Citations

Abstract Objectives Understanding whether the novel long-T ITC complex might assist in interpreting clinical prognostic utility compared to established cardiac biomarkers is needed. We determined long term major adverse cardiac events (MACE) and all-cause mortality (ACM) predicated on novel long-T ITC complex and high sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) assays in the emergency department (ED). Methods cTn assays were measured on the Mindray CL-1200i platform at presentation in consecutive patients enrolled in ‘Mindray hs-cTnI Assay Analytical and Clinical Evaluation for the Diagnosis and RIsk Assessment of Myocardial InfarctIon’ (MERITnI) (NCT05853042) trial with suspected ischemia. Sex specific 99th percentiles upper reference limits (URLs) were: hs-cTnI female 14 ng/L, male 15 ng/L; hs-cTnT female 10 ng/L, male 19 ng/L; long-T ITC complex 0.9 ng/L, same for female and male. Results Of 1,070 patients, 59.4 % were male, 43.4 % White, 45.5 % Black, and 39.5 % ≥65 years. Independent of biomarkers, a continuum of risk over 1 year showed MACE increased to 16.1 % and ACM to 16.5 %. Long-T ITC complex did not show a continuum change, increasing only 0.1 % (HR: 1.001 (1.0–1.001) per ng/L. However, hs-cTnI increased 1.8 % (HR: 1.018 [1.009–1.027] for each ng/L (p<0.0001) and hs-cTnT increased 0.3 % per ng/L (HR: 1.003 [1.001–1.006]) (p=0.0028). Between subjects ≤URLs and >URLs, MACE and ACM all biomarkers showed significant (p<0.0001) differences over 1 year. For MACE in those >URL long-T ITC complex increased 11.2–25.2 %, hs-cTnI 18.0–35.0 % and hs-cTnT 8.9–24.2 %. For ACM in those >URL long-T ITC complex increased 4.5–23.3 %, hs-cTnI 5.0–26.2 %, and hs-cTnT 3.6–24.1 %. Conclusions Novel long-T ITC complex did not provide new prognostic value to either hs-cTnI or hs-cTnT. Patients with increased hs-cTnI and hs-cTnT concentrations had marked increases in MACE and ACM risk at 1-year.

Objectives Long-term symptoms following infection with acute respiratory syndrome coronavirus-2 (SARS-CoV-2), termed post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID (LC), persist beyond 90 days and may impact at least 10% of patients with acute infection. The exact cause of LC remains unknown, but several theories include persistent viral particles, immune dysfunction, and autonomic nervous system (ANS) imbalance, particularly involving the vagus nerve. Given the role of the vagus nerve in inflammation regulation, vagal nerve stimulation (VNS) is being explored as a treatment option. The present study aimed to evaluate the feasibility, safety, and exploratory effects of a handheld external transcutaneous cervical non-invasive VNS (tcVNS) on the primary endpoint of Post-COVID Functional Status (PCFS) grade, alongside secondary outcomes such as LC-related fatigue and other symptoms. Methods Participants from our Post COVID Care Clinic were randomized into treatment (tcVNS treatments two minutes, three times a day) and control (no VNS) groups for a study period of 12 weeks. Participants completed validated questionnaires, PET-CT scans, and inflammatory cytokines at baseline and 12 weeks. Results All randomized patients (8 tcVNS, 10 control) completed the 12-week study. Participants randomized to tcVNS were observed to have improvements in PHQ-9, PROMIS-F, and COMPASS-31 when compared to controls, but these differences were not statistically significant. Cortisol and DHEA were also observed to increase less in the tcVNS group when compared to the control group, but these changes were also not statistically significant. Conclusions tcVNS was well tolerated and may be a promising therapeutic approach for LC, a chronic disease with no approved treatments and very low rates of complete recovery.

Abstract Background We determined whether circulating cardiac troponin I–cardiac troponin T–troponin C (ITC) complex containing long-form cardiac troponin T (long-T ITC) complex and ratios of high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) could differentiate myocardial infarction (MI) from chronic and acute non-MI myocardial injuries in patients with suspected acute coronary syndrome. Methods We measured long-T ITC complex, hs-cTnI, and hs-cTnT (Mindray) at 0- and 2-h in consecutive patients enrolled in the Mindray hs-cTnI Assay Analytical and Clinical Evaluation for the Diagnosis and RIsk Assessment of Myocardial InfarctIon (MERITnI) trial. Results Among the 882 subjects studied (median 3.0 h presentation), 47 had acute MI (5.3%), 116 had acute non-MI myocardial injury, and 90 had chronic myocardial injury. At 0 and 2 h, areas under the curve (AUC) significantly differentiated acute MI from chronic myocardial injury for long-T ITC complex (0.72 and 0.81, respectively; P = 0.0082) but not acute non-MI myocardial injury (AUC, 0.65 and 0.69, respectively; P = 0.23). 0 and 2 h AUCs for long-T ITC complex/hs-cTnT and hs-cTnI/hs-cTnT ratios also significantly differentiated acute MI from chronic myocardial injury (AUC, 0.79 and 0.86, respectively) and acute non-MI myocardial injury (AUC, 0.68 and 0.71, respectively). There was no biomarker concentration or ratio value discrimination between type 1 and type 2 MIs. Conclusions Long-T ITC concentrations and long-T ITC complex/hs-cTnT and hs-cTnI/hs-cTnT ratios may clinically assist in differentiating acute MI from non-MI myocardial injuries when evaluating patients with suspected acute coronary syndrome. ClinicalTrials.gov Registration Number: NCT05853042.

