome were as follows: with first-trimester combined screening, 87 percent, 85 percent, and 82 percent for measurements performed at 11, 12, and 13 weeks, respectively; with second-trimester quadruple screening, 81 percent; with stepwise sequential screening, 95 percent; with serum integrated screening, 88 percent; and with fully integrated screening with first-trimester measurements performed at 11 weeks, 96 percent. Paired comparisons found significant differences between the tests, except for the comparison between serum integrated screening and combined screening. CONCLUSIONS First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection ofDown's syndrome, with low false positive rates

Thyroid hormone action on mitochondria

Measurements of fluorescence at >420 nm and extracted NADPH in mitochondria obtained from the livers of hypothyroid rats show that the addition of Pi, ADP and glutamate rapidly reduces over 90% of the total reducible intrinsic pyridine nucleotides in State 3, compared with 20% in normals. The total fluorescence intensity change and reducible NADP + is about twice normal in hypothyroid mitochondria. Adding 6–30 µM l -thyroxine to hypothyroid mitochondria in vitro decreases and delays the substrate-induced reduction of pyridine nucleotides, and excludes both NADP + from such reduction and NADPH from oxidation by added ADP + Pi, without changing the high NADP(H) content. The correcting actions of the hormone are rapidly reversed by albumin, probably by binding free hormone. Changes in respiration do not appear to account for these observations. There is indirect evidence for decreased phosphorylation of added ADP in hypothyroid mitochondria, and a correction by added hormone. The hormonal actions on NADP(H) redox reactions are not reproduced by 1 to 6 µM dinitrophenol in vitro . l -Thyroxine appears to specifically block the participation of NADP (H) in redox reactions in mitochondria from hypothyroid rats, perhaps by effecting a sequestration of the nucleotide, by inhibiting the pyridine nucleotide transhydrogenase, or by activating an energy-linked process that competes with transhydrogenation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44803/1/10863_2004_Article_BF00761448.pd