Citations

Abstract The paradigm in the field of oncolytic virotherapy proposes that tumor cell killing by an oncolytic virus (OV) culminates in the priming of antitumor CD8 T cells. However, this ignores the impact a highly immunodominant antiviral response against the OV has on the antitumor response which has been weakened by mechanisms of central tolerance. Here, we show that inflammatory Vesicular Stomatitis Virus (VSV) failed to prime an adoptively transferred, or pre-existing, population of tumor-reactive T cells.Combination with αPD1 immune checkpoint blockade therapy improved survival only when VSV expressed tumor associated antigens (TAA). These data show that, in this model, the highly inflammatory OV VSV alone actively outcompetes antitumor immunity. However, we also show that viral expression of a mutant near-self TAA can break central tolerance expanding heteroclitic self-reactive and near-self-reactive T cells, thus overcoming viral immunodominance by promoting tumor-specific T cell proliferation in parallel with expanding antiviral T cells.

ABSTRACT Background Mitral annular disjunction (MAD) carries an increased risk of complex ventricular arrhythmias, which can lead to sudden cardiac death. Many of these patients undergo implantable cardioverter defibrillator (ICD) implantation, but their ICD outcomes are not known. Objective The aim of this study was to assess the outcomes of ICD implantation and the predictors of appropriate ICD therapies in patients with MAD. Methods The study included patients with MAD who underwent ICD implantation. Clinical, electrocardiographic, cardiac imaging, and device therapy data were collected. Results Forty‐nine patients with MAD and ICD were included. Median age was 49 (21) years, and 29 (59%) were female. 13 (27%) patients underwent ICD implantation for primary prevention and 36 (73%) patients for secondary prevention. Over a median follow‐up of 27.3 (35.3) months, 23 (47%) patients received ICD therapies. 18 (37%) patients had appropriate ICD therapies, and 5 (10%) patients had inappropriate ICD shocks. Median time to first appropriate therapy was 22.3 (63.3) months. In patients with a secondary prevention ICD indication, the rate of appropriate ICD therapies was 44%, while in patients with a primary prevention ICD indication, it was 15%. Among patients with appropriate ICD therapies, the first therapies were delivered for monomorphic ventricular tachycardia (VT) in 7 (39%) patients and polymorphic VT or ventricular fibrillation (VF) in 11 (61%) patients. Patients with appropriate ICD therapies were more likely to have a history of SCA ( p = 0.003) and/or low left ventricular ejection fraction (LVEF) ( p = 0.022) before ICD implantation as compared to patients without appropriate ICD therapies. Conclusions In our cohort of patients with MAD and ICD, appropriate ICD therapies were common. Most appropriate ICD therapies were delivered for polymorphic VT or VF. Larger studies are needed to elucidate the mechanisms of VAs and refine risk stratification in MAD.

AbstractAlthough endoscopic submucosal dissection (ESD) is associated with higher en-bloc and R0 resection rates than cap-assisted endoscopic mucosal resection (cEMR), its comparative impact on achieving complete remission of dysplasia (CRD) and intestinal metaplasia (CRIM) in BE endoscopic eradication therapy (EET) is not well defined. We aimed to compare the journey of patients from initial endoscopic resection (ER) with ESD and cEMR to achieving CRD and CRIM.Patients undergoing ESD or cEMR followed by ablation for BE neoplasia at two academic institutions in the United States were included. Primary outcomes included CRD and CRIM rates following ER in the two groups. Secondary outcomes included the number of resection/ablative procedures from initial ER to achieving CRD and CRIM. Inverse probability treatment weighting (IPTW) was used to balance confounding variables between groups.A total of 801 patients (606 cEMR, 195 ESD) were included. ESD group patients had higher en-bloc resection rates (ESD 94.4%, cEMR 44.7%). Higher rates of CRD were observed in patients undergoing initial ESD (HR 1.53, P < 0.01). With time-to-event and IPTW analyses, rates of achieving CRD and CRIM were comparable between the groups. There were no significant differences in mean number of endoscopic resection or ablative procedures among patients undergoing initial cEMR resection compared with those treated with initial ESD.Despite larger lesion sizes and more cancers in patients undergoing ESD, the EET journey to achieving CRD and CRIM was comparable to that in patients receiving cEMR. Prospective studies are required to further study differences between these two treatment approaches.

