Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand.

Background: Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure.

Methods: We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection.

Biology and management of ependymomas.

Ependymomas are rare primary tumors of the central nervous system in children and adults that comprise histologically similar but genetically distinct subgroups. The tumor biology is typically more associated with the site of origin rather than being age-specific. Genetically distinct subgroups have been identified by genomic studies based on locations in classic grade II and III ependymomas.

Endometrial Expression of Steroidogenic Factor 1 Promotes Cystic Glandular Morphogenesis.

Epigenetic silencing of steroidogenic factor 1 (SF1) is lost in endometriosis, potentially contributing to de novo local steroidogenesis favoring inflammation and growth of ectopic endometrial tissue. In this study, we examine the impact of SF1 expression in the eutopic uterus by a novel mouse model that conditionally expresses SF1 in endometrium. In vivo SF1 expression promoted the development of enlarged endometrial glands and attenuated estrogen and progesterone responsiveness.

Achieving remarkable mechanochromism and white-light emission with thermally activated delayed fluorescence through the molecular heredity principle.

Achieving high contrast mechanochromism (Δ > 100 nm) and white-light emission under mild conditions from a single compound with a simple structure is a great challenge. Herein, we report a novel dual-emissive compound, namely SCP, with an asymmetric molecular structure that fully inherits the photophysical properties of the parent molecules SC and SP. SCP shows high contrast, linearly tunable mechanochromism and bright white-light emission arising from a combination of traditional fluorescence and thermally activated delayed fluorescence (TADF).

Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone.

Context: During aging, total testosterone (TT) declines and SHBG increases, resulting in a greater decrease in calculated free T (cFT). Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT.

Objective: Our objective was to investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints.

Intermolecular Electronic Coupling of Organic Units for Efficient Persistent Room-Temperature Phosphorescence.

Although persistent room-temperature phosphorescence (RTP) emission has been observed for a few pure crystalline organic molecules, there is no consistent mechanism and no universal design strategy for organic persistent RTP (pRTP) materials. A new mechanism for pRTP is presented, based on combining the advantages of different excited-state configurations in coupled intermolecular units, which may be applicable to a wide range of organic molecules. By following this mechanism, we have developed a successful design strategy to obtain bright pRTP by utilizing a heavy halogen atom to further increase the intersystem crossing rate of the coupled units.

Comparison of Clinical and Automated Breast Density Measurements: Implications for Risk Prediction and Supplemental Screening.

Purpose To compare the classification of breast density with two automated methods, Volpara (version 1.5.0; Matakina Technology, Wellington, New Zealand) and Quantra (version 2.

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Background: The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.

Methods: In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69).

Inhibition of DYRK1A and GSK3B induces human β-cell proliferation.

Insufficient pancreatic β-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from β-cells in diabetic patients, no pharmacological agents have been described that increase β-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust β-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B.

Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury.

Sepsis and sepsis-induced lung injury remain a leading cause of death in intensive care units. We identified protein kinase C-δ (PKCδ) as a critical regulator of the acute inflammatory response and demonstrated that PKCδ inhibition was lung-protective in a rodent sepsis model, suggesting that targeting PKCδ is a potential strategy for preserving pulmonary function in the setting of indirect lung injury. In this study, whole-body organ biodistribution and pulmonary cellular distribution of a transactivator of transcription (TAT)-conjugated PKCδ inhibitory peptide (PKCδ-TAT) was determined following intratracheal (IT) delivery in control and septic [cecal ligation and puncture (CLP)] rats to ascertain the impact of disease pathology on biodistribution and efficacy.

Effect of Blood Pressure Lowering in Early Ischemic Stroke: Meta-Analysis.

Background And Purpose: Elevated blood pressure is common in acute stage of ischemic stroke and the strategy to manage this situation is not well established. We therefore conducted a meta-analysis of randomized controlled trials comparing active blood pressure lowering and control groups in early ischemic stroke.

Methods: Pubmed, EMBASE, and Clinicaltrials.

Associations of Perfluoroalkyl Substances (PFAS) with Lower Birth Weight: An Evaluation of Potential Confounding by Glomerular Filtration Rate Using a Physiologically Based Pharmacokinetic Model (PBPK).

Background: Prenatal exposure to perfluoroalkyl substances (PFAS) has been associated with lower birth weight in epidemiologic studies. This association could be attributable to glomerular filtration rate (GFR), which is related to PFAS concentration and birth weight.

Objectives: We used a physiologically based pharmacokinetic (PBPK) model of pregnancy to assess how much of the PFAS-birth weight association observed in epidemiologic studies might be attributable to GFR.

Oxidative Stress Biomarkers and Incidence of Postoperative Atrial Fibrillation in the Omega-3 Fatty Acids for Prevention of Postoperative Atrial Fibrillation (OPERA) Trial.

Background: Animal study results point to oxidative stress as a key mechanism triggering postoperative atrial fibrillation (PoAF), yet the extent to which specific biomarkers of oxidative stress might relate to PoAF risk in humans remains speculative.

Methods And Results: We assessed the association of validated, fatty acid-derived oxidative stress biomarkers (F2-isoprostanes, isofurans, and F3-isoprostanes) in plasma and urine, with incident PoAF among 551 cardiac surgery patients. Biomarkers were measured at enrollment, the end of surgery, and postoperative day 2.

The relationship between corticosteroids and symptoms in patients with primary brain tumors: utility of the Dexamethasone Symptom Questionnaire-Chronic.

Background: Corticosteroids can have many side effects that impact the patient's quality of life and functional status. The Dexamethasone Symptom Questionnaire-Chronic (DSQ-C) was developed to report corticosteroid side effects. This study's objective was to evaluate the utility of the DSQ-C and report associated signs and symptoms in brain tumor patients.

Pre-emptive peritonsillar infiltration of magnesium sulphate and ropivacaine vs. ropivacaine or magnesium alone for relief of post-adenotonsillectomy pain in children.

Objectives: The randomized, double-blinded, placebo-controlled study evaluated the administration of local infiltration of magnesium combined with ropivacaine to reduce pain scores after pediatric adenotonsillectomy.

Methods: Sixty one subjects received 5ml solution contained 0.25% ropivacaine plus 5mg/kg magnesium sulphate (Group M+R), 5ml 0.

Associations between sex steroids and the development of metabolic syndrome: a longitudinal study in European men.

Context: Low testosterone (T) has been associated with incident metabolic syndrome (MetS), but it remains unclear if this association is independent of sex hormone binding globulin (SHBG). Estradiol (E2) may also be associated with MetS, but few studies have investigated this.

Objective: To study the association between baseline sex steroids and the development of incident MetS and to investigate the influence of SHBG, body mass index (BMI) and insulin resistance on this risk.

Hydrogels with integrin-binding angiopoietin-1-derived peptide, QHREDGS, for treatment of acute myocardial infarction.

Background: Hydrogels are being actively investigated for direct delivery of cells or bioactive molecules to the heart after myocardial infarction (MI) to prevent cardiac functional loss. We postulate that immobilization of the prosurvival angiopoietin-1-derived peptide, QHREDGS, to a chitosan-collagen hydrogel could produce a clinically translatable thermoresponsive hydrogel to attenuate post-MI cardiac remodeling.

Methods And Results: In a rat MI model, QHREDGS-conjugated hydrogel (QHG213H), control gel, or PBS was injected into the peri-infarct/MI zone.

Pheochromocytoma and paraganglioma in cyanotic congenital heart disease.

Context: Aberrant cellular oxygen sensing is a leading theory for development of pheochromocytoma (PHEO) and paraganglioma (PGL).

Objective: The objective of the study was to test the hypothesis that chronic hypoxia in patients with cyanotic congenital heart disease (CCHD) increases the risk for PHEO-PGL.

Design/setting/participants: We investigated the association between CCHD and PHEO-PGL with two complementary studies: study 1) an international consortium was established to identify congenital heart disease (CHD) patients with a PHEO-PGL diagnosis confirmed by pathology or biochemistry and imaging; study 2) the 2000-2009 Nationwide Inpatient Survey, a nationally representative discharge database, was used to determine population-based cross-sectional PHEO-PGL frequency in hospitalized CCHD patients compared with noncyanotic CHD and those without CHD using multivariable logistic regression adjusted for age, sex, and genetic PHEO-PGL syndromes.

Characteristics and outcomes of patients with advanced chronic systolic heart failure receiving care at the Veterans Affairs versus other hospitals: insights from the Beta-blocker Evaluation of Survival Trial (BEST).

Background: Characteristics and outcomes of patients with heart failure and reduced ejection fraction receiving care at Veterans Affairs (VA) versus non-VA hospitals have not been previously reported.

Methods And Results: In the randomized controlled Beta-blocker Evaluation of Survival Trial (BEST; 1995-1999), of the 2707 (bucindolol=1353; placebo=1354) patients with heart failure and left ventricular ejection fraction ≤35%, 918 received care at VA hospitals, of which 98% (n=898) were male. Of the 1789 receiving care at non-VA hospitals, 68% (n=1216) were male.

Bone marrow characteristics associated with changes in infarct size after STEMI: a biorepository evaluation from the CCTRN TIME trial.

Rationale: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, selected patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear.

Objective: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size after ST-segment-elevation-myocardial infarction.

Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-αVβ3 integrin cross talk.

Objective: Plasminogen activator inhibitor-1 (PAI-1) regulates angiogenesis via effects on extracellular matrix proteolysis and cell adhesion. However, no previous study has implicated PAI-1 in controlling vascular endothelial growth factor (VEGF) signaling. We tested the hypothesis that PAI-1 downregulates VEGF receptor-2 (VEGFR-2) activation by inhibiting a vitronectin-dependent cooperative binding interaction between VEGFR-2 and αVβ3.

Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease.

Objective: Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease.

Approach And Results: Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls.

Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system.

Nearly 8% of the human population carries an inactivating point mutation in the gene that encodes the cardioprotective enzyme aldehyde dehydrogenase 2 (ALDH2). This genetic polymorphism (ALDH2*2) is linked to more severe outcomes from ischemic heart damage and an increased risk of coronary artery disease (CAD), but the underlying molecular bases are unknown. We investigated the ALDH2*2 mechanisms in a human model system of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from individuals carrying the most common heterozygous form of the ALDH2*2 genotype.

Sphingosine kinase 1 isoform-specific interactions in breast cancer.

Sphingosine kinase 1 (SK1) is a signaling enzyme that catalyzes the formation of sphingosine-1-phosphate. Overexpression of SK1 is causally associated with breast cancer progression and resistance to therapy. SK1 inhibitors are currently being investigated as promising breast cancer therapies.

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.

Methods: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL.