Citations

ABSTRACT Background Treatment options for medically‐refractory faecal incontinence ( FI )—including anorectal biofeedback, dextranomer injection, and sacral nerve stimulation—are limited and outcomes are often suboptimal. Anal or vaginal insert devices are infrequently used. Aims We evaluated the safety and effectiveness of a new anal insert device (StaySure) in patients with FI. Methods Patients with FI for ≥ 6 months and ≥ 4 moderate or large FI episodes during a 4‐week baseline entered a 2–4 week fitting/run‐in period to individualise device size (10 or 13 mm) followed by a 4‐week treatment period. Outcomes included effectiveness, safety, and quality of life (QoL). The primary outcome was the proportion achieving a ≥ 50% reduction in FI frequency. Results Of 124 enrolled patients, 98, 71, and 61 progressed through the baseline, fitting/run‐in, and treatment phases respectively, with few exclusions due to device intolerance. In the intent‐to‐treat cohort of 59 participants (93% women), mean ( SD ) number of days with FI declined from 13.2 (7.0) to 6.3 (6.9), and FI weekly episodes declined from 5.4 (6.9) to 2.1 (5.1) (69% reduction; p < 0.001) with similar results for both device sizes. The primary endpoint was achieved in 76.3% of participants; 54.2% achieved ≥ 75% reduction. The FIQoL overall score increased from a mean ( SD ) of 1.9 (0.6) to 2.3 (0.6) ( p < 0.001), indicating improved QoL . Improvements in FI frequency, FIQoL exceeded minimal clinically important difference thresholds, confirming clear clinical benefit. No treatment‐related serious adverse events were reported. Conclusions The StaySure anal insert device is safe, well tolerated, and effective in reducing FI in patients with moderate to severe symptoms refractory to conservative therapies. Trial Registration ClinicalTrials.gov identifier: NCT03898778

ABSTRACT Introduction Chronic gastroduodenal disorders remain challenging to manage, and new diagnostic approaches are needed to better delineate underlying causes and guide therapeutic decisions. Body Surface Gastric Mapping (BSGM) technologies combine high‐resolution gastric myoelectrical activity measurements with symptom and psychological profiling to provide mechanistic insights into gastric motor and sensory dysfunction. An International Working Group convened to derive the first consensus classification of BSGM phenotypes (the “Auckland Classification”). Methods A Technical Group conducted a systematic literature and clinical database review to identify objective test biomarkers and candidate disease mechanisms. Evidence was synthesized across 50 studies (primarily in gastroparesis, chronic nausea and vomiting, and functional dyspepsia), and BSGM phenotypes were mapped to existing treatment guidelines. Subsequently, iterative review and development of consensus was performed by a Consensus Group composed of international clinical experts familiar with BSGM. Eleven statements underlying the classification were then derived and circulated as a final survey to establish agreement. Results Six BSGM phenotypes were endorsed: three defined by myoelectrical abnormalities (Dysrhythmic, High Frequency, and Low Meal Response) and three by characteristic symptom associations (Sensorimotor, Continuous, and Delayed Onset Symptoms). Published studies plausibly linked these phenotypes to mechanisms including interstitial cell of Cajal depletion, vagal impairment, hypomotility, visceral hypersensitivity, gut‐brain dysregulation, and small bowel dysfunction. Phenotypes were also mapped to existing mechanism‐based treatment guidelines. Ten out of the eleven statements had > 80% agreement. Conclusions The Auckland Classification, derived by international consensus, presents a structured framework for BSGM‐defined patient phenotypes. Evidence and mechanism‐based treatment options are suggested for each phenotype to provide a foundation for research, further validation, and a pathway for integrating BSGM into clinical care.

ABSTRACT Background Chronic megacolon is an uncommon neurogastrointestinal disorder typically characterized by a persistent increase in colonic diameter. Methods Our aim was to identify adults with medical treatment‐refractory constipation without radiographic criteria for megacolon but with increased colonic compliance (refractory constipation with colonic hypercompliance (RCCH)), and to compare the colonic compliance in 7 identified patients with “RCCH” to colonic compliance in 10 patients with chronic megacolon by radiographic criteria (i.e., megacolon) and 40 healthy volunteers. After endoscopic placement, compliance of left or transverse colon was measured using a 10‐cm‐long infinitely compliant balloon connected to an electronically controlled rigid piston barostat. The barostat inflated the balloon from 0 to 44 mmHg in 4‐mmHg steps at 30‐s intervals to measure colonic compliance (pressure‐volume relationship). Eligibility criteria for inclusion were increased colonic compliance based on a functional assessment without meeting radiographic criteria for megacolon (i.e., RCCH). In the three groups, we compared colonic volumes at intra‐balloon pressure of 8, 16, 20, 32, and 44 mmHg, the pressure at half maximum volume, and the slope of the colonic compliance curve using ANOVA on ranks and Dunn's pairwise comparison test. Other features of colonic motility were documented. Results Colonic volumes at all pressures (8‐44 mmHg) and the pressure at half maximum volume were significantly greater in patients with megacolon and RCCH than in healthy controls ( p < 0.001 for both), but compliance was not significantly different between RCCH and megacolon. Conclusion A subset of patients with medically‐refractory chronic constipation has colonic compliance similar to that of patients with megacolon.

