Invasive Group B Streptococcus Infections Caused by Hypervirulent Clone of S. agalactiae Sequence Type 283, Hong Kong, China, 2021.

During September-October 2021, group B Streptococcus bloodstream infections surged among patients hospitalized in Hong Kong. Of 95 cases, 57 were caused by the hypervirulent strain sequence type 283, which at the time was also found in freshwater fish and wet market environments and thus poses a transmission threat.

AMH protects the ovary from doxorubicin by regulating cell fate and the response to DNA damage.

Unlabelled: Anti-Müllerian hormone (AMH) protects the ovarian reserve from chemotherapy, and this effect is most pronounced with Doxorubicin (DOX). However, the mechanisms of DOX toxicity and AMH rescue in the ovary remain unclear. Herein, we characterize these mechanisms in various ovarian cell types using scRNAseq.

Incomplete Data and Potential Risks of Drugs in People with Obesity.

Purpose Of Review: To provide examples of knowledge gaps in current pharmaceutical treatments for people with obesity and call for changes to regulatory and pharmaceutical clinical research requirements during the drug discovery and development process.

Recent Findings: Treatment of obesity and its comorbidities often require the use of prescription drugs, many of which have not been fully evaluated in people with obesity. Despite a growing body of research on this topic, the impact of obesity on the pharmacokinetics and pharmacodynamics of drugs is often under-studied by drug sponsors and regulators, and subsequently underappreciated by clinicians and caretakers.

Clinical Consequences of Altered Drug Disposition in Obesity: Call for Change.

Obesity is a serious condition with many known comorbid conditions and other health risks. Despite the rising global rates of obesity, drug disposition in this population is typically understudied, which results in limited information guiding the use of drugs in patients with obesity. Presently, dosing adjustments for patients with obesity typically focus on addressing altered drug clearance with body size and are therefore limited to chronic dosing recommendations.

Estimation of Absolute and Relative Body Fat Content Using Noninvasive Surrogates: Can DXA Be Bypassed?

Dual-energy x-ray absorptiometry (DXA) scanning is used for objective determination of body composition, but instrumentation is expensive and not generally available in customary clinical practice. Anthropometric surrogates are often substituted as anticipated correlates of absolute and relative body fat content in the clinical management of obesity and its associated medical risks. DXA and anthropometric data from a cohort of 9230 randomly selected American subjects, available through the ongoing National Health and Nutrition Examination Survey, was used to evaluate combinations of surrogates (age, height, total weight, waist circumference) as predictors of DXA-determined absolute and relative body fat content.

Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies.

Background: Progressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by the common, typically benign polyomavirus 2, also known as JC virus (JCV). In a small percentage of immunosuppressed individuals, JCV is reactivated and infects the brain, causing devastating neurological defects. A wide range of immunosuppressed groups can develop PML, such as patients with: HIV/AIDS, hematological malignancies (e.

Drug Disposition in Subjects With Obesity: The Research Work of Darrell R. Abernethy.

In 1979, the late Dr. Darrell R. Abernethy and colleagues began a series of clinical studies aimed at understanding the pertinent determinants of drug distribution, elimination, and clearance in obesity, and how those variables are interconnected.

Reducing Metabolic Dysregulation in Obese Latina and/or Hispanic Breast Cancer Survivors Using Physical Activity (ROSA) Trial: A Study Protocol.

Background: Latina and Hispanic breast cancer survivors (LHBCS) are at increased risk for long-term complications and poorer metabolic health, including metabolic dysregulation (MetD) before and following breast cancer diagnosis. MetD can increase risk of cancer recurrence, death, and comorbid conditions by increasing inflammation and cancer cell proliferation. While exercise improves physical fitness and metabolic outcomes in breast cancer survivors, there is a lack of studies including underrepresented and disadvantaged minority groups such as LHBCS.

Coronavirus Disease 2019 Messenger RNA Vaccines Associated With Delayed Onset of Breakthrough Infections and Fewer Radiographic Abnormalities.

This retrospective study of incoming travelers with coronavirus disease 2019 showed that individuals immunized by messenger RNA vaccines had significantly longer postvaccination intervals (median, 30.5 days) to breakthrough infection, lower white blood cell counts and lactate dehydrogenase levels on admission, and fewer radiographic abnormalities than those immunized by inactivated virus vaccine, who paradoxically had lower respiratory viral load.

Impact of Obesity on Brexpiprazole Pharmacokinetics: Proposal for Improved Initiation of Treatment.

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia or as adjunctive treatment for major depressive disorder. As obesity (body mass index ≥35 kg/m ) has the potential to affect drug pharmacokinetics and is a common comorbidity of both schizophrenia and major depressive disorder, it is important to understand changes in brexpiprazole disposition in this population. This study uses a whole-body physiologically based pharmacokinetic model to compare the pharmacokinetics of brexpiprazole in obese and normal-weight (body mass index 18-25 kg/m ) individuals known to be cytochrome P450 2D6 extensive metabolizers (EMs) and poor metabolizers (PMs).

Brexpiprazole Pharmacokinetics in CYP2D6 Poor Metabolizers: Using Physiologically Based Pharmacokinetic Modeling to Optimize Time to Effective Concentrations.

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia, or as adjunctive treatment for major depressive disorder. As cytochrome P450 (CYP) 2D6 contributes significantly to brexpiprazole metabolism, there is a label-recommended 50% reduction in dose among patients with the CYP2D6 poor metabolizer phenotype. This study uses a whole-body physiologically based pharmacokinetic (PBPK) model to compare the pharmacokinetics of brexpiprazole in patients known to be extensive metabolizers (EMs) and poor metabolizers (PMs).

Effect of lipophilicity on drug distribution and elimination: Influence of obesity.

Aims: For a given passively-distributed lipophilic drug, the extent of in vivo distribution (pharmacokinetic volume of distribution, V ) in obese individuals increases in relation to the degree of obesity. The present study had the objective of evaluating drug distribution in relation to in vitro lipophilicity, and the relative increase in V associated with obesity across a series of drugs.

Methods: Cohorts of normal-weight control and obese subjects received single doses of drugs ranging from hydrophilic (acetaminophen, salicylate) to lipophilic (imipramine, verapamil).

Prehabilitative Exercise for the Enhancement of Physical, Psychosocial, and Biological Outcomes Among Patients Diagnosed with Cancer.

Purpose Of Review: This review summarizes the effects of prehabilitative exercise interventions on the physical, psychosocial, and biological outcomes among patients with cancer. Current gaps and future directions in prehabilitative exercise research will be addressed.

Recent Findings: Prehabilitative exercise mitigates the detrimental impact of cancer surgery on physical fitness, noted by increases in maximal oxygen consumption and 6-min walk distance.

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the brain caused by reactivation of the JC virus (JCV), a polyomavirus that infects at least 60% of the population but is asymptomatic or results in benign symptoms in most people. PML occurs as a secondary disease in a variety of disorders or as a serious adverse event from immunosuppressant agents, but is mainly found in three groups: HIV-infected patients, patients with hematological malignancies, or multiple sclerosis (MS) patients on the immunosuppressant therapy natalizumab. It is severely debilitating and is deadly in ~50% HIV cases, ~90% of hematological malignancy cases, and ~24% of MS-natalizumab cases.

HLA associations with infliximab-induced liver injury.

Biomarkers that are able to identify patients at risk of drug-induced liver injury (DILI) after treatment with infliximab could be important in increasing the safety of infliximab use. We performed a genetic analysis to identify possible human leukocyte antigen (HLA) associations with DILI in European Caucasian users of infliximab in a retrospective study of 16 infliximab-DILI patients and 60 matched controls. In infliximab-associated liver injury, multiple potentially causal individual HLA associations were observed, as well as possible haplotypes.

Quantitative Method to Track Proteolytic Invasion in 3D Collagen.

Since many tumors are associated with a pronounced collagen-rich stromal reaction, there is increasing interest in understanding mechanisms by which cancer cells invade through the collagen barrier. Here we describe a quantitative method to track cell invasion in 3D collagen I gels. We analyze invasion by quantifying proteolytic tracks generated by invading cancer cells through a 3D collagen microenvironment.

Sustained Impairment of Lurasidone Clearance After Discontinuation of Posaconazole: Impact of Obesity, and Implications for Patient Safety.

Purpose/background: The antipsychotic agent lurasidone (Latuda®) is metabolized by Cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors (such as ketoconazole, posaconazole, and ritonavir) is contraindicated due to the risk of sedation and movement disorders from high levels of lurasidone. This study evaluated the time-course of recovery from the posaconazole drug interaction, and the effect of obesity on the recovery process.

Persistence of a Posaconazole-Mediated Drug-Drug Interaction With Ranolazine After Cessation of Posaconazole Administration: Impact of Obesity and Implications for Patient Safety.

