Citations

632 Background: Paltusotine is an oral, nonpeptide, selective somatostatin receptor 2 agonist. In a phase 2 study, treatment with once-daily paltusotine reduced the frequency and severity of carcinoid syndrome (CS) symptoms and was well tolerated. The effect of paltusotine on biomarkers of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was further explored. Methods: This exploratory study, without formal power calculations, included an 8-week randomized treatment phase (completed) and a 102-week open-label extension phase (currently ongoing). The purpose was to evaluate safety, pharmacokinetics, and exploratory efficacy endpoints, including changes in biomarkers of paltusotine treatment. Enrolled patients were adults with a stable, documented grade 1 or 2 neuroendocrine tumor (NET) and CS. These patients were actively symptomatic and either untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day in ≥2 days over a 2-week period) or washed out of SRL therapy (symptoms previously controlled on SRL), with demonstrated symptom worsening after washout. Patients were randomized to once-daily paltusotine 40 mg or 80 mg; one optional uptitration (from 40 mg to 80 mg or 80 mg to 120 mg) was permitted. Blood samples for assessment of biomarkers (serum serotonin and plasma 5-HIAA) were collected longitudinally from screening to end of treatment. Upper limit of normal was prespecified as 541 ng/mL for serotonin and 22 ng/mL for 5-HIAA. This analysis focuses on changes in biomarker from baseline to the end of 8-week randomized treatment phase and after approximately one year (48 weeks). Results: Thirty-six patients (n=9 untreated; n=27 SRL washout) were randomized. Mean age was 60.8 years (range 35-83), and 52.8% were female. Nineteen patients had grade 1 NETs, and 17 had grade 2 NETs. As reported previously, treatment with once-daily, oral paltusotine was well tolerated and reduced the frequency and severity of CS symptoms, justifying further clinical development of the 80 mg dose. Mean serum serotonin decreased from 1553.0 ng/mL at baseline to 643.9 ng/mL at Week 8, and mean plasma 5-HIAA decreased from 245.1 ng/mL to 159.7 ng/mL. There was a trend of untreated patients achieving a greater reduction in comparison to washout patients. At 48-week follow-up, mean serum serotonin was stabilized at 791.50 ng/mL (n=20), and mean plasma 5-HIAA was stabilized at 190.45 ng/mL (n=20). Conclusions: Paltusotine significantly reduced serotonin and 5-HIAA levels, with effects maintained at 48 weeks. Biomarker reductions paralleled reductions in BM and flushing frequency. These findings support further investigation in the ongoing phase 3 study (CAREFNDR, NCT07087054). Clinical trial information: NCT05361668 .

