Citations

INTRODUCTION: Chronic gastroduodenal disorders are highly prevalent and encompass heterogeneous pathophysiology. Autonomic dysfunction may contribute, but its relative contribution to disease pathophysiology and symptoms is unclear. This study aimed to clarify the contributions of autonomic dysfunction in gastroduodenal disorders and symptom associations using multimodal testing, hypothesizing that distinct disorder subgroups would be revealed. METHODS: This prospective observational cohort study included 80 patients with chronic gastroduodenal symptoms. Participants underwent expert clinician-led autonomic evaluation, body surface gastric mapping (BSGM; Gastric Alimetry, New Zealand), and gastric emptying scintigraphy testing. BSGM phenotyping, gastric emptying cutoffs, and autonomic criteria followed standard criteria. RESULTS: Gastroparesis was diagnosed in 27 (33.8%) patients. Autonomic dysfunction was present in 21 (26.3%) patients, and abnormal BSGM in 20 (25%). Autonomic dysfunction and abnormal BSGM were both more prevalent in gastroparesis (51.9% vs 13.2%, P = 0.001; and 44.4% vs 15.1%, P = 0.005, respectively). However, these diagnoses tended not to overlap, with patients having autonomic dysfunction generally exhibiting normal BSGM tests. Autonomic dysfunction independently predicted delayed gastric emptying (OR 13.8, P < 0.001) and was associated with earlier meal responses (higher meal response ratio, P = 0.04) and worse postprandial distress symptoms ( P < 0.05). DISCUSSION: Autonomic dysfunction independently predicted delayed gastric emptying and revealed a gastroparesis mechanism distinct from gastric myoelectrical impairment. Autonomic dysfunction altered the postprandial gastric motor response and was associated with a greater symptom burden. Multimodal physiological testing including autonomic profiling reveals distinct mechanistic subgroups in patients with chronic gastroduodenal symptoms.

Background Patient complaints provide a complementary lens on surgical safety, yet prior analyses have been small and specialty specific. We aimed to characterise themes, perioperative processes, system factors and outcomes in surgical complaints using a scalable, large language model (LLM)-assisted approach. Methods We performed a national, retrospective, cross-sectional, sequential methods study of publicly available investigation reports from the Aotearoa New Zealand Health and Disability Commissioner. All reports published since 1998 were retrieved and screened for relevance across all surgical specialties. A fixed-parameter LLM workflow extracted demographics, clinical context, complications, breached patient rights, system factors and outcomes. An inductive LLM-supported thematic synthesis generated complaint themes, followed by rescoring of theme relevance across reports. Human validation supported the LLM-assisted process (Cohen’s κ >0.85). Results Of 1827 reports screened, 650 involved surgical care. Postoperative complications were frequent (84.2%), commonly accompanied by permanent disability (33.2%) or death (24.2%). Delays in recognition of deterioration (76.1%), escalation (58.3%) and definitive management (49.5%) of complications were common and associated with higher mortality. Prominent themes concerned postoperative clinical management/monitoring, communication/informed consent and professional conduct/competence. Technical/procedural errors and medication errors were comparatively less common. Breaches are most often related to reasonable care and skill, and to informed consent, with marked variation across specialties. Conclusions Complaints about surgical care predominantly reflect postoperative monitoring, escalation and communication rather than intraoperative technical errors. System priorities should include robust deterioration recognition and response, reliable handover and escalation pathways, and strengthened consent and communication processes. An LLM-assisted pipeline can scale complaint analysis to support organisational learning and quality improvement.

