High-throughput specificity profiling of antibody libraries using ribosome display and microfluidics.

In this work, we developed PolyMap (polyclonal mapping), a high-throughput method for mapping protein-protein interactions. We demonstrated the mapping of thousands of antigen-antibody interactions between diverse antibody libraries isolated from convalescent and vaccinated COVID-19 donors and a set of clinically relevant SARS-CoV-2 spike variants. We identified over 150 antibodies with a variety of distinctive binding patterns toward the antigen variants and found a broader binding profile, including targeting of the Omicron variant, in the antibody repertoires of more recent donors.

Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons.

Background: Twice-yearly subcutaneous lenacapavir has been shown to be efficacious for prevention of HIV infection in cisgender women. The efficacy of lenacapavir for preexposure prophylaxis (PrEP) in cisgender men, transgender women, transgender men, and gender-nonbinary persons is unclear.

Methods: In this phase 3, double-blind, randomized, active-controlled trial, we randomly assigned participants in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF).

Estimates of actual and potential lives saved in the United States from the use of COVID-19 convalescent plasma.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data.

SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.

Background: Dysregulated metabolism of bioactive sphingolipids, including ceramides and sphingosine-1-phosphate, has been implicated in cardiovascular disease, although the specific species, disease contexts, and cellular roles are not completely understood. Sphingolipids are produced by the serine palmitoyltransferase enzyme, canonically composed of 2 subunits, SPTLC1 (serine palmitoyltransferase long chain base subunit 1) and SPTLC2 (serine palmitoyltransferase long chain base subunit 2). Noncanonical sphingolipids are produced by a more recently described subunit, SPTLC3 (serine palmitoyltransferase long chain base subunit 3).

Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial.

Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint.

GMP Manufacturing and IND-Enabling Studies of a Recombinant Hyperimmune Globulin Targeting SARS-CoV-2.

Conventionally, hyperimmune globulin drugs manufactured from pooled immunoglobulins from vaccinated or convalescent donors have been used in treating infections where no treatment is available. This is especially important where multi-epitope neutralization is required to prevent the development of immune-evading viral mutants that can emerge upon treatment with monoclonal antibodies. Using microfluidics, flow sorting, and a targeted integration cell line, a first-in-class recombinant hyperimmune globulin therapeutic against SARS-CoV-2 (GIGA-2050) was generated.

Discovery of VU6028418: A Highly Selective and Orally Bioavailable M Muscarinic Acetylcholine Receptor Antagonist.

Herein, we report the SAR leading to the discovery of VU6028418, a potent M mAChR antagonist with high subtype-selectivity and attractive DMPK properties and across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered.

Validation of non-invasive transcutaneous measurement for glomerular filtration rate in lean and obese C57BL/6J mice.

Aim: The measurement of glomerular filtration rate (GFR) in experimental rodents is pivotal to understanding the progression of kidney disease and benefits of treatment strategies. A non-invasive clearance device has been developed, which measures transcutaneous decay of injected FITC-sinistrin in conscious rodents. The technique was validated against the well-established plasma clearance method in the same mice, but on consecutive days, using only models of uninephrectomy and polycystic kidney disease.

TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study.

Background: Most evidence for TSC-associated neuropsychiatric disorders (TAND) to date have come from small studies and case reports, and very little is known about TAND in adults. We explored baseline TAND data from the large-scale international TOSCA natural history study to compare childhood and adult patterns, describe age-based patterns, and explore genotype-TAND correlations.

Results: The study enrolled 2216 eligible participants with TSC from 170 sites across 31 countries at the data cut-off for the third interim analysis (data cut-off date: September 30, 2015).

Heat Stress and Hepatic Laser Thermal Ablation Induce Hepatocellular Carcinoma Growth: Role of PI3K/mTOR/AKT Signaling.

Purpose To determine if heat stress and hepatic laser thermal ablation induce hepatocellular carcinoma (HCC) growth and to identify growth factors induced by heat stress. Materials and Methods Non-heat-stressed HCC cells were cocultured with HCC cells or hepatocytes that were heat stressed at 37°C (physiologic), 45°C (moderate), or 50°C (severe) for 10 minutes and proliferation monitored with bioluminescence imaging for up to 6 days after heat stress (three experiments). Rats bearing orthotopic N1S1 HCC were randomly assigned to undergo immediate sham or laser thermal (3 W for 60 or 90 seconds; hereafter, 3W×60s and 3W×90s, respectively) ablation of the median (local) or left (distant) hepatic lobe, and tumor growth was monitored with magnetic resonance imaging for up to 18 days after ablation (six or more rats per group).

Systematic genomic and translational efficiency studies of uveal melanoma.

To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays.

PARENTAL REPORTS OF EARLY SOCIOEMOTIONAL AND BEHAVIORAL PROBLEMS: DOES THE FATHER'S VIEW MAKE A DIFFERENCE?

Although both mothers and fathers are essential sources of information to address early socioemotional/behavioral (SEB) problems, there continues to be a dearth of studies considering both parental views. A sample of 208 toddlers (M = 19.3 months) was recruited through public child health centers.

Research Needs to Improve Hypertension Treatment and Control in African Americans.

Additional targeted research and customized training programs could spearhead strategies for elimination of the disparities in prevalence and control of high BP between African Americans and the remainder of the US general population.

Evidence for Shear Stress-Mediated Dilation of the Internal Carotid Artery in Humans.

Increases in arterial carbon dioxide tension (hypercapnia) elicit potent vasodilation of cerebral arterioles. Recent studies have also reported vasodilation of the internal carotid artery during hypercapnia, but the mechanism(s) mediating this extracranial vasoreactivity are unknown. Hypercapnia increases carotid shear stress, a known stimulus to vasodilation in other conduit arteries.

Leukocyte-Expressed β2-Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury.

Background: Immune cell-mediated inflammation is an essential process for mounting a repair response after myocardial infarction (MI). The sympathetic nervous system is known to regulate immune system function through β-adrenergic receptors (βARs); however, their role in regulating immune cell responses to acute cardiac injury is unknown.

Methods: Wild-type (WT) mice were irradiated followed by isoform-specific βAR knockout (βARKO) or WT bone-marrow transplantation (BMT) and after full reconstitution underwent MI surgery.

Impact of Long-Term Poor and Good Glycemic Control on Metabolomics Alterations in Type 1 Diabetic People.

Context: Poor glycemic control in individuals with type 1 diabetes (T1D) is associated with both micro- and macrovascular complications, but good glycemic control does not fully prevent the risk of these complications.

Objective: The objective of the study was to determine whether T1D with good glycemic control have persistent abnormalities of metabolites and pathways that exist in T1D with poor glycemic control.

Design: We compared plasma metabolites in T1D with poor (glycated hemoglobin ≥ 8.

Effects of Low- Versus High-Fidelity Simulations on the Cognitive Burden and Performance of Entry-Level Paramedicine Students: A Mixed-Methods Comparison Trial Using Eye-Tracking, Continuous Heart Rate, Difficulty Rating Scales, Video Observation and Interviews.

Introduction: High-fidelity simulation-based training is often avoided for early-stage students because of the assumption that while practicing newly learned skills, they are ill suited to processing multiple demands, which can lead to "cognitive overload" and poorer learning outcomes. We tested this assumption using a mixed-methods experimental design manipulating psychological immersion.

Methods: Thirty-nine randomly assigned first-year paramedicine students completed low- or high-environmental fidelity simulations [low-environmental fidelity simulations (LF(en)S) vs.

Cost-Effectiveness of a Physician-Pharmacist Collaboration Intervention to Improve Blood Pressure Control.

Previous studies have demonstrated the cost-effectiveness of physician-pharmacist collaborations to improve hypertension control. However, most studies have limited generalizability, lacking minority and low-income populations. The Collaboration Among Pharmacist and Physicians to Improve Blood Pressure Now (CAPTION) trial randomized 625 patients from 32 medical offices in 15 states.

Clinical Placement Before or After Simulated Learning Environments?: A Naturalistic Study of Clinical Skills Acquisition Among Early-Stage Paramedicine Students.

Background: There is conflicting evidence surrounding the merit of clinical placements (CPs) for early-stage health-profession students. Some contend that early-stage CPs facilitate contextualization of a subsequently learned theory. Others argue that training in simulated-learning experiences (SLEs) should occur before CP to ensure that students possess at least basic competency.

Development of and Recovery from Secondary Hypogonadism in Aging Men: Prospective Results from the EMAS.

Context: Secondary hypogonadism is common in aging men; its natural history and predisposing factors are unclear.

Objectives: The objectives were 1) to identify factors that predispose eugonadal men (T ≥ 10.5 nmol/L) to develop biochemical secondary hypogonadism (T < 10.

Increasing trend in admissions for malignant hypertension and hypertensive encephalopathy in the United States.

Malignant hypertension and hypertensive encephalopathy are life-threating manifestations of hypertension. These syndromes primarily occur in patients with a history of poorly controlled hypertension. The purpose of this study was to investigate national trends in hospital admissions for malignant hypertension, hypertensive encephalopathy, and essential hypertension.