334 Background: Sarcopenia, or decreased skeletal muscle mass, has been associated with worse surgical and oncologic outcomes across multiple malignancies. This study investigates the impact of sarcopenia on outcomes after multimodal therapy for esophageal cancer. Methods: Retrospective observational cohort study including adult patients who underwent neoadjuvant therapy followed by esophagectomy for primary esophageal cancer from January 2000 - December 2021. A fully automated abdominal segmentation using deep convolutional neural network was utilized to calculate skeletal muscle index (SMI) from preoperative CT scans performed at our institution. Males with SMI <52.4 cm 2 /m 2 and females with SMI <38.5 cm 2 /m 2 at any point before surgery were classified as sarcopenic. The relationship between sarcopenia and patient demographics, operative details, and complications were explored using chi-square tests. The relationship between sarcopenia and disease-free survival and overall survival were investigated using parsimonious multivariable analysis retaining variables with p-value <0.05 using backward selection method. Results: We identified 200 patients meeting the study criteria with 142 (71%) having sarcopenia at any time prior to surgery. Patients with sarcopenia were significantly older [65.2 (59.6, 71.2) vs 63 (53.6, 67.5), p = .023] and more likely to have had open surgery [129 (90.8%) vs 46 (79.3%), p = .034]. There were no significant differences in sex, history of diabetes, coronary artery disease, renal disease, smoking, cancer type, cancer stage, tumor size, tumor location, or margin status between sarcopenic groups ( p > .05). Sarcopenic patients were significantly more likely to require blood transfusion ≥3 units after esophagectomy [79 (55.6%) vs 8 (13.8%), p < .001] or to experience complications requiring surgical intervention [36 (24.6%) vs 7 (12.1%), p = .048]. Multivariate analysis revealed that sarcopenia was associated with disease-free and overall survival (Table). Conclusions: Sarcopenia is a prognostic factor in patients undergoing multimodal therapy for esophageal cancer. Interventions that aim to prevent decreases in SMI after initiating neoadjuvant therapy should be investigated. Multivariate analysis with sarcopenia predicting outcomes. Disease free survivalHR (95% CI) p-value Overall survivalHR (95% CI) p-value Age 1.04 (1.02, 1.06) < .001 1.04 (1.02, 1.07) < .001 Epicenter Middle Upper 1.88 (1.21, 2.86)3.16 (1.67, 5.98) .001.005< .001 1.96 (1.26, 3.04)4.00 (1.90, 8.44) < .001.003< .001 Stage Stage II Stage III Stage IV 1.88 (0.95, 3.71)2.90 (1.46, 5.75)16.02 (6.12, 41.93) < .001.069.002< .001 1.65 (0.83, 3.25)2.76 (1.37, 5.55)10.14 (4.03, 25.53) < .001.151.005< .001 Cancer type - - 1.76 (1.03, 3.02) .039 Transfusion > 3 pRBC - - 1.54 (0.99, 2.40) .057 BMI prior to cancer diagnosis - - 0.98 (0.94, 1.01 .208 Sarcopenic 1.76 (1.16, 2.67) .007 1.64 (1.04, 2.60) .033

Abstract Background Bipolar disorder (BD) is associated with impairments in facial emotion recognition (FER), affecting social functioning and quality of life. Understanding FER deficits in BD is crucial for tailoring interventions and improving treatment outcomes. This systematic review and meta-analysis aims to evaluate FER differences among individuals with BD, unaffected first-degree relatives (FDRs), and healthy controls (HCs), exploring predictors related to patient and study characteristics. Methods We systematically searched PubMed/MEDLINE, Scopus, EMBASE, and PsycINFO databases from inception to March 28, 2024. Random-effects meta-analyses were conducted to explore differences in accuracy and reaction time during FER identification and discrimination tasks. Results A total of 100 studies were included, comprising 4920 individuals with BD (females = 56%, mean age = 34.1 ± 9.1), 676 FDRs (females = 55%, mean age = 36.1 ± 12), and 4909 HCs (females = 53.2%, mean age = 32.5 ± 9.5). Compared to HCs, adults with BD exhibited significantly lower accuracy (SMD = −0.47; 95% CIs = −0.56, −0.38) and higher reaction time (SMD = 0.57; 95%CIs = 0.33, 0.81) during facial emotion identification tasks. During facial emotion discrimination tasks, adults with BD had significantly lower accuracy than HCs (SMD = −0.59; 95%CIs = −0.78, −0.4), but similar speed. No significant differences were observed between BD and FDRs. Meta-regressions identified several predictors of FER performance, including manic symptom severity, stimulus duration, and presence of practice before task. Conclusions FER deficits appear to be a core feature of BD and require specialized, systematic assessment. Identifying these deficits may help guide interventions aimed at improving affective cognition and social outcomes in individuals with BD.

Abstract Background Spinal cord injury causes motor, sensory, and autonomic impairments. Transcutaneous spinal cord stimulation (tSCS) has shown potential to improve autonomic regulation, particularly cardiovascular and bladder control. Heart rate variability (HRV) serves as a non-invasive marker of autonomic balance, reflecting modulation of cardiac sympathetic and parasympathetic activity. The purpose of this study was to evaluate the effect of combined tSCS and physical therapy (tSCS + PT) on HRV and autonomic function metrics in chronic spinal cord injury. Methods. Eight participants (2 with tetraplegia, 6 with paraplegia) received tSCS at 30 Hz targeting T11–L1 or C5–T1, depending on injury level. Each underwent two tSCS + PT sessions per week for 12 weeks, followed by a 4-week washout period. Autonomic assessments included the Autonomic Standard Evaluation Form (ASAF), Neurologic Bladder Symptoms Score (NBSS), blood pressure, heart rate, SpO2%, and core temperature. Electrocardiograms were recorded pre- and post-tSCS + PT at baseline, 12, and 16 weeks. Results. Baseline effects of tSCS + PT revealed increased time-domain HRV parameters, suggesting enhanced cardiac parasympathetic activation (PSA). After 12 weeks, these parameters decreased, suggesting reduced cardiac PSA and enhanced sympathetic activation (SA). Similar results were found with frequency-domain parameters. Time-and frequency-domain parameters tended to return toward baseline after the 4-week therapy suspension. Two commonly reported HRV parameters, SDNN and RMSSD, showed large effects (g = 1.64, CI 95% [0.30, 2.98], and g = 1.23, CI 95% [0.11, 2.42], respectively) at 12 weeks when comparing pre- vs. post-tSCS + PT. Moderate, subject-related differences across evaluations were found in ASAF and NBSS (p > 0.05). Physiological metrics across time points did not show statistically significant differences (p > 0.05). Physiological metrics across time points did not show statistically significant differences (p > 0.05). Conclusions Combined tSCS + PT elicited improvements in autonomic clinical measures, without statistically significant changes in time-domain or frequency-domain HRV parameters. Nonetheless, trends and size effect in SDNN and RMSSD suggested that tSCS + PT induced midterm SA and a transient PSA immediately post-tSCS + PT. The partial recovery of HRV after tSCS withdrawal indicates that the observed autonomic changes were therapy-related.

Abstract Background Isolated REM sleep behavior disorder (iRBD) is a parasomnia that reflects an evolving α‐synucleinopathy disorder, providing an opportunity to study early pathological changes. While diffusion tensor imaging (DTI) studies have shown white matter changes in iRBD, Neurite Orientation Dispersion and Density Imaging (NODDI) may offer better biological specificity in characterizing microstructural alterations through measures of Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and Free Water Fraction (FWF). Method We included 77 participants with polysomnography‐confirmed iRBD from the North American Prodromal Synucleinopathy (NAPS) Consortium and 154 age‐ and sex‐matched cognitively unimpaired controls from the Mayo Clinic Study of Aging. White matter microstructure was evaluated using standardized multi‐shell diffusion on 3T MRI, quantifying DTI metrics (fractional anisotropy, FA; and mean diffusivity, MD) and NODDI parameters across bilateral white matter tracts defined by the JHU “Eve” WM atlas. Group differences were assessed using conditional logistic regression, with correlations to motor performance evaluated using the Purdue Pegboard and Alternating Finger Tapping tests. Result Compared to controls, iRBD participants demonstrated widespread and bidirectional white matter changes across major white matter pathways (see Figure 1 for glass brain visualizations). While predominantly showing decreases, FA exhibited some increases, particularly in the corticospinal tract. MD showed a largely opposite pattern with predominantly increased values across tracts. NODDI metrics revealed complex bidirectional patterns: ODI was broadly increased across multiple tracts with focal decreases, while NDI showed a pattern of predominantly decreased values alongside localized increases. FWF demonstrated a mixed pattern with predominant decreases across most tracts. In addition, both DTI and NODDI metrics showed extensive, moderate correlations with the Purdue Pegboard Test and Alternating Finger Tapping performance ( T = 2.0, p < 0.05, Figure 2). Conclusion Our study highlighted widespread and complex bidirectional white matter microstructural alterations in individuals with iRBD, demonstrating significant correlations with dexterity and motor performance even during the prodromal stage. These results suggest that extensive white matter abnormalities occur early in prodromal α‐synucleinopathies and highlight the value of advanced diffusion imaging techniques in characterizing iRBD and its potential prediction of phenoconversion to overt neurodegenerative disorders.

Abstract Background Amyloid related imaging abnormality edema (ARIA‐E) occurs in about 19% of individuals with autosomal dominant Alzheimer disease (ADAD) treated with an anti‐amyloid‐b monoclonal antibody (Salloway et al., 2021). In a previously reported case, ARIA‐E appeared to colocalize with decreases in PiB‐PET uptake (Joseph‐Mathurin, Llibre‐Guerra, et al, 2022), suggesting an association between amyloid‐b (Aβ) removal and ARIA‐E. Here, we compare longitudinal neuroimaging and corresponding neuropathology in an ADAD individual treated with gantenerumab, who experienced multiple ARIA‐E episodes as sulcal effusions that resolved by the end of the four‐year trial. Methods PiB‐PET and MRI were collected pre‐ and post‐randomization (2 and 4 years). The participant consented to brain donation, which was received a year after trial completion. Four tissue samples were taken from the location of the ARIA‐E in the parieto‐occipital left hemibrain as identified by MRI (one block contained the sulcus affected by ARIA‐E; the rest of the coronal section was captured in the remaining three blocks). Area fractions (AFs) of Aβ (10D5 immunohistochemistry (IHC)), tauopathy (PHF1), microglia (Iba1), and astrocytes (GFAP) in one sulcal region of interest (ROI) from each block and PiB‐PET SUVRs of corresponding ROIs were extracted ( n = 4, Figure 1). Additionally, we included PiB‐PET SUVRs corresponding to ARIA‐E findings observed in the right hemisphere at baseline, two‐year, and four‐year visits ( n = 6). Results Overall PiB‐PET uptake increased during the first two years (before ARIA‐E) and decreased during the last two years (including ARIA‐E episodes) (0.03±0.05 vs. ‐0.04±0.04 SUVR/year, p ‐value=0.01, Figure 2). The decrease seemed more pronounced in ARIA‐E ROIs versus normal‐appearing sulcus ROIs (‐0.05±0.04 vs. ‐0.02±0.03 SUVR/year). Lower PiB uptake at last visit appeared associated with lower Aβ AF (estimates=0.03±0.01, p ‐value=0.07). The ARIA‐E ROI had an Aβ AF of 0.009 while normal‐appearing sulcus ROIs had a mean of 0.02+0.003 (Figure 3). AFs for tauopathy, microglia, and astrocytes were within the range of those of normal‐appearing sulcus ROIs, suggesting an Aβ‐specific effect, although unexamined markers may play a role. Conclusions Our preliminary findings indicated that ARIA‐E is associated with longitudinal PiB‐PET decrease and Aβ AF, supporting the link between ARIA‐E, changes in PiB‐PET, and local Aβ removal observed at autopsy. Funding : K01AG080123; U01AG042791; R01AG046179; R01AG053267

Abstract Background Aortic valve calcification (AVC), as measured by gold-standard computed tomography (CT) Agatston score, provides an anatomic assessment of aortic stenosis (AS) severity and is a key predictor of AS progression and need for valve replacement. AVC detection and quantification from transthoracic echocardiography (TTE) could expand AS early diagnosis and risk stratification, currently limited by CT availability and radiation exposure. Methods A multi-view video-based deep learning framework was developed using 1166 TTE aortic valve videos from 187 TTE studies acquired in 110 patients with available AVC score by CT. EchoAVC architecture includes a feature extraction model followed by a quality-aware model that aggregates video-level information to obtain patient-level predictions for AVC detection and quantification (score). The framework was validated internally with 173 TTE studies from 86 patients across seven centres, and externally using 430 TTE studies from 280 patients across four different centres. The associations between EchoAVC estimations and AS severity, progression, and need for aortic valve replacement were examined. Results EchoAVC demonstrated excellent performance in AVC detection (AUROC 0.98, accuracy 94.4%), and quantification (R = 0.64) in the external multi-centre testing set. EchoAVC score was correlated with echocardiographic AS severity descriptors, including aortic valve mean pressure gradient (ρ = 0.749) and peak velocity (ρ = 0.757), and predicted future increase in mean pressure gradient (ρ = 0.382), peak velocity (ρ = 0.433) and calcium score by CT (ρ = 0.650). In 361 patients followed for a median of 3.8 years, 139 underwent aortic valve replacement. Baseline presence and extent of AVC as predicted by EchoAVC showed strong risk-stratification power for aortic valve replacement, remarkably in line with those obtained by CT, and incremental over TTE AS descriptors. EchoAVC was further tested in routine clinical practice images, confirming strong associations with AS severity and progression, including stratification for incident AS in previously unaffected individuals (p<0.001). Conclusions EchoAVC enables accurate and non-invasive detection and quantification of AVC, offering substantial diagnostic and prognostic value for aortic stenosis progression and need for valve replacement. This technique holds promise as a scalable tool for early detection and clinical management of aortic valve stenosis. Clinical Perspective What Is New? * Aortic valve calcification can be detected and quantified on standard, two-dimensional transthoracic echocardiography * EchoAVC score is associated with echocardiographic metrics of aortic stenosis severity * EchoAVC predicts progressive increase in aortic stenosis severity and need for aortic valve replacement What Are the Clinical Implications? * This openly available deep learning framework can be used to estimate aortic valve calcium in patients at risk of or presenting aortic stenosis to predict aortic stenosis progression * EchoAVC may help identify patients likely to have high aortic valve calcium and prioritize them for confirmatory CT assessment, thereby supporting earlier identification of calcific aortic valve disease in clinical pathways.

