BACKGROUND:Gastroparesis is a debilitating disorder with limited treatment options, and metoclopramide remains the only FDA-approved pharmacologic therapy. Concerns about metoclopramide-induced tardive dyskinesia (TD) are based on older studies with inconsistent incidence estimates (1%-15%). A reassessment of metoclopramide's TD risk is needed. METHODS:A retrospective cohort study using the MarketScan Research database analyzed TD incidence in adults (2011-2020) with at least 12 months of medical and pharmacy benefits. TD rates were compared among metoclopramide-treated gastroparesis patients, those untreated, and the general population. Poisson regression models adjusted for person-years (p-yrs) at risk. KEY RESULTS:The incidence of TD among metoclopramide-treated gastroparesis patients was 159.4 per 100,000 p-yrs (0.37%), notably lower than guideline estimates (1%-15%). Comparatively, TD incidence was 121.3 (0.26%) in untreated gastroparesis patients, 51.4 (0.12%) among all metoclopramide users, and 7.6 (0.02%) in the general population. Higher TD rates were observed in older adults (≥ 65 years), females, and in patients with prolonged metoclopramide use, diabetes, psychiatric conditions, Parkinson's disease, or concurrent use of dopamine receptor-blocking agents. Adjusted analyses found no significant independent association between metoclopramide use and increased TD risk in gastroparesis patients. CONCLUSIONS & INFERENCES:TD incidence is uncommon with metoclopramide use and lower than previously estimated in gastroparesis patients. These findings suggest metoclopramide may be a viable treatment option and warrant a reassessment of its risk-benefit profile in gastroparesis management.

BACKGROUND AND AIM:Irritable bowel syndrome with constipation (IBS-C) is characterized by multiple sensory symptoms, including abdominal pain, bloating, and bowel habit alterations. Therapeutic response should address all components. This study assesses a new exploratory trisymptom composite efficacy endpoint in an IBS-C population of young adults with bloating treated with plecanatide. METHODS:Pooled data were analyzed from two phase 3, randomized, double-blind trials. Patients (18-40 years) with IBS-C and baseline bloating (score ≥ 1) received plecanatide 3 mg or placebo for 12 weeks. The composite response definition was simultaneous improvement from baseline in three symptoms (abdominal pain, bloating, and complete spontaneous bowel movements [CSBMs]/week) for ≥ 6 of 12 weeks using several thresholds (≥ 2-point or ≥ 30% or ≥ 40% improvement in abdominal pain and bloating plus an increase of ≥ 1 or ≥ 2 CSBMs in the same week). RESULTS:Six hundred and five adults were included (plecanatide [n = 313]; placebo [n = 292]). Plecanatide/placebo baseline mean symptom scores were 6.2/6.4 for abdominal pain and 6.4/6.6 for bloating; both had a mean of 0.2 CSBMs/week. Significantly more patients in plecanatide versus placebo groups (p ≤ 0.01 for all comparisons) were trisymptom composite responders by several stringent thresholds, including ≥ 30% improvement in pain and bloating plus ≥ 1 CSBM/week increase (23.3% vs. 13.4%; p = 0.002) and ≥ 30% improvement in pain and bloating plus ≥ 2 CSBMs/week increase (19.5% vs. 8.9%; p < 0.001). Plecanatide was well tolerated. CONCLUSION:Plecanatide simultaneously and significantly improved combined symptoms of abdominal pain, bloating, and CSBM frequency at varying thresholds. Plecanatide is effective in improving global IBS-C symptoms in individuals with bloating. TRIAL REGISTRATION:ClinicalTrials.gov identifiers-NCT02387359 and NCT02493452.

Increased intestinal permeability has been identified as one of the many pathophysiological factors associated with the development of irritable bowel syndrome (IBS), a common disorder of gut-brain interaction. The layer of epithelial cells that lines the intestine is permeable to a limited degree, and the amount of paracellular permeability is tightly controlled to enable the absorption of ions, nutrients, and water from the lumen. Increased intestinal permeability to macromolecules can be triggered by a variety of insults, including infections, toxins from food poisoning, or allergens, which in turn cause an inflammatory response and are associated with abdominal pain in patients with IBS. This review article discusses increased intestinal permeability in IBS, focusing on IBS with constipation (IBS-C) through the lens of a patient case with a reported prior diagnosis of "leaky gut syndrome" upon initial contact with a gastrointestinal specialist. We review advantages and disadvantages of several methods of measuring intestinal permeability in patients and discuss when measuring intestinal permeability is appropriate in the therapeutic journey of patients with IBS-C. Furthermore, we discuss a possible mechanism of restoring the intestinal barrier to its healthy state through altering intracellular pH by inhibiting sodium-hydrogen exchanger isoform 3 (NHE3). Tenapanor is a minimally absorbed, small-molecule inhibitor of NHE3 that has been approved by the US Food and Drug Administration for the treatment of IBS-C in adults. Preclinical studies showed that tenapanor may restore the intestinal barrier in IBS-C by affecting the conformation of tight junction proteins via NHE3 inhibition to block the paracellular transport of macromolecules from the intestinal lumen. Testing for increased permeability in patients with IBS-C who experience abdominal pain may help inform the choice of therapeutics and alter patients' misconceptions about "leaky gut syndrome".

INTRODUCTION Cardiac amyloidosis is an underrecognized cause of heart failure, and gastrointestinal (GI) amyloidosis can result in gut dysmotility and small intestinal bacterial overgrowth (SIBO). SIBO has various consequences, such as mucosal injury and nutrient malabsorption, impacting overall patient health. The interplay between cardiac and GI amyloidosis, especially in the context of SIBO, is largely undefined. This study evaluates associations between cardiac biomarkers (NT-proBNP level, echocardiographic indices) and extracardiac biomarkers in the gut, specifically non-invasive GI breath testing for SIBO. HYPOTHESIS We hypothesize that patients with more severe cardiac amyloidosis may have a higher prevalence of SIBO and altered gut motility patterns, as detected via non-invasive GI breath testing. METHODS Nine patients presenting to tertiary referral cardiology and gastroenterology clinics for evaluation of AL or ATTR amyloidosis were analyzed. Demographic data, baseline echocardiogram, and NT-proBNP levels were collected. Patients underwent 3-hour lactulose breath testing with hydrogen and methane gas levels measured at 15-min intervals. Pearson correlation coefficients were calculated between cardiac indices, peak methane gas production (marker of delayed motility), and rise in hydrogen gas from baseline to 90 minutes (small intestinal phase, diagnostic of SIBO when >20 ppm) on breath testing. RESULTS Nine patients (mean age 60 [48-77], 44% F) were assessed; five with AL amyloidosis and four with ATTR amyloidosis. Eight patients had preserved ejection fraction (EF>55%). NT-proBNP levels correlated significantly with the rise in hydrogen gas at 90 min (r=.80, p=.009) [Figure 1a]. A negative correlation was observed between overall methane gas peak and NT-proBNP levels (r=-0.48, p=.009) [Figure 1b]. The correlation between the rise in hydrogen gas and grade of diastolic dysfunction was significant (r=.83, p=.04) [Figure 1c]. CONCLUSIONS A positive association was identified between NT-proBNP levels and early, excessive rise in hydrogen gas on GI breath testing, suggesting cardiac biomarkers may predict extracardiac manifestations of amyloidosis in the gut, particularly SIBO. This association enables earlier screening and treatment of SIBO in patients with advanced cardiac amyloidosis, addressing symptoms like bloating, malabsorption, and interference with anticoagulant dosing. The positive association between diastolic dysfunction grade and hydrogen gas rise [Figure 1c] and the negative association between NT-proBNP levels and overall methane peak, a marker of delayed motility [Figure 1b], further support this relationship.

INTRODUCTION Cardiac amyloidosis, characterized by progressive amyloid deposition, can lead to cardiomyopathy and heart failure. Concurrent gastrointestinal involvement may exacerbate the disease burden. Limited studies examine caregiver burden in cardiac amyloidosis patients. This study aims to assess primary caregiver burden in this population, focusing on the impact of gastrointestinal involvement. HYPOTHESIS We hypothesize high demand, difficulty, and poor outcomes in caregivers of cardiac amyloidosis patients upon initial presentation, worsening with concurrent gastrointestinal involvement. METHODS We studied 7 caregivers of cardiac amyloidosis patients (6 ATTR, 1 AL) with an initial presentation to a tertiary referral cardiac amyloidosis program. Caregiver burden was assessed using voluntary questionnaires employing Bakas Caregiving Outcomes Scale and Oberst Caregiving Demand and Difficulty sub-scales. Gastrointestinal involvement was assessed via EGD and colonoscopy with biopsy, and Congo red staining, dividing patients into three groups: no, partial, or pan-gut amyloid involvement (Figure 1a and 1b). RESULTS The caregiver sample (mean age 68.4) comprised of 4 spouses, 1 uncle, and 2 partners. Most caregivers experienced low demand (71.4%) and difficulty (85.7%), with the primary drivers being emotional support, symptom monitoring, and transportation provision. Caregivers mainly reported no significant change in outcomes (85.7%), improving family relationships but diminishing social activities with friends. Figure 1a and 1b display gastrointestinal involvement findings stratified by caregiver burden. Caregivers of patients with no and partial gut involvement reported no significant change in outcomes (Bakas score of 0), while caregivers of patients with pan-GI involvement experienced slightly worse outcomes (Bakas score of -29). Greater difficulty and demand were observed in caregivers of patients with total gastrointestinal involvement. CONCLUSIONS Upon initial patient presentation, caregiver burden for patients with cardiac amyloidosis was generally mild in terms of Oberst demand and difficulty, with symptom monitoring strongly affecting both. Most caregivers experienced no significant change in outcomes. Our study demonstrates a trend towards worsening difficulty, demand, and caregiver outcomes with increasing gastrointestinal involvement, suggesting a positive correlation between caregiver burden and systemic amyloidosis involvement. Early gastrointestinal screening for amyloidosis may offer opportunities for intervention and caregiver burden reduction by healthcare teams. Further research is needed to analyze caregiver burden over time.

BackgroundAmyloidosis, a rare multisystem condition, often requires complex, multidisciplinary care. Its low prevalence underscores the importance of efforts to ensure the availability of high-quality patient education materials for better outcomes. ChatGPT (OpenAI) is a large language model powered by artificial intelligence that offers a potential avenue for disseminating accurate, reliable, and accessible educational resources for both patients and providers. Its user-friendly interface, engaging conversational responses, and the capability for users to ask follow-up questions make it a promising future tool in delivering accurate and tailored information to patients. ObjectiveWe performed a multidisciplinary assessment of the accuracy, reproducibility, and readability of ChatGPT in answering questions related to amyloidosis. MethodsIn total, 98 amyloidosis questions related to cardiology, gastroenterology, and neurology were curated from medical societies, institutions, and amyloidosis Facebook support groups and inputted into ChatGPT-3.5 and ChatGPT-4. Cardiology- and gastroenterology-related responses were independently graded by a board-certified cardiologist and gastroenterologist, respectively, who specialize in amyloidosis. These 2 reviewers (RG and DCK) also graded general questions for which disagreements were resolved with discussion. Neurology-related responses were graded by a board-certified neurologist (AAH) who specializes in amyloidosis. Reviewers used the following grading scale: (1) comprehensive, (2) correct but inadequate, (3) some correct and some incorrect, and (4) completely incorrect. Questions were stratified by categories for further analysis. Reproducibility was assessed by inputting each question twice into each model. The readability of ChatGPT-4 responses was also evaluated using the Textstat library in Python (Python Software Foundation) and the Textstat readability package in R software (R Foundation for Statistical Computing). ResultsChatGPT-4 (n=98) provided 93 (95%) responses with accurate information, and 82 (84%) were comprehensive. ChatGPT-3.5 (n=83) provided 74 (89%) responses with accurate information, and 66 (79%) were comprehensive. When examined by question category, ChatGTP-4 and ChatGPT-3.5 provided 53 (95%) and 48 (86%) comprehensive responses, respectively, to “general questions” (n=56). When examined by subject, ChatGPT-4 and ChatGPT-3.5 performed best in response to cardiology questions (n=12) with both models producing 10 (83%) comprehensive responses. For gastroenterology (n=15), ChatGPT-4 received comprehensive grades for 9 (60%) responses, and ChatGPT-3.5 provided 8 (53%) responses. Overall, 96 of 98 (98%) responses for ChatGPT-4 and 73 of 83 (88%) for ChatGPT-3.5 were reproducible. The readability of ChatGPT-4’s responses ranged from 10th to beyond graduate US grade levels with an average of 15.5 (SD 1.9). ConclusionsLarge language models are a promising tool for accurate and reliable health information for patients living with amyloidosis. However, ChatGPT’s responses exceeded the American Medical Association’s recommended fifth- to sixth-grade reading level. Future studies focusing on improving response accuracy and readability are warranted. Prior to widespread implementation, the technology’s limitations and ethical implications must be further explored to ensure patient safety and equitable implementation.

Amyloidosis is a rare, multisystem disease with several subtypes including AA (secondary), AL (amyloid light chain), and ATTR (transthyretin amyloidosis). In addition to variable symptoms and multidisciplinary management, amyloidosis being a rare disease further contributes to patients being at risk for decreased health literacy regarding their condition. Increased access to education materials containing simple, plain language may bridge literacy gaps and improve outcomes for patients with rare diseases such as amyloidosis. The large language model (LLM), Chat Generative Pre-Trained Transformer (ChatGPT), may be a powerful tool for improving the availability of accurate and easy to understand education materials. Amyloidosis-related questions from cardiology, gastroenterology, and neurology were sourced from esteemed medical societies and institutions along with amyloidosis Facebook support groups and inputted into ChatGPT-3.5 and GPT-4. Answers were graded on 4-point scale with both models responding to the majority of questions with either “comprehensive” or “correct but inadequate” answers with only 1 (1.2%) answer by GPT-3.5 graded as “completely inaccurate”. When assessing reproducibility, GPT-3.5 scored reliably on more than 83.3% of responses, while GPT-4 produced above 98.2% consistent answers. Our findings show that ChatGPT can potentially serve as a supplemental tool in disseminating vital health education to patients living with amyloidosis.