Abstractα-synucleinopathies are a complex group of progressive neurodegenerative disorders with an increasingly recognized long prodromal period, during which sleep dysfunction is a hallmark. Sleep disorders during the prodromal synucleinopathy period, primarily isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and daytime hypersomnolence correlate best with the recently proposed “body-first” Lewy body disease progression. iRBD is the most widely recognized form of prodromal α-synucleinopathy, and patients with iRBD show abnormal α-synuclein in tissues and biofluids even in the absence of cognitive or motor symptoms. More importantly, individuals with iRBD have an elevated risk for near-term development of a clinically diagnosable symptomatic synucleinopathy. Other sleep disorders such as hypersomnia and circadian rhythm dysfunction also occur across the synucleinopathy spectrum, although their prognostic significance is less well understood than iRBD. Finally, isolated REM sleep without atonia may represent an even earlier stage of prodromal synucleinopathy, but further studies are needed.

ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) is a non-malignant state characterized by hematopoietic stem cells exhibiting clonality driven by acquired mutations during aging. Using next-generation sequencing, it has been reported that the prevalence of CHIP increases exponentially with age. Thus far, epigenetic mutations including DNMT3A, TET2 and ASXL1 are the most common mutations identified in driving CHIP. CHIP is considered a pre-malignant state, however with reports of its associations with non-malignant disease states, the clinical impact of CHIP has been of great interest, in particular its effect on the renal and cardiac systems. CHIP has been associated with a higher rate of estimated glomerular filtration rate decline and increased risk of acute kidney injury. CHIP and its driver mutations have also been shown to increase cardiovascular disease and atherosclerosis through various inflammatory pathways. In this review, we discuss the pathophysiology of CHIP through aging, its impact on kidney disease and implications on cardiovascular health. We also compare CHIP to another pre-malignant clonal disorder, monoclonal gammopathy of undetermined significance (MGUS).

Background and purpose: Aortic stenosis (AS) poses significant healthcare challenges, particularly in aging populations like Lebanon. Aortic valve replacement (AVR) is the primary treatment; however the choice between transcatheter aortic valve replacement (TAVR) and surgical AVR (SAVR) varies based on patient-specific factors. This study aimed to compare clinical outcomes between TAVR and SAVR in patients with severe AS at a Lebanese tertiary care center. Methods: This retrospective study included 453 patients aged ≥60 with severe AS who underwent either TAVR or SAVR at the American University of Beirut Medical Center from 2011 to 2022. Primary outcomes were 30-day mortality and hospital readmission rates. Secondary outcomes included length of stay, complications, and changes in echocardiographic parameters. Statistical analysis included Chi-squared tests, t-tests, and propensity score matching. Results: Of the 453 patients, 306 underwent TAVR, and 147 underwent SAVR, with a mean age of 79.0 ± 6.8 years. The TAVR group had higher Society of Thoracic Surgeons (STS) scores (4.7 ± 3.2 vs. 2.6 ± 1.7; P < 0.001). TAVR patients had shorter hospital stays (2 [0-93] vs. 6 [4-41] days; P < 0.001), lower 30-day readmission rates (8.2% vs. 18.5%; P = 0.002), and similar all-cause mortality rates (hazard ratio [HR]: 0.69; 95% confidence interval [95% CI]: 0.14–3.42; P = 0.647). Post-procedural new-onset left bundle branch block (LBBB) was more common in TAVR group (13.0% vs. 0.6%; P < 0.001), and new-onset atrial fibrillation (Afib) was more frequent in the SAVR group (34% vs. 1%; P < 0.001). There were no significant differences in the rates of complete heart block (CHB) or pacemaker implantation. The effective orifice area index (EOAi) was higher in the TAVR group (1.2 ± 0.4 vs. 0.9 ± 0.2 cm2/m2; P < 0.001). Major bleeding complications were significantly lower in TAVR patients (7.9% vs. 65.8%; P < 0.001), with no significant differences in neurological events. Conclusions: Both TAVR and SAVR show comparable safety and efficacy, with TAVR offering advantages in terms of recovery time and bleeding risk. These findings support a tailored approach to procedural choice based on individual patient risk profiles.