Background Cysteine–cysteine chemokine receptors 2 (CCR2) and 5 (CCR5) contribute to immune suppression in tumor microenvironments. CCR2 and CCR5 antagonists have demonstrated antitumor activity in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), respectively. This phase 1b/2, open-label study evaluated BMS-813160, a CCR2/5 dual antagonist, in combination with chemotherapy±nivolumab in advanced PDAC or metastatic CRC. Methods Part 1 included patients with metastatic untreated (first-line (1L)) PDAC, 1L CRC, or previously treated (second or third line (2/3L)) microsatellite stable (MSS) CRC. Patients received 2 weeks of BMS-813160 monotherapy (300 mg two times a day, 600 mg once daily, 300 mg once daily, or 150 mg once daily) and then BMS-813160+chemotherapy (gemcitabine+nab-paclitaxel (gem/nabP; 1L PDAC), 5-fluorouracil+leucovorin+irinotecan (FOLFIRI; 1L CRC)), or nivolumab (2/3L MSS CRC). Part 2 included patients with metastatic 1L PDAC or 2L CRC. Patients received BMS-813160 300 mg two times a day+gem/nabP±nivolumab (1L PDAC), BMS-813160 300 mg two times a day or 150 mg once daily+FOLFIRI (2L CRC), or chemotherapy alone. Primary endpoints were safety and pharmacodynamics (Part 1) and efficacy (Part 2). Results In Part 1, 22 of 75 (29%) and 54 of 72 (72%) patients experienced a treatment-related adverse event during monotherapy lead-in and overall, respectively. Two dose-limiting toxicities (rash and pericardial effusion with pericarditis, both grade 3) occurred. In Part 2, patients with 1L PDAC who received BMS-813160 300 mg two times a day+gem/nabP+nivolumab achieved an overall response rate (ORR) of 37% (13/35); the median duration of response (DOR) was 45 weeks (95% CI 26.1 to not evaluable). ORRs with BMS-813160 300 mg two times a day+gem/nabP and gem/nabP alone were 26% (9/35) and 28% (9/32), respectively; median DORs were 121 and 31 weeks, respectively. Progression-free survival rates at 24 weeks were 56% (BMS-813160 300 mg two times a day+gem/nabP+nivolumab), 56% (BMS-813160 300 mg two times a day+gem/nabP), and 50% (gem/nabP). ORRs in 2L CRC were 19% (6/32; BMS-813160 300 mg two times a day+FOLFIRI), 13% (4/32; BMS-813160 150 mg once daily+FOLFIRI), and 27% (7/26; FOLFIRI). Conclusions In 1L PDAC, BMS-813160 300 two times a day+gem/nabP±nivolumab demonstrated durable antitumor response and was well tolerated. BMS-813160 combination regimens were tolerable in other cohorts, but clinical efficacy was not demonstrated. Trial registration number NCT03184870 .

ABSTRACT Objective This study compared the effects of phentermine‐topiramate‐ER (mid‐dose 7.5/46 mg) versus placebo on weight loss and cardiovascular disease (CVD) risk outcomes when used as an adjunct to a digitally enhanced lifestyle intervention (DELI). Methods We conducted a 12‐month, randomized, double‐blind, placebo‐controlled trial at a single tertiary academic center in the United States (June 2020–June 2022). Eighty participants with obesity (BMI ≥ 30 kg/m 2 ) were enrolled in the DELI program, consisting of in‐person and telehealth modalities, dietary and physical activity goals, and use of a smartphone application integrated with digital devices (Apple Watch and Bluetooth‐enabled weight scale and blood pressure monitor). Participants were randomized 1:1 to receive either phentermine‐topiramate‐ER ( n = 42) or placebo ( n = 38) in addition to the DELI. Results At 3 months, the phentermine‐topiramate group lost a mean of 10.82 kg versus 4.04 kg in the placebo group (mean difference −6.78 kg; p = 0.002). At 12 months, weight loss was 15.32 kg versus 5.85 kg, respectively (mean difference −9.48 kg; p < 0.001). Participants receiving phentermine‐topiramate‐ER experienced a 3.35% reduction in the estimated atherosclerotic CVD risk compared to baseline ( p = 0.004). Conclusions Phentermine‐topiramate‐ER, when combined with a DELI, produced significant and sustained weight loss and reduced CVD risk in adults with obesity. Trial Registration ClinicalTrials.gov : NCT04408586

ABSTRACT Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS) 1,2 . We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET) 3 , termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) 4 , which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD) 5,6 , which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewing’s sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold 3 . Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.

