Overview of the Epidemiology and Clinical Care Considerations for Adolescents and Young Adults Living with or at Risk of Human Immunodeficiency Virus.

This article provides an updated examination of human immunodeficiency virus (HIV) epidemiologic trends among adolescents and young adults (AYAs) in the United States, highlighting the significant public health challenge posed by HIV within this demographic. Despite a notable decline in HIV diagnoses among AYAs, challenges remain, particularly due to 50% of AYAs living with HIV being unaware of their status. The article aims to evaluate current clinical recommendations, identify deficiencies, and propose evidence-based improvements for HIV prevention, diagnosis, and care, with the goal of enhancing health outcomes and reducing HIV prevalence among AYAs.

Closing the Opioid Treatment Gap Through Advance Practice Nursing Activation: Curricular Design and Initial Outcomes.

Introduction: Buprenorphine, an effective medication for opioid use disorder (MOUD), reduces opioid-related harms including overdose, but a significant gap exists between MOUD need and treatment, especially for marginalized populations. Historically, low MOUD treatment capacity is rising, driven by advanced practice registered nurses (APRNs). A graduate nursing course was designed to increase equitable buprenorphine treatment delivery by APRNs.

Phthalazinone-based lactams and cyclic ureas as ROCK2 selective inhibitors.

Derivatives of lactam, cyclic urea and carbamate were explored as aniline amide replacements in a series of phthalazinone-based ROCK inhibitors. Potent ROCK2 inhibitors such as 22 were identified with excellent overall kinase selectivity as well as good isoform selectivity over ROCK1.

Prevalence and correlates of methamphetamine use in transitional age youth experiencing homelessness or housing instability in San Francisco, CA.

Introduction: Substance use, including methamphetamine use, is a contributing factor in HIV acquisition and treatment. Stimulant use is linked to mental health yet there is limited data from youth in community-based settings.

Design: One hundred marginally housed or homeless transitional age youth (TAY) were recruited at Larkin Street Youth Services and completed a survey on mental health and substance use.

Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model.

Myocardial fibrosis is a key pathologic feature of hypertrophic cardiomyopathy (HCM). However, the fibrotic pathways activated by HCM-causing sarcomere protein gene mutations are poorly defined. Because lysophosphatidic acid is a mediator of fibrosis in multiple organs and diseases, we tested the role of the lysophosphatidic acid pathway in HCM.

The syndemic effects of adverse mental health conditions and polysubstance use on being at risk of clinical depression among marginally housed and homeless transitional age youth living in San Francisco, California.

The objective of this study was to identify the correlates of being at risk of clinical depression and examine the role of syndemic factors among marginally housed and homeless transitional age youth (TAY). From 2017-2018, 100 TAY between the ages of 18 and 24 in San Francisco were recruited from Larkin Street Youth Services into a cross-sectional study. Participants completed surveys on mental health, substance use, and HIV risk behaviors.

Prevalence of Pre-Existing Neutralizing Antibodies Against Adeno-Associated Virus Serotypes 1, 2, 5, 6, 8, and 9 in Sera of Different Pig Strains.

Pre-existing neutralizing antibodies (NAb) to adeno-associated virus (AAV) may diminish the efficacy of AAV-based therapies depending on the titer. To support gene therapy studies in pigs, the seroprevalence of NAb to AAV1, 2, 5, 6, 8, and 9 serotypes were assessed in the sera of 3 different strains of pigs consisting of 60 Norsvin Topigs-20 strain, 22 Gottingen minipigs, and 40 Yucatan minipigs. Cell-based NAb assays were developed for various AAV serotypes.

Plasma biomarkers associated with adverse outcomes in patients with calcific aortic stenosis.

Aims: Enhanced risk stratification of patients with aortic stenosis (AS) is necessary to identify patients at high risk for adverse outcomes, and may allow for better management of patient subgroups at high risk of myocardial damage. The objective of this study was to identify plasma biomarkers and multimarker profiles associated with adverse outcomes in AS.

Methods And Results: We studied 708 patients with calcific AS and measured 49 biomarkers using a Luminex platform.

Comparing substance use and mental health among sexual and gender minority and heterosexual cisgender youth experiencing homelessness.

Youth homelessness has been demonstrated to disproportionately affect sexual and gender minority (SGM) youth compared to heterosexual cisgender peers. In this context, we aimed to compare health risks between service-seeking SGM and heterosexual cisgender youth experiencing homelessness, including harmful risks stemming from substance use and severity of symptoms of mental health disorders. We recruited 100 racially diverse, unstably housed participants aged 18-24 who access services at an urban non-profit organization in San Francisco, CA.

Quantitative Proteomic Analysis of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction.

Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p < 0.

