Orthogonalized human protease control of secreted signals.

Synthetic circuits that regulate protein secretion in human cells could support cell-based therapies by enabling control over local environments. Although protein-level circuits enable such potential clinical applications, featuring orthogonality and compactness, their non-human origin poses a potential immunogenic risk. In this study, we developed Humanized Drug Induced Regulation of Engineered CyTokines (hDIRECT) as a platform to control cytokine activity exclusively using human-derived proteins.

Bilateral hip exoskeleton assistance enables faster walking in individuals with chronic stroke-related gait impairments.

Millions of individuals surviving a stroke have lifelong gait impairments that reduce their personal independence and quality of life. Reduced walking speed is one of the major problems limiting community mobility and reintegration. Previous studies have shown positive effect of robot-assisted gait training utilizing hip exoskeletons for individuals with gait impairments due to a stroke, leading to increased walking speed in post-treatment compared to pre-treatment assessments.

Simulation of clinical trials of oral treprostinil in pulmonary arterial hypertension using a virtual population.

Challenges in drug development for rare diseases such as pulmonary arterial hypertension can be addressed through the use of mathematical modeling. In this study, a quantitative systems pharmacology model of pulmonary arterial hypertension pathophysiology and pharmacology was used to predict changes in pulmonary vascular resistance and six-minute walk distance in the context of oral treprostinil clinical studies. We generated a virtual population that spanned the range of clinical observations and then calibrated virtual patient-specific weights to match clinical trials.

Aqueous Angiography Guided Bent Ab Interno Needle Goniectomy in High versus Low Aqueous Humor Outflow Regions in POAG: A Pilot RCT.

Prcis: Trabecular cutting minimally invasive glaucoma surgery like bent ab interno needle goniectomy (BANG) when performed in baseline aqueous angiography identified low aqueous humor outflow regions, results in greater success of intraocular pressure reduction.

Purpose: To study the efficacy of Bent Ab Interno Needle Goniectomy (BANG) in high versus low aqueous humor outflow (AHO) regions as determined by Aqueous Angiography(AA) in patients with primary open angle glaucoma (POAG).

Methods: A prospective, single-centre, pilot, randomized control trial recruited 30 eyes of 30 patients of POAG and visually significant cataract (45-80 y) and were randomised into two groups ("A": BANG performed in the high-flow regions and "B": BANG performed in the low-flow regions) of 15 each.

Opioid Prescriptions for Low Back Pain among Military-Connected Older Adults Across Multiple Care Systems.

Background: Untreated low back pain (LBP) in older adults can lead to disability and development of chronicity. Due to the potential development of medical comorbidities and negative risks associated with pharmacological use, chronic LBP management for older adults requires a responsive approach.

Methods: The objective of this study is to evaluate the probability of (1) opioid prescription receipt and (2) opioid-sedative coprescription, in a sample of military-service-connected patients enrolled in the Veterans Health Administration (VHA) or TRICARE, ages 30-85 years, receiving care in three systems: VHA, Military Health System (MHS), and nonfederal (civilian) healthcare facilities.

Pharmacodynamic characterization and evaluation of oxidative stress effects of digitoxigenin derivatives on HeLa cells.

Cancer is a leading cause of death worldwide and its treatment is hampered by the lack of specificity and side effects of current drugs. Cardiotonic steroids (CTS) interact with Na/K-ATPase (NKA) and induce antineoplastic effects, but their narrow therapeutic window is key limiting factor. The synthesis of digitoxigenin derivatives with glycosidic unit modifications is a promising approach to develop more selective and effective antitumor agents.

sp. nov., a bacterium isolated from the roots of the aquatic plant .

A polyphasic taxonomic study was carried out on strain T9W2-O, isolated from the roots of the aquatic plant . This isolate is rod-shaped, forms yellow/orange pigmented colonies and produces the pigment flexirubin. Nearly complete 16S rRNA gene sequence homology related the strain to , with 98.

Genetically Predicted Gene Expression Effects on Changes in Red Blood Cell and Plasma Polyunsaturated Fatty Acids.

