Resting Heart Rate and Associations With Clinical Measures From the Project Baseline Health Study: Observational Study.

Background: Though widely used, resting heart rate (RHR), as measured by a wearable device, has not been previously evaluated in a large cohort against a variety of important baseline characteristics.

Objective: This study aimed to assess the validity of the RHR measured by a wearable device compared against the gold standard of ECG (electrocardiography), and assess the relationships between device-measured RHR and a broad range of clinical characteristics.

Methods: The Project Baseline Health Study (PHBS) captured detailed demographic, occupational, social, lifestyle, and clinical data to generate a deeply phenotyped cohort.

Total liquid ventilation in an ovine model of extreme prematurity: a randomized study.

Background: This study aimed at comparing cardiorespiratory stability during total liquid ventilation (TLV)-prior to lung aeration-with conventional mechanical ventilation (CMV) in extremely preterm lambs during the first 6 h of life.

Methods: 23 lambs (11 females) were born by c-section at 118-120 days of gestational age (term = 147 days) to receive 6 h of TLV or CMV from birth. Lung samples were collected for RNA and histology analyses.

Hemodynamic impacts of apelin-13 in a neonatal lamb model of septic peritonitis.

Background: Apelins are potential candidate therapeutic molecules for hemodynamic support. The objective of this study was to assess the hemodynamic impacts of apelin-13 in a neonatal lamb model of septic shock.

Methods: Lambs were randomized to receive apelin-13 or normal saline.

Multi-institutional distributed data networks for real-world evidence about medical devices: building unique device identifiers into longitudinal data (BUILD).

Objectives: To support development of a robust postmarket device evaluation system using real-world data (RWD) from electronic health records (EHRs) and other sources, employing unique device identifiers (UDIs) to link to device information.

Methods: To create consistent device-related EHR RWD across 3 institutions, we established a distributed data network and created UDI-enriched research databases (UDIRs) employing a common data model comprised of 24 tables and 472 fields. To test the system, patients receiving coronary stents between 2010 and 2019 were loaded into each institution's UDIR to support distributed queries without sharing identifiable patient information.

Exposure-Response Modeling and Simulation to Support Human Dosing of Botulism Antitoxin Heptavalent Product.

Botulism antitoxin heptavalent (A, B, C, D, E, F, and G - Equine; BAT) product is a sterile solution of F(ab') and F(ab') -related antibody fragments prepared from plasma obtained from horses that have been immunized with a specific serotype of botulinum toxoid and toxin. BAT product is indicated for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A to G in adults and pediatric patients. Pharmacokinetic and exposure-response models were used to explore the relationship between BAT product exposure and the probability of survival, and the occurrence of relevant moderate clinical signs observed during the preclinical development of BAT product to justify the clinical dose.

Applying computable phenotypes within a common data model to identify heart failure patients for an implantable cardiac device registry.

Background: Use of existing data in electronic health records (EHRs) could be used more extensively to better leverage real world data for clinical studies, but only if standard, reliable processes are developed. Numerous computable phenotypes have been validated against manual chart review, and common data models (CDMs) exist to aid implementation of such phenotypes across platforms and sites. Our objective was to measure consistency between data that had previously been manually collected for an implantable cardiac device registry and CDM-based phenotypes for the condition of heart failure (HF).

Pharmacokinetics and Macrophage Inhibitory Cytokine-1 Pharmacodynamics of the Murine Double Minute 2 Inhibitor, Navtemadlin (KRT-232) in Fed and Fasted Healthy Subjects.

This single 60-mg dose, 4-period crossover study assessed the effect of food and formulation change on navtemadlin (KRT-232) pharmacokinetics (PK) and macrophage inhibitory cytokine-1 (MIC-1) pharmacodynamics. Healthy subjects (N = 30) were randomized to 3 treatment sequences, A: new tablet, fasted (reference, dosed twice); B: new tablet, 30 minutes after a high-fat meal (test 1); C: old tablet, fasted (test 2). PK/pharmacodynamic parameters were measured over 0 to 96 hours.

Pharmacokinetics and pharmacodynamics of Abelacimab (MAA868), a novel dual inhibitor of Factor XI and Factor XIa.

