Real-world, Multicenter Experience With Meropenem-Vaborbactam for Gram-Negative Bacterial Infections Including Carbapenem-Resistant Enterobacterales and Pseudomonas Aeruginosa

Background: We aimed to describe the clinical characteristics and outcomes of patients treated with meropenem-vaborbactam (MEV) for a variety of gram-negative infections (GNIs), primarily including carbapenem-resistant Enterobacterales (CRE). Methods: This is a real-world, multicenter, retrospective cohort within the United States between 2017 and 2020. Adult patients who received MEV for ≥72 hours were eligible for inclusion. The primary outcome was 30-day mortality. Classification and regression tree analysis (CART) was used to identify the time breakpoint (BP) that delineated the risk of negative clinical outcomes (NCOs) and was examined by multivariable logistic regression analysis (MLR). Results: Overall, 126 patients were evaluated from 13 medical centers in 10 states. The most common infection sources were respiratory tract (38.1%) and intra-abdominal (19.0%) origin, while the most common isolated pathogens were CRE (78.6%). Thirty-day mortality and recurrence occurred in 18.3% and 11.9%, respectively. Adverse events occurred in 4 patients: nephrotoxicity (n = 2), hepatoxicity (n = 1), and rash (n = 1). CART-BP between early and delayed treatment was 48 hours (P = .04). MEV initiation within 48 hours was independently associated with reduced NCO following analysis by MLR (adusted odds ratio, 0.277; 95% CI, 0.081-0.941). Conclusions: Our results support current evidence establishing positive clinical and safety outcomes of MEV in GNIs, including CRE. We suggest that delaying appropriate therapy for CRE significantly increases the risk of NCOs

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Biological differences underlying sex and gender disparities in bladder cancer: current synopsis and future directions

Abstract Sex and gender disparities in bladder cancer have long been a subject of interest to the cancer research community, wherein men have a 4 times higher incidence rate than women, and female patients often present with higher-grade disease and experience worse outcomes. Despite the known differences in disease incidence and clinical outcomes between male and female bladder cancer patients, clinical management remains the same. In this review, we critically analyze studies that report on the biological differences between men and women and evaluate how these differences contribute to sex and gender disparities in bladder cancer. Distinct characteristics of the male and female immune systems, differences in circulating hormone levels and hormone receptor expression, and different genetic and epigenetic alterations are major biological factors that all likely contribute to disparate incidence rates and outcomes for male and female bladder cancer patients. Future preclinical and clinical studies in this area should employ experimental approaches that account for and consider sex and gender disparities in bladder cancer, thereby facilitating the development of precision medicine for the effective treatment of bladder cancer in all patients

STAG2 expression is associated with adverse survival outcomes and regulates cell phenotype in muscle-invasive bladder cancer

Stromal antigen 2 (STAG2), in healthy somatic cells, functions in sister chromatid cohesion, DNA damage repair, and genome organization, but its role in muscle-invasive bladder cancer (MIBC) remains unknown. Here, using whole-exome and targeted sequencing (n = 119 bladder cancer clinical samples), we found several STAG2 mutations in MIBC that correlate with loss of protein expression. The analysis of a bladder cancer tissue microarray (n = 346) revealed that decreased STAG2 protein expression is associated with improved overall and progression-free survival for patients with MIBC. In mouse xenograft studies, STAG2 knockdown (KD) decelerated MIBC tumor growth, whereas STAG2 overexpression accelerated tumor growth. In cell line studies, STAG2 loss augmented treatment with cisplatin, a first-line therapy for MIBC. STAG2 KD or overexpression did not alter degree of aneuploidy, copy-number variations, or cell-cycle distribution. However, unbiased RNA-sequencing analysis revealed that STAG2 KD altered gene expression. STAG2 KD led to significant downregulation of several gene sets, such as collagen containing extracellular matrix, external encapsulating structure organization, and regulation of chemotaxis. Therefore, we investigated the effect of STAG2 KD on cell migration and invasion in vitro. We found that STAG2 KD minimized cell speed, displacement, and invasion. Altogether, our results present a noncanonical function of STAG2 in promoting cell motility and invasion of MIBC cells. This work forms the basis for additional investigation into the role of STAG2 in transcriptional regulation and how it becomes dysregulated in STAG2-mutant MIBC. Significance: The cohesin component STAG2 regulates cell motility and invasion. STAG2 expression is associated with decreased MIBC survival and may be a useful biomarker to guide bladder cancer treatment

Real-world, Multicenter Experience With Meropenem-Vaborbactam for Gram-Negative Bacterial Infections Including Carbapenem-Resistant Enterobacterales and Pseudomonas aeruginosa

Abstract Background We aimed to describe the clinical characteristics and outcomes of patients treated with meropenem-vaborbactam (MEV) for a variety of gram-negative infections (GNIs), primarily including carbapenem-resistant Enterobacterales (CRE). Methods This is a real-world, multicenter, retrospective cohort within the United States between 2017 and 2020. Adult patients who received MEV for ≥72 hours were eligible for inclusion. The primary outcome was 30-day mortality. Classification and regression tree analysis (CART) was used to identify the time breakpoint (BP) that delineated the risk of negative clinical outcomes (NCOs) and was examined by multivariable logistic regression analysis (MLR). Results Overall, 126 patients were evaluated from 13 medical centers in 10 states. The most common infection sources were respiratory tract (38.1%) and intra-abdominal (19.0%) origin, while the most common isolated pathogens were CRE (78.6%). Thirty-day mortality and recurrence occurred in 18.3% and 11.9%, respectively. Adverse events occurred in 4 patients: nephrotoxicity (n = 2), hepatoxicity (n = 1), and rash (n = 1). CART-BP between early and delayed treatment was 48 hours (P = .04). MEV initiation within 48 hours was independently associated with reduced NCO following analysis by MLR (adusted odds ratio, 0.277; 95% CI, 0.081–0.941). Conclusions Our results support current evidence establishing positive clinical and safety outcomes of MEV in GNIs, including CRE. We suggest that delaying appropriate therapy for CRE significantly increases the risk of NCOs