Background While SARS-CoV-2 vaccines are highly effective in healthy individuals, the magnitude and durability of humoral and cellular responses in patients with solid malignancies receiving chemotherapy remain understudied. Previous reports suggest that patients with cancer may not mount adequate immune response after SARS-CoV-2 vaccination. Additionally, most studies focused on humoral responses, while data regarding cellular immune responses are scarce. In this study, we evaluated humoral and cellular responses in patients with solid tumors receiving chemotherapy compared to healthy individuals up to one year after vaccinations. Methods Patients aged ≥18 who were willing to receive the SARS-CoV-2 vaccine were enrolled. Anti-SARS-CoV-2 immunoassays were used to detect antibodies against nucleocapsid and spike proteins. Human IFN-γ Fluorospot assay was used to determine antigen−specific T-cell responses. Data were compared between groups using Mann−Whitney test for continuous variables and Fisher’s exact test for categorical variables. Results A total of 67 subjects (47 patients with cancer and 20 healthy individuals) were included. 1–3 months following the second vaccine doses, 96% of patients with cancer and 100% of healthy individuals demonstrated a positive humoral response. While the positivity rate was not significantly different, patients with cancer had significantly lower spike IgG antibodies than healthy individuals. However, this difference diminished at 6 months when patients with cancer had increased antibodies compared to decreased antibodies in the healthy cohort and no difference was noticed at 12-month. Patients with cancer developed a similar antigen-specific T-cell response as healthy individuals at 1–3 months, 6 months and 12 months. There were no significant differences when comparing patients aged ≤ 55 years vs. &gt;55 years, stages I-III vs. IV, single vs. multiple chemotherapy, and BNT162b2 vs. mRNA-1273 vaccines. There was a significant moderate correlation between neutralization and antibody levels at 12 months. However, despite patients with cancer having a significantly higher COVID risk score, there were no significant differences in COVID-19 infection and hospitalization between patients with cancer and healthy individuals. Conclusion Despite initial impaired antibody responses to SARS-CoV-2 vaccinations, patients with solid malignancies receiving chemotherapy effectively generated long-term cellular and humoral responses by 6 and 12 months, leading to similar infection and hospitalization rates compared to healthy individuals.

INTRODUCTION: To perform a proof-of-concept study to evaluate the performance of individual and combined anorectal manometry and balloon expulsion testing (BET) parameters for diagnosing dyssynergic defecation (DD) using machine learning (ML). METHODS: A single gastrointestinal motility specialist assessed (2008–2018) 307 patients. A ML model was constructed on anorectal manometry/BET data. BET was weight-based in 235 patients and time-based in 72 patients. Missing data were imputed. Data were split 75% train/25% test with preprocessing performed. Five common ML models were trained, and performance was compared using receiver operating characteristic (ROC) area under the curve and accuracy based on 100 bootstrapped samples. The most accurate models were fine-tuned and evaluated on the test set. RESULTS: The median age was 40 years, body mass index 22.2 kg/m 2 , and 81% were women. Two-hundred and 22 (72.3%) patients had a clinical diagnosis of DD. Compared with patients without clinical diagnosis of DD, patients with DD had significantly lower rectoanal pressure gradient (RAG) (median −34.7 [IQR −57.1, −13.0] vs −24.6 [IQR −44.5, −2.4] mm Hg, P = 0.009) and more abnormal BET (59.5% vs 11.8%, P < 0.001). Four features were retained in the optimized model as predictors of DD: abnormal BET, greater resting anal pressure (RAP), and more negative RAG. The optimal parameter was abnormal BET ( P = 0.003), but combinations of 2 manometry results (RAP and RAG) yielded positive predictive values (PPVs) >80%. The optimized logistic regression model had an area under the curve of 0.878, with a sensitivity of 75.0% and specificity of 81.8% at a probability threshold of 0.704. DISCUSSION: Abnormal BET, or a combination of 2 manometric parameters (RAP and RAG), provides >80% positive predictive value for diagnosing DD in patients with chronic constipation.

