Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Hypertension is a risk factor for the development and progression of chronic kidney disease (CKD). It is unclear whether different thiazide diuretics have a differential impact on kidney outcomes.

Objective: To compare kidney outcomes in patients with hypertension taking chlorthalidone and hydrochlorothiazide.

Asynchronous teledentistry program in two long-term care facilities: Iowa's virtual dental home pilot project.

Introduction: Older adults living in long-term care facilities (LTCFs) often have poor oral health and difficulty accessing dental services. The aim was to implement a virtual dental home (VDH) program for residents in two LTCFs utilizing asynchronous teledentistry techniques and mobile dental equipment.

Methods: This pilot project was a 6-month longitudinal cohort study in two LTCFs.

Weight management medications for chronic use in 37 veterans affairs medical centers-A medication use evaluation.

Rationale: Controlled trials have demonstrated successful weight loss associated with certain weight management medications (WMMs). However, there are limited real-world data on prescribing patterns and efficacy and safety profiles of WMMs in Veterans Affairs (VA) patients.

Objective: To evaluate: utilization patterns of WMMs liraglutide, naltrexone/bupropion, orlistat, phentermine, phentermine/topiramate, and semaglutide; weight loss at three, six, twelve, and more than 12 months; safety; and treatment barriers.

Nanocarriers' repartitioning of drugs between blood subcompartments as a mechanism of improving pharmacokinetics, safety, and efficacy.

For medical emergencies, such as acute ischemic stroke, rapid drug delivery to the target site is essential. For many small molecule drugs, this goal is unachievable due to poor solubility that prevents intravenous administration, and less obviously, by extensive partitioning to plasma proteins and red blood cells (RBCs), which greatly slows delivery to the target. Here we study these effects and how they can be solved by loading into nanoscale drug carriers.

Development of a predictive algorithm for the efficacy of half-life extension strategies.

A challenge in development of peptide and protein therapeutics is rapid elimination from the body, necessitating frequent dosing that may lead to toxicities and/or poor patient compliance. To solve this issue, there has been great investment into half-life extension of rapidly eliminated drugs using approaches such as albumin binding, fusion to albumin or Fc, or conjugation to polyethylene glycol. Despite clinical successes of half-life extension products, no clear relationship has been drawn between properties of drugs and the pharmacokinetic parameters of their half-life extended analogues.

Chlorthalidone vs Hydrochlorothiazide for Hypertension Treatment After Myocardial Infarction or Stroke: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events.

Objective: To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke.

Design, Setting, And Participants: This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or switch to CTD at pharmacologically comparable doses.

Physiologically based modeling of LNP-mediated delivery of mRNA in the vascular system.

RNA therapeutics are an emerging, powerful class of drugs with potential applications in a wide range of disorders. A central challenge in their development is the lack of clear pharmacokinetic (PK)-pharmacodynamic relationship, in part due to the significant delay between the kinetics of RNA delivery and the onset of pharmacologic response. To bridge this gap, we have developed a physiologically based PK/pharmacodynamic model for systemically administered mRNA-containing lipid nanoparticles (LNPs) in mice.

Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke.

Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase in the infarct volume.

Early Mortality After the First Dose of COVID-19 Vaccination: A Target Trial Emulation.

Background: Vaccine hesitancy persists alongside concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines. We aimed to examine the effect of COVID-19 vaccination on risk of death among US veterans.

Methods: We conducted a target trial emulation to estimate and compare risk of death up to 60 days under two COVID-19 vaccination strategies: vaccination within 7 days of enrollment versus no vaccination through follow-up.

Long-term opioid therapy trajectories and overdose in patients with and without cancer.

Objective: Pain is experienced by most patients with cancer and opioids are a cornerstone of management. Our objectives were (1) to identify patterns or trajectories of long-term opioid therapy (LTOT) and their correlates among patients with and without cancer and (2) to assess the association between trajectories and risk for opioid overdose, considering the potential moderating role of cancer.

Methods And Analysis: We conducted a retrospective cohort study among individuals in the US Veterans Health Administration (VHA) database with incident LTOT with and without cancer (N=44,351; N=285,772, respectively) between 2010-2017.

Strategies for secondary use of real-world clinical and administrative data for outcome ascertainment in pragmatic clinical trials.

Background: Pragmatic trials are gaining popularity as a cost-effective way to examine treatment effectiveness and generate timely comparative evidence. Incorporating supplementary real-world data is recommended for robust outcome monitoring. However, detailed operational guidelines are needed to inform effective use and integration of heterogeneous databases.

Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors.

PD-1 checkpoint inhibitors have revolutionized the treatment of patients with different cancer histologies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. However, only a subset of patients show a dramatic clinical response to treatment. Despite intense biomarker discovery efforts, no single robust, prognostic correlation has emerged as a valid outcome predictor.