Background: Papillary Muscle (PM) related ventricular arrhythmia ablation is associated with lower acute success and suboptimal long-term outcomes due to complex anatomy, variable arrhythmogenic sites and dynamic exit points. Objective: To evaluate clinical and procedural outcomes of patients undergoing PM vs non-PM ablation. Methods: A retrospective analysis of adults (≥18 years) undergoing PVC ablation at Mayo Clinic (2019–2024) matched PM PVC ablations to controls (1:2) using propensity scoring based on age, sex, comorbidities and baseline LVEF. Chi-square and t-tests compared baseline and procedural characteristics. Logistic regression estimated odds ratios for immediate procedural success, PVC burden reduction and LVEF improvement at 3 months. Results: Of the 720 ablations, 392 cases were included after propensity matching: 132 PM and 260 non-PM. Patients in the PM group exhibited higher rates of complicated diabetes (9.8% vs 4.6%, p =0.045) and prior MI (18.2% vs 9.2%, p =0.011). Preprocedural ECG PVCs in the PM group showed a shorter intrinsicoid deflection (89.1 ± 35.0 msec vs 100.7 ± 24.3 msec, p <0.001) and longer coupling intervals (532.7 ± 100.3 vs 512.2 ± 81.4 msec, p =0.048).Moderate-to-severe MR was more prevalent in the PM group (17.4% vs 10.0%, p =0.036). Intraoperatively, the PM group had higher total energy delivery times (1939 ± 1336 sec vs 1227 ± 1033 sec, p <0.001) and more frequent cryoablation use (46.2% vs 7.3%, p <0.001). During post-ablation testing, non-clinical PVC was inducible in 39.5% of the cases in PM group compared to 25.7% in non-PM group ( p =0.005). More patients in the PM group were discharged on atleast one antiarrhythmic drug (AAD)(35.9% vs 18.5%, p <0.001) and AAD use persisted at 3 months (31.3% vs 18.4%, p =0.004). Outcomes were similar between groups, with no significant differences observed in immediate ablation success (aOR 0.64, p = 0.063, CI = 0.40-1.03), or >5% improvement in LVEF (aOR 0.76, p = 0.29) and PVC burden reduction (aOR 0.93, p = 0.81) at 3 months follow up. Conclusion: Patients undergoing PM ablation exhibited higher baseline rates of comorbidities. Intraoperatively they required greater energy delivery times, and an increased use of cryoablation. Postoperatively, a larger proportion of PM ablation patients required antiarrhythmic drug therapy. Despite these complexities, PM ablation showed no significant differences in PVC burden reduction, LVEF improvement, or procedural success compared to non-PM ablation.

Introduction: Older age and multimorbidity observed in individuals with dementia may impact both the care they receive and their outcomes in the setting of acute coronary syndrome (ACS). We conducted an analysis of ACS hospitalizations in the US to examine whether disparities exist between patients with and without dementia in percutaneous coronary intervention (PCI) use and ACS-related outcomes after accounting for age and comorbidities. Methods: We used the Nationwide Readmissions Database 2021 to identify adults hospitalized with a primary diagnosis of ACS, including STEMI and NSTEMI. Propensity scores for dementia were calculated using 33 baseline characteristics, including age, sex, insurance, income, hospital characteristics, Charlson comorbidity index, and other relevant comorbidities. We performed 1:1 nearest-neighbor matching with a caliper of 0.2 standard deviations. After matching, we compare the following outcomes of people with and without dementia: receipt of PCI, mechanical complications of ACS, cardiogenic shock, mechanical circulatory support, inpatient mortality, length of stay, and hospitalization cost, and reported odds ratios or mean difference, 95% confidence interval, p-value. Survey weights were applied to ensure national representativeness. Results: Among 295,396 patients hospitalized with ACS, 7,143 had dementia. After matching, 7,142 patients with and without dementia were identified for analysis ( Figure 1 ). Covariate balance was achieved (all standardized mean differences <.1). Patients with dementia were 28% less likely to undergo PCI (0.72 [0.67–0.77], p<.001) and 78% more likely to develop cardiogenic shock (1.76 [1.58–1.95], p<.001), 82% more likely to require mechanical circulatory support (1.82 [1.61–2.05], p<.001), and 16% more likely to die during hospitalization (1.16 [1.04–1.30], p<.01) ( Figure 2 ). No significant difference was observed in mechanical complications of ACS (0.89 [0.33–2.33], p=.81). Patients with dementia had longer hospital stays (9.27 vs. 5.89 days; mean difference 3.38 [3.06-3.7] days, p<.001) and higher hospitalization costs ($182,649 vs. $130,233; mean difference $52,416 [$44,618- $60,215], p<.001). Conclusion: In this analysis of US hospitalizations for ACS, dementia was independently associated with lower PCI rates and worse ACS-related outcomes despite accounting for age and comorbidities. Further research is needed to understand and address these inequities in ACS management in patients with dementia.

