Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis.

Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes.

Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy.

Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation and changes in brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation and lipid metabolism, is produced by cholesterol 25-hydroxylase encoded by Ch25h expressed as a "disease-associated microglia" signature gene. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown.

Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies.

Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients.

Metabolomic profiles of sleep-disordered breathing are associated with hypertension and diabetes mellitus development.

Sleep-disordered breathing (SDB) is a prevalent disorder characterized by recurrent episodic upper airway obstruction. Using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we apply principal component analysis (PCA) to seven SDB-related measures. We estimate the associations of the top two SDB PCs with serum levels of 617 metabolites, in both single-metabolite analysis, and a joint penalized regression analysis.

Cardiovascular and Locomotor Effects of Binary Mixtures of Common "Bath Salts" Constituents: Studies with Methylone, MDPV, and Caffeine in Rats.

Background And Purpose: The use of "Bath Salts" drug preparations has been associated with high rates of toxicity and death. Preparations often contain mixtures of drugs including multiple synthetic cathinones or synthetic cathinones and caffeine; however, little is known about whether interactions among "Bath Salts" constituents contribute to the adverse effects often reported in users.

Experimental Approach: This study used adult male Sprague-Dawley rats to characterize the cardiovascular effects, locomotor effects, and pharmacokinetics of methylone, MDPV, and caffeine, administered alone and as binary mixtures.

Cannabis Use and Biomarkers of Inflammation, Immune Activation, and Microbial Translocation in Persons with HIV.

The relationship between cannabis and inflammation among persons with HIV (PWH) remains unclear. We examined whether the cannabis metabolite 11-nor-9-carboxy THC (THC-COOH) is associated with lower levels of plasma biomarkers of inflammation, immune activation, and microbial translocation in PWH. We hypothesized that cannabis use would be associated with lower levels of plasma inflammatory biomarkers than noncannabis use.

Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission.

The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau.

Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3.

Purpose: Pembrolizumab is standard therapy for patients with metastatic urothelial cancer (mUC) who progress after first-line platinum-based chemotherapy; however, only approximately 21% of patients respond. Sacituzumab govitecan (SG) is a trophoblast cell surface antigen-2-directed antibody-drug conjugate with US Food and Drug Administration-accelerated approval to treat patients with locally advanced or mUC who previously received platinum-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report the primary analysis of TROPHY-U-01 cohort 3.

Peritoneal Microenvironment Promotes Appendiceal Adenocarcinoma Growth: A Multi-omics Approach Using Patient-Derived Xenografts.

Unlabelled: Appendiceal adenocarcinoma (AA) is unique from other gastrointestinal malignancies in that it almost exclusively metastasizes to the peritoneal cavity. However, few studies have investigated the molecular interaction of the peritoneal microenvironment and AA. Here, we use a multi-omics approach with orthotopic and flank-implanted patient-derived xenografts (PDX) to study the effect of the peritoneal microenvironment on AA.

Microwave disinfection of facial silicone prostheses, part 2: Mechanical properties.

Statement Of Problem: Part 1 of this 2-part study determined that microwave disinfection did not degrade the color stability of facial silicone prostheses. However, investigations on the effects of microwave disinfection on the mechanical properties of different silicone elastomers are lacking.

Purpose: The purpose of this in vitro study was to examine the mechanical properties of commonly used colored facial silicone elastomers before and after microwave disinfection over a simulated 1.

Mediators of necroptosis: from cell death to metabolic regulation.

Necroptosis, a programmed cell death mechanism distinct from apoptosis, has garnered attention for its role in various pathological conditions. While initially recognized for its involvement in cell death, recent research has revealed that key necroptotic mediators, including receptor-interacting protein kinases (RIPKs) and mixed lineage kinase domain-like protein (MLKL), possess additional functions that go beyond inducing cell demise. These functions encompass influencing critical aspects of metabolic regulation, such as energy metabolism, glucose homeostasis, and lipid metabolism.

Enriching Real-world Data with Social Determinants of Health for Health Outcomes and Health Equity: Successes, Challenges, and Opportunities.

Objective: To summarize the recent methods and applications that leverage real-world data such as electronic health records (EHRs) with social determinants of health (SDoH) for public and population health and health equity and identify successes, challenges, and possible solutions.

Methods: In this opinion review, grounded on a social-ecological-model-based conceptual framework, we surveyed data sources and recent informatics approaches that enable leveraging SDoH along with real-world data to support public health and clinical health applications including helping design public health intervention, enhancing risk stratification, and enabling the prediction of unmet social needs.

Results: Besides summarizing data sources, we identified gaps in capturing SDoH data in existing EHR systems and opportunities to leverage informatics approaches to collect SDoH information either from structured and unstructured EHR data or through linking with public surveys and environmental data.

Shifts in stimulus control over opioid use with increasing periods of recovery.

Background: Periods of engaging in an alternative behavior diminishes behavioral control by stimuli occasioning alcohol use. This increase in relapse resistance with increasing recovery suggests that changing stimulus control over substance use may be a mechanism responsible for decreased relapse rates with longer recovery. However, the generality of this phenomenon to other drugs of abuse, including opioid self-administration, remains unclear.

Design and optimization of piperlongumine analogs as potent senolytics.

Selective removal of senescent cells (SnCs) offers a promising therapeutic strategy to treat chronic and age-related diseases. Our prior investigations led to the discovery of piperlongumine (PL) and its derivatives as senolytic agents. In this study, our medicinal chemistry campaign on both the α,β-unsaturated δ-valerolactam ring and the phenyl ring of PL culminated in the identification of compound 24, which exhibited an impressive 50-fold enhancement in senolytic activity against senescent WI-38 fibroblasts compared to PL.

Integrated omics analysis of coronary artery calcifications and myocardial infarction: the Framingham Heart Study.

Gene function can be described using various measures. We integrated association studies of three types of omics data to provide insights into the pathophysiology of subclinical coronary disease and myocardial infarction (MI). Using multivariable regression models, we associated: (1) single nucleotide polymorphism, (2) DNA methylation, and (3) gene expression with coronary artery calcification (CAC) scores and MI.

Outcomes of mechanical thrombectomy in stroke patients with extreme large infarction core.

Background: Recent clinical trials have demonstrated that patients with large vessel occlusion (LVO) and large infarction core may still benefit from mechanical thrombectomy (MT). In this study, we evaluate outcomes of MT in LVO patients presenting with extremely large infarction core Alberta Stroke Program Early CT Score (ASPECTS 0-2).

Methods: Data from the Stroke Thrombectomy and Aneurysm Registry (STAR) was interrogated.

Circulating metabolites may illustrate relationship of alcohol consumption with cardiovascular disease.

Background: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD.

Methods: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women).

Metabolomic profiles associated with physical activity in White and African American adult men.

Background: Physical activity (PA) is associated with various health benefits, especially in improving chronic health conditions. However, the metabolic changes in host metabolism in response to PA remain unclear, especially in racially/ethnically diverse populations.

Objective: This study is to assess the metabolic profiles associated with the frequency of PA in White and African American (AA) men.