In vivo affinity maturation of the CD4 domains of an HIV-1-entry inhibitor.

Human proteins repurposed as biologics for clinical use have been engineered through in vitro techniques that improve the affinity of the biologics for their ligands. However, the techniques do not select against properties, such as protease sensitivity or self-reactivity, that impair the biologics' clinical efficacy. Here we show that the B-cell receptors of primary murine B cells can be engineered to affinity mature in vivo the human CD4 domains of the HIV-1-entry inhibitor CD4 immunoadhesin (CD4-Ig).

Prolonged Venous Transit on Perfusion Imaging is Associated with Longer Lengths of Stay in Acute Large Vessel Occlusions.

Background And Purpose: Prolonged venous transit (PVT+) is a marker of venous outflow; it is defined as the presence or absence of time-to-maximum ≥10 seconds timing in either the superior sagittal sinus or torcula. This novel perfusion imaging-based metric has been associated with higher odds of mortality and lower odds of functional recovery. This study aims to assess the relationship between PVT on admission perfusion imaging and length of hospital stay in large vessel occlusion strokes successfully reperfused with mechanical thrombectomy.

Feasibility and safety of endomyocardial biopsy by lumenless pacing lead sheath-directed method during cardiac implantable electronic device implantation.

Background: Patients with an indication for a cardiovascular implantable electronic device (CIED) are complicated with special cardiomyopathy or other unspecified cardiac abnormalities and may need endomyocardial biopsy (EMB). However, EMB by a bioptome is usually avoided to reduce the risk of lead displacement in the CIED periprocedural period.

Objective: We aimed to assess the safety and feasibility of a novel approach for transvenous right ventricular (RV) EMB using the lead sheath method (L-S-M) during CIED implantation and compared it with the traditional bioptome method (T-B-M).

Association of Pretreatment Perfusion Imaging Parameters With 90-Day Excellent Functional Outcomes in Anterior Circulation Distal Medium Vessel Occlusion Stroke.

Background And Purpose: Acute ischemic strokes caused by distal medium vessel occlusions (DMVO) represent a significant proportion of all stroke cases, yet the predictors of excellent functional outcomes in these patients remain poorly understood. This study aims to identify pretreatment computed tomography perfusion (CTP) parameters associated with excellent functional outcomes, defined as a modified Rankin Scale (mRS) score of 0-1 at 90 days, in patients with anterior circulation DMVO.

Materials And Methods: We conducted a retrospective multicenter study involving patients with anterior DMVO, from three stroke centers within the Johns Hopkins Medical Enterprise.

Role of Hypoperfusion Intensity Ratio in Vessel Occlusions: A Review on Safety and Clinical Outcomes.

The hypoperfusion intensity ratio (HIR) is a quantitative metric used in vascular occlusion imaging to evaluate the extent of brain tissue at risk due to hypoperfusion. Defined as the ratio of tissue volume with a time-to-maximum (Tmax) of >10 seconds to that of >6 seconds, HIR assists in differentiating between the salvageable penumbra and the irreversibly injured core infarct. This review explores the role of HIR in assessing clinical outcomes and guiding treatment strategies, including mechanical thrombectomy and thrombolytic therapy, for patients with large vessel occlusions (LVOs).

Preclinical Profile of the HIV-1 Maturation Inhibitor VH3739937.

The HIV-1 maturation inhibitor (MI) VH3739937 (VH-937) inhibits cleavage between capsid and spacer peptide 1 and exhibits an oral half-life in humans compatible with once-weekly dosing. Here, the antiviral properties of VH-937 are described. VH-937 exhibited potent antiviral activity against all HIV-1 laboratory strains, clinical isolates, and recombinant viruses examined, with half-maximal effective concentration (EC) values ≤ 5.

Feasibility of snapshot testing using wearable sensors to detect cardiorespiratory illness (COVID infection in India).