Background: Factor XI (FXI) inhibition offers the promise of hemostasis-sparing anticoagulation for the prevention and treatment of thromboembolic events. Abelacimab (MAA868) is a novel fully human monoclonal antibody that targets the catalytic domain and has dual activity against the inactive zymogen Factor XI and the activated FXI.

Objectives: To investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single dose intravenous and multiple dose subcutaneous administration of abelacimab in healthy volunteers and patients with atrial fibrillation, respectively.

Prevalence and Characteristics of Individuals with Preserved Ratio Impaired Spirometry (PRISm) and/or Impaired Lung Function in Japan: The OCEAN Study.

Purpose: Many individuals with obstructive airway disease (OAD), including chronic obstructive pulmonary disease (COPD) and asthma, remain undiagnosed, despite the potential for reducing disease burden through early detection and treatment. OCEAN aimed to determine the prevalence of, and characteristics associated with, impaired lung function in a Japanese population, with the goal of improving strategies for early OAD detection.

Methods: OCEAN was an observational, cross-sectional study in sequentially recruited Japanese individuals ≥40 years of age undergoing routine health examinations.

Utility of Self-Administered Questionnaires for Identifying Individuals at Risk of COPD in Japan: The OCEAN (Okinawa COPD casE finding AssessmeNt) Study.

Purpose: A considerable proportion of patients with chronic obstructive pulmonary disease (COPD) remain undiagnosed and untreated even though they may have a burden of respiratory symptoms that impact quality of life. The OCEAN study assessed the ability of screening questionnaires to identify individuals with, or at risk of, COPD by comparing questionnaire outcomes with spirometric measures of lung function.

Methods: This observational study included participants ≥40 years of age presenting for their annual health examination at a single medical center in Okinawa, Japan.

Discovery of fifteen new geroprotective plant extracts and identification of cellular processes they affect to prolong the chronological lifespan of budding yeast.

In a quest for previously unknown geroprotective natural chemicals, we used a robust cell viability assay to search for commercially available plant extracts that can substantially prolong the chronological lifespan of budding yeast. Many of these plant extracts have been used in traditional Chinese and other herbal medicines or the Mediterranean and other customary diets. Our search led to a discovery of fifteen plant extracts that significantly extend the longevity of chronologically aging yeast not limited in calorie supply.

Mechanisms by which PE21, an extract from the white willow , delays chronological aging in budding yeast.

We have recently found that PE21, an extract from the white willow , slows chronological aging and prolongs longevity of the yeast more efficiently than any of the previously known pharmacological interventions. Here, we investigated mechanisms through which PE21 delays yeast chronological aging and extends yeast longevity. We show that PE21 causes a remodeling of lipid metabolism in chronologically aging yeast, thereby instigating changes in the concentrations of several lipid classes.

Interplay between intracellular loop 1 and helix VIII of the angiotensin II type 2 receptor controls its activation.

The signaling mechanisms of the angiotensin II type 2 receptor (ATR), a heptahelical receptor, have not yet been clearly and completely defined. In the present contribution, we set out to identify the molecular determinants involved in ATR activation. Although ATR has not been shown to engage G, G, G, and β-arrestin (βarr) pathways as does the ATR upon angiotensin II (AngII) stimulation, the atypical positioning of helix VIII in the recently published ATR structure may play a role in the receptor's capacity to couple to downstream effectors.

Exacerbations and health care resource use among patients with COPD in relation to blood eosinophil counts.

Purpose: Current understanding of the relationship between COPD phenotype and health care resource utilization (HCRU) is limited. This real-world study evaluated disease burden and HCRU for COPD subgroups prone to exacerbation as defined by blood eosinophil (EOS) count and multiple inhaler triple therapy (MITT) use.

Methods: This was a large-scale, retrospective, longitudinal, observational cohort study using data from the US IBM Watson Explorys real-world database (GSK Study HO-17-18395).

Pairwise combinations of chemical compounds that delay yeast chronological aging through different signaling pathways display synergistic effects on the extent of aging delay.

We have recently discovered six plant extracts that delay yeast chronological aging. Most of them affect different nodes, edges and modules of an evolutionarily conserved network of longevity regulation that integrates certain signaling pathways and protein kinases; this network is also under control of such aging-delaying chemical compounds as spermidine and resveratrol. We have previously shown that, if a strain carrying an aging-delaying single-gene mutation affecting a certain node, edge or module of the network is exposed to some of the six plant extracts, the mutation and the plant extract enhance aging-delaying efficiencies of each other so that their combination has a synergistic effect on the extent of aging delay.