Background: While patients may report painful or prominent hardware after tibial tubercle osteotomy (TTO), little is known about the frequency, associated factors, and outcomes after removal of symptomatic hardware. Purpose/Hypothesis: The purpose was to investigate the incidence of hardware removal after TTO due to pain or complications, factors associated with hardware removal, and postoperative outcomes after removal. It was hypothesized that clinical outcomes would be similar between patients who underwent TTO without hardware removal and those who underwent TTOs and subsequently hardware removal. Study Design: Case-control study; Level of evidence, 3. Methods: A retrospective analysis was performed on patients who underwent TTO at a single institution from 2000 to 2023. Age at the time of the index surgery, sex, race, body mass index, number and size of screws, tibial tubercle–trochlear groove distance, and reason for hardware removal were collected retrospectively. Knee radiographs were reviewed for measurement of soft tissue–hardware distance. Patients were contacted via email to capture final patient-reported outcome measures (PROMs). A univariate logistic regression model was used to determine factors associated with hardware removal. Results: A total of 152 patients representing 171 knees were included. Of the overall cohort, 38 knees (22.2%) in 32 patients underwent TTO with subsequent hardware removal. The most common reason for hardware removal was anterior knee pain (79%). Compared with patients aged 11 to 20 years, patients aged 21 to 30 years demonstrated higher odds of undergoing hardware removal (OR, 3.67; 95% CI, 1.51-9.44; P = .009). Compared with a soft tissue–hardware distance of 0 to 4.9 mm, a distance of 10.0 to 14.9 mm demonstrated lower odds of hardware removal (OR, 0.24; 95% CI, 0.07-0.84; P = .027). Visual analog scale scores (0-10 scale) improved by a mean of 3.6 points after hardware removal ( P = .003). In patients undergoing hardware removal for pain, no difference in final PROMs was found compared with patients who underwent TTO without hardware removal. Conclusion: Hardware removal in patients undergoing TTO was mainly attributed to hardware-related pain/irritation. On average, pain scores improved after hardware removal. There was no difference in final PROMs between patients who had their hardware removed due to pain (eg, without any clinically relevant concomitant pathology) and patients who did not require hardware removal. Size and number of screws were not associated with a subsequent hardware removal procedure. The thickness of the soft tissue envelope overlying implanted hardware was inconsistently associated with lower odds of hardware removal.

Abstract Purpose Ultra‐low field MRI scanners have the potential to improve health care delivery, both through improved access in areas where there are few MRI scanners and allowing more frequent monitoring of disease progression and treatment response. This may be particularly true in white matter disorders, including leukodystrophies and multiple sclerosis, in which frequent myelin‐sensitive imaging, such as magnetization transfer (MT) imaging, might improve clinical care and patient outcomes. Methods We implemented an on‐resonance approach to MT imaging on a commercial point‐of‐care 64 mT scanner using a non‐balanced steady‐state free precession sequence. Phantom and in vivo experiments were used to evaluate and optimize the sequence sensitivity and reproducibility, and to demonstrate in vivo performance and inter‐site reproducibility. Results From phantom experiments, T 1 and T 2 effects were determined to have a negligible effect on the differential MT weighting. MT ratio (MTR) values in white matter were 23.1 ± 1.0% from 10 healthy volunteers, with an average reproducibility coefficient of variation of 1.04%. Normal‐appearing white matter MTR values in a multiple sclerosis participant (21.5 ± 6.2%) were lower, but with a similar spread of values, compared to an age‐matched healthy volunteer (23.3 ± 6.2%). Conclusion An on‐resonance MT imaging approach was developed at 64 mT that can be performed in as little as 4 min. A semi‐quantitative myelin‐sensitive imaging biomarker at this field strength is available for assessing both myelination and demyelination.