Background/Objectives: Speech and motor control share overlapping neural mechanisms, yet their quantitative relationships in Parkinson’s disease (PD) remain underexplored. This study investigated bidirectional associations between acoustic voice features and objective motor metrics to better understand how vocal and motor systems relate in PD. Methods: Cross-sectional baseline data from participants in a randomized neuromodulation trial were analyzed (n = 13). Motor performance was captured using an Integrated Motion Analysis Suite (IMAS), which enabled quantitative, objective characterization of motor performance during balance, gait, and upper- and lower-limb tasks. Acoustic analyses included harmonic-to-noise ratio (HNR), smoothed cepstral peak prominence (CPPS), jitter, shimmer, median fundamental frequency (F0), F0 standard deviation (SD F0), and voice intensity. Univariate linear regressions were conducted in both directions (voice ↔ motor), as well as partial correlations controlling for PD motor symptom severity. Results: When modeling voice outcomes, faster motor performance and shorter movement durations were associated with acoustically clearer voice features (e.g., higher elbow flexion-extension peak speed with higher voice HNR, β = 8.5, R2 = 0.56, p = 0.01). Similarly, when modeling motor outcomes, clearer voice measures were linked with faster movement speed and shorter movement durations (e.g., higher voice HNR with higher peak movement speed in elbow flexion/extension, β = 0.07, R2 = 0.56, p = 0.01). Conclusions: Voice and motor measures in PD showed significant bidirectional associations, suggesting shared sensorimotor control. These exploratory findings, while limited by sample size, support the feasibility of integrated multimodal assessment for future longitudinal studies.

Purpose: Irreversible corneal blindness disproportionately affects low- and middle-income countries where there remains a critical demand for surgeons skilled in corneal transplantation. Penetrating keratoplasty (PK) is a critical skill for ophthalmologists, especially as it remains the most widely performed type of corneal transplant in these parts of the world. Tools to teach and assess trainees in corneal transplantation are needed to help standardize training internationally. Here, we present an Ophthalmology Surgical Competency Assessment Rubric (OSCAR) aimed at assessing the competence and progress of residents in PK. Methods: A team of cornea specialists developed a rubric for PK using previously published OSCARs as a template. The draft included 11 key steps of PK and six global indices, with a grading scale based on a modified Dreyfus model. The rubric was then reviewed for face and content validity by a panel of eight international experts using an iterative feedback process. The draft underwent multiple cycles of feedback and revisions until a consensus was reached among the authors and the international expert panel. Results: The rubric contains 11 essential steps and six global indices with descriptions of expected functioning at four levels of competency (novice, beginner, advanced beginner, and competent). Conclusions: This OSCAR for PK contributes to the global standardization of ophthalmology training, helping to meet the increasing demand for corneal transplant services with high-quality care for all.