Optimisation of a novel series of ENaC inhibitors, leading to the selection of the long-acting inhaled clinical candidate ETD001, a potential new treatment for cystic fibrosis.

Cystic Fibrosis (CF) results from the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel of key importance in the airway epithelia. CFTR helps control optimal hydration of the airways, a crucial requirement for healthy lungs. CFTR modulators have recently been approved as an effective treatment option for many genetic variants of CF.

Microencapsulation of and within a Novel Polysaccharide-Based Core-Shell Formulation: Improving Probiotic Viability and Mucoadhesion.

Probiotics health benefits are hampered by long-term storage, gastrointestinal transit, and lack of adequate colonization within the colon. To this end, we have designed a core-shell structure that features an acid resistant core formulation with low water activity composed of alginate, hydroxypropyl methyl cellulose, and gellan gum (AHG) and a mucoadhesive shell made from chemically modified carboxymethyl chitosan with polyethylenimine (PEI-CMC). The structure of the core-shell microparticles was examined using scanning electron microscopy, and rheological measurements confirmed the improved ionic interactions between the core and the shell using the PEI-modified CMC.

Assessment of the risks associated with the use of in vivo versus in vitro potency tests for vaccines.

Animal (in vivo) potency tests have been utilized for over a century in support of vaccine development and for quality testing. This is a legacy of the best science at the time of their introduction. Advances in knowledge and technology, however, have provided opportunities to utilize more sensitive assays during development and replace legacy animal tests with in vitro alternatives.

The Role of CMC Statisticians: Co-Practitioners of the Scientific Method.

Chemistry, manufacturing, and control (CMC) statisticians play a key role in the development and lifecycle management of pharmaceutical and biological products, working with their non-statistician partners to manage product quality. Information used to make quality decisions comes from studies, where success is facilitated through adherence to the scientific method. This is carried out in four steps: (1) an objective, (2) design, (3) conduct, and (4) analysis.

Anterior N2 enhancement is not a general electrophysiological index of concealed information.

Event-related potentials (ERPs) have been used with the concealed information test (CIT) to detect concealed recognition of specific stimuli (i.e., "probes").

ETD001: A novel inhaled ENaC blocker with an extended duration of action in vivo.

Background: Inhibiting ENaC in the airways of people with cystic fibrosis (pwCF) is hypothesized to enhance mucociliary clearance (MCC) and provide clinical benefit. Historically, inhaled ENaC blockers have failed to show benefit in pwCF challenging this hypothesis. It is however unknown whether the clinical doses were sufficient to provide the required long duration of action in the lungs and questions whether a novel candidate could offer advantages where others have failed?

Methods: Dose-responses with the failed ENaC blockers (VX-371, BI 1265162, AZD5634, QBW276) together with ETD001 (a novel long acting inhaled ENaC blocker) were established in a sheep model of MCC and were used to predict clinically relevant doses that would provide a long-lasting enhancement of MCC in pwCF.

Maintaining the quality of vaccines through the use of standards: Current challenges and future opportunities.

An international hybrid meeting held 21-22 June 2023 in Ottawa, Canada brought together regulators, scientists, and industry experts to discuss a set of principles and best practices in the development and implementation of standards. Although the use of international standards (ISs) and international units (IUs) has been an essential part of ensuring human and animal vaccine quality in the past decades, the types and uses of standards have expanded with technological advances in manufacture and testing of vaccines. The needs of stakeholders are evolving in response to the ever-increasing complexity, diversity, and number of vaccine products as well as increasing efforts to replace animal-based potency tests with in vitro assays that measure relevant quality attributes.

BMI1 regulates human erythroid self-renewal through both gene repression and gene activation.

The limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient numbers of in vitro-derived red blood cells (RBC) for clinical purposes. We and others have determined that BMI1, a member of the polycomb repressive complex 1 (PRC1), is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts (SREs). However, the mechanisms of BMI1 action remain poorly understood.

Guidelines for Specialized Epilepsy Centers: Executive Summary of the Report of the National Association of Epilepsy Centers Guideline Panel.

