Clinical applications of cell-free DNA-based liquid biopsy analysis.

Liquid biopsies, particularly those involving circulating tumor DNA (ctDNA) from patient blood, have emerged as crucial and minimally invasive adjuncts to standard tissue-based testing. ctDNA testing enables the identification of actionable mutations for targeted therapy and can be routinely used when tissue samples are unavailable for genotyping. Compared to tissue-based testing, ctDNA testing has the advantages of capturing spatial or temporal genomic heterogeneity and facilitating repeated assessments.

Prevalence and importance of coronary microvascular dysfunction in patients with heart failure and reduced or mildly reduced ejection fraction.

Aims: We investigated the prevalence of coronary microvascular dysfunction (CMD) and its association with severity of heart failure in patients with reduced or mildly reduced ejection fraction (HFrEF and HFmrEF).

Method: Patients with stable, symptomatic heart failure with left ventricular ejection fraction (LVEF) <50% were enrolled. Data collection included physical examination, blood samples, Kansas City Cardiomyopathy Questionnaire (KCCQ), carotid to femoral pulse wave velocity, echocardiography and adenosine-based transthoracic Doppler echocardiography to assess coronary flow reserve (CFR).

Anti-human TLR7 antibody for therapeutic intervention in systemic lupus erythematosus.

Toll-like receptor 7 (TLR7) is an endosomal sensor that responds to both pathogen-derived and self-derived single-stranded RNA (ssRNA). Responses of TLR7 to self-derived ssRNA have been implicated in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). TLR7 antagonists and inhibitory anti-TLR7 monoclonal antibodies (mAbs) can protect lupus-prone NZBWF1 mice from lethal nephritis.

Re-PERFUSE: Phase 1b study of AZD3427, a novel relaxin receptor agonist, on renal perfusion in HFrEF patients.

Aims: Renal impairment frequently coexists with heart failure (HF) and is associated with increased risk of poor clinical outcomes. This highlights the urgent need for therapies targeting both cardiac and renal dysfunction. AZD3427, a long-acting recombinant fusion protein and relaxin analogue that selectively activates the relaxin family peptide receptor 1 (RXFP1), showed trends of increased stroke volume and estimated glomerular filtration rate (eGFR) in HF patients (NCT04630067).

A Phase 1b Randomized Clinical Trial of AZD5642 and Dapagliflozin in Patients with Heart Failure and Moderate Renal Impairment.

AZD5462 is the first oral selective relaxin/insulin-like family peptide receptor 1 agonist in clinical development. The aim of this mechanistic study is to investigate the renal effects of AZD5462 when administered on top of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in participants with heart failure and moderate renal impairment. AURORA is a phase 1b, placebo-controlled, double-blind, 2-centre study of AZD5462 on top of dapagliflozin as standard of care in 2 arms.

Efficacy and Safety of Zabedosertib, an Interleukin-1 Receptor-Associated Kinase 4 Inhibitor, in Patients with Moderate-to-Severe Atopic Dermatitis: A Phase II Randomized Study.

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is expressed in various immune cells and regulates proinflammatory cytokine production. Its inhibition represents a novel, promising therapeutic option in the treatment of atopic dermatitis (AD). Zabedosertib (BAY1834845) is a potent, selective IRAK4 inhibitor that suppresses markers of local and systemic immune responses.

Cost-benefit of dementia insurance for cognitively-unimpaired ε4 homozygotes: A simulation study.

Background: Dementia insurance, a private insurance product covering the first diagnosis of dementia of the insured, may be beneficial for asymptomatic individuals who recognize their own high genetic risk for Alzheimer's disease.

Objective: We aimed to examine the cost-benefit of dementia insurance in cognitively unimpaired individuals, stratified by ε4 genotype.

Methods: A simulation study using 18 years of longitudinal data from National Alzheimer's Coordinating Center study to simulate the income and expenses of dementia insurance from the insured's perspective.

Multicenter Bioavailability Study of Long-Acting Paliperidone in Patients With Schizophrenia or Schizoaffective Disorder.

Purpose/background: Schizophrenia is often associated with nonadherence to oral antipsychotic therapy, which increases the risk of relapse, hospitalization, and higher health care costs. To overcome this challenge, long-acting injectable (LAI) antipsychotics, such as paliperidone palmitate, offer a solution by reducing relapse rates. Also, the bioequivalent formulations can enhance treatment accessibility while maintaining efficacy and safety.

Retinoic acid receptor-related orphan receptor α regulates bystander activation of memory CD8 T cells.

Background: Memory CD8 T cells sense inflammation and rapidly produce interferon-γ (IFN-γ) independent of cognate antigens. This innate-like property, called bystander activation, is involved in early host defense before the antigen-specific memory response. However, the molecular mechanisms underlying this activation remain unknown.

Anthropometric Measures, Cardiovascular Outcomes, and Treatment Effects of Finerenone in Cardiovascular-Kidney-Metabolic Disease: Pooled Participant-Level Analysis of Three Global Trials.

Background: Obesity is a core pathophysiological contributor to cardiovascular, kidney, and metabolic (CKM) conditions. However, the association between different adiposity-related anthropometrics and cardiovascular outcomes in persons with CKM conditions has not been rigorously explored.

