Consistency in treatment effects and statistical significance between early-stage pregnancy endpoints and live birth in randomized controlled trials of infertility: a systematic meta-epidemiological study.

Importance: Live births are the 'gold standard' for assessing infertility treatments but are less frequently reported than clinical pregnancy. Identifying approaches to interpret randomized controlled trials (RCTs) without live birth data is essential.

Objective: To evaluate the correlation between treatment effects and the consistency of statistical significance in conclusions drawn from live birth versus early-stage pregnancy endpoints (an umbrella term defined as biochemical, clinical, or ongoing pregnancy) in RCTs reporting both outcomes.

Effect of pemafibrate on high-density lipoprotein cholesterol levels and subspecies in a patient with cholesteryl ester transfer protein deficiency: A case report with mechanistic insights.

Cholesteryl ester transfer protein (CETP) deficiency is a representative molecular abnormality in familial hyperalphalipoproteinemia, a hereditary disorder of lipid metabolism characterized by markedly elevated plasma high-density lipoprotein cholesterol (HDL-C) levels. In this condition, dysfunction of CETP, which mediates the transfer of cholesteryl esters from HDL particles to apolipoprotein (Apo)B-containing lipoproteins, leads to the abnormal accumulation of HDL-C. These HDL particles are unusually large and enriched in cholesteryl esters, ApoCIII, and ApoE, whereas low-density lipoprotein (LDL) particles are small, depleted of cholesteryl esters, and enriched in triglycerides.

Hepatocellular Carcinoma Recurrence in Patients with Chronic Hepatitis C Infection Treated with Direct-Acting Antivirals: A Systematic Review and Meta-Analysis.

Introduction: Reports of direct-acting antivirals (DAA) use for chronic hepatitis C virus (HCV) infection after successful treatment of hepatocellular carcinoma (HCC) have suggested higher rates of HCC recurrence. However, other studies have indicated no increased risk of HCC recurrence.

Methods: To estimate the comparative risk of early HCC recurrence in adults successfully treated for HCC and subsequently treated with interferon (IFN)-free DAAs versus not treated with DAAs for chronic HCV, we conducted a systematic literature review and meta-analysis following established guidelines.

Safety and Immunogenicity of a Pneumococcal Conjugate Vaccine When Administered Concomitantly With Routine Pediatric Vaccines in Healthy Toddlers and Infants.

Background: A 21-valent pneumococcal conjugate vaccine, PCV21, was developed to provide broader coverage against Streptococcus pneumoniae serotypes. PCV21 comprises 13 serotypes common to a licensed 13-valent pneumococcal conjugate vaccine (PCV13) and 8 additional serotypes. This study evaluated 3 PCV21 formulations with differences in antigen content for some serotypes, compared with PCV13, administered concomitantly with routine pediatric vaccines.

Significance of Pulmonary Vascular Dysfunction in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is frequently accompanied by abnormalities of the pulmonary vasculature. This vasculopathy spans the spectrum from mild vascular dysfunction to pulmonary hypertension, which on rare occasions can be severe. Given the worldwide prevalence of COPD, it is conceivable that the morbidity and mortality associated with pulmonary vascular dysfunction have been vastly underappreciated, especially in countries and regions where the infrastructure and resources to define the magnitude of the problem are often limited.

Efficacy of Revolution® Plus (selamectin plus sarolaner) against Amblyomma americanum (lone star ticks) in cats.

Background: The efficacy of a topical combination product, Revolution® Plus, containing selamectin and sarolaner was evaluated for efficacy against Amblyomma americanum ticks in cats.

Methods: Four laboratory dose confirmation efficacy studies were conducted in different geographical regions of the USA using three distinct US isolates of A. americanum.

Immunogenicity and Safety of a Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) Administered with Routine Pediatric Vaccines: A European Randomized Controlled Trial.

Introduction: The immunogenicity and safety of MenACYW-TT (MenQuadfi) were compared to another quadrivalent meningococcal conjugate vaccine, MCV4-TT (Nimenrix), when administered in infants alongside routine childhood vaccines in Europe.

Methods: One set of healthy infants was randomized 1:1 to receive MenACYW-TT (group 1; n = 714) or MCV4-TT (group 2; n = 726) at age 2, 4, and 12-18 months (2 + 1 regimen) concomitantly with routine vaccines (including 10-valent pneumococcal conjugate vaccine). Another set was randomized 1:1 to receive MenACYW-TT in a 2 + 1 regimen (group 3; n = 112) or a 3 + 1 regimen at age 2, 4, 6, and 12-18 months (group 4; n = 108) concomitantly with routine vaccines (including 13-valent pneumococcal conjugate vaccine).

Therapeutic potential of targeting LAG-3 in cancer.

Immune checkpoint inhibitors targeting negative regulatory checkpoints including programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 have produced significant improvements in progression-free survival (PFS) and overall survival in multiple solid tumors. Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that is highly expressed by exhausted T cells. Dual blockade of LAG-3 and PD-1 with monoclonal antibodies relatlimab and nivolumab has improved PFS in advanced melanoma, leading to Food and Drug Administration approval for this indication.

A phase 3, randomized trial to evaluate lot-to-lot consistency of V116, an adult-specific pneumococcal conjugate vaccine (STRIDE-4).

Background: Streptococcus pneumoniae infection can lead to community-acquired pneumonia and invasive pneumococcal disease (IPD), conditions associated with substantial morbidity and mortality. V116 (Merck & Co., Inc.

Immunogenicity risk assessment for tailored mitigation and monitoring of biotherapeutics during development: recommendations from the European Immunogenicity Platform.

Bringing safe and effective drugs to patients is of utmost importance for the pharmaceutical industry, with immunogenicity (IG) being a critical factor that influences both aspects. Biotherapeutics can elicit unwanted immune responses, potentially leading to (severe) safety implications, reduced patient benefits, and may result in termination of development. Therefore, understanding IG risks throughout drug development is essential for both drug developers and health agencies (HAs).

Effects of Pemafibrate on Cholesterol Synthesis and Absorption: a Post-Hoc Subgroup Analysis of a Phase 2 Clinical Trial.

Aim: Recently, we reported that a pemafibrate extended-release (XR) formulation lowered low-density lipoprotein cholesterol (LDL-C) and cholesterol synthesis and absorption markers in a phase 2 clinical pharmacology study. Here we describe our post-hoc analysis of that study, discuss the mechanism by which pemafibrate lowers LDL-C, and suggest which patients may respond favorably to pemafibrate treatment.

Methods: In the phase 2 study, patients with hypertriglyceridemia received treatment with pemafibrate immediate-release (IR) 0.

Evaluation of Anti-SARS-CoV-2 IgG Responses in a Clinical Study of a Biosimilar Candidate to Denosumab Using Singlicate Analysis.

Background And Objectives: During the coronavirus disease-2019 (COVID-19) pandemic there was the uncertainty that the long-term immune response generated upon natural infection or triggered by available severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) vaccines could impact the clinical endpoints of ongoing clinical trials, in particular, whether the immunogenicity of biotherapeutics could be affected.

Methods: Here, we describe the different stages to build an adequate COVID-19 serology testing strategy to ultimately assess whether the presence of anti-SARS-CoV-2 antibodies could impact the immunogenicity data of a clinical trial supporting the approval of GP2411 (Jubbonti/Wyost; a denosumab biosimilar to Prolia/XGeva) conducted during the pandemic. We first assessed the sensitivity and specificity of US Food and Drug Administration Emergency Use Authorization (FDA EUA)-approved commercial SARS-CoV-2 anti-IgG enzyme-linked immunosorbent (ELISA) assay.

Evaluating the Impact of Hepatic or Renal Impairment on Tanimilast (CHF6001) Pharmacokinetics: Two Open-Label, Parallel-Group, Single-Center Studies.

Tanimilast is an inhaled phosphodiesterase-4 inhibitor in development for chronic obstructive pulmonary disease and asthma. We conducted two studies to evaluate tanimilast pharmacokinetics, one in subjects with mild, moderate, or severe hepatic impairment and matched healthy controls, and one in subjects with mild, moderate, or severe renal impairment and matched healthy controls. Both studies were single-center, open-label, and parallel group; all subjects inhaled a single 800 μg dose of tanimilast.

Nerandomilast in Patients with Progressive Pulmonary Fibrosis.

Background: Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory properties. Nerandomilast has been shown to slow the progression of idiopathic pulmonary fibrosis, but an assessment of its effects in other types of progressive pulmonary fibrosis is needed.

Methods: In a phase 3, double-blind trial, we randomly assigned patients with progressive pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background therapy (nintedanib vs.

Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis.

Background: Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory effects. In a phase 2 trial involving patients with idiopathic pulmonary fibrosis, treatment with nerandomilast stabilized lung function over a period of 12 weeks.