Abstract Disclosure: S.R. Chacko: None. C.A. Villavicencio Torres: None. K. Yu: None. S.G. Waguespack: None. L. Lu: None. Z. Belaya: None. T. Bandgar: None. A. Sada: None. O. Ragnarsson: None. B. Altieri: None. A. Newman: None. P. Vibhatavata: None. M. Tóth: None. E.V. Varlamov: None. C. Badiu: None. A. Paissan: None. M. St-Jean: None. H. Falhammar: None. N. Imamudeen: None. L. Haberbosch: None. M. Bobrowicz: None. A. Tabarin: None. R. Shah: None. M.R. Gadelha: None. A. Peersen: None. W.F. Young: None. J. Kaplan: None. J. Varghese: None. M.A. Habra: None. O. Golounina: None. G.A. Melnichenko: None. A.R. Lila: None. C. Yamichannaiah: None. I. Bancos: None. Context: Cushing syndrome (CS) due to ectopic ACTH secretion (EAS) is a rare condition, associated with severe hypercortisolism and consequent morbidity and mortality. Its varied and often emergent presentation make diagnosis and treatment challenging. Objectives: 1.Characterize clinical and biochemical presentation of EAS. 2.Describe the scope of hypercortisolism-related complications, overall and CS-specific mortality. 3.Identify factors associated with CS-specific mortality. Methods: We conducted a multicenter retrospective cohort study in patients with EAS at 37 centers. Outcomes were clinical/biochemical severity scores, complications, overall and CS-specific mortality. Results: In 1053 patients [median age at diagnosis 52 years (IQR 37-64), 57% women], metastatic disease was present at diagnosis in 585 (56%). The most common sources of EAS were bronchial neuroendocrine neoplasm (NEN) (304, 29%), pancreatic NEN (114, 11%) and small cell lung carcinoma (114, 11%), with the source of EAS being occult in 192 (18%). Clinical and biochemical severity scores were severe in 475 (45%) and 873 patients (92%) respectively. Hypokalemia was present in 819 patients (78%) in the year prior to diagnosis. Of 342 patients (32%) who had IPSS, 301 (88%) suggested an ectopic source, 7 (2%) a pituitary source, and 23 (7%) were non-diagnostic. Of 595 patients who had both functional and cross-sectional imaging, discordant findings were seen in 122 (21%), concordant lesion was seen on both in 326 (55%), and no lesion in 147 (25%). Of those with discordant results, cross-sectional imaging was accurate in 66 (54%) and functional imaging in 56 (46%).Management included medical therapy alone in 237 (23%), surgical excision of the source of EAS in 158 (15%), bilateral adrenalectomy in 77 (7%) and multimodal therapies in 498 patients (47%). Complications within 5 years after diagnosis included hospitalization related to CS or its therapy in 351 (33%), infection in 337 (32%), thromboembolic event in 102 (10%), cardiovascular event in 83 (8%) and cerebrovascular event in 27 (3%). During a median follow-up of 35 months (IQR 20-122) from CS diagnosis, death occurred in 462 patients (44%), with the cause of death related to CS in 149 (14%). CS-specific mortality was higher in metastatic compared with non-metastatic disease (19% vs. 7%, P&lt;0.001). On multivariable analysis of age, sex, clinical and biochemical severity, older age (HR 1.03, 95% CI: 1.02-1.04) and lower clinical severity score (HR 0.97, 95% CI: 0.94-0.99), were associated with higher CS-specific mortality. Conclusion: Our interim analysis, the largest worldwide, found that most patients with EAS had severe hypercortisolism and hypokalemia. Metastatic disease was present in 56%, and the source of EAS was occult in 18%. CS-related death occurred in 14%, emphasizing the need for urgent management. Presentation: Monday, July 14, 2025