Objectives: To examine cardiovascular outcomes and treatment effects of finerenone according to different adiposity-related anthropometrics.

Congenital aniridia: European COST action ANIRIDIA-NET guidelines for diagnosis, management and care.

Congenital aniridia is a rare ocular disorder affecting the majority of eye structures and can be associated with systemic manifestations. The main visible phenotypic characteristic is the partial or complete absence of the iris; however, foveal hypoplasia is a more frequent and reliable clinical sign. Other ocular comorbidities are associated with the disease, such as cataract, keratopathy and optic nerve hypoplasia.

Kidney transcriptomics signature of prospective rapid diabetic kidney disease progression.

Background: Previous cross-sectional transcriptomics studies on diabetic kidney disease (DKD) kidney tissue have shown correlations between gene expression and both disease status and kidney function at the time of biopsy; however, longitudinal data are scarce.

Methods: We utilized clinical follow-up data up to five years post-biopsy, linking the transcriptomes of diagnostic kidney biopsies to progression rates and outcomes in 19 patients with DKD. Patients were stratified into “rapid progressors” and “non-rapid progressors” based on clinical parameters (eGFR slope, CKD stage advancement, degree of albuminuria, composite outcome of kidney failure or 40% eGFR decline).

AZD0449, an inhaled JAK1 inhibitor, in healthy participants and patients with mild asthma.

Aims: Inhaled corticosteroids (ICS) plus bronchodilator are recommended for the treatment of asthma. Targeting the JAK1-dependent pathway may be an alternative for asthma management in patients with incomplete response to ICS. The aim of this study was to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD0449, a novel JAK1 selective inhibitor, following inhaled (dry powder, nebulized) and intravenous administration to healthy participants and patients with mild asthma.

Network of doctors for multimorbidity and diabetes: Development of the NOMAD intervention - a multidisciplinary team for patients with diabetes and multimorbidity.

Purpose: This article reports the development of the NOMAD intervention, a model of multidisciplinary team conferences designed to improve care coordination and treatment for patients with multimorbidity and diabetes. Managing multiple chronic conditions increases care complexity, and multidisciplinary approaches may enhance care coherence, optimise treatment, and improve quality of life.

Method: Guided by the Medical Research Council framework for developing complex interventions, we established a working group, formulated a programme theory, and conducted a preliminary test with qualitative interviews of patients and physicians.

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.

Comparison of dissolution profiles: 90% confidence intervals of different f estimators using bootstrap methodology versus the Euclidean Distance of the Non-standardized Expected (EDNE) values.

The most widely used method to compare dissolution profiles is the similarity factor f method. When the regulatory requirements to apply the f method are not fulfilled, alternative methods should be used. In the current study two commonly used methods, 90% confidence intervals (CI) of different f estimators using bootstrap methodology and the Euclidean Distance of the Non-standardized Expected (EDNE) values, are compared using two different simulation approaches.

infection is linked to increases in cardiovascular events post exacerbation in bronchiectasis.

Introduction: (PsA) infection contributes to disease progression in bronchiectasis (BE), particularly exacerbations which are known to increase the risk of cardiovascular (CV) events. However, the link between PsA infection and CV events in BE is unknown. Thus, we investigated whether there is an association between PsA airway infection and the risk of CV events post-exacerbation.

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.

Complete genome sequence of isolated from foot of bovine digital dermatitis in Japan.

species are the primary causative bacteria of bovine digital dermatitis. This report describes the isolation and complete genome sequencing of strain T1 isolated from a hoof sole swab of a bovine in Japan. Genome sequences were obtained using a combination of long- and short-read sequencing technologies.

Development of a Work-Related Quality of Life Questionnaire for Medical Doctors (WQMD-9) in Japan: Questionnaire Design and Quantitative Survey.

: With the ongoing development of game-changing technologies, assessing healthcare provider burden is desirable. This requires developing and evaluating subjective outcome measures, but there is no single scale that measures this burden. We developed a measure of quality of life (QOL) to address this, focusing on medical doctors (MDs).

Temporal Changes in Biomarkers, Functional Status, and Quality of Life Prior to Adverse Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction.

Background: Mapping clinical, biomarker, and diuretic dosing trajectories before adverse clinical outcomes in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) may inform population monitoring approaches.

Objectives: We assessed temporal patterns of 2 biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and estimated glomerular filtration rate [eGFR]), physician assigned functional status (NYHA functional class), a patient-reported outcome (Kansas City Cardiomyopathy Questionnaire Total Symptom Score [KCCQ-TSS]), and diuretic dosing leading up to a clinical event.

Methods: FINEARTS-HF was a double-blind, randomized clinical trial testing finerenone vs placebo in 6,001 patients with symptomatic HF and a left ventricular ejection fraction of ≥40%.

SYHA1813, A VEGFR and CSF1R Inhibitor, in Patients With Recurrent High-Grade Gliomas: A Multicenter, Open-Label Phase I Study.

Objective: Recurrent high-grade gliomas have a poor prognosis and limited therapeutic options. This study aimed to evaluate the safety and efficacy of SYHA1813, a dual inhibitor of VEGFR and CSF1R, in patients with recurrent high-grade gliomas.

Methods: Eligible patients (aged ≥ 18) with histologically or cytologically confirmed recurrent high-grade gliomas were included.

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.