Abstract Background Appendectomy has been proposed to influence ulcerative colitis (UC) outcomes, but its effect based on timing before or after diagnosis and long-term UC outcomes remains unclear. Materials and Methods Using TriNetX U.S. Collaborative Network, we identified adults with UC (2010-2024) who underwent appendectomy before or after diagnosis. Two 1:1 propensity score-matched comparisons were performed: appendectomy-before-UC and appendectomy-after-UC versus controls. The primary outcome was a 5-year composite of oral/intravenous (IV) corticosteroid use or colectomy. Secondary outcomes included individual composite outcomes and advanced therapy initiation in biologic-naive patients. Subgroup analyses stratified by age and biologic exposure were also performed. Results After matching, appendectomy after UC diagnosis showed no association with the composite outcome (aHR 0.98, 95% CI, 0.83-1.16), oral steroids (aHR 0.90, 95% CI, 0.75-1.09), IV steroids (aHR 1.11, 95% CI, 0.87-1.43), colectomy (aHR 1.24, 95% CI, 0.77-1.99), or advanced therapy initiation (aHR 0.97, 95% CI, 0.63-1.48). Appendectomy before UC diagnosis also showed no difference in the composite outcome (aHR 0.91, 95% CI, 0.76-1.09), oral steroids (aHR 0.88, 95% CI, 0.72-1.08), colectomy (aHR 0.99, 95% CI, 0.60-1.63), or advanced therapy initiation (aHR 0.77, 95% CI, 0.53-1.13). However, IV steroid use was reduced (aHR 0.68, 95% CI, 0.51-0.90, P = .006). In subgroup analyses, advanced therapy initiation was lower in patients aged 18-40 years following appendectomy after UC diagnosis (aHR 0.56, 95% CI, 0.33-0.96, P = .03). Conclusion Appendectomy was not associated with improved long-term UC outcomes of oral/IV steroid use, colectomy or initiation of advanced therapy regardless of timing.

Abstract Background: The limited efficacy of oncolytic virotherapy (OV) in gastrointestinal malignancies has been attributed to an immunologically inert tumor microenvironment. While cisplatin is widely used as a cytotoxic agent, its immunomodulatory effects remain incompletely defined. We hypothesized that cisplatin may reprogram the tumor immune landscape to enable more effective OV-mediated anti-tumor responses. Methods: We evaluated the effects of cisplatin in combination with two distinct oncolytic platforms, vesicular stomatitis virus (VSV) and adenovirus (AdV), across both in vitro and in vivo colorectal cancer models. In vivo efficacy was assessed using MC38 subcutaneous and peritoneal metastatic models, with analysis of tumor growth, survival, and toxicity. Immune profiling was performed using single-cell RNA sequencing (scRNA-seq), flow cytometry, and bulk RNA sequencing to interrogate changes in CD8+ T cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Cisplatin markedly enhanced OV-mediated anti-tumor efficacy across models, resulting in sustained tumor control and improved survival in both subcutaneous and peritoneal disease settings. This effect was conserved across viral platforms, indicating a virus-agnostic interaction. Mechanistically, cisplatin induced a robust interferon (IFN)–dominant transcriptional program, characterized by upregulation of interferon-stimulated genes, including IRF7, IRF9, and ISG15. Single-cell analysis revealed that combination therapy reshaped the CD8+ T cell compartment, promoting the expansion of a population with transcriptional and functional features of central memory T cells (Tcm), alongside reduced exhaustion signatures. These changes were accompanied by enhanced cytokine signaling pathways associated with T cell maintenance and function, including IL-2, IL-7, and IL-15. In vitro, the combination of cisplatin and OV increased tumor cell death and interferon-γ production, supporting a model in which cytotoxic and immunostimulatory effects are mechanistically linked. A phase I clinical trial has been initiated. In gastric cancer, patients with retroperitoneal metastases are being treated with OV in combination with PD-1 blockade (ongoing). In colorectal cancer, the strategy is being evaluated in the neoadjuvant setting with an rectal preservation approach. Conclusions: Our findings identify a previously unrecognized role for cisplatin in priming an interferon-driven immune program that promotes Tcm differentiation and function, thereby enabling durable responses to oncolytic virotherapy. This work provides a mechanistic rationale for leveraging chemotherapy-induced immune reprogramming to enhance viro-immunotherapy and supports the clinical translation of this strategy in gastrointestinal malignancies. Citation Format: Joseph Brandon. Parker, Zhongyi Dong, Tao Liu, Qisen Guo, Haoyu Zhang, Bo Ni, Long Bai, Yiwen Chen, Jiasheng Zong, Xiang Xia, Jiaojiao Zheng, Hoang Tran Pham, Aya Elalfy, Demarcus Ingram, Ahmed Abdel-Hakeem, Muhammad Ali, Shannon Hartzell, Zizhen Zhang, Vivienne Yang. Cisplatin primes an interferon-driven CD8+ central memory T cell program to enable oncolytic virotherapy in gastrointestinal cancer malignancies [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B024.

Abstract Seizure forecasting has progressed from theoretical aspiration to a rapidly advancing research domain, yet clinical translation remains limited. Over the past decades, advances in algorithm development, chronic electroencephalography (EEG), wearable sensors, and the characterization of seizure cycles have demonstrated that seizure risk is not random but fluctuates according to identifiable biological rhythms and patient‐specific patterns. Forecasting algorithms have shown promising performance across diverse retrospective datasets, including intracranial EEG, subscalp recordings, wearable physiological signals, and even self‐reported diaries. However, the clinical value of forecasting is contentious. Prospective real‐world validation and regulatory approval of patient‐facing forecasting systems remain rare. This review incorporates perspectives presented at the 5th International Congress on Mobile Health and Digital Technology in Epilepsy (2025). We examine barriers impeding clinical translation and current attempts to address them. Crucially, forecasting performance cannot be evaluated in isolation from intended use. Applications range from low‐risk uses, like scheduling diagnostic monitoring or visualization of historical trends, to higher risk interventions, including medication titration and adaptive neuromodulation. Each application entails distinct performance thresholds, ethical considerations, and regulatory requirements. Translational challenges include reliable seizure annotation, nonstationarity dynamics of biological cycles, and practical constraints for real‐time deployment. Ethical concerns center on miscalibrated reliance on low‐risk states, potential anxiety associated with high‐risk advisories, and the heterogeneity of patient preferences and risk tolerance. Regulatory pathways are likely to depend on clearly defined use cases and clinically meaningful endpoints, which may extend beyond seizure counts to include quality of life, anxiety, locus of control, and other patient‐reported outcomes. Ultimately, translation will require rigorous prospective evaluation against transparent benchmarks, sustainable scientific–commercial partnerships, and integration of probabilistic risk information into clinical workflows. With careful implementation, seizure forecasting may evolve from proof‐of‐concept research into a clinically meaningful component of epilepsy management, and we remain cautiously optimistic.

Background: Midfoot arthritis can cause debilitating dorsal midfoot pain and functional limitation. Deep peroneal nerve (DPN) neurectomy is a minimally invasive surgical option that addresses pain through selective denervation. Although favorable midterm outcomes have been reported, long-term durability remains unclear. The purpose of this study was to evaluate changes in patient-reported physical function and pain interference between midterm and long-term follow-up after DPN neurectomy using validated Patient-Reported Outcomes Measurement Information System (PROMIS) instruments. Methods: A retrospective review identified patients who underwent isolated DPN neurectomy for midfoot arthritis between 2017 and 2021 and completed PROMIS Physical Function (PF) and Pain Interference (PI) questionnaires at midterm and long-term follow-up. Mean follow-up was 2.9 years (midterm) and 6.1 years (long-term). PROMIS scores were compared using paired t tests. Clinically meaningful improvement was defined using established minimal clinically important difference (MCID) thresholds (+5.88 for PF, −5.49 for PI). Results: The final cohort included 32 patients (81.2% female, mean age 68.4 ± 7.3 year). PF improved from 37.7 ± 6.2 to 39.0 ± 7.5 (Δ = +1.3, 95% CI [−0.7 to +3.4], P = .188), whereas PI decreased from 62.6 ± 8.8 to 59.2 ± 9.0 (Δ = −3.4, 95% CI [−6.3 to −0.5], P = .020). Clinically meaningful improvement was achieved by 7 of 32 (21.9%) for PF and 15 of 32 (46.9%) for PI. Five patients experienced clinically meaningful worsening, including patients with stroke, chronic pain syndrome, or contralateral foot and ankle pathology or surgery. Conclusion: DPN neurectomy was associated with stable longitudinal PROMIS outcomes through extended follow-up, with a nonsignificant mean PF change of +1.3 points and a statistically significant but sub-MCID mean PI decrease of −3.4 points over approximately 6 years. Outcomes were heterogeneous; fewer than half of patients achieved clinically meaningful improvement in pain interference, and a subset experienced worsening. These findings suggest that DPN neurectomy may provide durable symptom stability in appropriately selected patients with refractory dorsal midfoot pain, although clinically meaningful benefit at the individual level is not universal. Level of Evidence: Level III, comparative series.

ABSTRACT Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty-six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid–Schiff, and Jones’ silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet’s agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet’s AC1, 0.55; 95% CI, 0.47–0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR/TI) and antibody-mediated/microvascular (AMR/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.