Citations

Intravoxel incoherent motion MRI parameters derived from two software packages demonstrated diagnostic value for breast cancer, with multivariable combinations of histogram metrics achieving high diagnostic accuracy.

Acute-on-chronic liver failure (ACLF) has been associated with excellent post-liver transplant (LT) outcomes at 1 year; however, the impact of alcohol as ACLF precipitant, specifically alcohol-associated hepatitis (AH), and as etiology of chronic liver disease remains uncertain. This study aimed to assess the effect of alcohol as ACLF precipitant and chronic liver disease etiology (alcohol-associated liver disease vs. non–alcohol-associated liver disease) on posttransplant outcomes. We performed a retrospective study using the Multi-Organ Dysfunction and Evaluation for LT Consortium database and included 640 patients with ACLF who underwent LT across 15 transplant centers in North America. The primary outcome was 1-year posttransplant survival. We used logistic regression and Cox proportional hazards to compare posttransplant survival, mortality risk, and health care utilization, adjusting for age, ACLF grade, comorbid diabetes mellitus, chronic kidney disease, and HCC. The median follow-up from LT was 2.8 years (P25–P75, 2.2–5.5 y) for patients with AH-ACLF (n=42) and 3.1 years (P25–P75, 1.6–4.9 y) for patients without AH (n=598). No significant difference was observed in 1-year survival after LT in patients with AH-ACLF versus those without AH ( p =0.36). Patients with AH had significantly higher health care utilization evidenced by greater length of stay (28.5 vs. 19.0 d, p =0.004; adjusted linear estimate 16.89, 95% CI: 7.66–26.11, p <0.001), higher rates of rehabilitation placement (71.4% vs. 41.8%, p =0.002; adjusted odds ratio: 4.13, 95% CI: 2.04–8.89, p <0.001), and non-ambulatory status (39.0% vs. 21.0%, p =0.005; adjusted odds ratio: 4.54, 95% CI: 1.90–10.79, p <0.001). Compared with other etiologies, alcohol-associated liver disease was not associated with differences in 1-year mortality, mortality risk over time, or health care utilization, after excluding patients with AH as ACLF precipitant. While there were no differences in 1-year survival, AH-ACLF was associated with higher health care resource utilization compared with other ACLF precipitants. LT centers should ensure adequate resources are allocated for the management of these patients.

Background: Breast cancer is the most common cancer that causes death among women worldwide. In Ethiopia, though there has not been an adequate study, the incidence of new cases of breast cancer is currently increasing and has become one of the most common cancer types, causing high rates of morbidity and mortality. Mutation in the BRCA1 gene in 5832insC regions has been demonstrated as the most common genetic factor that increases the occurrence of breast cancer. Thus, this study aimed to detect the frequency of 5832insC gene polymorphism in the BRCA1 gene and its associated risk factors among breast cancer-positive patients visiting the study sites. Materials and Methods: A cross-sectional study was conducted on 100 blood samples of females with breast cancer. Following genomic DNA isolation, PCR amplification was done using specific primer pairs for 5832insC BRCA1 regions. The amplified products were digested with restriction enzymes (HinfI) to detect 5382insC polymorphism. Results: Based on the findings of this study, family history was the only variable that had a significant association (P = 0.001) with 5382insC mutation in the BRCA1 gene. On the other hand, alcohol consumption (P = 0.542), age (P = 0.376), and residence zone (P = 0.856) of the participant did not show any association for this mutation. The total frequency of 5382insC BRCA1 gene mutations in the study participants was found to be 6%. Conclusion: The present study confirmed that 5382insC was the potential BRCA1 alterations that have been encountered in most breast cancer patients in the study area. The use of molecular techniques for early breast cancer detection is highly recommended to improve treatment efficiency and minimize the rate of mortality.

Rubella is typically a mild viral illness, but it can lead to severe complications when contracted during pregnancy, such as pregnancy loss or developmental defects in the fetus (congenital rubella syndrome). Therefore, it is crucial to develop and maintain protective immunity in women of childbearing age. In this study, we assessed the transcriptional factors associated with rubella-specific immune outcomes (IgG binding antibody and avidity, neutralizing antibody, and memory B cell ELISpot response) following a third MMR vaccine dose in women of reproductive age to identify key factors/signatures impacting the immune response. We identified baseline (Day 0) and differentially expressed (Day 28–Day 0) genes associated with several RV-specific immune outcomes, including the transferrin receptor 2 (TFR2), which is an important factor regulating iron homeostasis and macrophage functional activity, and a close functional homolog of TFR1, the cellular receptor of the New World hemorrhagic fever arenaviruses. We also identified enriched KEGG pathways, “cell adhesion molecules”, “antigen processing and presentation”, “natural killer cell-mediated cytotoxicity”, and “immune network for IgA production”, relevant to immune response priming and immune activation to be associated with RV-specific immune outcomes. This study provides novel insights into potential biomarkers of rubella-specific immunity in women of childbearing age.

ABSTRACT Background To explore the prevalence of serious adverse events ( SAEs ) associated with retinal viral gene therapy and to examine trends influencing SAE occurrences in human gene therapy surgeries and pre‐clinical animal trials. Methods Literature review was performed to identify peer‐reviewed human and animal studies relevant to viral gene therapy, subretinal injections, and intravitreal injections. For clinical trials and post‐approval LUXTURNA studies, only those that examined SAEs were included. Results Of included clinical trial studies ( n = 31), SAEs were recorded in 51 out of 438 eyes (11.6%) that received subretinal injections and in 11 out of 348 eyes (3.2%) that received intravitreal injections. There were fewer intravitreal‐related SAEs and less vision loss compared to subretinal gene therapy. Inflammation was the predominant SAE following intravitreal injections, whereas unexplained vision loss was the most common for subretinal injections. Clinical trials utilising subretinal injections met primary or secondary efficacy endpoints more than intravitreal trials. Eighteen studies (429 eyes) of post‐approval LUXTURNA were reviewed, and SAEs were reported in 24.7% of eyes, retinal degeneration being most common (20.7%). For 58 animal studies, SAEs were recorded in 17.3% of eyes that received subretinal injections and 8.7% of eyes that received intravitreal injections. Conclusions Subretinal injections show higher efficacy than intravitreal injections but are associated with more serious adverse events. Consistent adverse event patterns in humans and large animals highlight their predictive value for safety. There is a need for optimised delivery methods, refined dosing protocols, and improved post‐treatment monitoring to improve safety and effectiveness in gene therapy.

Abstract Background and Aims Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. Methods KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). Results In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Conclusions This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

Abstract The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P&lt; .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P&lt; .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T–related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.