The impact of postbariatric hypoglycaemia on driving performance: A randomized, single-blind, two-period, crossover study in a driving simulator.

Postbariatric hypoglycaemia (PBH) is an increasingly recognized complication of bariatric surgery, but its effect on daily functioning remains unclear. In this randomized, single-blind, crossover trial we assessed driving performance in patients with PBH. Ten active drivers with PBH (eight females, age 38.2 ± 14.7 years, body mass index 27.2 ± 4.6 kg/m2 ) received 75 g glucose to induce PBH in the late postprandial period and aspartame to leave glycaemia unchanged, on two different occasions. A simulator was driven during 10 minutes before (D0) and 20 (D1), 80 (D2), 125 (D3) and 140 minutes (D4) after the glucose/aspartame ingestion, reflecting the expected blood glucose (BG) increase (D1), decrease (D2) and hypoglycaemia (D3, D4). Seven driving features indicating impaired driving were integrated in a Bayesian hierarchical regression model to assess the difference in driving performance after glucose/aspartame ingestion. Mean ± standard deviation peak and nadir BG after glucose were 182 ± 24 and 47 ± 14 mg/dL, while BG was stable after aspartame (85 ± 4 mg/dL). Despite the lack of a difference in symptom perception, driving performance was significantly impaired after glucose versus aspartame during D4 (posterior probability 98.2%). Our findings suggest that PBH negatively affects driving performance.

The prenatal maternal representations of mothers at risk of recurrent care proceedings in the Family Drug and Alcohol Court: A thematic analysis.

BACKGROUND: A substantial number of birth mothers experience repeat removals of their infants and children due to child protection concerns. The perspectives of mothers going through repeat removals and their experiences of pregnancy are insufficiently researched. AIMS AND METHODS: The current qualitative study aimed to explore the maternal representations of five pregnant mothers at risk of recurrent care proceedings. A thematic analysis of these mothers' responses to the Pregnancy Interview focused on their representations of themselves as mothers, of their babies, and of the mother-baby relationship. RESULTS: Seven key themes were identified: (1a) "Uncertainty and fear of losing the baby," (1b) "Uncertainty but hope of becoming a mother," (2) "Not wanting to be like their own mother," (3) "Experiencing recovery and pregnancy as two interdependent processes," (4) "Struggling to imagine the baby," (5) "The omnipresence of previous children," (6) "Pleasure at starting to have a connection with the baby," and (7) "Noting the baby's dependency." CONCLUSION: The results are clinically relevant as they highlight grief, maternal self-identity, recovery from substance abuse, and ability to manage uncertainty as critical areas of intervention for these mothers.

Trasfondo: Un número considerable de madres que dan a luz experimentan la repetida separación de sus infantes y niños debido a las preocupaciones de protección infantil. Las perspectivas de las madres que pasan repetidamente por el proceso de separación y las experiencias de su embarazo no están suficientemente investigadas. Metas y Métodos: El presente estudio cualitativo se propuso explorar las representaciones maternas de cinco madres embarazadas bajo riesgo de un proceso recurrente relacionado con el cuidado. Un Análisis Temático de las respuestas de estas madres a la Entrevista del Embarazo (Slade, 2007) se enfocó en las representaciones sobre ellas mismas como madres, de sus bebés, así como de la relación madre-bebé. Resultados: Se identificaron siete temas claves: (1a) 'Incertidumbre y temor de perder el bebé,' (1b) 'Incertidumbre, pero con la esperanza de llegar a ser madre,' (2) 'No querer ser como su propia madre,' (3) 'Experimentar el recobro y el embarazo como dos procesos interdependientes,' (4) 'Dificultad en imaginarse al bebé,' (5) 'La omnipresencia de niños anteriores,' (6) 'Comenzar a tener una conexión con el bebé que trae alegría,' y (7) 'Notar la dependencia del bebé.' Conclusión: Los resultados son clínicamente relevantes ya que ellos subrayan el hecho de que la aflicción de estas madres, la auto-identidad materna, el recobro del abuso de sustancias, así como la habilidad para arreglárselas con la incertidumbre constituyen áreas críticas de intervención. Palabras claves: procedimientos relacionados con el cuidado, madres biológicas, relación madre-bebé, Entrevista de Embarazo, representaciones maternas prenatales.

