Efficacy of Fecal Microbiota, Live-jslm (REBYOTA®), Among Patients Exposed to Non-Clostridioides difficile Infection Antibiotics: Post Hoc Subgroup Analysis of a Phase 2 Open-Label Study.

Background: Antibiotic use is a major risk factor for recurrent Clostridioides difficile infection (CDI) due to the associated disruption in gut microbiota. Fecal microbiota, live-jslm (REBYOTA®; RBL, previously RBX2660), is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent CDI in adults following standard-of-care antibiotic treatment. To investigate the impact of non-CDI antibiotics on the durability of RBL, a subgroup analysis was conducted on PUNCH™ Open-Label study participants who received non-CDI antibiotics during the period between RBL administration and up to 2 years after. Methods: Participants in PUNCH™ Open-Label who received non-CDI antibiotics after RBL administration were included in this subgroup analysis. Treatment response was defined as the absence of CDI diarrhea needing retreatment at the last evaluable time point (8 weeks, 6 months, 1 year, or 2 years) after RBL administration. Results: Among participants from PUNCH™ Open-Label, 43 received non-CDI antibiotics after RBL administration but before CDI recurrence as evaluated over a 2-year period. Across all evaluable time points, 86% (37/43) of participants had a treatment response regardless of when non-CDI antibiotic exposure occurred. Treatment response was sustained for a median 470 days (IQR, 212-648) from the first day of non-CDI antibiotic use. Most participants (5/6) with CDI recurrences received a high-risk antibiotic. Conclusions: RBL remained efficacious in participants with a history of recurrent CDI after subsequent non-CDI antibiotic exposure. Clinical Trials Registration: NCT02589847 (https://clinicaltrials.gov/study/NCT02589847).

A Closer Look into Gastrointestinal Bleeding in Heart Failure Patients.

BACKGROUND: The frequency and risk factors for gastrointestinal bleed (GIB) in patients with heart failure with reduced ejection fraction (HFrEF) have not been extensively researched. OBJECTIVE: We aim to assess the frequency of GIB in this subset of patients and identify potential risk factors for bleeding. This study will evaluate the frequency of commonly used antiplatelet and anticoagulation agents in the HFrEF population, as well as look at some of the endoscopic features of the GIB. METHODS: A retrospective cohort analysis of 670 patients admitted between November 2021 to August 2023 to a single urban, tertiary teaching institution with acute HFrEF ICD-10 codes. Upper or lower GIB (hematemesis, coffee ground emesis, melena or hematochezia during admission) was identified on a manual chart review. Patients with GIB were defined as our cases. No GIB was defined as our controls. Sub analysis included comparing the use of anticoagulant and antiplatelet between the cohort. Independent t test assessed statistical differences in the case and control groups RESULTS: Out of the 670 patients, 134 (20%) were identified with GIB. The cases were older than the controls (median age 77 vs. 70 years) (p = 0.001), had a lower hemoglobin (9 g/dL vs. 12 g/dL) (p =<0.05), and had higher BNP levels (7,938 pg/ml vs. 6472 pg/ml) (IQR: 3,239, 23,701) (p =<0.01). Among the anticoagulant users, 64% of cases were on an anticoagulant compared to 42% of the controls (p<0.05). Among the antiplatelet users, 68% of the controls were on one or more antiplatelet agents, compared to 52% in the controls (p = 0.01). When combining AC and AP treatment, there was no statistical difference between cases and controls. Ninety-three (69%) patients from cases had cross-sectional imaging with only 23 (25%) showing abnormal findings which included diverticulosis, colitis, and GI masses. When comparing upper endoscopy findings, the presence of esophageal diseases (esophagitis and esophageal varices) and gastric/duodenal diseases (gastritis, gastric ulcer, duodenal ulcer and AVM) were significantly higher in cases compared to controls (p < 0.05). In addition to the colonoscopy findings, polyps and diverticulosis were more prevalent in the cases compared to the controls (p = 0.01). CONCLUSION: Heart failure patients are at risk of developing GIB. Age and high BNP on admission are risk factors for GIB, the higher the BNP levels the higher risk of GIB. Anticoagulant and antiplatelet use are associated with a higher risk of bleeding. However, the addition of dual antiplatelet therapy or concurrent antiplatelet and anticoagulation does not increase the risk of GIB. Some of the most common upper endoscopy findings include esophagitis/gastritis and esophageal/gastric ulcer. In terms of colonoscopy, findings include colonic mass, diverticulosis and hemorrhoids.

Malnutrition as a potential predictor of mortality in chronic kidney disease patients on dialysis: A systematic review and meta-analysis.

BACKGROUND & AIMS: Malnutrition, a significant problem in patients with chronic kidney disease (CKD), is linked to lower health-related quality of life, longer and more frequent hospital admissions, worse functional capacity, and higher levels of morbidity. However, the extent of its impact on mortality is poorly elucidated. This systematic review and meta-analysis aimed to investigate the impact of malnutrition on mortality among CKD patients on dialysis. METHODS: This meta-analysis was designed and performed in accordance with the PRISMA guidelines (CRD42023394584). A systematic electronic literature search was conducted in PubMed, ScienceDirect, and Embase to identify relevant cohort studies. The studies that reported nutritional status and its impact on mortality in patients were considered for analysis. The generic inverse variance method was used to pool the hazard ratio effect estimates by employing a random effects model. The Newcastle-Ottawa scale was used for the quality assessment. The statistical analysis was performed by utilizing RevMan and CMA 2.0. RESULTS: A total of 29 studies that comprised 11,063 patients on dialysis whose nutritional status was evaluated were eligible for quantitative analysis. Based on a comparison between the "malnutrition" category and the reference "normal nutrition status" category, the results showed that the overall pooled hazard risk (HR) for mortality was (HR 1.49, 95% CI: 1.36-1.64, p < 0.0001). According to the subgroup analysis, the hemodialysis subgroup had greater mortality hazards (HR 1.53; 95% CI 1.38-1.70, p < 0.0001), compared to the peritoneal dialysis subgroup (HR 1.26; 95% CI 1.15-1.37, p < 0.00001). Additionally, the overall incidence of mortality was explored but the authors were unable to combine the results due to limitations with the data. CONCLUSION: The findings conclude that malnutrition is a strong predictor of mortality among patients on dialysis, with the hemodialysis subgroup having a higher mortality hazard compared to the peritoneal dialysis subgroup. The results of this study will advocate for early nutritional evaluation and timely dietary interventions to halt the progression of CKD and death.

Recruiting a prospective community cohort to study Alzheimer's disease and structural and social determinants of health among adults racialized as Black: The ARCHES cohort.

INTRODUCTION: This ongoing, prospective study examines the effectiveness of methods used to successfully recruit and retain 238 Black older adults in a longitudinal, observational Alzheimer's disease (AD) study. METHODS: Recruitment strategies included traditional media, established research registries, speaking engagements, community events, and snowball sampling. Participants were asked to complete an annual office testing session, blood-based biomarker collection, optional one-time magnetic resonance imaging (MRI) scan, and community workshop. RESULTS: Within the first 22 months of active recruitment, 629 individuals expressed interest in participating, and 238 enrolled in the ongoing study. Of the recruitment methods used, snowball sampling, community events, and speaking engagements were the most effective. DISCUSSION: The systemic underrepresentation of Black participants in AD research impacts the ability to generalize research findings and determine the effectiveness and safety of disease-modifying treatments. Research to slow, stop, or prevent AD remains a top priority but requires diversity in sample representation. Highlights: Provide flexible appointments in the evening or weekends, offering transportation assistance, and allowing participants to complete study visits at alternative locations, such as senior centers or community centers.Continuously monitor and analyze recruitment data to identify trends, challenges, and opportunities for improvement.Implement targeted strategies to recruit participants who are underrepresented based on sex, gender, or education to increase representation.Diversify the research team to include members who reflect the racial and cultural backgrounds of the target population, to enhance trust and rapport with prospective participants.

The Gut-Brain Axis in Parkinson's Disease.

Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps in knowledge about the underlying mechanisms. In this article, we review the clinical presentation and management of gastrointestinal dysfunction in PD. In addition, we discuss the current understanding of disease pathophysiology in the gut, including controversies about early involvement of the gut in disease pathogenesis. We also review current knowledge about gut α-synuclein and the microbiome, discuss experimental models of PD-linked gastrointestinal pathophysiology, and highlight areas for further research. Finally, we discuss opportunities to use the gut-brain axis for the development of biomarkers and disease-modifying treatments.

Characterizing Multimorbidity Prevalence and Adverse Outcomes in Ethnically and Culturally Diverse Sub-Populations in India: Gaps, Opportunities, and Future Directions.

India is a large middle-income country and has surpassed China in overall population, comprising 20% of the global population (over 1.43 billion people). India is experiencing a major demographic shift in its aging population. Chronic diseases are common among older adults and can be persistent over the life course, lead to the onset of disability, and be costly. Among older adults in India, the existence of multiple comorbid chronic conditions (i.e., multimorbidity) is rapidly growing and represents a burgeoning public health burden. Prior research identified greater rates of multimorbidity (e.g., overweight/obesity diabetes, hypertension, cardiovascular disease, stroke, and malignancies) in minority populations in the United States (U.S.); however, limited studies have attempted to characterize multimorbidity among older adult sub-populations residing in India. To address this gap, we conducted a narrative review of studies on multimorbidity using the data from the Longitudinal Aging Study of India (LASI), the largest nationally representative longitudinal survey study of adults in India. Our definition of multimorbidity was the presence of more than two conditions in the same person. Our findings, based on 15 reviewed studies, aim to (1) characterize the definition and measurement of multimorbidity and to ascertain its prevalence in ethnically and culturally diverse sub-populations in India; (2) identify adverse outcomes associated with multimorbidity in the Indian adult population; and (3) identify gaps, opportunities, and future directions.

Delivering bad or difficult news. An innovative simulation-based education approach to prepare interdisciplinary fellowships.

BACKGROUND: There is limited data on the effectiveness of training interventions to improve the delivery of bad news. METHODS: This preliminary research included pre-post assessments and an open-ended survey to evaluate the effectiveness and perceived value of training on delivering bad news for 26 first- and second-year fellows from five adult and pediatric fellowship programs. RESULTS: There was a significant increase in faculty assessment scores (34.5 vs. 41.0, respectively, Z = -3.661, p < 0.001) and Standardized Patient (SP) assessment scores (37.5 vs .44.5, respectively, Z = -2.244, p = 0.025). Fellows valued having a standard framework to aid in the delivery of bad news; receiving targeted feedback and having the opportunity to apply their skills in a subsequent case. CONCLUSIONS: A one-hour, four-phase lesson plan that includes an individualized training approach and simulation do-overs can be effective and valuable for preparing fellows to deliver bad news.

Fecal Microbiota, Live-jslm for the Prevention of Recurrent Clostridioides difficile Infection : Subgroup Analysis of PUNCH CD2 and PUNCH CD3.

GOALS: To assess fecal microbiota, live-jslm (REBYOTA, abbreviated as RBL, formerly RBX2660) efficacy and safety in participants grouped by recurrent Clostridioides difficile infection (rCDI) risk factors and treatment-related variables. BACKGROUND: RBL is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration for the prevention of rCDI in adults after antibiotic treatment for rCDI. STUDY: Treatment success rates across subgroups for PUNCH CD3 (NCT03244644) were estimated using a Bayesian hierarchical model, borrowing data from PUNCH CD2 (NCT02299570). Treatment-emergent adverse events were summarized for the double-blind treatment period within 8 weeks. RESULTS: Treatment differences between RBL and placebo at 8 weeks were similar to the total population for most subgroups. Treatment effect sizes were similar between CDI tests, higher for oral vancomycin courses >14 days versus ≤14 days and higher for antibiotic washout periods of 3 days versus ≤2 days. The largest reductions in the rate of rCDI with RBL versus placebo were observed for participants with a 3-day CDI antibiotic washout period and participants with ≥4 previous CDI episodes. Most RBL-treated participants experienced TEAEs that were mild or moderate in severity and related to preexisting conditions. CONCLUSION: This analysis provides further evidence of RBL efficacy and safety across subgroups, including those at high risk for rCDI.

Time-Temperature-Transformation (TTT) Diagram of Battery-Grade Li-Garnet Electrolytes for Low-Temperature Sustainable Synthesis.

Efficient and affordable synthesis of Li+ functional ceramics is crucial for the scalable production of solid electrolytes for batteries. Li-garnet Li7 La3 Zr2 O12-d (LLZO), especially its cubic phase (cLLZO), attracts attention due to its high Li+ conductivity and wide electrochemical stability window. However, high sintering temperatures raise concerns about the cathode interface stability, production costs, and energy consumption for scalable manufacture. We show an alternative "sinter-free" route to stabilize cLLZO as films at half of its sinter temperature. Specifically, we establish a time-temperature-transformation (TTT) diagram which captures the amorphous-to-crystalline LLZO transformation based on crystallization enthalpy analysis and confirm stabilization of thin-film cLLZO at record low temperatures of 500 °C. Our findings pave the way for low-temperature processing via TTT diagrams, which can be used for battery cell design targeting reduced carbon footprints in manufacturing.

Gastric development of pancreatic acinar cell metaplasia after Vonoprazan therapy in rats.

BACKGROUND: Vonoprazan is a new acid-suppressing drug that received FDA approval in 2022. It reversibly inhibits gastric acid secretion by competing with the potassium ions on the luminal surface of the parietal cells (potassium-competitive acid blockers or P-CABs). Vonoprazan has been on the market for a short time and there are many clinical trials to support its clinical application. However, medical experience and comprehensive clinical data is still limited, especially on how and if, gastric histology is altered due to therapy. METHODS: A 12-week experiment trial with 30 Wistar rats was to assess the presence of gastrointestinal morphologic abnormalities upon administration of omeprazole and vonoprazan. At six weeks of age, rats were randomly assigned to one of 5 groups: (1) saline as negative control group, (2) oral omeprazole (40 mg/kg), as positive control group, (3) oral omeprazole (40 mg/kg) for 4 weeks, proceeded by 8 weeks off omeprazole, (4) oral vonoprazan (4 mg/kg), as positive control group, and (5) oral vonoprazan (4 mg/kg) for 4 weeks, proceeded by 8 weeks off vonoprazan. RESULTS: We identified non-inflammatory alterations characterized by parietal (oxyntic) cell loss and chief (zymogen) cell hyperplasia and replacement by pancreatic acinar cell metaplasia (PACM). No significant abnormalities were identified in any other tissues in the hepatobiliary and gastrointestinal tracts. CONCLUSION: PACM has been reported in gastric mucosa, at the esophagogastric junction, at the distal esophagus, and in Barrett esophagus. However, the pathogenesis of this entity is still unclear. Whereas some authors have suggested that PACM is an acquired process others have raised the possibility of PACM being congenital in nature. Our results suggest that the duration of vonoprazan administration at a dose of 4 mg/kg plays an important role in the development of PACM.

Acute turbidity exposures with Port of Miami sediments impact Orbicella faveolata tissue regeneration.

We evaluated acute turbidity effects on a threatened coral species (Orbicella faveolata) under three short-term challenge scenarios using a Port of Miami sediment homogenate to simulate turbid conditions during dredging. For these experiments we designed a simple coral challenge test system that kept turbidity stable, without adverse effects to the coral. A 96-h coral challenge experiment demonstrated that low turbidity levels (≥4 NTU) have negative effects on O. faveolata tissue regeneration. A 48-h turbidity exposure (maximum 30 NTU) had no effect on O. faveolata tissue regeneration, showing that short term turbidity exposures may not be detrimental to coral health. In a 13-day test, treated coral fragments (maximum 30 NTU) exhibited significant delays in tissue regeneration, but recovery was observed after approximately one week. The results presented here can be used to inform management decisions for proposed dredging activities proximal to coral reef habitats.

Long-term potassium-competitive acid blockers administration causes microbiota changes in rats.

BACKGROUND: Vonoprazan is a new potassium-competitive acid blocker (P-CAB) that was recently approved by the FDA. It is associated with a fast onset of action and a longer acid inhibition time. Vonoprazan-containing therapy for helicobacter pylori eradication is highly effective and several studies have demonstrated that a vonoprazan-antibiotic regimen affects gut microbiota. However, the impact of vonoprazan alone on gut microbiota is still unclear.Please check and confirm the authors (Maria Cristina Riascos, Hala Al Asadi) given name and family name are correct. Also, kindly confirm the details in the metadata are correct.Yes they are correct.  METHODS: We conducted a prospective randomized 12-week experimental trial with 18 Wistar rats. Rats were randomly assigned to one of 3 groups: (1) drinking water as negative control group, (2) oral vonoprazan (4 mg/kg) for 12 weeks, and (3) oral vonoprazan (4 mg/kg) for 4 weeks, followed by 8 weeks off vonoprazan. To investigate gut microbiota, we carried out a metagenomic shotgun sequencing of fecal samples at week 0 and week 12.Please confirm the inserted city and country name is correct for affiliation 2.Yes it's correct. RESULTS: For alpha diversity metrics at week 12, both long and short vonoprazan groups had lower Pielou's evenness index than the control group (p = 0.019); however, observed operational taxonomic units (p = 0.332) and Shannon's diversity index (p = 0.070) were not statistically different between groups. Beta diversity was significantly different in the three groups, using Bray-Curtis (p = 0.003) and Jaccard distances (p = 0.002). At week 12, differences in relative abundance were observed at all levels. At phylum level, short vonoprazan group had less of Actinobacteria (log fold change = - 1.88, adjusted p-value = 0.048) and Verrucomicrobia (lfc = - 1.76, p = 0.009).Please check and confirm that the author (Ileana Miranda) and their respective affiliation 3 details have been correctly identified and amend if necessary.Yes it's correct. At the genus level, long vonoprazan group had more Bacteroidales (lfc = 5.01, p = 0.021) and Prevotella (lfc = 7.79, p = 0.001). At family level, long vonoprazan group had more Lactobacillaceae (lfc = 0.97, p = 0.001), Prevotellaceae (lfc = 8.01, p < 0.001), and less Erysipelotrichaceae (lfc = - 2.9, p = 0.029). CONCLUSION: This study provides evidence that vonoprazan impacts the gut microbiota and permits a precise delineation of the composition and relative abundance of the bacteria at all different taxonomic levels.

A call to address structural barriers to Hispanic/Latino representation in clinical trials on Alzheimer's disease and related dementias: A micro-meso-macro perspective.

Introduction: This perspective paper addresses the US Hispanic/Latino (herein, Latino) experience with regards to a significant public health concern-the underrepresentation of Latino persons in Alzheimer's disease and related dementias (AD/ADRD) clinical trials. Latino individuals are at increased risk for AD/ADRD, experience higher disease burden, and low receipt of care and services. We present a novel theoretical framework-the Micro-Meso-Macro Framework for Diversifying AD/ADRD Trial Recruitment-which considers multi-level barriers and their impact on Latino trial recruitment. Methods: Based on a review of the peer-reviewed literature and our lived experience with the Latino community, we drew from our interdisciplinary expertise in health equity and disparities research, Latino studies, social work, nursing, political economy, medicine, public health, and clinical AD/ADRD trials. We discuss factors likely to impede or accelerate Latino representation, and end with a call for action and recommendations for a bold path forward. Results: In the 200+ clinical trials conducted with over 70,000 US Americans, Latino participants comprise a fraction of AD/ADRD trial samples. Efforts to recruit Latino participants typically address individual- and family-level factors (micro-level) such as language, cultural beliefs, knowledge of aging and memory loss, limited awareness of research, and logistical considerations. Scientific efforts to understand recruitment barriers largely remain at this level, resulting in diminished attention to upstream institutional- and policy-level barriers, where decisions around scientific policies and funding allocations are ultimately made. These structural barriers are comprised of inadequacies or misalignments in trial budgets, study protocols, workforce competencies, healthcare-related barriers, criteria for reviewing and approving clinical trial funding, criteria for disseminating findings, etiological focus and social determinants of health, among others. Conclusion: Future scientific work should apply and test the Micro-Meso-Macro Framework for Diversifying AD/ADRD Trial Recruitment to examine structural recruitment barriers for historically underrepresented groups in AD/ADRD research and care.

Sensitivity optimization of a rhodopsin-based fluorescent voltage indicator.

The ability to optically image cellular transmembrane voltages at millisecond-timescale resolutions can offer unprecedented insight into the function of living brains in behaving animals. Here, we present a point mutation that increases the sensitivity of Ace2 opsin-based voltage indicators. We use the mutation to develop Voltron2, an improved chemigeneic voltage indicator that has a 65% higher sensitivity to single APs and 3-fold higher sensitivity to subthreshold potentials than Voltron. Voltron2 retained the sub-millisecond kinetics and photostability of its predecessor, although with lower baseline fluorescence. In multiple in vitro and in vivo comparisons with its predecessor across multiple species, we found Voltron2 to be more sensitive to APs and subthreshold fluctuations. Finally, we used Voltron2 to study and evaluate the possible mechanisms of interneuron synchronization in the mouse hippocampus. Overall, we have discovered a generalizable mutation that significantly increases the sensitivity of Ace2 rhodopsin-based sensors, improving their voltage reporting capability.

Weak-anchoring effects in a thin pinned ridge of nematic liquid crystal.

A theoretical investigation of weak-anchoring effects in a thin two-dimensional pinned static ridge of nematic liquid crystal resting on a flat solid substrate in an atmosphere of passive gas is performed. Specifically, we solve a reduced version of the general system of governing equations recently derived by Cousins et al. [Proc. R. Soc. A 478, 20210849 (2022)10.1098/rspa.2021.0849] valid for a symmetric thin ridge under the one-constant approximation of the Frank-Oseen bulk elastic energy with pinned contact lines to determine the shape of the ridge and the behavior of the director within it. Numerical investigations covering a wide range of parameter values indicate that the energetically preferred solutions can be classified in terms of the Jenkins-Barratt-Barbero-Barberi critical thickness into five qualitatively different types of solution. In particular, the theoretical results suggest that anchoring breaking occurs close to the contact lines. The theoretical predictions are supported by the results of physical experiments for a ridge of the nematic 4^{'}-pentyl-4-biphenylcarbonitrile (5CB). In particular, these experiments show that the homeotropic anchoring at the gas-nematic interface is broken close to the contact lines by the stronger rubbed planar anchoring at the nematic-substrate interface. A comparison between the experimental values of and the theoretical predictions for the effective refractive index of the ridge gives a first estimate of the anchoring strength of an interface between air and 5CB to be (9.80±1.12)×10^{-6}Nm^{-1} at a temperature of (22±1.5)^{∘}C.