Polyunsaturated fatty acids (PUFAs) including omega-3 and omega-6 are obtained from diet and can be measured objectively in plasma or red blood cells (RBCs) membrane biomarkers, representing different dietary exposure windows. In vivo conversion of omega-3 and omega-6 PUFAs from short- to long-chain counterparts occurs via a shared metabolic pathway involving fatty acid desaturases and elongase. This analysis leveraged genome-wide association study (GWAS) summary statistics for RBC and plasma PUFAs, along with expression quantitative trait loci (eQTL) to estimate tissue-specific genetically predicted gene expression effects for delta-5 desaturase (FADS1), delta-6 desaturase (FADS2), and elongase (ELOVL2) on changes in RBC and plasma biomarkers.

Using patient preference to inform ritlecitinib dose selection for alopecia areata treatment.

Ritlecitinib is an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma (JAK3/TEC) family kinase inhibitor approved for the treatment of severe alopecia areata (AA). Benefit-risk profiles of two doses of ritlecitinib (50 mg vs 30 mg once daily) were evaluated by integrating patient preferences and clinical efficacy and safety estimates for ritlecitinib. A discrete-choice experiment (DCE) was utilized to elicit preferences for benefit and safety attributes of systemic AA treatments.

Population exposure-response analysis of the effect of ritlecitinib on eyebrow assessment and eyelash assessment in patients with alopecia areata.

Ritlecitinib is an orally bioavailable, small molecule that has been approved by the U.S. Food and Drug Administration (FDA) as a once-daily oral treatment option for people 12 years of age and older with severe alopecia areata.

Hybrid Arch Aneurysm Repair With Ascending Aortic Wrap and TEVAR.

Introduction: Management of patients with large aortic arch aneurysms who are considered high risk for frozen elephant trunk technique have been challenging, especially when they have a dilated ascending aorta (AA) that precludes total endovascular branched repair (arch BEVAR). A viable option in our armamentarium is wrapping of the AA (AW), and zone 0 Ishimaru TEVAR.

Methods: Retrospective analysis of our aortic database from 2013 to 2024 to select high-risk patients with aortic arch aneurysm that had an AW and TEVAR.

CD137 agonism enhances anti-PD1 induced activation of expanded CD8 T cell clones in a neoadjuvant pancreatic cancer clinical trial.

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy requires therapeutic combinations that induce quality T cells. Tumor microenvironment (TME) analysis following therapeutic interventions can identify response mechanisms, informing design of effective combinations. We provide a reference single-cell dataset from tumor-infiltrating leukocytes (TILs) from a human neoadjuvant clinical trial comparing the granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDAC vaccine GVAX alone, in combination with anti-PD1 or with both anti-PD1 and CD137 agonist.

Cannabis use and alcohol-related outcomes among sober living house residents with alcohol use disorders.

Background: Evidence supporting cannabis substitution along with liberalized cannabis laws have left recovery homes such as sober living houses (SLHs) in a difficult position regarding policies relating to cannabis use among SLH residents. Moreover, there are few studies of cannabis use among SLH residents that can be used to inform cannabis use policies. Here we assess whether cannabis is related to alcohol use among SLH residents.

Value-Based Pricing for Drugs With Uncertain Clinical Benefits.

Policymakers can use cost-effectiveness analysis to set value-based prices (VBP) for new pharmaceuticals. However, the uncertainty of investigational drug benefits complicates this pricing strategy. Such complexity stems from decision-makers' risk aversion and the potential change in the estimated value with emerging evidence.

ROAR-CAT: Rapid Online Assessment of Reading ability with Computerized Adaptive Testing.

The Rapid Online Assessment of Reading (ROAR) is a web-based lexical decision task that measures single-word reading abilities in children and adults without a proctor. Here we study whether item response theory (IRT) and computerized adaptive testing (CAT) can be used to create a more efficient online measure of word recognition. To construct an item bank, we first analyzed data taken from four groups of students (N = 1960) who differed in age, socioeconomic status, and language-based learning disabilities.

Single-molecule analysis of transcription activation: dynamics of SAGA coactivator recruitment.

Transcription activators are said to stimulate gene expression by 'recruiting' coactivators, yet this vague term fits multiple kinetic models. To directly analyze the dynamics of activator-coactivator interactions, single-molecule microscopy was used to image promoter DNA, a transcription activator and the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex within yeast nuclear extract. SAGA readily but transiently binds nucleosome-free DNA without an activator, while chromatin association occurs primarily when an activator is present.

Modeling, synthesis and cell-based evaluation of pyridine-substituted analogs of CD3254 and fluorinated analogs of CBt-PMN as novel therapeutics.

Six pyridine analogs of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid-or CD3254 (11)-in addition to two novel analogs of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (CBt-PMN or 23) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), an FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Treatment with 1 often elicits side-effects by disrupting or provoking other RXR-dependent nuclear receptors and cellular pathways. All analogs were assessed through modeling for their ability to bind RXR and then evaluated in human colon and kidney cells employing an RXR-RXR mammalian-2-hybrid (M2H) system and in an RXRE-controlled transcriptional assay.

The Relationship Between Novel Inflammatory Markers and Serum 25-Hydroxyvitamin D Among US Adults.

Background: Vitamin D is the focus of extensive medical research globally. Recent studies have investigated the correlation between serum 25-hydroxyvitamin D (25(OH)D) and common inflammatory markers. However, few studies have incorporated novel inflammatory markers such as the platelet-to-lymphocyte ratio (PLR), platelet-to-high density lipoprotein cholesterol ratio (PHR), systemic inflammatory index (SII), neutrophil-to-lymphocyte ratio (NLR), systemic inflammatory response (SIRI), and neutrophil-to-high-density lipoprotein cholesterol ratio (NHR).

Cognitive aging outcomes are related to both tau pathology and maintenance of cingulate cortex structure.

Introduction: Successful cognitive aging is related to both maintaining brain structure and avoiding Alzheimer's disease (AD) pathology, but how these factors interplay is unclear.

Methods: A total of 109 cognitively normal older adults (70+ years old) underwent amyloid beta (Aβ) and tau positron emission tomography (PET) imaging, structural magnetic resonance imaging (MRI), and cognitive testing. Cognitive aging was quantified using the cognitive age gap (CAG), subtracting chronological age from predicted cognitive age.

The Safety of Multiple-Dose Liquid Blend Containing Kava and Kratom in Healthy Adults.

This study investigates the safety of three different daily dosages of a liquid blend containing kava and kratom (Feel Free® Classic Tonic {FFCT}) in healthy adults over six consecutive days of supplementation. Both kava and kratom have been used traditionally for hundreds of years, but there is limited data on the combined safety of these ingredients. In this randomized, double-blind, placebo-controlled trial, the participants were assigned to receive one of three daily dosages of FFCT or placebo.

Detecting early cognitive deficits in preclinical Alzheimer's disease using a remote digital multi-day learning paradigm.

Remote, digital cognitive testing on an individual's own device provides the opportunity to deploy previously understudied but promising cognitive paradigms in preclinical Alzheimer's disease (AD). The Boston Remote Assessment for NeuroCognitive Health (BRANCH) captures a personalized learning curve for the same information presented over seven consecutive days. Here, we examined BRANCH multi-day learning curves (MDLCs) in 167 cognitively unimpaired older adults (age = 74.

A broad spectrum Shigella vaccine based on VirG multiepitope region produced in a cell-free system.

Dysentery caused by Shigella species remains a major health threat to children in low- and middle-income countries. There is no vaccine available. The most advanced candidates, i.

Glucagon-Like Peptide 1 Receptor Agonists and Chronic Lower Respiratory Disease Among Type 2 Diabetes Patients: Replication and Reliability Assessment Across a Research Network.

Introduction: The aim of this study is to use observational methods to evaluate reliability of evidence generated by a study of the effect of glucagon-like peptide 1 receptor agonists (GLP-1RA) on chronic lower respiratory disease (CLRD) outcomes among Type-2 diabetes mellitus (T2DM) patients.

Research Design And Methods: We independently reproduced a study comparing effects of GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP4-i) on CLRD outcomes among patients with T2DM and prior CLRD. We reproduced inputs and outputs using the original study data (national administrative claims) and evaluated the robustness of results in comparison to alternate design/analysis decisions.

Characterization of Spray-Dried Powders Using a Coated Alberta Idealized Nasal Inlet.

Dry powders offer the potential to increase stability and reduce cold-chain requirements associated with the distribution of vaccines and other thermally sensitive products. The Alberta Idealized Nasal Inlet (AINI) is a representative geometry for characterization of nasal products that may prove useful in examining intranasal delivery of powders. Spray-dried trehalose powders were loaded at 10, 20, and 40 mg doses into active single-dose devices.