Contexte: Un nombre important de mères ayant donné naissance font l'expérience du retrait répété de leurs nourrissons et de leurs enfants à cause d'inquiétudes liées à la protection de l'enfant. Les perspectives de ces mères faisant face à des retraits répétés et leurs expériences de leur grossesse n'ont pas fait l'objet d'assez de recherches. Buts et Méthodes: Cette étude qualitative s'est donné pour but d'explorer les représentations maternelles de cinq mères enceintes à risques de procédures de soins récurrents. Une Analyse Thématique des réponses de ces mères durant l'Entretien de Grossesse (Slade, 2007) a porté sur leurs représentations d'elles-mêmes en tant que mères, et de leurs bébés, et de la relation mère-bébé. Résultats: Sept thèmes clés ont été identifiés: (1a) 'L'incertitude et la peur de perdre le bébé', (1b) 'L'incertitude mais l'espoir de devenir mère', (2) 'Ne pas vouloir être comme leur propre mère', (3) 'Faire l'expérience du rétablissement de la toxicomanie et de la grossesse comme deux processus interdépendants', (4) 'Le fait d'avoir des difficultés à imaginer le bébé', (5) 'L'omniprésence des enfants précédents', (6) 'Commencer à avoir une connexion avec le bébé qui apporte une joie', et (7) 'Le fait de notre la dépendance du bébé'. Conclusion: Les résultats sont cliniquement importants dans la mesure où ils mettent en évidence que le deuil de ces mères, leur auto-identité maternelle, leur rétablissement de toxicomanie, et leur capacité à gérer l'incertitude constituent des domaines critiques d'intervention. Mots clés: procédure de prise en charge, mère biologique, relation mère-bébé, Entretien de Grossesse, représentations maternelles avant la naissance.

Unraveling, contributing factors to the severity of postprandial hypoglycemia after gastric bypass surgery.

BACKGROUND: Despite the increasing prevalence of postbariatric hypoglycemia (PBH), a late metabolic complication of bariatric surgery, our understanding of its diverse manifestations remains incomplete. OBJECTIVES: To contrast parameters of glucose-insulin homeostasis in 2 distinct phenotypes of PBH (mild versus moderate hypoglycemia) based on nadir plasma glucose. SETTING: University Hospital (Bern, Switzerland). METHODS: Twenty-five subjects with PBH following gastric bypass surgery (age, 41 ± 12 years; body mass index, 28.1 ± 6.1kg/m2) received 75g of glucose with frequent blood sampling for glucose, insulin, C-peptide, and glucagon-like peptide 1 (GLP)-1. Based on nadir plasma glucose (

Modeling Colorectal Cancer Progression Reveals Niche-Dependent Clonal Selection.

Colorectal cancer (CRC) is among the deadliest cancers worldwide, with metastasis being the main cause of patient mortality. During CRC progression the complex tumor ecosystem changes in its composition at virtually every stage. However, clonal dynamics and associated niche-dependencies at these stages are unknown. Hence, it is of importance to utilize models that faithfully recapitulate human CRC to define its clonal dynamics. We used an optical barcoding approach in mouse-derived organoids (MDOs) that revealed niche-dependent clonal selection. Our findings highlight that clonal selection is controlled by a site-specific niche, which critically contributes to cancer heterogeneity and has implications for therapeutic intervention.

Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs.

Disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk invoked at perivascular sites is still rudimentary. Here, we identify intercellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in the lung. We show that specific secreted factors, induced in metastasis-associated endothelial cells (ECs), promote metastasis in mice by enhancing stem cell properties and the viability of cancer cells. Perivascular macrophages, activated via tenascin C (TNC) stimulation of Toll-like receptor 4 (TLR4), were shown to be crucial in niche activation by secreting nitric oxide (NO) and tumor necrosis factor (TNF) to induce EC-mediated production of niche components. Notably, this mechanism was independent of vascular endothelial growth factor (VEGF), a key regulator of EC behavior and angiogenesis. However, targeting both macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis resulted in added potency to curb lung metastasis in mice. Together, our findings provide mechanistic insights into the formation of vascular niches in metastasis.

MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.

Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs.

Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke phenotypic changes in lung fibroblasts, forming a supportive metastatic niche. Colonization of the lungs confers an inflammatory phenotype in metastasis-associated fibroblasts. Specifically, IL-1α and IL-1ß secreted by breast cancer cells induce CXCL9 and CXCL10 production in lung fibroblasts via NF-κB signaling, fueling the growth of lung metastases. Notably, we find that the chemokine receptor CXCR3, that binds CXCL9/10, is specifically expressed in a small subset of breast cancer cells, which exhibits tumor-initiating ability when co-transplanted with fibroblasts and has high JNK signaling that drives IL-1α/ß expression. Importantly, disruption of the intercellular JNK-IL-1-CXCL9/10-CXCR3 axis reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for the molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis.

Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.

Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c-Jun N-terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer. We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis. We demonstrate that both SPP1 and TNC are direct targets of the c-Jun transcription factor. Exposure to multiple chemotherapies further exploits this JNK-mediated axis to confer treatment resistance. Importantly, JNK inhibition or disruption of SPP1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer.