Citations

Abstract Precise localization of the epileptogenic zone is pivotal for planning minimally invasive surgeries in drug-resistant epilepsy. Here, we present a graph neural network (GNN) framework that integrates interictal intracranial EEG features, electrode topology, and MRI features to automate epilepsy surgery planning. We retrospectively evaluated the model using leave-one-patient-out cross-validation on a dataset of 80 drug-resistant epilepsy patients treated at St. Anne's University Hospital (Brno, Czech Republic), comprising 31 patients with good postsurgical outcomes (Engel I) and 49 with poor outcomes (Engel II–IV). The GNN predictions demonstrated a significantly better (P < 0.05, Mann–Whitney-U test) area under the precision-recall curve in patients with good outcomes (area under the precision-recall curve: 0.69) compared with those with poor outcomes (area under the precision-recall curve: 0.33), indicating that the model captures clinically relevant targets in successful cases. In patients with poor outcomes, the graph neural network proposed alternative intervention sites that diverged from the original clinical plans, highlighting its potential to identify alternative therapeutic targets. We show that topology-aware GNNs significantly outperformed (P < 0.05, Wilcoxon signed-rank test) traditional neural networks while using the same intracranial EEG features, emphasizing the importance of incorporating implantation topology into predictive models. These findings uncover the potential of GNNs to automatically suggest targets for epilepsy surgery, which can assist the clinical team during the planning process.

BACKGROUND: Data registries lack a definitive classification system that distinguishes different locations of colon cancer from one another. OBJECTIVE: To establish an international consensus on the definition of primary colon cancer segment locations. DESIGN: Between December 2022 and June 2023, Delphi survey study was conducted to seek opinions from relevant international experts and eventually develop a consensus definition of each colon cancer segment. SETTING: Three-round online-based Delphi survey study. INTERVENTIONS: Online survey included 17 questions. In the first two rounds, participating experts were asked to rank each statement on a scale of 1–9 (9 is the most relevant). Consensus statements and definitions were revised according to results, obtaining a consensus score of 7–9. During the third round and online meeting, definitions and statements reached a moderate or high consensus(above 4 in more than 70% of participants) were included. MAIN OUTCOME AND MEASURE: Primary goal of our project was focused on precisely localizing the specific segment affected by primary colon cancer, rather than to identify surgical treatment or type of resection needed for particular segment. RESULTS: The first round included 331 experts, 301 (91%) completed the second round, and 295 (98%) completed the final round. Experts strongly supported the use of a “10 cm rule” to describe colon cancer sites at the flexures and anatomical landmarks for other segments. Regarding the definition of rectosigmoid cancer, experts from America and Europe reached a high consensus that the term rectosigmoid as a colon cancer location must be abolished in contrast to experts from Asia. Description of cancers overlapping segments achieved a consensus of 64%. LIMITATIONS: Subjective decisions are based on individual expert clinical experience. CONCLUSIONS: This Delphi survey, the first internationally conducted consensus study, achieved a remarkable level of consensus among a panel of global experts. Ambiguity still exists regarding overlapping lesions. See Video Abstract .

Abstract Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel–Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic VHL germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in ≥30 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma in carriers of the most frequent VHL mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P < 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.

Abstract Acute Myocarditis (AM) encompasses a broad spectrum of clinical presentations and causes. Despite the recent advances in cardiovascular imaging, pathology, virology, and genetics, specific therapies are still lacking. This collaborative review aims to analyse the current evidence to answer practical questions that physicians may face during the early management of patients presenting with an acute form of the disease, complicated or not. This review analyses current evidence to address practical questions posed by acute cardiovascular physicians during the early management of acute, or potentially, myocarditis. Based on the current literature, this review provides a step-by-step approach to treat AM patients from their admission in the cardiac intensive care unit (CICU) to discharge, by answering 10 clinical questions: Might this patient be suffering from an AM? Should I hospitalize this patient and, if so, where? Which cardiac imaging exam should I perform and what can I learn from it? Is this patient requiring an EMB? What should the non-invasive aetiological work-up be? Is her/his episode of AM of viral, toxic, or other origin? Does this patient need specific treatments or mechanical circulatory support? Is there an indication for guideline-directed medical heart failure treatment? When can the patient be discharged and resume physical activity? Notably, this review highlights the need to build a multidisciplinary response team to address the many diagnostic and therapeutic challenges of AM patients. It also points out the lack of evidence to guide the treatment of these patients.