Identification of 5H-chromeno[3,4-c]pyridine and 6H-isochromeno[3,4-c]pyridine derivatives as potent and selective dual ROCK inhibitors.

A novel series of 5H-chromeno[3,4-c]pyridine, 6H-isochromeno[3,4-c]pyridine and 6H-isochromeno[4,3-d]pyrimidine derivatives as dual ROCK1 and ROCK2 inhibitors is described. Optimization led to compounds with sub-nanomolar inhibitory affinity for both kinases and excellent kinome selectivity. Compound 19 exhibited ROCK1 and ROCK2 IC of 0.

Initiation of HIV pre-exposure prophylaxis in adolescents and young adults: Barriers and opportunities.

Background: Adolescents and young adults (AYA) ages 13 to 24 years comprise a quarter of the new HIV diagnoses in the United States. Lack of access to HIV-preventive biomedical tools such as pre-exposure prophylaxis (PrEP) reduces opportunities to prevent HIV infection in this population. Initiating PrEP in AYA significantly reduces the negative health outcomes of HIV, but many providers are still reluctant to initiate PrEP in their AYA patients based on perceived threats and barriers.

Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies.

Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.

LC/MS/MS-based quantitation of pig and human S100A1 protein in cardiac tissues: Application to gene therapy.

The S100A1 protein is a target of interest for the treatment of heart failure as it has been previously reported to be depleted in failing cardiomyocytes. A gene therapy approach leading to increased expression levels of the protein directly in the heart could potentially lead to restoration of contractile function and improve overall cell survival. S100A1 is a relatively small soluble protein that is extremely well conserved across species with only a single amino acid difference between the sequences in human and pig, a commonly used pre-clinical model for evaluation of efficacy, biodistribution and safety for cardiac-directed gene therapy approaches.

Trauma, substance use, and mental health symptoms in transitional age youth experiencing homelessness.

Objective: This descriptive study examined the prevalence and correlates of trauma, substance use, and mental health symptoms in homeless transitional age youth (TAY) in San Francisco.

Design & Sample: One hundred homeless TAY were recruited from a community-based organization to complete a survey on trauma, mental health symptoms, and substance use.

Measurements: We used these measures: National Institute on Drug Abuse (NIDA)-Modified Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) for frequency and risk level of substance use; the 10-item Adverse Childhood Experiences (ACEs) for prevalence of trauma; the Post-traumatic Stress Disorder Checklist for DSM-5 for post-traumatic stress disorder (PTSD) symptoms; Center for Epidemiologic Studies Depression Scale for depression symptoms; and Generalized Anxiety Disorder 7-item for anxiety symptoms.

Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL-C Increase In Vivo.

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound .

Benzothiazole-based compounds as potent endothelial lipase inhibitors.

A series of benzothiazoles with a cyano group was synthesized and evaluated as endothelial lipase (EL) inhibitors for the potential treatment of cardiovascular diseases. Efforts to reduce molecular weight and polarity in the series led to improved physicochemical properties of these compounds, as well as selectivity for EL over hepatic lipase (HL). As a benchmark compound, 8i demonstrated potent EL activity, an acceptable absorption, distribution, metabolism and elimination (ADME) profile and pharmacokinetic (PK) exposure which allowed further evaluation in preclinical animal efficacy studies.

Discovery of a Lead Triphenylethanamine Cholesterol Ester Transfer Protein (CETP) Inhibitor.

Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the -terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino--(()-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide ().

Identification of substituted benzothiazole sulfones as potent and selective inhibitors of endothelial lipase.

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL).

Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase.

Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL.

Development of a Chemiluminescent ELISA Method for the Detection of Total Anti-Adeno Associated Virus Serotype 9 (AAV9) Antibodies.

Recombinant adeno associated viruses (rAAV) have become an important tool for the delivery of gene therapeutics due to long-standing safety and success in clinical trials. Since humans often become exposed to AAVs and develop anti-AAV antibodies (Abs), a potential impediment to the success of gene therapeutics is neutralization of the viral particle before it has had a chance to bind and enter target cells to release the transgene. Identification of subjects with preexisting Abs having neutralizing potential, and exclusion of such subjects from clinical studies is expected to enhance drug efficacy.

Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors.

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides.

PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor.

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, -(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (; EL IC = 61 nM, EL IC = 454 nM). Deck mining identified a related hit, -(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1-pyrrole-3-carboxamide (; EL IC = 41 nM, EL IC = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL).

Oral Delivery of Highly Lipophilic, Poorly Water-Soluble Drugs: Self-Emulsifying Drug Delivery Systems to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a Cholesteryl Ester Transfer Protein Inhibitor in Preclinical Species.

BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.