The antianginal agent ranolazine (Ranexa®) is metabolized primarily by cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors, such as ketoconazole and posaconazole, is contraindicated due to risk of QT prolongation from high levels of ranolazine. This study evaluated the time course of recovery from the posaconazole drug interaction in normal-weight and otherwise healthy obese subjects.

Vortioxetine Disposition in Obesity: Potential Implications for Patient Safety.

Background: Obesity and depression are common comorbid conditions. The objective of the study was to evaluate the effect of obesity on the pharmacokinetics of the serotonergic antidepressant vortioxetine.

Methods: Vortioxetine pharmacokinetics were evaluated in 16 otherwise healthy obese volunteers (mean weight, 119 kg; mean body mass index (BMI) 41.

Minimal Physiologically Based Pharmacokinetic and Drug-Drug-Disease Interaction Model of Rivaroxaban and Verapamil in Healthy and Renally Impaired Subjects.

Current dosing recommendations for rivaroxaban advocate dosage reduction in patients with moderate to severe renal impairment and avoidance of concomitant strong inhibitors of CYP3A or P-glycoprotein. However, rivaroxaban dosing in patients with mild renal impairment taking concomitant moderate inhibitors of CYP3A and P-glycoprotein is not addressed. To quantify the impacts of concomitant verapamil administration and renal impairment on rivaroxaban pharmacokinetics, a minimal physiologically based pharmacokinetic model system was developed and used to evaluate potential increases in rivaroxaban exposure and the consequent increase in risk of major bleeding.

Impaired Rivaroxaban Clearance in Mild Renal Insufficiency With Verapamil Coadministration: Potential Implications for Bleeding Risk and Dose Selection.

Pharmacokinetics and antithrombotic effects of the Factor Xa inhibitor rivaroxaban were studied in subjects with mild renal insufficiency concurrently taking the P-glycoprotein and moderate CYP3A inhibitor verapamil, a drug commonly administered to patients with hypertension, ischemic heart disease, or atrial fibrillation. Age-matched controls with normal renal function were studied concurrently. Subjects' overall mean age was 59 years.

Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia.

Cells in the pancreas that have undergone acinar-ductal metaplasia (ADM) can transform into premalignant cells that can eventually become cancerous. Although the epithelial-mesenchymal transition regulator Snail (Snai1) can cooperate with Kras in acinar cells to enhance ADM development, the contribution of Snail-related protein Slug (Snai2) to ADM development is not known. Thus, transgenic mice expressing Slug and Kras in acinar cells were generated.

Interaction of tRNA with MEK2 in pancreatic cancer cells.

Although the translational function of tRNA has long been established, extra translational functions of tRNA are still being discovered. We previously developed a computational method to systematically predict new tRNA-protein complexes and experimentally validated six candidate proteins, including the mitogen-activated protein kinase kinase 2 (MEK2), that interact with tRNA in HEK293T cells. However, consequences of the interaction between tRNA and these proteins remain to be elucidated.

Differential Regulation of ZEB1 and EMT by MAPK-Interacting Protein Kinases (MNK) and eIF4E in Pancreatic Cancer.

Unlabelled: Human pancreatic ductal adenocarcinoma (PDAC) tumors are associated with dysregulation of mRNA translation. In this report, it is demonstrated that PDAC cells grown in collagen exhibit increased activation of the MAPK-interacting protein kinases (MNK) that mediate eIF4E phosphorylation. Pharmacologic and genetic targeting of MNKs reverse epithelial-mesenchymal transition (EMT), decrease cell migration, and reduce protein expression of the EMT-regulator ZEB1 without affecting ZEB1 mRNA levels.

Cancer Cell Invasion in Three-dimensional Collagen Is Regulated Differentially by Gα13 Protein and Discoidin Domain Receptor 1-Par3 Protein Signaling.

Cancer cells can invade in three-dimensional collagen as single cells or as a cohesive group of cells that require coordination of cell-cell junctions and the actin cytoskeleton. To examine the role of Gα13, a G12 family heterotrimeric G protein, in regulating cellular invasion in three-dimensional collagen, we established a novel method to track cell invasion by membrane type 1 matrix metalloproteinase-expressing cancer cells. We show that knockdown of Gα13 decreased membrane type 1 matrix metalloproteinase-driven proteolytic invasion in three-dimensional collagen and enhanced E-cadherin-mediated cell-cell adhesion.