Abstract Background Patient age can impact the safety and efficacy of ulcerative colitis (UC) treatments. Etrasimod is an oral, once daily (QD), selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active UC. Here, we evaluate the impact of age on etrasimod safety and efficacy in patients with UC in the phase 3 ELEVATE UC clinical program. Methods Data were pooled from ELEVATE UC 52 and ELEVATE UC 12 in patients receiving etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) per 100 patient-years of treatment-emergent adverse events (AEs) were stratified by age (<40, 40-59, and ≥60 years). With the same age stratifications, efficacy was evaluated in patients with baseline Modified Mayo scores of 5-9 and 4-9 for the primary efficacy endpoint (clinical remission) and secondary efficacy endpoints. Results Overall, 787 patients were enrolled (<40 years, n = 420 [53.4%]; 40-59 years, n = 276 [35.1%]; and ≥60 years, n = 91 [11.6%]). Arthralgia, fatigue, and hypertension IRs were higher in older patients, irrespective of treatment. Serious AEs and AEs leading to treatment discontinuation were low and consistent across age groups. Significantly more patients receiving etrasimod 2 mg QD vs placebo achieved efficacy endpoints, regardless of age. Conclusions The safety profile of etrasimod 2 mg QD in the ELEVATE UC population was consistent across age groups, with no change in the incidence of AEs. Patients receiving etrasimod vs placebo showed significant clinical benefit, regardless of age. ClinicalTrials.gov NCT03945188; NCT03996369.

Background/Purpose APS ACTION Registry was created to study the natural course of antiphospholipid syndrome (APS) over 10 years in persistently antiphospholipid antibody (aPL) positive patients with or without systemic autoimmune rheumatic diseases (SARDs). Our primary objective was to compare the characteristics of aPL-positive patients with or without thrombocytopenia (TP) and/or autoimmune hemolytic anemia (AIHA). Methods The registry inclusion criteria are positive aPL based on the Revised Sapporo APS Classification Criteria, tested at least twice within 1 year prior to enrollment. For the primary comparison of demographic, clinical, and serologic characteristics in this retrospective study, we divided patients into two groups: TP/AIHA ever and never. Thrombocytopenia was defined as a platelet count of <100,000 x 10 9 /L tested twice at least 12 weeks apart, and AIHA was defined as anemia with hemolysis and a positive direct antiglobulin test (DAT). For the secondary analysis, we compared patients with TP versus AIHA, and the immunosuppressive use stratified by systemic lupus erythematosus (SLE) classification. Results As of April 2022, of 1,039 patients (primary aPL/APS: 618 [59%]; SLE classification: 334 [31%]) included in the registry, 228 (22%) had baseline (historical or current) TP and/or AIHA (TP only: 176 [17%]; AIHA only: 35 [3%], and both: 17 [2%]). Thrombocytopenia and/or AIHA was significantly associated with Asian race, SLE classification, cardiac valve disease, catastrophic/microvascular APS, triple aPL (lupus anticoagulant, anticardiolipin antibody, and anti-β 2 -glycoprotein-I antibody) positivity, and SLE-related serologic and inflammatory markers. When 101/618 (16%) primary aPL/APS patients and 101/334 (34%) SLE patients with TP and/or AIHA were compared, azathioprine and mycophenolate mofetil were more commonly reported in lupus patients, however corticosteroid, intravenous immunoglobulin, and rituximab use were similar between groups. Conclusion In our large multi-center international cohort of persistently aPL-positive patients, approximately one-fifth had active or historical TP and/or AIHA at registry entry; half of these patients had additional SLE. Cardiac valve disease, catastrophic/microvascular APS, and triple aPL-positivity were aPL-related clinical and laboratory manifestations associated with TP and/or AIHA, suggesting a more severe APS clinical phenotype in aPL-patients with TP and/or AIHA.

Abstract Oscillations in the high gamma and ripple frequency ranges are known to coordinate local hippocampal and neocortical neuronal assemblies during memory encoding and recall. Here, we explored spatiotemporal dynamics and the role of global coordination of these fast oscillatory discharges across the sensory and associational cortical areas in distinct phases of memory processing. Individual bursts of high frequency oscillations were detected in intracranial recordings from epilepsy patients remembering word lists for immediate free recall. We found constant coincident bursting across visual and higher order processing areas, peaking before recall and elevated during encoding of words. This global co-bursting was modulated by memory processing, engaged approximately half of the recorded electrode sites, and clustered into a sequence of multiple consecutive bursting discharges. Our results suggest a general role of global coincident high frequency oscillations in organizing large-scale information processing across the brain necessary especially, but not exclusively, for memory functions.

Fungal pericarditis is a rare disease but its incidence has risen in parallel with the global increase in invasive fungal infections. This systematic review analyzes data from previously reported cases of fungal pericarditis to provide an improved understanding of the etiology, clinical presentation, management, and outcomes of this rare disease. We reviewed Medline and Scopus databases from 1 January 1990 to 29 January 2024 for case reports that documented the isolation of a fungal pathogen from pericardial fluid or tissue. Of the 2330 articles screened, 101 cases met the inclusion criteria. Patients with fungal pericarditis and the involvement of at least one other organ—usually the lungs, brain, or kidney—had worse outcomes than patients with isolated pericardial disease. Immunosuppression was reported in 50% of cases and was associated with worse outcomes in adults. Patients who presented with chest pain, received adequate empiric antifungal therapy, and underwent pericardiocentesis and pericardiectomy had improved survival. The most common isolated pathogens were Candida spp., followed by Aspergillus spp. and Mucor spp., with the latter two linked to worse outcomes. Only 35% of patients received empiric antifungal medications before the causative pathogen was identified, and mortality was associated with a delay in appropriate therapy. Immunosuppression, disseminated disease, and presence of shock/multiorgan failure were additional risk factors associated with death. Fungal pericarditis carries a mortality rate of up to 50%, with nearly half of patients being immunocompromised. Clinicians frequently do not consider fungal pericarditis in the differential diagnoses, which leads to delays in treatment and poorer outcomes. Further prospective multicenter studies are urgently needed to better understand the epidemiology, improve diagnostic testing and management, and decrease unacceptably high mortality in patients with fungal pericarditis.

AbstractINTRODUCTIONAlzheimer's disease (AD) pathology causes corticobasal syndrome (CBS) in 21%–50% of patients. Studies have assessed hypometabolism in CBS according to β‐amyloid (A) positron emission tomography (PET), but the understanding of the association of both AD‐tau (T) and A with hypometabolism is incomplete.METHODSThirty‐three CBS patients and 45 controls underwent fluorodeoxyglucose (FDG), flortaucipir, and Pittsburgh compound‐B PET and were classified as A± and T±. FDG‐PET uptake was extracted for 12 regions‐of‐interest in dominant (most affected) and non‐dominant hemispheres and compared across A/T groups.RESULTSA+T+ patients had greater hypometabolism in temporo‐parieto‐occipital cortices than A+T‐ and A‐T‐ groups, with no differences observed between the A+T‐ and A‐T‐ groups. FDG asymmetry was more accentuated in A+T+ patients. Medial temporal and basal ganglia metabolism were similar across AT groups.DISCUSSIONAmyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in temporo‐parieto‐occipital cortices in CBS, with AD‐like patterns of hypometabolism observed only in A+T+ patients.Highlights Amyloid (A) and tau PET (T) status can be used to stratify CBS patients. A+T+ CBS patients show more hypometabolism in temporo‐parieto‐occipital cortices. Medial temporal metabolism (typical AD pattern) is similar across AT groups. Parieto‐occipital cortices should be assessed when investigating AT pathology in CBS. Amyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in CBS.