Challenges and Possible Strategies to Address Them in Rare Disease Drug Development: A Statistical Perspective.

Developing drugs for rare diseases presents unique challenges from a statistical perspective. These challenges may include slowly progressive diseases with unmet medical needs, poorly understood natural history, small population size, diversified phenotypes and genotypes within a disorder, and lack of appropriate surrogate endpoints to measure clinical benefits. The Real-World Evidence (RWE) Scientific Working Group of the American Statistical Association Biopharmaceutical Section has assembled a research team to assess the landscape including challenges and possible strategies to address these challenges and the role of real-world data (RWD) and RWE in rare disease drug development.

Charge matters: how flanking substrate charge modulates O-glycan Core elongation.

Mucin type O-glycan core elongation is typically performed by the C1GALT1, B3GNT6, and ST6GalNAc-I/-II O-glycosyltransferases. These enzymes target the Tn antigen (GalNAc-O-Thr/Ser) dictating the fate of O-glycan elongation, playing important roles in health and disease. Changes in transferase expression and glycan structure are commonly associated with diseases such as cancer, Tn-syndrome, and ulcerative colitis.

CpG oligodeoxynucleotides and pan-serotype inhibitors control neurotropic Dengue infection in novel immune competent neonatal mouse model.

Dengue virus (DENV) is a growing global public health threat. The lack of symptomatic immune competent animal models for Dengue has hindered the screening and development of effective therapeutics that can be used to control dengue virus replication and thereby control the progression to severe dengue disease. To address this, we established an infection model in neonatal C57BL/6 mice and showed that a systemic Dengue challenge leads to ataxia, seizures, paralysis, and death within 15 days.

Changes in Phytochemical Content and Antioxidant Activities of Soybean Oil during Germination.

In this study, we investigated the effects of germination on the phytochemical content, antioxidant activity, and oxidative stability of soybean oil. Soybeans were germinated for different periods (0, 2, 4, 6-days). The germinated soybean oil (GSO) contained more α-tocopherol, phytosterols, and carotenoids, while there were no significant differences in fatty acid content.

Decentralized Clinical Trials in the Era of Real-World Evidence: A Statistical Perspective.

There has been a growing trend that activities relating to clinical trials take place at locations other than traditional trial sites (hence decentralized clinical trials or DCTs), some of which are at settings of real-world clinical practice. Although there are numerous benefits of DCTs, this also brings some implications on a number of issues relating to the design, conduct, and analysis of DCTs. The Real-World Evidence Scientific Working Group of the American Statistical Association Biopharmaceutical Section has been reviewing the field of DCTs and provides in this paper considerations for decentralized trials from a statistical perspective.

Use of Real-World Data and Real-World Evidence in Rare Disease Drug Development: A Statistical Perspective.

Real-world data (RWD) and real-world evidence (RWE) have been increasingly used in medical product development and regulatory decision-making, especially for rare diseases. After outlining the challenges and possible strategies to address the challenges in rare disease drug development (see the accompanying paper), the Real-World Evidence (RWE) Scientific Working Group of the American Statistical Association Biopharmaceutical Section reviews the roles of RWD and RWE in clinical trials for drugs treating rare diseases. This paper summarizes relevant guidance documents and frameworks by selected regulatory agencies and the current practice on the use of RWD and RWE in natural history studies and the design, conduct, and analysis of rare disease clinical trials.

Evaluation of metabolite profiles and neuroprotective potential in four pomegranate cultivars for Alzheimer's disease prevention.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss, with oxidative stress and neuroinflammation playing crucial roles in its progression. Current treatments, such as acetylcholinesterase (AChE) inhibitors, offer limited symptomatic relief and can have side effects. With growing interest in functional foods that have fewer side effects, pomegranate (Punica granatum L.

High-dimensional multiple imputation (HDMI) for partially observed confounders including natural language processing-derived auxiliary covariates.

