Synchronization with mismatched synaptic delays: A unique role of elastic neuronal latency

We show that the unavoidable increase in neuronal response latency to ongoing stimulation serves as a nonuniform gradual stretching of neuronal circuit delay loops and emerges as an essential mechanism in the formation of various types of neuronal timers. Synchronization emerges as a transient phenomenon without predefined precise matched synaptic delays. These findings are described in an experimental procedure where conditioned stimulations were enforced on a circuit of neurons embedded within a large-scale network of cortical cells in-vitro, and are corroborated by neuronal simulations. They evidence a new cortical timescale based on tens of microseconds stretching of neuronal circuit delay loops per spike, and with realistic delays of a few milliseconds, synchronization emerges for a finite fraction of neuronal circuit delays.Comment: 12 pages, 4 figures, 13 pages of Supplementary materia

Risk factors for abnormally invasive placenta: a systematic review and meta-analysis.

Purpose of the article. To explore the strength of association between different maternal and pregnancy characteristics and the occurrence of abnormally invasive placenta (AIP). MATERIALS AND METHODS: Pubmed, Embase, CINAHL databases were searched. The risk factors for AIP explored were: obesity, age > 35 years, smoking before or during pregnancy, placenta previa, prior cesarean section (CS), placenta previa and prior CS, prior uterine surgery, abortion and uterine curettage, in vitro fertilization (IVF) pregnancy and interval between a previous CS and a subsequent pregnancy. Random-effect head-to-head meta-analyses were used to analyze the data. RESULTS: Forty-six were included in the systematic review. Maternal obesity (Odd ratio, OR: 1.4, 95% CI 1.0-1.8), advanced maternal age (OR: 3.1, 95% CI 1.4-7.0) and parity (OR: 2.5, 95% CI 1.7-3.6), but not smoking were associated with a higher risk of AIP. The presence of placenta previa in women with at least a prior CS was associated with a higher risk of AIP compared to controls, with an OR of 12.0, 95% CI 1.6-88.0. Furthermore, the risk of AIP increased with the number of prior CS (OR of 2.6, 95% CI 1.6-4.4 and 5.4, 95% CI 1.7-17.4 for two and three prior CS respectively). Finally, IVF pregnancies were associated with a high risk of AIP, with an OR of 2.8 (95% CI 1.2-6.8). CONCLUSION: A prior CS and placenta previa are among the strongest risk factors for the occurrence of AIP

WAPM-World Association of Perinatal Medicine Practice Guidelines: Fetal central nervous system examination

These practice guidelines follow the mission of the World Association of Perinatal Medicine in collaboration with the Perinatal Medicine Foundation, bringing together groups and individuals throughout the world, with the goal of improving the ultrasound assessment of the fetal Central Nervous System (CNS) anatomy. In fact, this document provides further guidance for healthcare practitioners for the evaluation of the fetal CNS during the mid-trimester ultrasound scan with the aim to increase the ability in evaluating normal fetal anatomy. Therefore, it is not intended to establish a legal standard of care. This document is based on consensus among perinatal experts throughout the world, and serves as a guideline for use in clinical practice

Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model

Thirty-five percent of patients with Rett syndrome carry nonsense mutations in the MECP2 gene. We have recently shown in transfected HeLa cells that readthrough of nonsense mutations in the MECP2 gene can be achieved by treatment with gentamicin and geneticin. This study was performed to test if readthrough can also be achieved in cells endogenously expressing mutant MeCP2 and to evaluate potentially more effective readthrough compounds. A mouse model was generated carrying the R168X mutation in the MECP2 gene. Transfected HeLa cells expressing mutated MeCP2 fusion proteins and mouse ear fibroblasts isolated from the new mouse model were treated with gentamicin and the novel aminoglycosides NB30, NB54, and NB84. The localization of the readthrough product was tested by immunofluorescence. Readthrough of the R168X mutation in mouse ear fibroblasts using gentamicin was detected but at lower level than in HeLa cells. As expected, the readthrough product, full-length Mecp2 protein, was located in the nucleus. NB54 and NB84 induced readthrough more effectively than gentamicin, while NB30 was less effective. Readthrough of nonsense mutations can be achieved not only in transfected HeLa cells but also in fibroblasts of the newly generated Mecp2R168X mouse model. NB54 and NB84 were more effective than gentamicin and are therefore promising candidates for readthrough therapy in Rett syndrome patients

