BACTERIAL EXTRACELLULAR VESICLES IN THE REGULATION OF INFLAMMATORY RESPONSE AND HOST-MICROBE INTERACTIONS.

ABSTRACT: Extracellular vesicles (EVs) are a new revelation in cross-kingdom communication, with increasing evidence showing the diverse roles of bacterial EVs (BEVs) in mammalian cells and host-microbe interactions. Bacterial EVs include outer membrane vesicles released by gram-negative bacteria and membrane vesicles generated from gram-positive bacteria. Recently, BEVs have drawn attention for their potential as biomarkers and therapeutic tools because they are nano-sized and can deliver bacterial cargo into host cells. Importantly, exposure to BEVs significantly affects various physiological and pathological responses in mammalian cells. Herein, we provide a comprehensive overview of the various effects of BEVs on host cells (i.e., immune cells, endothelial cells, and epithelial cells) and inflammatory/infectious diseases. First, the biogenesis and purification methods of BEVs are summarized. Next, the mechanisms and pathways identified by BEVs that stimulate either proinflammatory or anti-inflammatory responses are highlighted. In addition, we discuss the mechanisms by which BEVs regulate host-microbe interactions and their effects on the immune system. Finally, this review focuses on the contribution of BEVs to the pathogenesis of sepsis/septic shock and their therapeutic potential for the treatment of sepsis.

Raloxifene increases the risk of gastroesophageal reflux disease, Barrett's esophagus, and esophageal stricture in postmenopausal women with osteoporosis.

BACKGROUND AND AIMS: Estrogen-based therapies may increase the risk of gastroesophageal reflux (GERD) and its complications. We aimed to determine the effect of raloxifene on the development of GERD, Barrett's esophagus, and esophageal stricture in postmenopausal women with osteoporosis. METHODS: This was a population-based, propensity-matched cohort study using the TriNetX platform. Patients 50 years and older with a diagnosis of "menopause" and "osteoporosis" were included in this study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for new GERD, esophageal stricture and Barrett's esophagus after raloxifene exposure. The control cohort consisted of patients who did not start any hormonal replacement therapy. We conducted a multivariable logistic regression analysis to evaluate the effect of confounding variables and also addressed common confounding medications with 1:1 propensity score-matching. Internal validity was confirmed by comparing to negative controls (lisinopril, atorvastatin) and positive controls (metformin, ibuprofen, aspirin). RESULTS: Five thousand four hundred and seventy two postmenopausal women with osteoporosis were on raloxifene of which 1908 (34.86%) developed GERD, compared to 296,067 postmenopausal who were not on raloxifene of which 90,643 (30.62%) developed GERD (OR 1.2; 95% CI 1.10-1.31, p < 0.0001). This persisted after adjusting for common medications known to affect GERD. Raloxifene was identified as a risk factor for GERD in a multivariate analysis, controlling for factors including age, obesity, smoking, and alcohol use (OR 1.51, 95% Wald CI 1.47-1.53). Raloxifene was associated with esophageal stricture (OR 1.60; 95% Wald CI 1.51-1.69) and Barrett's esophagus (OR 1.50; 95% Wald CI 1.37-1.63) in multivariate analysis. These associations persisted using sensitivity analyses. CONCLUSION: Raloxifene increases the risk of GERD, esophageal stricture and Barrett's esophagus in postmenopausal women with osteoporosis. Further studies are needed to confirm our findings.

Review article: Functional dyspepsia and pregnancy-Effects and management in a special population.

BACKGROUND: Around 10% of Americans meet the Rome IV criteria for functional dyspepsia (FD), with a significantly higher rate in women. FD also has a higher prevalence in women below the age of 50, suggesting that women who are affected are likely to be of reproductive age. Unfortunately, there is a lack of research or evidence-based guidelines on managing FD in pregnancy. AIMS AND METHODS: To address this issue, we aimed to perform a systematic review of the interactions between FD and pregnancy and managing pre-existing FD in the peripartum and post-partum phases using current lifestyle, pharmacological, non-pharmacological and alternative medicine interventions. RESULTS: Due to the lack of Rome IV FD-specific data in pregnancy, we instead performed a narrative review on how existing FD interventions could be extrapolated to the pregnant population. Where possible we use the highest level of available evidence or official guidelines to answer these questions, which often involves synthesising treatment and safety evidence of these interventions in other diseases during pregnancy. Finally, we highlight current substantial knowledge gaps requiring further research for the safe management of a pregnant patient with pre-existing FD. CONCLUSIONS: Overall, despite the paucity of knowledge of treating FD during pregnancy, providers can mitigate this uncertainty by planning ahead with the patient. Patients should ideally minimise treatment until after breastfeeding. However, interdisciplinary resources are available to ensure that minimal-risk interventions are maximised, while interventions with more risks, if necessary, are justifiable by both the patient and the care team. Future investigations should continue to elicit the mechanistic relationship between FD and pregnancy while cautiously expanding prospective research on promising and safe therapies in pregnant patients with pre-existing FD.

The effect of combined oral contraceptives and Nexplanon on gastroesophageal reflux disease in premenopausal women: A nationwide database analysis.

BACKGROUND: Pregnancy, combined oral contraceptives (COC), and hormone replacement therapy have been reported to increase the risk of gastroesophageal reflux disease (GERD). To date, no study has evaluated the effect of Nexplanon, a commonly used progesterone-based contraceptive, on GERD. We aimed to determine the effect of Nexplanon and COC on GERD. METHODS: We performed a population-based analysis using the IBM Explorys national database (1999-2021). The study group included premenopausal women, defined as women less than 50 years of age while excluding the diagnosis of menopause. The effect of Nexplanon and COC on GERD (at least 30 days after Nexplanon/COC was initiated) was assessed by comparing it to premenopausal women who were not on contraceptives. Foregut surgery, esophageal dysmotility disorders, hiatal hernia, and delayed gastric emptying were excluded. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. A multivariate logistic regression analysis was conducted. KEY RESULTS: A total of 23,299,470 patients were identified as being premenopausal, of which 47,260 were on Nexplanon and 5480 on COCs. As compared to premenopausal women with GERD on no contraceptives (n = 565,880), 690 patients developed GERD at least 30 days after being on Nexplanon (OR = 0.55, 95% CI [0.51-0.59], p < 0.001) and 280 developed GERD after COC (1.93, [1.71-2.18], p < 0.001). A multivariate analysis accounting for Caucasian race, obesity, smoking, alcohol use, and NSAIDs revealed that COC is an independent risk factor for GERD (1.16, [1.12-1.20], p < 0.001), and Nexplanon was protective against GERD (0.90, [0.89-0.92], p < 0.001). Hydralazine was used as a control medication for data reliability. A total of 8420 patients developed GERD after initiating hydralazine, which was not statistically nor clinically significant (OR = 1.02, 95% CI [0.99-1.04], p = 0.08) when compared to those not on contraceptives. CONCLUSIONS & INFERENCES: Combined oral contraceptives is an independent risk factor for GERD, while Nexplanon has a limited protective effect. Further studies are needed to confirm the different effects on GERD of these two contraceptives.

Two Cases of Post-Moderna COVID-19 Vaccine Encephalopathy Associated With Nonconvulsive Status Epilepticus.

Coronavirus disease 2019 (COVID-19) infections can cause many complications, including central nervous system (CNS) complications. One of the most common COVID-19 CNS complications is COVID-19 encephalopathy, a disorder characterized by cognitive impairment, altered consciousness, and even seizures. The Moderna COVID-19 vaccine is a recently approved mRNA-based vaccine aimed at preventing COVID-19 infections and their complications. Here, we describe two patients with no known neurological or psychiatric history who presented with encephalopathy and seizures that began after part one of their Moderna COVID-19 vaccine series. To our knowledge, there are no other reports of post-Moderna COVID-19 vaccine encephalopathy in the literature. We suggest a mechanism for this complication and thoroughly discuss why the Moderna vaccine is possibly responsible, by addressing confounders in our patients.

Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents.

Fetal lung underdevelopment, also known as pulmonary hypoplasia, is characterized by decreased lung growth and maturation. The most common birth defect found in babies with pulmonary hypoplasia is congenital diaphragmatic hernia (CDH). Despite research and clinical advances, babies with CDH still have high morbidity and mortality rates, which are directly related to the severity of lung underdevelopment. To date, there is no effective treatment that promotes fetal lung growth and maturation. Here, we describe a stem cell-based approach in rodents that enhances fetal lung development via the administration of extracellular vesicles (EVs) derived from amniotic fluid stem cells (AFSCs). Using fetal rodent models of pulmonary hypoplasia (primary epithelial cells, organoids, explants, and in vivo), we demonstrated that AFSC-EV administration promoted branching morphogenesis and alveolarization, rescued tissue homeostasis, and stimulated epithelial cell and fibroblast differentiation. We confirmed this regenerative ability in in vitro models of lung injury using human material, where human AFSC-EVs obtained following good manufacturing practices restored pulmonary epithelial homeostasis. Investigating EV mechanism of action, we found that AFSC-EV beneficial effects were exerted via the release of RNA cargo. MicroRNAs regulating the expression of genes involved in lung development, such as the miR17-92 cluster and its paralogs, were highly enriched in AFSC-EVs and were increased in AFSC-EV-treated primary lung epithelial cells compared to untreated cells. Our findings suggest that AFSC-EVs hold regenerative ability for underdeveloped fetal lungs, demonstrating potential for therapeutic application in patients with pulmonary hypoplasia.