The National Association of Epilepsy Centers first published the guidelines for epilepsy centers in 1990, which were last updated in 2010. Since that update, epilepsy care and the science of guideline development have advanced significantly, including the importance of incorporating a diversity of stakeholder perspectives such as those of patients and their caregivers. Currently, despite extensive published data examining the efficacy of treatments and diagnostic testing for epilepsy, there remain significant gaps in data identifying the essential services needed for a comprehensive epilepsy center and the optimal manner for their delivery.

Neighborhood selection by parent personality, depression, and coparent support: A two-study replication.

This study addresses the degree to which three selection factors (parent personality, depression, and coparent support) drive movement into neighborhoods and predict changes in youth externalizing behavior. Two studies followed children from birth to age 15 ( = 1,364 for Study 1; = 4,898 for Study 2). Neighborhood socioeconomic disadvantage, family income, and youth externalizing behavior were consistently and significantly correlated cross sectionally and longitudinally.

Synthesis and Evaluation of Functionalized Polyurethanes for pH-Responsive Delivery of Compounds in Chronic Wounds.

Chronic wounds, depending on the bacteria that caused the infection, can be associated with an extreme acidic or basic pH. Therefore, the application of pH-responsive hydrogels has been instigated for the delivery of therapeutics to chronic wounds. Herein, with the aim of developing a flexible pH-responsive hydrogel, we functionalized hydrophilic polyurethanes with either cationic (polyethylene imine) or anionic (succinic anhydride) moieties.

Diabetic retinopathy screenings in West Virginia: an assessment of teleophthalmology implementation.

Background: The prevalence of diabetes in the state of West Virginia (WV) is amongst the highest in the United States, making diabetic retinopathy (DR) and diabetic macular edema (DME) a major epidemiological concern within the state. Several challenges exist regarding access to eye care specialists for DR screening in this rural population. A statewide teleophthalmology program has been implemented.

Targeted postnatal knockout of Sclerostin using a bone-targeted adeno-associated viral vector increases bone anabolism and decreases canalicular density.

Purpose: The creation of murine gene knockout models to study bone gene functions often requires the resource intensive crossbreeding of Cre transgenic and gene-floxed strains. The developmental versus postnatal roles of genes can be difficult to discern in such models. For example, embryonic deletion of the Sclerostin (Sost) gene establishes a high-bone mass phenotype in neonatal mice that may impact on future bone growth.

Digital Devices for Assessing Motor Functions in Mobility-Impaired and Healthy Populations: Systematic Literature Review.

Background: With the advent of smart sensing technology, mobile and wearable devices can provide continuous and objective monitoring and assessment of motor function outcomes.

Objective: We aimed to describe the existing scientific literature on wearable and mobile technologies that are being used or tested for assessing motor functions in mobility-impaired and healthy adults and to evaluate the degree to which these devices provide clinically valid measures of motor function in these populations.

Methods: A systematic literature review was conducted by searching Embase, MEDLINE, CENTRAL (January 1, 2015, to June 24, 2020), the United States and European Union clinical trial registries, and the United States Food and Drug Administration website using predefined study selection criteria.

Does receipt of unemployment benefits change recruiter perceptions of candidates' personality, work relevant skills and employability?

Background: Growing experimental evidence shows that unemployment benefit recipients are generally perceived negatively in terms of their personality and employability by the general public. Welfare stigma tied to unemployment or receipt of income support may disproportionately negatively impact individuals who have been out of work due to disability, or chronic health conditions.

Objective: The current study examined whether welfare stigma and/or unemployment stigma, translate to perceptions and hiring decisions made by individuals working in recruitment, potentially creating barriers to re-employment for those without work and relying on unemployment benefits.

Biopolymer-Based Multilayer Microparticles for Probiotic Delivery to Colon.

The potential health benefits of probiotics may not be realized because of the substantial reduction in their viability during food storage and gastrointestinal transit. Microencapsulation has been successfully utilized to improve the resistance of probiotics to critical conditions. Owing to the unique properties of biopolymers, they have been prevalently used for microencapsulation of probiotics.

Sulfated Hydrogels in Intervertebral Disc and Cartilage Research.

Hydrogels are commonly used for the 3D culture of musculoskeletal cells. Sulfated hydrogels, which have seen a growing interest over the past years, provide a microenvironment that help maintain the phenotype of chondrocytes and chondrocyte-like cells and can be used for sustained delivery of growth factors and other drugs. Sulfated hydrogels are hence valuable tools to improve cartilage and intervertebral disc tissue engineering.

Novel Functional, Health, and Genetic Determinants of Cognitive Terminal Decline: Kuakini Honolulu Heart Program/Honolulu-Asia Aging Study.

To investigate interindividual differences in cognitive terminal decline and identify determinants including functional, health, and genetic risk and protective factors, data from the Honolulu Heart Program/Honolulu-Asia Aging Study, a prospective cohort study of Japanese American men, were analyzed. The sample was recruited in 1965-1968 (ages 45-68 years). Longitudinal performance of cognitive abilities and mortality status were assessed from Exam 4 (1991-1993) through June 2014.

Corneal Ulcers with NOD2 Mutations Presenting with Mixed Syndromic Phenotype.

Purpose: To report a case of corneal ulcers in a patient with NOD2 mutations unique to but phenotypically resembling well-characterized syndromic phenotypes like Blau syndrome.

Observation: A 25-year-old female with a medical history of type I diabetes mellitus, Asperger syndrome, and neuropathy presented with bilateral corneal ulcers. Her visual acuity was 20/200 OU.

Evaluation and validation of next-generation sequencing to support lot release for a novel type 2 oral poliovirus vaccine.

A novel, genetically-stabilized type 2 oral polio vaccine (nOPV2), developed to assist in the global polio eradication program, was recently the first-ever vaccine granted Emergency Use Listing by the WHO. Lot release tests for this vaccine included-for the first time to our knowledge-the assessment of genetic heterogeneity using next-generation sequencing (NGS). NGS ensures that the genetically-modified regions of the vaccine virus genome remain as designed and that levels of polymorphisms which may impact safety or efficacy are controlled during routine production.

Characterisation of a tripartite α-pore forming toxin from Serratia marcescens.

Tripartite members of the ClyA family of α-PFTs have recently been identified in a number of pathogenic Gram-negative bacteria, including the human pathogen Serratia marcescens. Structures of a Gram-negative A component and a tripartite α-PFT complete pore are unknown and a mechanism for pore formation is still uncertain. Here we characterise the tripartite SmhABC toxin from S.

The A component (SmhA) of a tripartite pore-forming toxin from Serratia marcescens: expression, purification and crystallographic analysis.

Tripartite α-pore-forming toxins are constructed of three proteins (A, B and C) and are found in many bacterial pathogens. While structures of the B and C components from Gram-negative bacteria have been described, the structure of the A component of a Gram-negative α-pore-forming toxin has so far proved elusive. SmhA, the A component from the opportunistic human pathogen Serratia marcescens, has been cloned, overexpressed and purified.

The Impact of Distal Influences and Proximal Resources on the Mental Health of African American Older Adults: Findings From the Georgia Centenarian Study.

Background And Objectives: Over the years, a large amount of research has been devoted to the investigation of factors that led to mental health outcomes in older adults. For African American older adults, their lived experiences place them at high risk for mental health problems. The purpose of this study was to examine the impact of early life influences (i.

Unemployment, Employability and COVID19: How the Global Socioeconomic Shock Challenged Negative Perceptions Toward the Less Fortunate in the Australian Context.

Unemployed benefit recipients are stigmatized and generally perceived negatively in terms of their personality characteristics and employability. The COVID19 economic shock led to rapid public policy responses across the globe to lessen the impact of mass unemployment, potentially shifting community perceptions of individuals who are out of work and rely on government income support. We used a repeated cross-sections design to study change in stigma tied to unemployment and benefit receipt in a pre-existing pre-COVID19 sample ( = 260) and a sample collected during COVID19 pandemic ( = 670) by using a vignette-based experiment.