Effectiveness of continuous glucose monitoring during diabetic pregnancy (GlucoMOMS trial); a randomised controlled trial

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SK channel-mediated metabolic escape to glycolysis inhibits ferroptosis and supports stress resistance in C. elegans

Metabolic flexibility is an essential characteristic of eukaryotic cells in order to adapt to physiological and environmental changes. Especially in mammalian cells, the metabolic switch from mitochondrial respiration to aerobic glycolysis provides flexibility to sustain cellular energy in pathophysiological conditions. For example, attenuation of mitochondrial respiration and/or metabolic shifts to glycolysis result in a metabolic rewiring that provide beneficial effects in neurodegenerative processes. Ferroptosis, a non-apoptotic form of cell death triggered by an impaired redox balance is gaining attention in the field of neurodegeneration. We showed recently that activation of small-conductance calcium-activated K+ (SK) channels modulated mitochondrial respiration and protected neuronal cells from oxidative death. Here, we investigated whether SK channel activation with CyPPA induces a glycolytic shift thereby increasing resilience of neuronal cells against ferroptosis, induced by erastin in vitro and in the nematode C. elegans exposed to mitochondrial poisons in vivo. High-resolution respirometry and extracellular flux analysis revealed that CyPPA, a positive modulator of SK channels, slightly reduced mitochondrial complex I activity, while increasing glycolysis and lactate production. Concomitantly, CyPPA rescued the neuronal cells from ferroptosis, while scavenging mitochondrial ROS and inhibiting glycolysis reduced its protection. Furthermore, SK channel activation increased survival of C. elegans challenged with mitochondrial toxins. Our findings shed light on metabolic mechanisms promoted through SK channel activation through mitohormesis, which enhances neuronal resilience against ferroptosis in vitro and promotes longevity in vivo

Quality Improvement with Outcome Data in Integrated Obstetric Care Networks: Evaluating Collaboration and Learning Across Organizational Boundaries with an Action Research Approach

Introduction: Patient-reported outcome and experience measures (PROM and PREM) are used to guide individual care and quality improvement (QI). QI with patient-reported data is preferably organized around patients, which is challenging across organisations. We aimed to investigate network-broad learning for QI with outcome data. Methods: In three obstetric care networks using individual-level PROM/PREM, a learning strategy for cyclic QI based on aggregated outcome data was developed, implemented and evaluated. The strategy included clinical, patient-reported, and professional-reported data; together translated into cases for interprofessional discussion. This study’s data generation (including focus groups, surveys, observations) and analysis were guided by a theoretical model for network collaboration. Results: The learning sessions identified opportunities and actions to improve quality and continuity of perinatal care. Professionals valued the data (especially patient-reported) combined with in-dept interprofessional discussion. Main challenges were professionals’ time constraints, data infrastructure, and embedding improvement actions. Network-readiness for QI depended on trustful collaboration through connectivity and consensual leadership. Joint QI required information exchange and support including time and resources. Conclusions: Current fragmented healthcare organization poses barriers for network-broad QI with outcome data, but also offers opportunities for learning strategies. Furthermore, joint learning could improve collaboration to catalyse the journey towards integrated, value-based care

Continuous glucose monitoring metrics and pregnancy outcomes in insulin-treated diabetes : A post-hoc analysis of the GlucoMOMS trial

Funding Information: BWM is supported by a NHMRC investigatorgrant (GNT1176437) and BWM reports consultancy, travel support and research funding from Merck. All other authors declare no conflict of interest. The GlucoMOMS trial was funded by ZonMw, the Dutch Organisation for Health Research and Development, project number 80‐82310‐97‐11157. Continuous Glucose Monitors were purchased at a discount price at Medtronic®, Heerlen, The Netherlands. Neither ZonMw nor Medtronic had a role in study design, data collection, data analysis, data interpretation, or writing of the reports of either the original study or the current post hoc analysis. 10 Publisher Copyright: © 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.Peer reviewedPublisher PD