Cognitive task analysis of clinicians' drug-drug interaction management during patient care and implications for alert design.

Background: Drug-drug interactions (DDIs) are common and can result in patient harm. Electronic health records warn clinicians about DDIs via alerts, but the clinical decision support they provide is inadequate. Little is known about clinicians' real-world DDI decision-making process to inform more effective alerts.

Effective Prevention of Arterial Thrombosis with Albumin-Thrombin Inhibitor Conjugates.

Thromboprophylaxis is indicated in patients at an elevated risk of developing thrombotic disorders, typically using direct oral anticoagulants or low-molecular-weight heparins. We postulated that transient thromboprophylaxis (days-weeks) could be provided by a single dose of an anticoagulant engineered for prolonged pharmacokinetics. In the present work, d-phenylalanyl-l-prolyl-l-arginine chloromethyl ketone (PPACK) was used as a model anticoagulant to test the hypothesis that conjugation of thrombin inhibitors to the surface of albumin would provide durable protection against thrombotic insults.

Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain.

-loaded white blood cells (WBC) can transfer cargo to pathological foci in the central nervous system (CNS). Here we tested affinity ligand driven loading of WBC in order to bypass the need for WBC manipulation. We used a mouse model of acute brain inflammation caused by local injection of tumor necrosis factor alpha (TNF-α).

Targeting lipid nanoparticles to the blood brain barrier to ameliorate acute ischemic stroke.

Unlabelled: After more than 100 failed drug trials for acute ischemic stroke (AIS), one of the most commonly cited reasons for the failure has been that drugs achieve very low concentrations in the at-risk penumbra. To address this problem, here we employ nanotechnology to significantly enhance drug concentration in the penumbra's blood-brain barrier (BBB), whose increased permeability in AIS has long been hypothesized to kill neurons by exposing them to toxic plasma proteins. To devise drug-loaded nanocarriers targeted to the BBB, we conjugated them with antibodies that bind to various cell adhesion molecules on the BBB endothelium.

Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases.

Diseases of the pulmonary alveolus, such as pulmonary fibrosis, are leading causes of morbidity and mortality, but exceedingly few drugs are developed for them. A major reason for this gap is that after inhalation, drugs are quickly whisked away from alveoli due to their high perfusion. To solve this problem, the mechanisms by which nano-scale drug carriers dramatically improve lung pharmacokinetics using an inhalable liposome formulation containing nintedanib, an antifibrotic for pulmonary fibrosis, are studied.

The impact of COVID-19 on a large pragmatic clinical trial embedded in primary care.

Introduction: The COVID-19 pandemic had significant impact on clinical care and clinical trial operations, but the impact on decentralized pragmatic trials is unclear. The Diuretic Comparison Project (DCP) is a Point-of Care (POC) pragmatic trial testing whether chlorthalidone is superior to hydrochlorothiazide in preventing major cardiovascular (CV) events and non-cancer death. DCP utilized telephone consent, data collection from the electronic health record and Medicare, forwent study visits, and limited provider commitment beyond usual care.

Comparison of hospitalization costs for the same adverse reaction associated with different medications.

Purpose: Costs of hospitalization due to severe adverse drug reactions (ADRs) were previously estimated within the Veterans Health Administration (VHA), but additional analyses are needed to infer potential interventions to mitigate these negative outcomes. The objective of this study was to compare specific adverse reaction-related hospitalization costs between medications with similar indications.

Methods: Mean hospitalization costs associated with the same ADR symptom were compared for different drugs with similar indications using adjusted generalized linear models with a Bonferroni correction for multiple comparisons as well as a gamma distribution.

Targeted drug delivery to the brain endothelium dominates over passive delivery via vascular leak in experimental intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is one of the most common causes of fatal stroke, yet has no specific drug therapies. Many attempts at passive intravenous (IV) delivery in ICH have failed to deliver drugs to the salvageable area around the hemorrhage. The passive delivery method assumes vascular leak through the ruptured blood-brain barrier will allow drug accumulation in the brain.

PCSK9 Inhibitor Use and Outcomes Using Concomitant Lipid-Lowering Therapies in the Veterans Health Administration.

Background: Real-world data on use of PCSK9 inhibitors (PCSK9-Is), with or without statins and/or ezetimibe, and associated outcomes, can inform more effective prescribing. The objective was to evaluate clinical effectiveness and safety of PCSK9-Is within the Veterans Health Administration (VHA).

Methods: In this retrospective cohort study, we included Veterans who had at least one outpatient prescription for alirocumab and/or evolocumab filled within VHA between August 21, 2015, and September 30, 2020.

Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.

Background: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear.

Methods: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg.