Investigation of etravirine uptake and distribution in single aortic endothelial cells using Raman imaging.

Etravirine (ETV) is an antiretroviral agent that belongs to the class of non-nucleoside reverse transcriptase inhibitors. This study explores the uptake and distribution of ETV in human aortic endothelial cells (HAECs) using Raman spectroscopy combined with chemometrics. The distinctive chemical structure of ETV facilitates tracking of its uptake by observing the Raman band at 2225 cm in the Raman-silent region.

Meta-analysis and public policy: Reconciling the evidence on deworming.

The WHO recommends mass drug administration (MDA) for intestinal worm infections in areas with over 20% infection prevalence. Recent Cochrane meta-analyses endorse treatment of infected individuals but recommend against MDA. We conducted a theory-agnostic random-effects meta-analysis of the effect of multiple-dose MDA and a cost-effectiveness analysis.

Mapping Interindividual Variability of Toxicodynamics Using High-Throughput Transcriptomics and Primary Human Hepatocytes from Fifty Donors.

Background: Understanding the variability across the human population with respect to toxicodynamic responses after exposure to chemicals, such as environmental toxicants or drugs, is essential to define safety factors for risk assessment to protect the entire population. Activation of cellular stress response pathways are early adverse outcome pathway (AOP) key events of chemical-induced toxicity and would elucidate the estimation of population variability of toxicodynamic responses.

Objectives: We aimed to map the variability in cellular stress response activation in a large panel of primary human hepatocyte (PHH) donors to aid in the quantification of toxicodynamic interindividual variability to derive safety uncertainty factors.

A Systematic Review of Human Challenge Trials, Designs, and Safety.

Background: Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective.

Methods: A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021.

Assessing the Combined Public Health Impact of Pharmaceutical Interventions on Pandemic Transmission and Mortality: An Example in SARS CoV-2.

To assess the combined role of anti-viral monoclonal antibodies (mAbs) and vaccines in reducing severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) transmission and mortality in the United States, an agent-based model was developed that accounted for social contacts, movement/travel, disease progression, and viral shedding. The model was calibrated to coronavirus disease 2019 (COVID-19) mortality between October 2020 and April 2021 (aggressive pandemic phase), and projected an extended outlook to estimate mortality during a less aggressive phase (April-August 2021). Simulated scenarios evaluated mAbs for averting infections and deaths in addition to vaccines and aggregated non-pharmaceutical interventions.

Testing fractional doses of COVID-19 vaccines.

Due to the enormous economic, health, and social costs of the COVID-19 pandemic, there are high expected social returns to investing in parallel in multiple approaches to accelerating vaccination. We argue there are high expected social returns to investigating the scope for lowering the dosage of some COVID-19 vaccines. While existing evidence is not dispositive, available clinical data on the immunogenicity of lower doses combined with evidence of a high correlation between neutralizing antibody response and vaccine efficacy suggests that half or even quarter doses of some vaccines could generate high levels of protection, particularly against severe disease and death, while potentially expanding supply by 450 million to 1.

Human variability in polymorphic CYP2D6 metabolism: Implications for the risk assessment of chemicals in food and emerging designer drugs.

The major human cytochrome P450 CYP2D6 isoform enzyme plays important roles in the liver and in the brain with regards to xenobiotic metabolism. Xenobiotics as CYP2D6 substrates include a whole range of pharmaceuticals, pesticides and plant alkaloids to cite but a few. In addition, a number of endogenous compounds have been shown to be substrates of CYP2D6 including trace amines in the brain such as tyramine and 5-methoxytryptamine as well as anandamide and progesterone.

Exploring Risks of Human Challenge Trials For COVID-19.

Human challenge trials (HCTs) are a potential method to accelerate development of vaccines and therapeutics. However, HCTs for COVID-19 pose ethical and practical challenges, in part due to the unclear and developing risks. In this article , we introduce an interactive model for exploring some risks of a severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) dosing study, a prerequisite for any COVID-19 challenge trials.

Secukinumab's effect on structural damage progression in psoriatic arthritis: longitudinal mixture modelling of FUTURE-1 and FUTURE-5.