The clinical diagnosis of pelvic inflammatory disease – reuse of electronic medical record data from 189 patients visiting a Swedish university hospital emergency department

BACKGROUND: The pelvic inflammatory disease (PID) diagnosis is mostly based on clinical findings. However, few studies have examined the clinical basis for the diagnostics of PID, which was the aim of this study. METHODS: A retrospective study was performed of 189 out-patients diagnosed as having PID at the obstetric and gynecological emergency department of a Swedish university hospital. Data on symptoms, signs, pelvic examination and laboratory tests were extracted from the electronic medical records in comparison with the diagnostic criteria of the PID Guideline of the US Center of Disease Control from 2002 (CDC 2002 Guidelines). RESULTS: Eight symptoms in varying combinations were associated with the PID diagnosis. Most of them are mentioned in the CDC 2002 Guidelines. Detected rates of C. Trachomatis (CT) and N. Gonorrhoeae (NG) were 5% and 0%, respectively, among the tested patients (CT = 52% and NG = 12%). The C-reactive protein was normal in the majority of tested patients. CONCLUSION: The clinical basis for the diagnostics of PID was largely in accordance with the criteria in the CDC 2002 Guidelines. The limited number of CT tests performed is somewhat disappointing, considering the fact that effective disease prevention includes widespread CT screening. Further studies in different settings are needed in order to analyze how the testing rate for CT can be improved in clinical praxis

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

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

Ex Vivo Treatment with a Novel Synthetic Aminoglycoside NB54 in Primary Fibroblasts from Rett Syndrome Patients Suppresses MECP2 Nonsense Mutations

BACKGROUND: Nonsense mutations in the X-linked methyl CpG-binding protein 2 (MECP2) comprise a significant proportion of causative MECP2 mutations in Rett syndrome (RTT). Naturally occurring aminoglycosides, such as gentamicin, have been shown to enable partial suppression of nonsense mutations related to several human genetic disorders, however, their clinical applicability has been compromised by parallel findings of severe toxic effects. Recently developed synthetic NB aminoglycosides have demonstrated significantly improved effects compared to gentamicin evident in substantially higher suppression and reduced acute toxicity in vitro. RESULTS: We performed comparative study of suppression effects of the novel NB54 and gentamicin on three MECP2 nonsense mutations (R294X, R270X and R168X) common in RTT, using ex vivo treatment of primary fibroblasts from RTT patients harboring these mutations and testing for the C-terminal containing full-length MeCP2. We observed that NB54 induces dose-dependent suppression of MECP2 nonsense mutations more efficiently than gentamicin, which was evident at concentrations as low as 50 µg/ml. NB54 read-through activity was mutation specific, with maximal full-length MeCP2 recovery in R168X (38%), R270X (27%) and R294X (18%). In addition, the recovered MeCP2 was translocated to the cell nucleus and moreover led to parallel increase in one of the most important MeCP2 downstream effectors, the brain derived neurotrophic factor (BDNF). CONCLUSION: Our findings suggest that NB54 may induce restoration of the potentially functional MeCP2 in primary RTT fibroblasts and encourage further studies of NB54 and other rationally designed aminoglycoside derivatives as potential therapeutic agents for nonsense MECP2 mutations in RTT

Incentives for retaining and motivating health workers in Pacific and Asian countries

This paper was initiated by the Australian Agency for International Development (AusAID) after identifying the need for an in-depth synthesis and analysis of available literature and information on incentives for retaining health workers in the Asia-Pacific region. The objectives of this paper are to