Health state utilities associated with invasive pneumococcal disease, pneumonia, and recurrent acute otitis media in young children.

Purpose: Cost-utility analyses examining the value of new vaccines for pneumococcal disease will require health state utilities as inputs. Existing utilities for pneumococcal infections in young children are limited. The purpose of this study was to estimate health state utilities associated with pneumococcal infections in young children.

Basic Science and Pathogenesis.

Background: Frontotemporal dementia (FTD) presents with a change in personality, behaviour and language and is the second most common cause of young-onset dementia after Alzheimer's disease. Loss of function mutations in GRN, encoding progranulin (PGRN), causes FTD in the heterozygous state, accounting for 5-10% of all FTD cases. PGRN is essential for normal lysosomal function and neuronal survival.

Basic Science and Pathogenesis.

Background: APOE is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOE is well known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology.

Method: To elucidate this potential effect, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOE and n = 5 APOE), using a combination of anti-pTau PHF1 (pS396/pS404) immunoprecipitation and mass spectrometry.

Basic Science and Pathogenesis.

Background: Prevalence of epilepsy is increased among Alzheimer's Disease (AD) patients and cognitive impairment is common among people with epilepsy, with seizures occurring in 10-22% of AD patients, subclinical epileptiform abnormalities in 22-54% of AD patients, and cognitive deficits in up to 80% of epilepsy patients. These shared pathophysiological changes remain poorly defined.

Methods: We aimed to identify protein differences associated with epilepsy and AD using published proteomics datasets, including our previous analysis in epilepsy hippocampus and from our searchable database of 38 AD proteomics studies (NeuroPro).

Clinical Manifestations.

Background: The Alzheimer's Association recommends early screening of Alzheimer's disease and related dementias(ADRD), urging the development of biomarkers and other tools for early risk/detection. However, the general public's willingness to be tested for early ADRD must be considered, particularly among minoritized populations. For example, Black older adults within the United States (U.

Clinical Manifestations.

Background: Beginning new Alzheimer's disease (AD) treatments before AD symptoms are prominent would optimize the benefits of these disease slowing treatments. To accomplish this goal, clinicians must identify measures of early disease progression. As a step in doing this, we set out to characterize the relationships between cognitive complaints, wellbeing, cognitive performance, and metacognitive calibration in older adults in order to inform a model of cognition in typical older adults.

Clinical Manifestations.

Background: Patients with dementia due to Alzheimer's disease may experience multiple different agitation symptoms - including excessive motor activity, verbal aggression, and physical aggression - at varying frequencies. The efficacy of brexpiprazole 2 or 3 mg/day on 29 individual agitation behaviors (Cohen-Mansfield Agitation Inventory [CMAI] items) was previously evaluated. Building upon that work, this post hoc analysis aimed to determine the efficacy of brexpiprazole on the same individual agitation behaviors, but specifically focusing on those patients who were frequently experiencing the behaviors at baseline.

Clinical Manifestations.

Background: Agitation associated with dementia due to Alzheimer's disease encompasses a wide range of behaviors, including excessive motor activity, verbal aggression, and physical aggression. In a survey of unpaid caregivers living with an individual with Alzheimer's disease, the "most bothersome" agitation behaviors (which may influence the decision to transfer the patient to long-term care) were: cursing or verbal aggression, spitting, repetitive sentences or questions, hitting, constant unwarranted requests for attention or help, trying to get to a different place, inappropriate dress or disrobing, pacing/aimless wandering, grabbing onto people, and throwing things. This post hoc analysis aimed to determine the efficacy of brexpiprazole on agitation in patients frequently exhibiting these bothersome behaviors.

Clinical Manifestations.

Background: A reduction in the frequency of agitation behaviors is a clinically meaningful outcome among patients with agitation associated with dementia due to Alzheimer's disease. This post hoc analysis aimed to determine the percentage of patients treated with brexpiprazole who achieved sustained clinically meaningful response (CMR), over 12 and 24 weeks.

