Maalouf, Elisia

Abstract Interstitial cells of Cajal (ICC) regulate gastrointestinal motility by generating electrical slow waves that orchestrate downstream calcium (Ca 2 + ) waves and coordinate smooth muscle contractions. A reduced ICC number has been reported in diabetic gastroparesis patients and in mouse models of delayed gastric emptying (DGE). However, functional changes in ICC propagating across the gastric regions in intact stomach are not well understood. The aim of this study was to develop an imaging approach to visualize ICC Ca 2+ waves in mouse stomach and determine spatiotemporal changes in mice with DGE. Tamoxifen‐treated B6.GCaMP5‐KitCreERT2 female mice were used as non‐diabetic controls (Non‐Db), while mice treated with streptozocin to induce diabetes were categorized as having normal (Db‐NGE) or delayed (Db‐DGE) gastric emptying based on emptying of solids. The ICC Ca 2+ network was imaged from excised intact mouse stomachs and subsequently opened along the lesser curvature and pinned flat. ICC Ca 2+ waves typically propagated along the greater curvature from the fundus–corpus line toward the antrum. The propagation length of ICC Ca 2+ activity was significantly decreased in Db‐DGE compared to Non‐Db and Db‐NGE and correlated to longer GE times. There was also a decrease in frequency, and the velocity was significantly faster in stomachs from Db‐DGE compared to Non‐Db and Db‐NGE. All experimental groups exhibited similar proportions of aberrant Ca 2+ propagation patterns (e.g., retrograde waves), but ectopic initiation only occurred in Db‐DGE stomachs. Thus, DGE is possibly driven by dysfunction in Ca 2+ activity in the ICC network that propagates rapidly over short distances, resulting in uncoordinated, non‐phasic muscle activity. image Key points Dysfunction of the interstitial cells of Cajal (ICC) has been implicated in diabetic gastroparesis but the changes in spatiotemporal properties of ICC network activity are not known. We developed an ex vivo Ca 2+ imaging approach to visualize ICC network activity across the entire stomach and determined changes in ICC Ca 2+ activity in a diabetic mouse model of delayed gastric emptying (GE). Decreased frequency and increased velocity of ICC Ca 2+ activity was observed in stomachs of diabetic mice with delayed GE. Ectopic initiation was a key feature associated with delayed GE. The propagation length of ICC Ca 2+ activity was inversely correlated to GE times and significantly reduced in stomach preparations from diabetic mice with delayed GE.

Introduction: Atrial fibrillation (AF) is a prevalent cardiovascular disease that significantly impacts public health in the United States. Although numerous clinical trials aim to optimize AF management, concerns about demographic disparities in trial participation persist. This study assesses the representation of age, sex, race, and ethnicity among participants in AF trials conducted in the US, highlighting potential biases that could affect the generalizability of trial outcomes. Methods: An extensive review of clinical trials registered on ClinicalTrials.gov involving patients with AF up to April 2024 was performed. The search was filtered to include all completed interventional trials across phases 2 to 4 without restrictions on the initiation or completion dates. Data were extracted concerning mean age, age distribution, sex, and the racial and ethnic composition of the trial participants. Results: From the 173 trials analyzed, a total of 1,355,239 participants were included, with an average age of 64.7 years. The demographic breakdown revealed a participant pool consisting predominantly of older adults (>65 years: 70.8%), with a significant underrepresentation of the younger age group (18-65 years: 29.2%). Males constituted 65.2% of the trial population, highlighting a gender imbalance. Racially, 74.1% of participants were White, while African Americans (7.7%) and Asians (5.9%) and other racial groups were notably underrepresented. Ethnic disparities were also evident, with Hispanic participants making up only 11.5% of the study population. Conclusion: The findings demonstrate significant disparities in the age, sex, race, and ethnic backgrounds of AF clinical trial participants in the US. These imbalances could potentially limit the applicability of trial results across the broader, diverse population. Efforts to enhance the diversity of clinical trial cohorts are essential to ensure more equitable health outcomes and the universal applicability of clinical research findings. Future strategies should focus on targeted recruitment and inclusive study designs to address these disparities.

AbstractBackgroundAnimal models and human data have suggested macrophage‐driven immune dysregulation in diabetic gastroparesis (DG). Translocator protein (TSPO) upregulation has been suggested to indicate activated state of macrophages and ER176 is a high affinity third generation TSPO‐specific radioligand. The aim of this study was to determine feasibility of dynamic 11C‐ER 176 PET to identify macrophage activation in DG.MethodsTwelve patients, all females, were recruited (4 DG, 4 diabetics, and 4 healthy volunteers) for 11C‐ER 176 PET/CT scanning. The standardized uptake value (SUVmax) in the gastric fundus, body, pylorus, and descending part of the duodenum were compared between three groups using Kruskal‐Wallis test to perform the comparisons, and a p‐value of 0.05 was considered statistically significant.Key ResultsAge was comparable among the three groups with a median of 53 years. The uptake was higher in pylorus in diabetics compared to DG and healthy (SUVmax healthy 4.6 ± 0.2, diabetics 8.4 ± 4.1, DG 5.5 ± 1.0, p = 0.04). The uptake was similar in gastric fundus (9.0 ± 1.6, 13.1 ± 8.3, 7.8 ± 1.9 respectively, p = 0.3), body (7.7 ± 1.9, 13 ± 9.2, 7.8 ± 1.9 respectively, p = 0.8), and duodenum (6.2 ± 2.1, 9.5 ± 6.8, 7.0 ± 1.8 respectively, p = 0.6). No correlation was observed between SUVmax uptake and either HbA1C or fasting blood glucose.Conclusions and InferencesFemale diabetic gastroparesis patients did not demonstrate increased TSPO ligand 11C‐ER 176 uptake in the stomach. Possible explanations include lack of specificity of ligand for specific macrophage phenotypes in DG, sex effect, or small sample size. Further studies investigating non‐invasive ways of analyzing immune dysregulation in neurogastrointestinal disorders are warranted.

LINKED CONTENTThis article is linked to Lembo et al paper. To view this article, visit https://doi.org/10.1111/apt.17274