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Background: Pancreatic resection (Pancreatoduodenectomy, PD, distal pancreatectomy, DP, or total pancreatectomy, TP) is the standard of care for resectable pancreatic adenocarcinoma (PDAC). Despite advances in multimodal therapy, recurrence rates remain high, approaching 80%, and continue to drive poor overall survival. Objective: This review evaluates the burden and clinical significance of localized recurrence in PDAC and critically examines the potential role of intraoperative radiation therapy (IORT) in improving locoregional disease control. Results: Distant recurrence remains the predominant pattern of failure, occurring in 55–75% of patients, most commonly involving the liver, lungs, and peritoneum. However, isolated local recurrence, observed in approximately 17–32% of patients, represents a clinically meaningful subset associated with significant morbidity and potential for subsequent metastatic progression. IORT, delivered as a single high-dose radiation treatment to the tumor bed at the time of surgery, enables precise targeting of areas at highest risk for residual microscopic disease while minimizing radiation exposure to adjacent radiosensitive structures. Retrospective and meta-analytic data, while limited, suggest that IORT is associated with improved local control and modest survival benefit without a significant increase in perioperative morbidity, though interpretation is limited by study heterogeneity and lack of randomized control trials. Conclusion: IORT represents a rational adjunct in the multimodal management of PDAC, particularly for patients at high risk of locoregional failure, including those with borderline resectable or locally advanced disease, nodal involvement, perineural invasion, or concern for margin positivity. Prospective studies are needed to better define optimal patient selection and to clarify the role of IORT in the modern treatment paradigm.

Abstract Objectives This study aimed to investigate the procedural characteristics, efficacy, and safety of atrioventricular junction (AVJ) ablation for atrial tachyarrythmia (AT) in patients with congenital heart disease (CHD). Background Although AVJ ablation is an established treatment option for intractable AT in the general population, there is no existing data on this treatment in patients with CHD. Methods Data were analyzed from an observational, retrospective, multicenter cohort, initiated jointly by the Pediatric and Congenital Electrophysiology Society and the International Society of Adult Congenital Heart Disease. Eleven centers contributed baseline, procedural and longitudinal data, including vital status, echocardiographic data, QRS duration, and NYHA class. Outcomes were assessed at early (3 months-1 year), and late follow-up (≥2 years) after AVJ ablation. Results A total of 66 patients (46.7 ± 20.2 years) underwent 71 AVJ ablations. In total, 58.5% had moderate or complex CHD, including 17.1% patients with a systemic RV or single ventricular circulation. The cumulative AVJ ablation success rate was 98.5%. An abnormal location of the atrioventricular conduction pathway was successfully targeted in 20.0% of the patients, which was significantly more common in patients with complex CHD compared to moderate or mild CHD (44.4%, 15.8%, and 3.6%, respectively; both P<0.05). Thirty-six patients (54.5%) underwent primary pacemaker implantation as part of the ‘pace and ablate’ strategy; final pacing modes were VVI pacing in 60.9%, and CRT/CSP in 39.1%. The transplant-free survival rates at 2, 5 and 10 years after AVJ ablation were 91.5%, 84.3%, and 69.0%, respectively. The acute and long-term complication rates were 3.0% and 13.6%, respectively. Conclusions AVJ ablation can be successfully performed in CHD patients with a high acute success rate and low complication rate. Anatomical challenges were common, which underscores the need for careful planning and operator experience. Given the acceptable long-term survival, these findings support the consideration of a ‘pace and ablate’ strategy in CHD patients with intractable AT.

Abstract Background Calcium release channel deficiency syndrome (CRCDS) arises from loss-of-function variants in the RYR2-encoded type 2 ryanodine receptor (RyR2), predisposing patients to sudden cardiac arrest/death (SCA/SCD) despite normal exercise testing. Previously, a novel homozygous RYR2 duplication causing ~ 80% RyR2 reduction was associated with exertion-related SCD. However, how Ca2+ homeostasis is maintained despite RyR2-loss remains unknown, as RYR2-/- animals are non-viable. Purpose To generate a RYR2-knockout (RYR2-KO-/-) induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model to dissect compensatory mechanisms sustaining Ca2+ homeostasis and identify arrhythmogenic pathways predisposing to SCD. Methods CRISPR/Cas9 editing was used to introduce a homozygous c.163delT variant into a wild-type iPSC line (control), generating a RYR2-KO-/- model. A patient-derived RYR2-duplication (RYR2-DUP+/+) iPSC line was used for comparison. RyR2 expression was assessed by western blot (WB) and immunofluorescence (IF). Proteome and phospho-proteome were assessed using omics approaches. Intracellular Ca2+ handling was evaluated by Fluo-4 AM imaging (0.5 Hz and long-burst–long-pause [LBLP] protocol). Electrophysiological properties (action potential [AP], and sarcolemmal currents [ICaL, INa and INCX]) were assessed by patch-clamp. Results Despite complete RyR2-loss in RYR2-KO-/- iPSC-CMs as confirmed by WB and IF, contractility and contractile machinery expression was preserved. Ca2+ transient amplitude (ΔF/F0) was reduced markedly in RYR2-KO (0.14±0.01, p<0.01) and RYR2-DUP (0.27±0.2, p<0.01) compared to control (0.52±0.02). Proteomics revealed a significant NCX1 up-regulation and IP3R-interacting protein (ITPRIP) down-regulation in RYR2-KO compared to control, with pathway-analyses showing significant up-regulation of IP3-related pathways. Pharmacological IP3Rs block (2-APB, 10μM) abolished Ca2+ transient generation in RYR2-KO iPSC-CMs (Amplitude: baseline: 0.15±0.01, 2-APB: 0.06±0.01, p<0.01). RyR2-ablation induced electrical remodeling (pA/pF), including ICaL reduction, INCX up-regulation and hyperpolarization of the INa window current in RYR2-KO (ICaL [at 0mV]: -8.5±1.6; INCX [at -110mV]: -4.1±1.1) as compared to control (ICaL:-7.5±3.7, p<0.01; INCX:-1.5±0.5, p=0.02). RYR2-KO CMs demonstrated increased delayed after-depolarizations and beat-to-beat variability as compared to control. Despite Ca2+ sparks abolishment, RYR2-KO CMs displayed higher erratic beating (at 0.5Hz) and arrhythmogenic propensity than control, showing ventricular tachycardia-like events during LBLP stimulation. Conclusions Genetic RYR2-ablation disrupts physiological Ca2+ cycling and triggers electrical remodeling, including INCX up-regulation, overall promoting arrhythmogenesis. Compensatory IP3Rs activation sustains Ca2+ transient generation, revealing a mechanism preserving excitation-contraction coupling that may paradoxically promote arrhythmogenesis in CRCDS.RYR2-KO: Generation and CharacterizationElectrophysiological Assessment

Abstract Background Type 8 long QT syndrome (LQT8) is characterised by prolonged QT interval and a high burden of ventricular repolarisation abnormalities including sudden cardiac death. Purpose Patients and clinicians face uncertainties about the daily risk of cardiac arrest, particularly during physical performance. Therefore, we aim to establish a risk assessment based on systematically collected data. Methods We analysed eight patients genetically confirmed to carry CACNA1C variants, of whom three had cardiac arrests in early childhood, while others were discovered incidentally. One patient met criteria for cardiac-only Timothy syndrome. All patients performed cardiopulmonary exercise testing (CPET) with several having multiple studies over time, resulting in a total of 19 CPETs. Echocardiograms were available for all patients, and Holter monitor results for all but one patient. All CPETs were conducted on beta-blockade. Results On resting ECG the average heart rate was 66.5 ± 10.7 beats per minute (bpm). Average QT at diagnosis was 476.8 ± 47.8 ms, with a corrected QTc of 487.9 ± 37.2 ms. Two patients had sinus arrhythmia and three were atrially paced at rest. No ventricular arrhythmias were observed at rest. On initial CPET, average peak oxygen uptake was 29.3 ± 8.5 ml/kg/min (82 ± 25% predicted) at a peak heart rate of 141.6 ± 24.3 bpm (73 ± 13% predicted). Peak respiratory exchange ratio averaged 1.09 ± 0.13. On initial CPET, four patients developed premature ventricular contractions (PVCs), but only in one patient were more than 5 per minute detected. That patient had a high PVC burden with multiple runs of non-sustained ventricular tachycardia. There were no episodes of syncope or cardiac arrest across all 19 CPETs. Conclusions Our cases demonstrate the safety and utility of exercise testing in CACNA1C-related disease. Longitudinal follow-up revealed diverse electrophysiological findings, including QT prolongation and reduced chronotropic response. From our data it is suggested that CPET is safe to perform on appropriate therapy and exercise should be encouraged.

ABSTRACT Background The brain–heart axis is central to vascular health, yet no imaging biomarkers capture integrated dysfunction across neural and coronary microvascular networks. Although coronary microvascular dysfunction links to cognitive decline, neural correlates connecting cerebral efficiency with coronary physiology remain unclear. Objectives To determine whether the Unified Structural and Functional Connectivity (USFC)—a multimodal magnetic resonance imaging (MRI) “traffic map” of brain network efficiency—predicts coronary endothelial function and cognition in women with ischemia and no obstructive coronary artery disease (INOCA). Methods Thirty‐three women with suspected INOCA from the Women's Ischemia Syndrome Evaluation (WISE) study (NCT03876223) underwent invasive coronary function testing, cardiac MRI, cognitive evaluation, and multimodal brain MRI. USFC, structural connectivity (SC), and functional connectivity (FC) were computed for predefined 10 backbone pathways. Support vector regression and logistic classification assessed predictive performance. Results USFC explained 16%–20% more variance in coronary endothelial function, myocardial perfusion reserve, and cognition than SC or FC alone ( p < 0.05). Connectivity between the left caudate–superior medial orbital gyrus and right calcarine–inferior occipital gyrus emerged as robust predictors of crystallized cognition ( r = –0.78, p FDR < 0.05) and coronary endothelial function ( r = 0.70, p FDR < 0.05), respectively. USFC also best discriminated low versus high coronary blood flow (area under the ROC curve [AUC]: USFC 0.622 vs. SC 0.349 and FC 0.425; p < 0.05). Conclusions USFC identifies neuro–cardiac pathways linking cerebral efficiency with coronary endothelial function. These results introduce a sensitive biomarker of systemic vulnerability, highlighting occipital and frontostriatal pathways as shared substrates of dysfunction. USFC offers a mechanistic framework for detecting vascular risk across metabolically demanding tissues. Trial Registration ClinicalTrials.gov identifier: NCT03876223

Abstract Objective Ceribell Inc.'s point‐of‐care electroencephalographic (EEG) system and artificial intelligence‐based Automated Seizure Burden Estimator (ASBE; ClarityPro) have US Food and Drug Administration clearance for diagnosing electrographic status epilepticus (ESE). The AccuRASE study using ASBE version 6 (V6) showed high negative predictive value (NPV) but limited sensitivity and positive predictive value (PPV) at certain thresholds. Version 8 (V8) is the updated algorithm trained with additional EEG samples. Methods We tested V8 on the previously used rapid‐response EEG test dataset (not used to train V8). Sensitivity, specificity, PPV, and NPV were compared against blinded expert annotations. ESE, ESE and possible ESE (ESE/pESE), electrographic seizures (ESz), and Esz with highly epileptiform patterns (Esz/HEPs) at burden thresholds of >1%, >10%, >20%, >50%, and >90% were analyzed. Additionally, we evaluated the built‐in ESE and ESE/pESE alerts (≥90% over 5 min, ≥20% over 1 h, or ≥10 continuous minutes of seizure). Results V8 showed 100% sensitivity at lower thresholds (>10%–20%) for ESE (V6 .86), without a specificity loss (V8 .9 vs. V6 .85), and retained NPV (V8 1.0 vs. V6 .99). Sensitivity at 50% threshold was .86 for ESE (V6 .71), and specificity was .94 (V6 .91); PPV for ESE was 30% for ESE and 80% for ESE/pESE. The specificity for ESE remained high for 90% burden (V8 .96, V6 .97) but the sensitivity dropped (.29 vs. V6 .43). Sensitivity was lower for ESz/HEPs (.54 → .44 at >10% threshold), although the algorithm is not designed to detect HEPs. Built‐in alert analysis showed significantly improved sensitivity for ESE (.57 → .86); specificity and NPV remained high (>.94). Significance ASBE V8 showed meaningful improvements in sensitivity, continued excellent NPV, and improved built‐in alert accuracy for ESE and ESE/pESE. The best seizure burden threshold for ruling out ESE now is 20% (vs. 10% with V6) and that for ruling in ESE/pESE with reasonable certainty is 50% (vs. 90% with V6).

ABSTRACT Objective Little is known about shifting from pediatric to adult‐focused multiple sclerosis (MS) care. This study aims to explore transition of care and follow‐up in the US pediatric‐onset MS (POMS) population. Methods Surveys were distributed to 10 sites in the US Network of Pediatric MS Centers (US NPMSC) about transition‐of‐care practices. A cohort of POMS/clinically isolated syndrome (CIS) at 12 US NPMSC sites was analyzed. The primary comparison was between < 18 and ≥ 18‐years of age. The primary outcome was 1‐ and 2‐year lapse in last follow‐up visit, measured from last recorded database visit to data lock date or, if ≥ 18 years of age, up to 1 year after a patient reached their site's typical transition age, if earlier. Secondary outcomes were baseline factors associated with follow‐up lapse. The model was adjusted for preidentified confounders. Results Compared with < 18 years, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse. In POMS/CIS, the estimated hazard was 1.61 for 1‐year lapse (95% confidence interval [CI] 1.32–1.97, p < 0.001) and 1.40 for 2‐year lapse (95% CI 1.11–1.76, p = 0.004). In POMS‐only, the estimated hazard was 1.70 for 1‐year lapse (95% CI 1.33–2.18, p < 0.001) and 1.49 for 2‐year lapse (95% CI 1.11–1.99, p = 0.007). Platform injectable disease‐modifying therapy was associated with greater and intravenous with lesser hazard of lapse in follow‐up, while MS was associated with lower hazard than CIS. Conclusion Variable transition‐of‐care practices and barriers were reported by major US POMS centers. Before typical transition age, age ≥ 18 was associated with greater hazard of 1‐ and 2‐year follow‐up lapse than < 18. Developing standardized, targeted transition‐of‐care practices in POMS may be important.

Abstract Aims Transcatheter mitral valve replacement (TMVR) with the Tendyne Mitral Valve System is a treatment option for patients with severe symptomatic mitral regurgitation (MR) unsuitable for conventional mitral valve surgery or transcatheter edge-to-edge repair (TEER). This study sought to evaluate the safety and effectiveness of TMVR through 5-year follow-up. Methods and Results The Tendyne Expanded Clinical Study is a prospective, single-arm, multicentre study that enrolled patients between November 2014 and June 2020. The study enrolled 191 patients (mean age 74.1 ± 8.0 years, 62.8% male, 70.2% New York Heart Association Class (NYHA) class III/IV, 88.5% secondary MR), of whom 186 (97.4%) underwent TMVR with Tendyne. MR grade decreased from ≥3+ in 99.5% patients at baseline to grade ≤1+ in 95.3% at 5 years. In those patients surviving to 5 years (n = 49), durable symptomatic improvement was evidenced by 73.5% patients being in NYHA class I/II at 5 years. The Kansas City Cardiomyopathy Questionnaire overall summary score increased from 48.5 ± 22.5 points at baseline to 67.6 ± 21.5 points at 5 years. Serious adverse events that occurred through 5 years included life-threatening bleeding (11.5%), fatal bleeding (2.6%), renal insufficiency/failure (28.8%), endocarditis (7.3%), device thrombosis (5.8%), and new onset atrial fibrillation (13.1%). No structural device degeneration or device embolism occurred through 5 years. Conclusions The Tendyne TMVR was effective at achieving immediate and sustainable elimination of MR, which was associated with symptomatic improvement and absence of structural valve degeneration in a high-risk cohort over 5 years. These findings support TMVR with the Tendyne System as an alternative for patients with appropriate mitral valve anatomy and symptomatic secondary MR unsuitable for mitral surgery or TEER.

Abstract Background Radiation-induced heart disease (RIHD) may develop months to years following radiation therapy for cancers near the heart such as lung or breast cancer. Several mouse models of RIHD exist to study the pathogenesis of disease, but to our knowledge no studies have examined whether sex differences exist in RIHD in mice. Methods Female and male BALB/cJ mice received one whole heart dose of 22 Gray (Gy) radiation via a C5 collimator vs. sham controls that received 0 Gy, anesthesia and were placed in the X-ray machine for the same length of time. Mechanisms of cardiotoxicity were examined at 24 h (innate cardiotoxicity), day 10 (acute cardiotoxicity) and day 35 (chronic cardiotoxicity) post irradiation. Results Females and males developed dsDNA breaks from radiation at day 10 but females had more damage than males ( p < 0.001). Vessel area and cardiac hypertrophy were increased by radiation at day 10 and 35 but were higher in males than females at day 35 ( p < 0.001, p = 0.001, respectively). Bulk RNA sequencing of the heart at day 10 revealed that females and males developed similar gene pathway responses to radiation by upregulating cellular repair pathways and downregulated mitochondrial function. However, females upregulated the master regulator of mitochondrial function, Pgc1α ( p = 0.0001), suggesting improved mitochondrial repair in females. By day 35, males developed heart failure with reduced ejection fraction (HFrEF), inflammatory dilated cardiomyopathy (iDCM) and fibrosis while females developed heart failure with preserved ejection fraction (HFpEF) without inflammation or fibrosis. Conclusions We observed sex differences in nearly every cardiac parameter that we examined following radiation exposure. BALB/c males exposed to 22 Gy radiation developed HFrEF and iDCM by day 35 while females developed HFpEF. Further research is needed to better understand mechanisms driving sex differences in RIHD using translational animal models.

Abstract The impact of microglia antigen presentation on CNS infiltrating CD8 T cells responses during neurotropic virus infection remains undefined. Using Theiler’s murine encephalomyelitis virus (TMEV) infection of neurons as a model system, we generated H-2K b and H-2D b Tmem119 conditional knockout mice. During TMEV infection, we determined using Tmem119 K b cKO mice that microglia H-2K b contributes to antiviral CD8 T cell proliferation in the brain. Meanwhile, using Tmem119 D b cKO mice we determined that microglia H-2D b increased antiviral CD8 T cell perforin levels and the capacity to induce blood-brain barrier (BBB) disruption. Furthermore, microglial H-2D b was essential for antigen-specific reactivation of CD8 tissue resident memory (TRM) cell recall responses and BBB disruption long after virus had been cleared. These findings demonstrate discrete roles of individual MHC class I genes on microglia in CD8 T cell proliferation, effector functions, memory recall and neuropathology.