Background: Etripamil nasal spray is a fast-acting, calcium channel blocker in development for the conversion of paroxysmal supraventricular tachycardia (PSVT) outside of a health-care setting. Studies have demonstrated the favorable safety and efficacy of self-administered etripamil in restoring sinus rhythm (SR) and reducing emergency department visits. Purpose: This report analyzes the efficacy, safety, and test-dose tolerability of etripamil across PSVT clinical studies. Methods: We systemically examined randomized, controlled and open-label trials evaluating etripamil in patients with PSVT. Efficacy measures included the proportion of patients converting from PSVT to SR within 30 minutes and the median times to conversion across all Phase 3 studies. Safety data for treatment-emergent adverse events (TEAEs), serious AEs, and test dose tolerability from Phase 2/3 studies were summarized descriptively. Results: NODE-1, NODE-301 Part 1, NODE-301 Part 2 (RAPID, including RAPID Extension, RAPID Open Label, RAPID Open Label Extension periods), NODE-302, and NODE-303 studies were analyzed (Table 1). The Kaplan-Meier estimate of etripamil exposed patients converting to SR within 30 minutes (n= 622) was 59.6% (range, 53.6% to 64.3%) with a median time to conversion of 18.5 minutes (95% CI, 15.7 to 21.0). The proportions of RCT placebo group patients converting from SVT to SR by 30 minutes ranged from 26.7% to 34.7%. Estimates of conversion of SVT to SR with etripamil at 60 minutes for individual studies ranged from 63.2% to 73.5% (Figure). Combined analysis showed mainly the occurrence of mild, transient TEAEs, primarily nasal discomfort, nasal congestion, rhinorrhea, throat irritation, and epistaxis (Table 2). 1,107 patients took at least one etripamil test dose while in SR; no significant change in average baseline heart rate or blood pressure was observed within 45 minutes of administration, and test dose failure occurred in only 16 patients (1.4%). Conclusions: Across multiple clinical studies of acute PSVT management, self-administered etripamil consistently demonstrated robust efficacy and a favorable safety profile for acute PSVT management. Safety data and the low rate of test dose failures indicate favorable tolerability, suggesting no need for a pretreatment test dose. These findings support the potential of etripamil as a patient-administered therapy for PSVT, which may reduce reliance on emergency care.

ABSTRACT Introduction Etripamil is a fast‐acting intranasally self‐administered calcium‐channel blocker developed for termination of paroxysmal supraventricular tachycardia (PSVT). Prior studies have demonstrated safety and efficacy of etripamil for PSVT termination following an initial medically supervised test dose during sinus rhythm. NODE‐303 is an open‐label, single‐arm study that evaluated etripamil for multiple, at‐home PSVT episodes, without test dose before first use. Methods Patients applied an ECG monitor at symptom onset and self‐administered etripamil (70 mg) if a vagal maneuver was unsuccessful. ECG monitoring occurred for ≥ 1 h following study drug administration. A repeat 70‐mg dose was introduced during the study for symptoms persisting 10 min after the first dose. Safety measures included treatment‐emergent adverse events (TEAEs) and ECG arrhythmia‐surveillance. Efficacy measures were captured for PSVT termination during treatment of each of the multiple episodes. Results 1054 perceived PSVT episodes were etripamil‐treated in 503 of 1116 patients enrolled. TEAEs within 24 h were mostly mild or moderate and localized: 30.2% of patients experienced nasal discomfort, nasal congestion (13.9%), rhinorrhea (13.1%), epistaxis (7.4%). TEAE frequencies decreased across multiple PSVT episodes and were similar for single versus repeat doses. For first PSVT episodes, 70.5% of patients converted to sinus rhythm by 60 min post etripamil (median time to conversion = 18.3 min [14.2–25.6]). Conversion in earlier episodes was consistently predictive of conversion in subsequent episodes. Conclusions Etripamil nasal spray self‐administered in a real‐world setting was well tolerated, effective, and had a consistent safety profile as a single‐ or repeat‐dose regimen across multiple PSVT episodes. Trial Registration: ClinicalTrials.gov NCT04072835

Abstract Background Up to 80% of persons with Parkinson's disease (PwPD) have dysphagia. However, existing studies are based on small cohorts and the relationship between dysphagia and other motor and nonmotor symptoms (NMS) remains incompletely understood. Objectives To evaluate the relationship between motor and NMS in PwPD with vs without dysphagia. Methods Among 20,365 PwPD in the Michael J. Fox Foundation database who completed ≥2 NMS surveys, 12,678 (62%) reported dysphagia on ≥1 survey. We examined associations between dysphagia and: (1) self‐reported motor symptoms (UPDRS Part II), other NMS, quality of life (QoL), comorbidity score, depression, and daily activities at baseline; and (2) development of new NMS. Results Compared to PwPD without dysphagia, those with dysphagia were more likely to have had PD for >5 years, more severe motor and NMS, higher comorbidity scores, and a greater impairment in daily activities ( P < 0.001). The prevalence of dysphagia increased with the severity of motor symptoms at the index survey ( P < 0.001). At baseline, all NMS were significantly associated with dysphagia. Compared to PwPD who did not have dysphagia, PwPD with dysphagia were at increased risk of developing every NMS, even after adjusting for ages at PD diagnosis and index survey, sex, cognitive impairment, UPDRS, NMS and comorbidity scores. For most NMS, the risk of progression was greater in those with cognitive impairment or elevated NMS scores. Conclusions Dysphagia in PwPD is associated with more severe motor and non‐motor symptoms, reduced QoL, and an increased risk of future NMS.