The CHANGED Score-A New Tool for the Prediction of Insulin Dependency in Gestational Diabetes.

Gestational diabetes (GDM) is a frequent complication during pregnancy. We aimed to develop a score to predict future insulin dependency in gestational diabetes (GDM). Data from 1611 patients from Charité Berlins gestational diabetes clinic from 2015 to 2022 were utilized. A stepwise backwards regression, including patient characteristics obtained at the initial presentation, was performed. Predictors examined included age, fasting blood glucose level, blood glucose levels one and two hours after oral glucose tolerance test, pre-pregnancy BMI, number of previous pregnancies and births, and fetal sex. The ideal cutoff value between high and low risk for insulin dependency was assessed and the score was internally validated. There were 1249 (77.5%) women diagnosed with dietary GDM and 362 (22.5%) were diagnosed with insulin-dependent GDM. The CHarité AssessmeNt of GEstational Diabetes (CHANGED) Score achieved an area under the curve of 0.77 (95% confidence interval 0.75-0.80; 0.75 in internal validation). The optimal cutoff value was calculated at a score value of 9 (72% sensitivity, 69% specificity). We developed an easily applicable tool to accurately predict insulin dependency in gestational diabetes. The CHANGED Score is routinely available and can potentially improve maternal and fetal outcomes.

Fetal de novo heterozygous variant in the isocitrate dehydrogenase 1 gene associated with growth restriction, skeletal, cerebral and vascular anomalies.

Germline pathogenic variants in isocitrate dehydrogenase 1 (IDH1) can lead to a rare neurodevelopmental disorder called metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, including severe skeletal and cerebral anomalies. To the best of our knowledge, no prenatal case of an IDH1 pathogenic variant has been reported in literature. Somatic sequence variants in IDH1/2 genes are described in distinct cancers, premalignant diseases and rare inherited metabolic disorders. Amniocentesis and further genetic testing including trio exome sequencing were performed due to suspicious findings on a second trimester routine prenatal ultrasound examination. The fetus was found to have growth restriction, cerebral abnormalities (ex vacuo hydrocephalus, cerebellar and vermian hypoplasia, corpus callosum dysgenesis), brachycephaly, narrow chest, persistent left superior vena cava, liver calcifications, hyperechogenic bowel, short tubular bones and joint contractures. A de novo heterozygous variant in the IDH1 gene was detected via trio exome sequencing. The prenatal diagnosis of a de novo pathogenic variant in IDH1 in a fetus with the described phenotype, obtained through trio exome sequencing, helped parents and providers with an informed decision making about pregnancy management.

Spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) including renal parenchymal malformations during fetal life and the implementation of prenatal exome sequencing (WES).

OBJECTIVES AND BACKGROUND: Congenital malformations of the kidney and urinary tract (CAKUT) have a prevalence of 4-60 in 10,000 livebirths and constitute for 40-50% of all end stage pediatric kidney disease. CAKUT can have a genetic background due to monogenetic inherited disease, such as PKD or ciliopathies. They can also be found in combination with extra-renal findings as part of a syndrome. Upon detection of genitourinary malformations during the fetal anomaly scan the question arises if further genetic testing is required. The purpose of this study was to determine the phenotypic presentation of CAKUT cases and the results of exome analysis (WES). METHODS: This is a retrospective analysis of 63 fetal cases with a diagnosis of CAKUT or DSD at a single center between August 2018 and December 2022. RESULTS: A total of 63 cases (5.6%) out of 1123 matched CAKUT phenotypes including renal parenchyma malformations. In 15 out of 63 WES analysis a pathogenic variant was detected (23.8%). In fetuses with isolated CAKUT the rate of detecting a pathogenic variant on exome sequencing was five out of 44 (11.4%). Ten out of 19 fetuses (52.6%) that displayed extra-renal findings in combination with CAKUT were diagnosed with a pathogenic variant. CONCLUSIONS: WES provides an increase in diagnosing pathogenic variants in cases of prenatally detected CAKUT. Especially in fetuses with extra-renal malformations, WES facilitates a gain in information on the fetal genotype to enhance prenatal counselling and management.

Advanced maternal age (AMA) and 75 g oGTT glucose levels are pedictors for insulin therapy in women with gestational diabetes (GDM).

OBJECTIVES: Gestational diabetes (GDM) is a common complication during pregnancy that is strongly associated with adverse fetal and maternal outcomes. Advanced maternal age (≥35 years) is a known risk factor for GDM. Studies advocate that GDM comprises distinctive metabolic entities, suggesting an individualized approach based on early pregnancy characteristics (such as 75 g oGTT values, maternal age, obstetric history). METHODS: The oGTT blood glucose levels of 1,664 women were categorized into isolated fasting hyperglycemia (GDM-IFH), isolated postprandial hyperglycemia (GDM-IPH) and combined hyperglycemia (GDM-CH), using the levels of the fasting, 1 h and 2 h values after glucose application. These three subtypes were analysed regarding baseline characteristics as well as fetal and maternal outcome in the context of maternal age. RESULTS: This analysis reveals that the 75 g oGTT levels and maternal age can distinguish metabolic phenotypes in women with GDM. The overall rate of insulin therapy required was higher in women from the GDM-CH group and increased with maternal age (31.7 %, 38.2 %, <35 years, ≥35-39 years respectively, vs. total insulin rate 22.3 %, p-value <0.001). Women ≥35 years displayed a significantly higher caesarean delivery (CD) rate (<35 years 34.6 %, 38.4 %, 41.1 % vs. ≥35 years 54.8 %, 47.6 %, 46.5 %, GDM-IFH, GDM-IPH, GDM-CH respectively, p-value <0.001). CONCLUSIONS: Women with fasting hyperglycemia, especially those with combined hyperglycemia and advanced maternal age (AMA) display a higher risk for unfavorable perinatal outcome. A categorization based on oGTT values and maternal age, as well as other characteristics can facilitate a basis for clinical risk stratification. Women at risk should receive an individualized and intensified perinatal care as well as interventional therapies.

Glucose Levels of the Oral Glucose Tolerance Test (oGTT) Can Predict Adverse Pregnancy Outcomes in Women with Gestational Diabetes (GDM).

OBJECTIVES AND BACKGROUND: Gestational diabetes (GDM) is a common pregnancy complication defined as a glucose intolerance diagnosis during pregnancy. GDM is strongly associated with adverse fetal and maternal outcomes. In Germany, to screen and diagnose GDM we use a 1 h 50 g oGCT (oral glucose challenge test) followed by a 2 h 75 g oGTT if the first was pathological. This analysis examines the correlation of 75 g oGTT glucose levels and fetomaternal outcome. METHODS: Data from 1664 patients from a gestational diabetes consultation clinic at the Charité University Hospital in Berlin, Germany, were analyzed retrospectively from 2015 to 2022. The 75 g oGTT blood glucose levels were categorized into isolated fasting hyperglycemia (GDM-IFH), isolated post-load hyperglycemia (GDM-IPH) and combined hyperglycemia (GDM-CH), using the levels of the fasting, 1 h and 2 h values, after glucose application. These subtypes were compared based on their baseline characteristics as well as fetal and maternal outcome. RESULTS: GDM-IFH and GDM-CH women displayed higher pre-conceptional BMI and required insulin therapy more frequently (p < 0.001). The GDM-IFH group was at higher risk of having a primary cesarean section (p = 0.047), while GDM-IPH women were significantly more likely to have an emergent cesarean section (p = 0.013). The offspring of GDM-IFH and GDM-CH women were born with a significantly higher mean birthweight (p < 0.001) and birth weight percentiles (p < 0.001) and were at increased risk of being large for gestational age (LGA) (p = 0.004). Women from the GDM-IPH group delivered significantly more neonates who were small for gestational age (p = 0.027) or with low fetal weight <30th percentile (p = 0.003). CONCLUSION: This analysis shows a strong association between the glucose response pattern in the 75 g oGTT and adverse perinatal fetomaternal outcome. The differences among the subgroups, specifically concerning insulin therapy, mode of delivery and fetal growth, suggest an individualized approach to prenatal care after a GDM diagnosis.

Perinatal Palliative Care: Additional Costs of an Interprofessional Service and Outcome of Pregnancies in a Cohort of 115 Referrals.

Background: An increasing number of life-limiting conditions (LLCs) is diagnosed prenatally, presenting providers with the ability to present perinatal palliative care (PnPC) services as an option. Objective: To (1) determine the profile characteristics of patients referred for prenatal palliative care counseling to Charité Universitätsmedizin Berlin, Germany; (2) evaluate pregnancy outcome; and (3) analyze the additional human resources per family required to provide specialized PnPC. Methods: Retrospective chart review of pregnant women and infants with potentially LLCs referred for prenatal palliative care counseling between 2016 and 2020. Results: A total of 115 women were referred for prenatal palliative care counseling. Most cases (57.6%) comprised trisomy 13 or 18 (n = 36) and complex congenital conditions (n = 32). Other life-limiting diagnoses included renal agenesis/severe dysplasia (n = 19), congenital heart diseases (n = 18), neurological anomalies (n = 8), and others (n = 5). In 72.0% of cases (n = 85) parents decided to continue pregnancy and plan for palliative birth. Fifty deliveries resulted in a liveborn infant: 33 of these died in the delivery room, 9 neonates died after admission to rooming-in on one of our neonatal wards, and 8 were discharged home or to a hospice. Total human resources (median, range) provided were 563 (0-2940) minutes for psychosocial and 300 (0-720) minutes for medical specialized PnPC per referral. Conclusions: Our data confirm previously observed characteristics of diagnoses, referrals, and outcomes. The provision of specialized and interprofessional PnPC services accounted for ∼14 hours per case of additional human resources.

Assessment of the urinary bladder prior to cesarean delivery in women with multiple abdominal scars through operation table ultrasonography: a case report.

Bladder injury is a rare but serious complication that can occur during cesarean deliveries with an incidence of between 0.25% and 0.9%. Most bladder injuries (53%) occur upon entering the peritoneal cavity as a consequence of either extensive adhesions, a distorted pelvic anatomy, or an unexpectedly high-situated bladder owing to previous operations including a previous cesarean delivery. Patients with a previous abdominal operation can benefit from a preoperative ultrasound to identify the upper limits of an unexpectedly enlarged urinary bladder, even after preoperative catheterization. A modified surgical approach can then be applied to allow entry into the peritoneum above the bladder, thus preventing severe bladder injury. Surgeons may consider the use of preoperative sonography before operating on women with a previous abdominal surgery, especially following midline incisions, to improve safety and to potentially modify abdominal entry into the peritoneal cavity to avoid bladder injury.

Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation.

BACKGROUND: Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. METHODS: We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. RESULTS: We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. CONCLUSION: For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.

3D Cancer Migration Assay with Schwann Cells.

In pancreatic cancer, neural invasion is one of the most common paths of cancer dissemination. Classically, cancer cells actively invade nerves and cause local recurrence and pain. Three-dimensional (3D) neural migration assay has become a standard tool for scientists to study neural invasion by confronting the involved cell types. This protocol introduces Schwann cells, i.e., the most prevalent cell type in peripheral nerves, in a novel heterotypic, glia-cancer-neuron, 3D migration assay for assessing their relevance in the early pathogenesis of neural invasion. Particularly, this assay allows the monitoring of the early Schwann cell migratory activity.

Do sintoma ao sinthoma: uma via para pensar a mãe, a mulher e a criança na clínica atual

Esse trabalho trata das questões da feminilidade e dos caminhos que percorre uma mulher para poder aceder ao feminino, focando na diferenciação entre mãe e mulher. Trata também sobre onde e como se estabelece o lugar que cabe à criança em relação a sua mãe e à mulher que vive nela, para poder subjetivar a sua existência(AU)