The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells

Selective elimination of BRCA1-deficient cells by inhibitors of poly(ADP-ribose) polymerase (PARP) is a prime example of the concept of synthetic lethality in cancer therapy. This interaction is counteracted by the restoration of BRCA1-independent homologous recombination through loss of factors such as 53BP1, RIF1, and REV7/MAD2L2, which inhibit end resection of DNA double-strand breaks (DSBs). To identify additional factors involved in this process, we performed CRISPR/SpCas9-based loss-of-function screens and selected for factors that confer PARP inhibitor (PARPi) resistance in BRCA1-deficient cells. Loss of members of the CTC1-STN1-TEN1 (CST) complex were found to cause PARPi resistance in BRCA1-deficient cells in vitro and in vivo. We show that CTC1 depletion results in the restoration of end resection and that the CST complex may act downstream of 53BP1/RIF1. These data suggest that, in addition to its role in protecting telomeres, the CST complex also contributes to protecting DSBs from end resection. Using CRISPR/SpCas9-based loss-of-function screens, Barazas et al. show that loss of the CTC1-STN1-TEN1 (CST) complex promotes PARP inhibitor resistance in BRCA1-deficient cells. Mechanistically, the CST complex maintains double-strand break end stability in addition to its role in protecting telomeric ends

SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands

Objective To investigate maternal, perinatal, and neonatal outcomes of pregnancies in women with type 1 diabetes in the Netherlands. Design Nationwide prospective cohort study. Setting All 118 hospitals in the Netherlands. Participants 323 women with type 1 diabetes who became pregnant between 1 April 1999 and 1 April 2000. Main outcome measures Maternal, perinatal, and neonatal outcomes of pregnancy. Results 84% (n = 271) of the pregnancies were planned. Glycaemic control early in pregnancy was good in most women (HbA(1c) ≤ 7.0% in 75% (n = 212) of the population), and folic acid supplementation was adequate in 70% (n = 226). 314 pregnancies that went beyond 24 weeks' gestation resulted in 324 infants. The rates of pre-eclampsia (40; 12.7%), preterm delivery (101; 32.2%), caesarean section (139; 44.3%), maternal mortality (2; 0.6%), congenital malformations (29; 8.8%), perinatal mortality (9; 2.8%), and macrosomia (146; 45.1%) were considerably higher than in the general population. Neonatal morbidity (one or more complications) was extremely high (260; 80.2%). The incidence of major congenital malformations was significantly lower in planned pregnancies than in unplanned pregnancies (4.2% (n = 11) v 12.2% (n = 6); relative risk 0.34, 95% confidence interval 0.13 to 0.88). Conclusion Despite a high frequency of planned pregnancies, resulting in overall good glycaemic control (early) in pregnancy and a high rate of adequate use of folic acid, maternal and perinatal complications were still increased in women with type 1 diabetes. Neonatal morbidity, especially hypoglycaemia, was also extremely high. Near optimal maternal glycaemic control (HbA(1c) ≤ 7.0%) apparently is not good enough

Human and rat precision-cut intestinal slices as ex vivo models to study bile acid uptake by the apical sodium-dependent bile acid transporter

The apical sodium-dependent bile acid transporter (ASBT) is the primary transporter for the uptake of bile acids in the small intestine. It is localized on the apical membrane of the ileal enterocytes and is known for its high capacity and affinity for taurocholic acid in vitro. However, less is known about its activity towards taurocholic acid and other bile acids in vivo due to the lack of a suitable model. The aim of this study was to validate precision-cut intestinal slices (PCIS) of rat and human intestine as ex vivo model to study the activity of ASBT-mediated transport, and subsequently to study regional and interspecies differences in ASBT function. PCIS maintain the natural cell polarization and communication, expression of transporters and metabolizing enzymes. Therefore this model is expected to be more relevant to the in vivo situation than in vitro cell culture models. PCIS of human and rat ileum were prepared and incubated with 0.04-2.00 mM taurocholic acid, deoxycholic acid and cholic acid, respectively at 4 and 37 degrees C. In this study, the respective contribution of active uptake appeared to be higher for taurocholic acid whereas the passive diffusion was higher for deoxycholic acid and cholic acid. Furthermore, the rank order of calculated (apparent) K-m and V-max for these bile acids is in line with literature reports. The active uptake of taurocholic acid in rat PCIS could be inhibited partly by simvastatin and fluvastatin and was fully inhibited by the specific inhibitor GSK2299027B, supporting the involvement of rat ASBT as uptake transporter. In both species, the ASBT-mediated active uptake of bile acids was observed only in the ileum whereas only passive diffusion was observed in the jejunum and colon. In addition, ASBT activity was higher in the human ileum compared to the rat ileum. In the future rat and human PCIS can be used to study the uptake of new ASBT substrates and as a screening method for potential ASBT inhibitors