Method: Data for brexpiprazole 2 or 3 mg/day were obtained from two trials of patients with agitation associated with dementia due to Alzheimer's disease: a 12-week, randomized, double-blind, placebo-controlled trial (ClinicalTrials.

Clinical Manifestations.

Background: Neuropsychological assessments are often affected by demographic factors, such as age, education, and sex. These demographic variables frequently lead to differences in test scores between minorities and non-minorities, lowering diagnostic accuracy of Alzheimer's disease (AD) among minoritized groups. A new test (quick Behavioral Exam to Advance Neuropsychological Screening, or qBEANS) has been developed to assess early signs of AD.

Monocyte Anisocytosis is Associated with Sepsis in Children with Suspected Infection.

Background: Early, accurate determination of disease severity in an emergency setting is paramount for improving patient outcomes and healthcare costs. Monocyte anisocytosis, quantified as monocyte distribution width (MDW), has been shown to correspond with immune dysregulation. We hypothesize that MDW is broadly associated with illness severity related to sepsis and serious infection in children.

Bringing Pandemic Science to the Classroom: Building Public Health Capacity at a Rural Kentucky High School.

In response to the COVID-19 pandemic, a multidisciplinary team at the University of Kentucky developed an interdisciplinary science, technology, engineering, and mathematics and environmental health unit-the Wastewater Assessment for Coronavirus in Kentucky: Implementing Enhanced Surveillance Technology (WACKIEST) Unit-for high school students in summer 2022. This case study outlines the WACKIEST Unit, which focused on wastewater surveillance and COVID-19, the obstacles faced during development and recruitment, and implementation of the WACKIEST Unit in conjunction with a rural wastewater surveillance initiative. The unit was implemented in spring 2023 at a rural high school in Kentucky, spanning 12 days and engaging 190 students.

Population Pharmacokinetics and Pharmacodynamics of Sotalol Following Expedited Intravenous Loading in Patients With Atrial Arrhythmias.

Sotalol, a class III antiarrhythmic agent, is used to maintain sinus rhythm in patients with atrial fibrillation or atrial flutter (AFIB/AFL). Despite its efficacy, sotalol's use is limited by its potential to cause life-threatening ventricular arrhythmias due to QT interval prolongation. Traditionally, sotalol administration required hospitalization to monitor these risks.

KPRR: a novel machine learning approach for effectively capturing nonadditive effects in genomic prediction.

Nonadditive genetic effects pose significant challenges to traditional genomic selection methods for quantitative traits. Machine learning approaches, particularly kernel-based methods, offer promising solutions to overcome these limitations. In this study, we developed a novel machine learning method, KPRR, which integrated a polynomial kernel into ridge regression to effectively capture nonadditive genetic effects.

Simple Isolation of Human Bone Marrow Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells.

Bone marrow adipose tissue (BMAT) has garnered significant attention due to its critical roles in leukemia pathogenesis, cancer metastasis, and bone marrow failure. BMAT is a metabolically active, distinct tissue that differs from other fat depots. Marrow adipocytes, closely interacting with hematopoietic stem/progenitor cells and osteoblasts, play a pivotal role in regulating their functions.

Post-acute sequela of COVID-19 infection in individuals with multiple sclerosis.

Background: Many common symptoms in post-acute sequelae following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) overlap with those of multiple sclerosis (MS). We examined symptoms and performance of the PASC score, developed in the general population, in MS based on infection history.

Methods: We surveyed North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants regarding infections and categorized participants based on infection history.

Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease.

Introduction: The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models.

Understanding recent advances in non-amyloid/non-tau (NANT) biomarkers and therapeutic targets in Alzheimer's disease.

Unlabelled: The Alzheimer's disease (AD) research community continues to make great strides in expanding approaches for early detection and treatment of the disease, including recent advances in our understanding of fundamental AD pathophysiology beyond the classical targets: beta-amyloid and tau. Recent clinical trial readouts implicate a variety of non-amyloid/non-tau (NANT) approaches that show promise in slowing cognitive decline for people with AD. The Alzheimer's Association Research Roundtable (AARR) meeting held on December 13-14, 2022, reviewed the current state of NANT targets on underlying AD pathophysiology and their contribution to cognitive decline, the current data on a diverse range of NANT biomarkers and therapeutic targets, and the integration of NANT concepts in clinical trial designs.

Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease.

This review demonstrates the value of central pharmacodynamics (PD), including positron emission tomography (PET) and computerized cognitive testing, to supplement pharmacokinetic (PK) and peripheral PD for determining the target dose range for clinical efficacy testing of emestedastat, an 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitor. Combined data from 6 clinical trials in cognitively normal volunteers and patients with Alzheimer disease included a population PK model, endocrine PD, a human PET trial (11β-HSD1 brain imaging), and computerized cognitive testing. PK and PET findings were similar in volunteers and patients with Alzheimer disease.

A Lactobacillus consortium provides insights into the sleep-exercise-microbiome nexus in proof of concept studies of elite athletes and in the general population.

Background: The complex relationship among sleep, exercise, and the gut microbiome presents a unique opportunity to improve health and wellness. Here, we conducted the first large-scale investigation into the influence of a novel elite athlete-derived probiotic, consisting of a multi-strain Lactobacillus consortium, on sleep quality, exercise recovery, and gut microbiome composition in both elite athletes (n = 11) and the general population (n = 257).

Results: Our two-phase study design, which included an open-label study followed by a controlled longitudinal study in a professional soccer team, allowed us to identify key interactions between probiotics, the gut microbiome, and the host.

Resolution of Neuropsychiatric Adverse Events After Switching to a Doravirine-Based Regimen in the Open-Label Extensions of the DRIVE-AHEAD and DRIVE-FORWARD Trials.

Background: Neuropsychiatric adverse events (NPAEs) are associated with several antiretrovirals. Doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor indicated for HIV-1 treatment, does not interact significantly with known neurotransmitter receptors in vitro. First-line therapy with DOR-based regimens resulted in significantly fewer NPAEs than efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) and similar rates to those of ritonavir-boosted darunavir (DRV/r) with 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) through Week 96 of the phase 3 DRIVE-AHEAD and DRIVE-FORWARD studies, respectively.

Heart-retina time analysis using electrocardiogram-coupled time-resolved dynamic optical coherence tomography.

The eye and the heart are two closely interlinked organs, and many diseases affecting the cardiovascular system manifest in the eye. To contribute to the understanding of blood flow propagation towards the retina, we developed a method to acquire electrocardiogram (ECG) coupled time-resolved dynamic optical coherence tomography (OCT) images. This method allows for continuous synchronised monitoring of the cardiac cycle and retinal blood flow dynamics.

Complement factor H targeting antibody GT103 in refractory non-small cell lung cancer: a phase 1b dose escalation trial.

GT103 is a first-in-class, fully human, IgG3 monoclonal antibody targeting complement factor H that kills tumor cells and promotes anti-cancer immunity in preclinical models. We conducted a first-in-human phase 1b study dose escalation trial of GT103 in refractory non-small cell lung cancer to assess the safety of GT103 (NCT04314089). Dose escalation was performed using a "3 + 3" schema with primary objectives of determining safety, tolerability, PK profile and maximum tolerated dose (MTD) of GT103.

Maximizing the clinical utility and performance of cytology samples for comprehensive genetic profiling.

Comprehensive molecular profiling by next-generation sequencing has revolutionized tumor classification and biomarker evaluation. However, routine implementation is challenged by the scant nature of diagnostic material obtained through minimally invasive procedures. Here, we describe our long-term experience in profiling cytology samples with an in-depth assessment of the performance, quality metrics, biomarker identification capabilities, and potential pitfalls.