Objectives: Peripheral and axial manifestations of psoriatic arthritis (PsA) can lead to irreversible structural damage and chronic disability. Our objective was to explore predictors of radiographic progression and to increase our understanding of treatment effects in subgroups of patients with different rates of structural damage progression.

Methods: We analysed data from two large Phase-3 trials of secukinumab in PsA patients, FUTURE-1 (NCT01392326, n=606) and FUTURE-5 (NCT02404350, n=996), where different posologies ranging from 75 mg to 300 mg were used.

Inter-phenotypic differences in CYP2C9 and CYP2C19 metabolism: Bayesian meta-regression of human population variability in kinetics and application in chemical risk assessment.

Quantifying variability in pharmacokinetics (PK) and toxicokinetics (TK) provides a science-based approach to refine uncertainty factors (UFs) for chemical risk assessment. In this context, genetic polymorphisms in cytochromes P450 (CYPs) drive inter-phenotypic differences and may result in reduction or increase in metabolism of drugs or other xenobiotics. Here, an extensive literature search was performed to identify PK data for probe substrates of the human polymorphic isoforms CYP2C9 and CYP2C19.

The Yin-Yang of CYP3A4: a Bayesian meta-analysis to quantify inhibition and induction of CYP3A4 metabolism in humans and refine uncertainty factors for mixture risk assessment.

Quantifying differences in pharmacokinetics (PK) and toxicokinetics (TK) provides a science-based approach to refine uncertainty factors (UFs) for chemical risk assessment. Cytochrome P450 (CYP) 3A4-the major hepatic and intestinal human CYP-and the P-glycoprotein (Pgp) transporter share a vast range of common substrates for which PK may be modulated through inhibition or induction in the presence of grapefruit juice (GFJ) or St. John's wort (SJW), respectively.

Cabozantinib Versus Standard-of-Care Comparators in the Treatment of Advanced/Metastatic Renal Cell Carcinoma in Treatment-naïve Patients: a Systematic Review and Network Meta-Analysis.

Background: Cabozantinib has recently been evaluated as a first-line treatment in advanced renal cell carcinoma (aRCC).

Objective: To indirectly assess efficacy of cabozantinib versus standard-of-care (SoC) comparators in the first-line treatment of aRCC.

Methods: We conducted a systematic literature review (SLR) to identify randomized controlled studies in the first-line setting for aRCC.

Impact of increased influenza vaccination in 2-3-year-old children on disease burden within the general population: A Bayesian model-based approach.

Introduction: During the 2013-2014 influenza season, Public Health England extended routine influenza vaccination to all 2- and 3-year-old children in England. To estimate the impact of this change in policy on influenza-related morbidity and mortality, we developed a disease transmission and surveillance model informed by real-world data.

Methods: We combined real-world and literature data sources to construct a model of influenza transmission and surveillance in England.

A retrospective observational analysis of post-pandemic influenza-related outcomes in the United Kingdom, 2010-2014.

This study set out to evaluate influenza- and respiratory-related illnesses recorded during primary care physician consultations in England following the H1N1 pandemic in 2009 and to enable the development of a dynamic disease model. Data were obtained from the Clinical Practice Research Datalink of primary care records over four influenza seasons (2010-2014). The primary outcome of the study was incidence of influenza- and respiratory-related diagnoses, calculated per practice and by season and age group.

Nivolumab versus Cabozantinib: Comparing Overall Survival in Metastatic Renal Cell Carcinoma.

Renal-cell carcinoma (RCC) affects over 330,000 new patients every year, of whom 1/3 present with metastatic RCC (mRCC) at diagnosis. Most mRCC patients treated with a first-line agent relapse within 1 year and need second-line therapy. The present study aims to compare overall survival (OS) between nivolumab and cabozantinib from two recent pivotal studies comparing, respectively, each one of the two emerging treatments against everolimus in patients who relapse following first-line treatment.

[Stress urinary incontinence treatment using Surgimesh® Sling, evolution on patient quality of life and sexual activity during 12 months follow-up].

Introduction: Evaluation of quality of life (QOL) and sexual activity after using sub-urethral Surgimesh® Sling for female stress urinary incontinence (SUI).

Methods: Study with a total duration of 12 months. One hundred and sixty-eight patients presenting a SUI underwent surgery for a Surgimesh® Sling implantation.