Methods: In this phase 3, double-blind trial, we randomly assigned patients with idiopathic pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background antifibrotic therapy (nintedanib or pirfenidone vs.

Liquid and Tissue Biopsies for Identifying MET Exon 14 Skipping NSCLC: Analyses from the Phase II VISION Study of Tepotinib.

Purpose: The VISION trial of tepotinib, a selective MET inhibitor, enrolled patients with non-small cell lung cancer and prospectively detected MET exon 14 (METex14) skipping in liquid biopsies (LBx) and/or tissue biopsies (TBx). We evaluated patient characteristics and outcomes according to METex14 positivity in LBx (LBx-positive) or TBx (TBx-positive).

Experimental Design: METex14 was centrally assessed by next-generation sequencing of ctDNA from LBx (Guardant360/ArcherMET) and/or RNA from TBx (Oncomine Focus/ArcherMET) or, in Japan only, local TBx PCR.

Pharmacokinetics and Safety of a Fixed-Dose Combination of Alogliptin and Extended-Release Metformin Under Fasting and/or Fed Conditions in Healthy Adults.

This phase 1, randomized, open-label, 2 × 2 crossover study evaluated the bioequivalence of fixed-dose combination (FDC) formulations of alogliptin (ALO) and metformin extended-release (MET XR) compared to their individual formulations and assessed the effect of food on FDC pharmacokinetics in healthy participants. The study comprised the high-dose bioequivalence study (ALO 25 mg/MET XR 1000 mg) and the low-dose bioequivalence study (ALO 12.5 mg/MET XR 500 mg), both conducted under fasting conditions, and the food effect study (ALO 12.

The low global warming potential propellant HFA-152a does not induce bronchoconstriction or impair mucociliary clearance.

Introduction: Use of propellants with high global warming potential (e.g., HFA-134a) for pressurised metered-dose inhalers is being phased down.

Up-regulated microRNAs in blastocoel fluid of human implanted embryos could control circuits of pluripotency and be related to embryo competence.

Purpose: The paper aims to investigate the biological role of microRNAs secreted by preimplantation embryo into the blastocoel fluid and to detect a distinctive molecular signature for identifying embryos with the highest implantation potential.

Methods: We carried on a multicenter retrospective study involving five European IVF centers. We collected 112 blastocoel fluid samples from embryos on day 5 post-fertilization, cultured individually, along with data on blastocyst grade and embryo transfer outcomes.

Population Pharmacokinetic Modeling of TV-46000, a Risperidone Long-Acting Subcutaneous Antipsychotic for the Treatment of Patients with Schizophrenia.

Introduction: TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) agent that combines risperidone and an innovative, copolymer-based drug delivery technology in a suspension suitable for subcutaneous administration from a prefilled syringe. The objective of the current analysis was to characterize the pharmacokinetics (PK) of TV-46000 based on pooled data from phase 1 and phase 3 studies, and to further support clinical use aspects of TV-46000.

Methods: A population PK (popPK) model was developed using TV-46000 PK data obtained from three phase 1 studies (n = 267) and two phase 3 trials (n = 425).

Tezepelumab in Adults with Severe Chronic Rhinosinusitis with Nasal Polyps.

Background: Treatment with tezepelumab has been effective for sinonasal symptoms in patients with severe, uncontrolled asthma and a history of chronic rhinosinusitis with nasal polyps, but its efficacy and safety in adults with severe, uncontrolled chronic rhinosinusitis with nasal polyps is unknown.

Methods: We randomly assigned adults with physician-diagnosed, symptomatic, severe chronic rhinosinusitis with nasal polyps to receive standard care and either tezepelumab (at a dose of 210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The coprimary end points were the changes from baseline in the total nasal-polyp score (range, 0 to 4 [for each nostril]; higher scores indicate greater severity) and the mean nasal-congestion score (range, 0 to 3; higher scores indicate greater severity) at week 52.

Comparative performance analysis of neoepitope prediction algorithms in head and neck cancer.

Background: Mutations in cancer cells can result in the production of neoepitopes that can be recognized by T cells and trigger an immune response. A reliable pipeline to identify such immunogenic neoepitopes for a given tumor would be beneficial for the design of cancer immunotherapies. Current methods, such as the pipeline proposed by the Tumor Neoantigen Selection Alliance (TESLA), aim to select short peptides with the highest likelihood to be MHC-I restricted minimal epitopes.