Multiple imputation (MI) models can be improved with auxiliary covariates (AC), but their performance in high-dimensional data remains unclear. We aimed to develop and compare high-dimensional MI (HDMI) methods using structured and natural language processing (NLP)-derived AC in studies with partially observed confounders. We conducted a plasmode simulation with acute kidney injury as outcome and simulated 100 cohorts with a null treatment effect, incorporating creatinine labs, atrial fibrillation (AFib), and other investigator-derived confounders in the outcome generation.

Contributing factors to the length of stay and discharge destination of home health care patients: 10-year electronic health record analysis using the Donabedian model.

Aim: To identify the factors affecting the length of stay (LOS) and discharge destination (DD) of home health care (HHC) patients in South Korea.

Methods: A retrospective cross-sectional study was conducted using the electronic health records of 1769 patients from a hospital in South Korea. Data were collected from January 2013 to December 2022.

Kindlin-1 promotes gastric cancer cell motility through the Wnt/β-catenin signaling pathway.

Despite advances in gastric cancer diagnosis and treatment, its prognosis remains poor owing to aggressive tumor progression and metastasis. As understanding the relevant molecular mechanisms is essential to effectively improve patient outcomes, we elucidated the role of Kindlin-1 in gastric cancer progression and metastasis. Kindlin-1 expression was analyzed in 359 gastric cancer tissue samples provided by Kangnam Sacred Heart Hospital and publicly available GSE datasets.

The Roles of Ninjurin1 and Estrogen in Modulating AOM/DSS-Induced Colitis-Associated Colorectal Cancer in Male Mice.

Purpose: Ninjury-induced protein 1 (Ninj1) is associated with inflammation and tumor progression and shows increased expression in various cancers. This study aimed to investigate the role of Ninj1 in colitis-associated colorectal cancer (CRC) by focusing on its interaction with 17β-estradiol (E2).

Materials And Methods: Using an azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of colitis-associated CRC, wild-type (WT) and Ninj1 knockout (KO) male mice were treated with or without E2.

Association between Bioelectrical Impedance Parameters, Magnetic Resonance Imaging Muscle Parameters, and Fatty Liver Severity in Children and Adolescents.

Background/aims: To evaluate the associations between pediatric fatty liver severity, bioelectrical impedance analysis (BIA), and magnetic resonance imaging parameters, including total psoas muscle surface area (tPMSA) and paraspinal muscle fat (PMF).

Methods: Children and adolescents who underwent BIA and liver magnetic resonance imaging between September 2022 and November 2023 were included. Linear regression analyses identified predictors of liver proton density fat fraction (PDFF) including BIA parameters, tPMSA, and PMF.

Sex-specific Molecular Markers NRF2 and PD-L1 in Colon Carcinogenesis: Implications for Right-sided Colon Cancer.

Purpose: This study examined the roles of nuclear factor erythroid 2-related factor 2 (NRF2) and programmed death ligand 1 (PD-L1) in colon carcinogenesis, underscoring on sex and differences in tumor location.

Materials And Methods: A total of 378 participants were enrolled from Seoul National University Bundang Hospital: 88 healthy controls (HC), 139 patients with colorectal adenoma (AD), and 151 patients with colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (PCR), methylation-specific PCR, and immunohistochemistry (IHC) were performed utilizing tumor samples from patients and normal mucosa in the HC group.

Flavonoid Derivatives Isolated from Ameliorate Insulin Resistance via Modulation of IRS-1/PI3K/Akt/FOXO1 Pathway in HepG2 Cells.

In this study, two high-content flavonoid derivatives [3-8 biapigenin (HM 104) and quercetin-3--β--galactopyranoside (HM 111)] were obtained through the bioactivity-guided isolation of antidiabetic compounds from flowers. HM 104 and HM 111 exhibited good glucose consumption in fatty acid-induced insulin-resistant HepG2 cells. Moreover, both active compounds enhanced glucose uptake by restoring the expression of key regulators of glucose metabolism, including insulin receptor substrate 1, phosphoinositide 3-kinase, protein kinase B, and glucose transporter type 4, and by mitigating the expression of forkhead box O1 and the factors involved in gluconeogenesis.

