Improved HIV-1 neutralization breadth and potency of V2-apex antibodies by in silico design.

Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency of neutralization. We employ the OSPREY computational protein design software to engineer variants of two apex-directed bNAbs, PGT145 and PG9RSH, resulting in increases in potency of over 100-fold against some viruses. The top designed variants improve neutralization breadth from 39% to 54% at clinically relevant concentrations (IC < 1 μg/mL) and improve median potency (IC) by up to 4-fold over a cross-clade panel of 208 strains.

The Metabolism of Lufotrelvir, a Prodrug Investigated for the Treatment of SARS-COV2 in Humans Following Intravenous Administration.

The metabolism of lufotrelvir, a novel phosphate prodrug of PF-00835231 for the treatment of COVID-19, was evaluated in healthy human volunteers and clinical trial participants with COVID-19 following intravenous infusion. The prodrug was completely converted to PF-00835231 that was subsequently cleared by hydrolysis, hydroxylation, ketoreduction, epimerization, renal clearance, and secretion into the feces. The main circulating metabolite was a hydrolysis product (M7) that was present at concentrations greater than PF-00835231, and this was consistent between healthy volunteers and participants with COVID-19.

Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential.

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.

Spatial and temporal organization of the genome: Current state and future aims of the 4D nucleome project.

The four-dimensional nucleome (4DN) consortium studies the architecture of the genome and the nucleus in space and time. We summarize progress by the consortium and highlight the development of technologies for (1) mapping genome folding and identifying roles of nuclear components and bodies, proteins, and RNA, (2) characterizing nuclear organization with time or single-cell resolution, and (3) imaging of nuclear organization. With these tools, the consortium has provided over 2,000 public datasets.

Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.

Background: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor . Early studies suggest that deletion of may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of loss is unknown.

Group Selection as a Basis for Screening Mutagenized Libraries of Public Goods (Bacillus thuringiensis Cry Toxins).

The pesticidal toxins of Bacillus thuringiensis (Bt) supply the active proteins for genetically modified insect-resistant crops. There is therefore keen interest in finding new toxins, or improving known toxins, in order to increase the mortality of various targets. The production and screening of large libraries of mutagenized toxins are among the means of identifying improved toxins.

Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants.

Curriculum Innovations: A Podcast-Based Neurologic Emergency Flipped Classroom Curriculum for Neurology Residents.

Introduction: Education on the management of neurologic emergencies is vital for neurology residents, and effective educational methods are needed. This study aims to implement and evaluate the impact of a podcast-based flipped classroom curriculum in neurologic emergencies. "Flipped classroom" instructional methods have been used in GME and informed by experiential learning theory.

Clinical trials in vascular cognitive impairment following SPRINT-MIND: An international perspective.

A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP < 120 vs. <140 mm Hg). In this perspective, we discuss key questions and make recommendations for clinical practice and for clinical trials, following SPRINT-MIND.

Once-daily roflumilast foam 0.3% for scalp and body psoriasis: a randomized, double-blind, vehicle-controlled phase IIb study.

Background: Scalp psoriasis affects most patients with psoriasis, but it can be difficult to treat.

Objectives: To evaluate the efficacy and safety of once-daily roflumilast foam 0.3% on scalp and body psoriasis.

Influence of Supervised Maternal Aerobic Exercise during Pregnancy on 1-Month-Old Neonatal Cardiac Function and Outflow: A Pilot Study.

Purpose: The objective of this study is to assess the effects of supervised, recommended levels of prenatal aerobic exercise on 1-month-old infant cardiac function.

Methods: Eligible pregnant women were randomly assigned to either an aerobic exercise group that participated in 150 min of supervised, moderate-intensity (40% to 59% V̇O 2peak , 12 to 14 on Borg rating of perceived exertion) aerobic exercise per week for 24 wk or more or a nonexercising group that consisted of 150 min·wk -1 of relaxation techniques. One-month-old infant echocardiogram was performed to assess infant cardiac function , including heart rate (HR), left-ventricular stroke volume, cardiac output, cardiac index, ejection fraction, fractional shortening, and velocity time integral at the aortic valve.

Spray Cryotherapy for Benign Large Airway Stenosis: A Multicenter Retrospective Cohort Study of Safety and Practice Patterns.

Background: Benign airway stenosis (BAS) represents a significant burden on patients, providers, and healthcare systems. Spray cryotherapy (SCT) has been proposed as an adjunctive treatment to reduce BAS recurrence. We sought to examine safety and practice variations of the latest SCT system when used for BAS.

New copper(I) complexes of bulky 5-substituted-2-iminopyrrolyl ligands as catalysts for azide-alkyne cycloaddition.

Five dinuclear copper(I) complexes of the type [Cu{κ,κ'-5-R-NCH-2-C(H)N(2,6-iPrCH)}] (1a-e; R = 2,4,6-iPrCH (a), R = 2,6-MeCH (b), R = 3,5-(CF)CH (c), R = 2,6-(OMe)CH (d), R = CPh (e)) were prepared by the reaction of the respective 5-R-2-iminopyrrolyl potassium salts KLa-e and [Cu(NCMe)]BF in moderate yields. These new copper(I) complexes were characterized by NMR spectroscopy, elemental analysis and, in selected cases, by single crystal X-ray diffraction and their structural and electronic features further analyzed by DFT calculations and cyclic voltammetry, respectively. X-ray diffraction studies reveal dimeric Cu structures assembled by 2-iminopyrrolyl bridging ligands adopting a transoid conformation (complexes 1a and 1d), while complexes 1c and 1e displayed a cisoid conformation of those moieties, with respect to the Cu(I) centers.

Trends in Gender and Racial/Ethnic Disparities in Physical Disability and Social Support Among U.S. Older Adults With Cognitive Impairment Living Alone, 2000-2018.

Background And Objectives: Informal care is the primary source of support for older adults with cognitive impairment, yet is less available to those who live alone. We examined trends in the prevalence of physical disability and social support among older adults with cognitive impairment living alone in the United States.

Research Design And Methods: We analyzed 10 waves of data from the U.

Early versus Later Anticoagulation for Stroke with Atrial Fibrillation.

Background: The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear.

Methods: We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke).

Protocol for predicting drug-resistant protein mutations to an ERK2 inhibitor using RESISTOR.

Prospective predictions of drug-resistant protein mutants could improve the design of therapeutics less prone to resistance. Here, we describe RESISTOR, an algorithm that uses structure- and sequence-based criteria to predict resistance mutations. We demonstrate the process of using RESISTOR to predict ERK2 mutants likely to arise in melanoma ablating the efficacy of the ERK1/2 inhibitor SCH779284.

Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy.

Background And Objectives: Neurologic outcomes in people with HIV (PWH) on long-duration antiretroviral therapy (ART) are not fully understood, and the underlying pathophysiology is unclear. To address this, we established a cohort of such individuals and compared them with HIV-negative controls using a novel matching technique. Both groups underwent extensive cognitive testing, evaluation for psychiatric measures, and MRI and CSF analyses.

A community-based study of dental fluorosis in rural children (6-12 years) from an aspirational district in Karnataka, India.

Objectives: The present study was planned to estimate the prevalence of dental fluorosis in 6-12 years of children and its association with various drinking water sources, water, and urine fluoride levels among the subset of children under the umbrella of a larger study to address iodine deficiency disorders and iron deficiency anemia in 17 villages of Manvi and Devadurga talukas of Raichur district of Karnataka.

Methods: Analysis of subset of data and urine samples of children under the umbrella of a larger cross-sectional community-based study was conducted in 17 villages of Manvi and Devadurga taluks of Raichur district. House to house survey was carried out to collect data using a semi-structured questionnaire in ODK software.

Paraneoplastic Syndromes from Head to Toe: Pathophysiology, Imaging Features, and Workup.

Patients often have symptoms due to the mass effect of a neoplasm on surrounding tissues or the development of distant metastases. However, some patients may present with clinical symptoms that are not attributable to direct tumor invasion. In particular, certain tumors may release substances such as hormones or cytokines or trigger an immune cross-reactivity between malignant and normal body cells, resulting in characteristic clinical features that are broadly referred to as paraneoplastic syndromes (PNSs).

Computational Assessment of Magnetic Nanoparticle Targeting Efficiency in a Simplified Circle of Willis Arterial Model.

This paper presents the methodology and computational results of simulated medical drug targeting via induced magnetism intended for administering intravenous patient-specific doses of therapeutic agents in a Circle of Willis (CoW) model. The multi-physics computational model used in this work is from our previous works. The computational model is used to analyze pulsatile blood flow, particle motion, and particle capture efficiency in a magnetized region using the magnetic properties of magnetite and equations describing the magnetic forces acting on particles produced by an external cylindrical electromagnetic coil.

Child Neurology: Infantile Biotin Thiamine Responsive Basal Ganglia Disease: Case Report and Brief Review.

Biotin thiamine responsive basal ganglia disease (BTRBGD) is an inherited autosomal recessive disorder that results from the inability of thiamine to cross the blood-brain barrier. It is considered a treatable condition if vitamin supplementation, most commonly with thiamine and biotin, is initiated early. BTRBGD can present as an infantile form, classical childhood form, or adult Wernicke-like encephalopathy.

Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123.

CD123, the alpha chain of the IL-3 receptor, is an attractive target for acute myeloid leukemia (AML) treatment. However, cytotoxic antibodies or T cell engagers targeting CD123 had insufficient efficacy or safety in clinical trials. We show that expression of CD64, the high-affinity receptor for human IgG, on AML blasts confers resistance to anti-CD123 antibody-dependent cell cytotoxicity (ADCC) in vitro.