Label-free cell signaling pathway deconvolution of angiotensin type 1 receptor reveals time-resolved G-protein activity and distinct AngII and AngIIIIV responses.

Angiotensin II (AngII) type 1 receptor (ATR) is a G protein-coupled receptor known for its role in numerous physiological processes and its implication in many vascular diseases. Its functions are mediated through G protein dependent and independent signaling pathways. ATR has several endogenous peptidic agonists, all derived from angiotensinogen, as well as several synthetic ligands known to elicit biased signaling responses.

HIV Infection and Survival of Lymphoma Patients in the Era of Highly Active Antiretroviral Therapy.

Highly active antiretroviral therapy (HAART) has extended the life expectancy of patients with HIV/AIDS to approach that of the general population. However, it remains unclear whether HIV infection affects the survival of patients with lymphoma in the HAART era. Patients diagnosed with Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, peripheral T-cell lymphoma (PTCL), or follicular lymphoma during 2004-2011 were identified from the National Cancer Database.

Real-world evidence of stroke prevention in patients with nonvalvular atrial fibrillation in the United States: the REVISIT-US study.

Background: Little data exists regarding the effectiveness and safety of rivaroxaban or apixaban versus warfarin in nonvalvular atrial fibrillation (NVAF) patients treated outside of clinical trials.

Methods: This was a retrospective study using MarketScan claims from January 2012 to October 2014. We included adults, newly initiated on rivaroxaban, apixaban or warfarin, with a baseline CHADS-VASc score ≥2, ≥2 diagnosis codes for NVAF and ≥180 days of continuous medical and prescription benefits.

Six plant extracts delay yeast chronological aging through different signaling pathways.

Our recent study has revealed six plant extracts that slow yeast chronological aging more efficiently than any chemical compound yet described. The rate of aging in yeast is controlled by an evolutionarily conserved network of integrated signaling pathways and protein kinases. Here, we assessed how single-gene-deletion mutations eliminating each of these pathways and kinases affect the aging-delaying efficiencies of the six plant extracts.

Disparities in cancer treatment among patients infected with the human immunodeficiency virus.

Background: Patients with cancer who are infected with the human immunodeficiency virus (HIV) are less likely to receive cancer treatment compared with HIV-uninfected individuals. However, to the authors' knowledge, the impact of insurance status and comorbidities is unknown.

Methods: Data from the National Cancer Data Base were used to study nonelderly adults diagnosed with several common cancers from 2003 to 2011.

Retrospective cohort study of cancer incidence and mortality by HIV status in a Georgia, USA, prisoner cohort during the HAART era.

Objective: Non-AIDS-defining cancers (NADCs) have emerged as significant contributors to cancer mortality and morbidity among persons living with HIV (PLWH). Because NADCs are also associated with many social and behavioural risk factors that underlie HIV, determining the extent to which each of these factors contributes to NADC risk is difficult. We examined cancer incidence and mortality among persons with a history of incarceration, because distributions of other cancer risk factors are likely similar between prisoners living with HIV and non-infected prisoners.

Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes.

We discovered six plant extracts that increase yeast chronological lifespan to a significantly greater extent than any of the presently known longevity-extending chemical compounds. One of these extracts is the most potent longevity-extending pharmacological intervention yet described. We show that each of the six plant extracts is a geroprotector which delays the onset and decreases the rate of yeast chronological aging by eliciting a hormetic stress response.

iRAGE as a novel carboxymethylated peptide that prevents advanced glycation end product-induced apoptosis and endoplasmic reticulum stress in vascular smooth muscle cells.

Advanced glycation end-products (AGE) and the receptor for AGE (RAGE) have been linked to numerous diabetic vascular complications. RAGE activation promotes a self-sustaining state of chronic inflammation and has been shown to induce apoptosis in various cell types. Although previous studies in vascular smooth muscle cells (VSMC) showed that RAGE activation increases vascular calcification and interferes with their contractile phenotype, little is known on the potential of RAGE to induce apoptosis in VSMC.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Background: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.