MG5368 and MG989 Regulates Skin Health in UVB-Induced HaCaT Cells and Hairless Mice Model.

Background: Photoaging, induced by chronic ultraviolet B (UVB) exposure, results in the degradation of extracellular matrix (ECM) components, leading to skin roughness, wrinkle formation, and reduced elasticity. Recent studies have explored probiotics as potential inhibitors of extrinsic aging, primarily through mechanisms that protect the skin barrier and reduce collagen breakdown.

Methods: This study investigates the anti-photoaging effects of MG5368 ( MG5368) and MG989 ( MG989) in UVB-exposed keratinocytes and an SKH-1 hairless mice model.

Comparison of SPISE and METS-IR and Other Markers to Predict Insulin Resistance and Elevated Liver Transaminases in Children and Adolescents.

Backgruound: Studies on predictive markers of insulin resistance (IR) and elevated liver transaminases in children and adolescents are limited. We evaluated the predictive capabilities of the single-point insulin sensitivity estimator (SPISE) index, metabolic score for insulin resistance (METS-IR), homeostasis model assessment of insulin resistance (HOMA-IR), the triglyceride (TG)/ high-density lipoprotein cholesterol (HDL-C) ratio, and the triglyceride-glucose index (TyG) for IR and alanine aminotransferase (ALT) elevation in this population.

Methods: Data from 1,593 participants aged 10 to 18 years were analyzed using a nationwide survey.

Avenanthramides Ameliorate Insulin Resistance by Modulating Gluconeogenesis and Glycogen Synthesis in HepG2 Cells.

Diabetes mellitus (DM) is a multifaceted metabolic condition, mainly defined by elevated blood glucose levels. A feature of type 2 DM includes insulin resistance (IR), which involves impairments within the insulin signaling pathways. Avenanthramides (AVNs) are phenolic alkaloids found in L.

Fine particulate matter induces osteoclast-mediated bone loss in mice.

Fine particulate matter (FPM) is a major component of air pollution and has emerged as a significant global health concern owing to its adverse health effects. Previous studies have investigated the correlation between bone health and FPM through cohort or review studies. However, the effects of FPM exposure on bone health are poorly understood.

Standardization and quality assessment for human intestinal organoids.

To enhance the practical application of intestinal organoids, it is imperative to establish standardized guidelines. This proposed standardization outlines a comprehensive framework to ensure consistency and reliability in the development, characterization, and application of intestinal organoids. The recommended guidelines encompass crucial parameters, including culture conditions, critical quality attributes, quality control measures, and functional assessments, aimed at fostering a standardized approach across diverse research initiatives.

Exposure to Valsartan Products Containing Nitrosamine Impurities in the United States, Canada, and Denmark.

Background: Following the mass recall of valsartan products with nitrosamine impurities in July 2018, the number of patients exposed to these products, the duration of exposure, and the potential for cancer remains unknown. Therefore, we assessed the extent and duration of use of valsartan products with a nitrosamine impurity in the United States, Canada, and Denmark.

Methods: We conducted a retrospective cohort study using administrative healthcare data from the US FDA Sentinel System, four Canadian provinces that contribute to the Canadian Network for Observational Drug Effect Studies (CNODES), and the Danish National Prescription Registry.

Long-Term Culture of Human Pluripotent Stem Cells in Xeno-Free Condition Using Functional Polymer Films.

Human pluripotent stem cells (hPSCs), encompassing human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), hold immense potential in regenerative medicine, offering new opportunities for personalized cell therapies. However, their clinical translation is hindered by the inevitable reliance on xenogeneic components in culture environments. This study addresses this challenge by engineering a fully synthetic, xeno-free culture substrate, whose surface composition is tailored systematically for xeno-free culture of hPSCs.