ABSTRACT Background Chronic gastroduodenal symptoms arise from heterogeneous gastric motor dysfunctions. This study applied multimodal physiological testing using gastric emptying scintigraphy (GES) with intragastric meal distribution (IMD) and Gastric Alimetry body surface gastric mapping (BSGM) to define motility and symptom associations. Methods Patients with chronic gastroduodenal symptoms underwent simultaneous supine GES and BSGM with a 30 m baseline, 99mTC‐labeled egg meal, and 4 h postprandial recording. IMD (ratio of counts in the proximal half of the stomach to the total gastric counts) was calculated immediately after the meal (IMD0), with < 0.568 defining abnormal IMD. BSGM phenotyping followed a consensus approach, based on normative spectral reference intervals. Results Among 67 patients (84% female, median age 40 years, median BMI 24 kg/m 2 ), median IMD0 was 0.76 (IQR: 0.69–0.86) with 5 (7.5%) meeting abnormal IMD criteria. Delayed gastric emptying ( n = 18) was associated with higher IMD0 (median 0.9 vs. 0.7, p = 0.004). On BSGM, 15 patients had abnormal spectrograms (5 [7.5%] high frequency and 10 [14.9%] low rhythm stability and/or amplitude); and in these patients, higher IMD0 (proximal retention) strongly correlated to delayed BSGM meal responses ( R = −0.71, p = 0.003). Lower IMD, indicating antral distribution, correlated with higher gastric frequencies ( R = −0.27, p = 0.03). BSGM abnormalities paired with abnormal IMD were associated with worse dyspeptic symptoms. Conclusion Proximal retention of food as assessed by IMD correlated with delayed emptying, and in the presence of neuromuscular spectral abnormalities (abnormal frequencies or rhythms), delayed motility responses on BSGM. Patients with multiple motor abnormalities experience worse dyspeptic symptoms.

ABSTRACT Background Chronic neurogastroduodenal disorders are challenging to manage, with therapy often initiated on a trial and error basis. Prokinetics play a significant role in management, but responses are variable and have been associated with adverse events, impacting widespread use. We investigated whether body surface gastric mapping (BSGM) biomarkers (using Gastric Alimetry) could inform patient selection for prokinetic therapy. Methods Patients with chronic gastroduodenal symptoms taking oral prokinetic agents, regardless of gastric emptying status, were prospectively recruited and underwent BSGM (30 m baseline, 482 kcal standardized meal, 4 h postprandial recording) while off‐prokinetic agents. Patients were followed up with daily symptom diaries. A subset was compared to matched patients not taking prokinetic agents. Prokinetic responders were defined based on symptom improvement greater than a minimum clinically important difference methodology. Key Results Forty‐two patients (88% female; median age 36; median BMI 26) taking prokinetics were analyzed. Prokinetic prescribing, compared to matched patients, was independent of BSGM metrics ( p > 0.15). In patients on existing prokinetics (withheld for BSGM), lower amplitudes predicted reduced symptom burden, whereas low rhythm stability predicted a worse symptom burden ( p < 0.05). In prokinetic‐naive patients (i.e., started on a prokinetic during the study), a lower postprandial amplitude predicted responders (mean 37.5 ± 10.6 uV in responders [ n = 5] vs. mean 54.8 ± 6.6 uV among nonresponders [ n = 3], p = 0.047). Conclusions Gastric Alimetry biomarkers may help in the prediction of prokinetic response in patients with chronic gastroduodenal symptoms. Lower postprandial amplitudes, indicating a reduced meal response, appear to predict benefit, while impaired rhythm stability predicted poorer therapeutic response.