The COVID-19 pandemic has challenged the current paradigm of clinical and community-based disease detection. We present a multimodal wearable sensor system paired with a two-minute, movement-based activity sequence that successfully captures a snapshot of physiological data (including cardiac, respiratory, temperature, and percent oxygen saturation). We conducted a large, multi-site trial of this technology across India from June 2021 to April 2022 amidst the COVID-19 pandemic (Clinical trial registry name: International Validation of Wearable Sensor to Monitor COVID-19 Like Signs and Symptoms; NCT05334680; initial release: 04/15/2022).

Hospital-Level Variation in COVID-19 Treatment Among Hospitalized Adults in the United States: A Retrospective Cohort Study.

Study Design: Retrospective cohort study.

Objective: To characterize variation in dexamethasone and remdesivir use over time among hospitals.

Background: Little is known about hospital-level variation in COVID-19 drug treatments in a large and diverse network in the United States.

Outcomes of Hyperbaric Oxygen Treatment for Central Retinal Artery Occlusion: A Single Center Experience.

Purpose: To describe the outcomes of hyperbaric oxygen therapy (HBOT) for patients with central retinal artery occlusion (CRAO) at a single tertiary care center.

Design: Retrospective clinical cohort study.

Methods: Medical records of all patients diagnosed with CRAO who received HBOT at Mayo Clinic in Rochester, Minnesota from January 1, 2009 to December 31, 2020 were reviewed to confirm diagnosis, time from onset to presentation, exam findings, treatments, and follow-up data.

Development and optimization of a diluted whole blood ELISpot assay to test immune function.

Sepsis remains a leading cause of death worldwide with no proven immunomodulatory therapies. Stratifying Patient Immune Endotypes in Sepsis ('SPIES') is a prospective, multicenter observational study testing the utility of ELISpot as a functional bioassay specifically measuring cytokine-producing cells after stimulation to identify the immunosuppressed endotype, predict clinical outcomes in septic patients, and test potential immune stimulants for clinical development. Most ELISpot protocols call for the isolation of PBMC prior to their inclusion in the assay.

A gain-of-function variant in SREBF1 causes generalized skin hyperpigmentation with congenital cataracts.

Background: Lipid metabolism has essential roles in skin barrier formation and the regulation of skin inflammation. Lipid homeostasis regulates skin melanogenesis, although the underlying mechanism remains largely unknown. Sterol regulatory element binding protein 1 (SREBP-1) is a key transcription factor essential for cellular lipid metabolism.

Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

Background: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical.

Methods: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients.

Effect of Activated Charcoal on Mavacamten Pharmacokinetics in Healthy Participants.

Objective: To assess the effect of activated charcoal on the single-dose pharmacokinetics of mavacamten when administered 2 h or 6 h after mavacamten dosing.

Methods: In this open-label, randomized, parallel-group study, healthy adults were randomized into three groups to receive mavacamten 15 mg alone or mavacamten 15 mg plus activated charcoal 50 g administered either 2 h or 6 h after mavacamten dosing. Pharmacokinetic parameters were derived from plasma concentration-time data using noncompartmental methods.

Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings.

Global, Regional, and National Burdens of Stroke in Children and Adolescents From 1990 to 2019: A Population-Based Study.

Background: Stroke is one of the leading causes of death among children, yet evidence on stroke incidence and prognosis in this population is largely neglected worldwide. The aim of this study was to estimate the latest burden of childhood stroke, as well as trends, risk factors, and inequalities from 1990 to 2019, at the global, regional, and national levels.

Methods: The Global Burden of Disease 2019 study was utilized to evaluate the prevalence, incidence, years lived with disability, years of life lost (YLLs), and average annual percentage changes in stroke among populations aged 0 to 19 years from 1990 to 2019.

Inferring neural activity before plasticity as a foundation for learning beyond backpropagation.

For both humans and machines, the essence of learning is to pinpoint which components in its information processing pipeline are responsible for an error in its output, a challenge that is known as 'credit assignment'. It has long been assumed that credit assignment is best solved by backpropagation, which is also the foundation of modern machine learning. Here, we set out a fundamentally different principle on credit assignment called 'prospective configuration'.

Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation.

Background: Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit.

Dual blockade of BRD4 and ATR/WEE1 pathways exploits loss in clear cell ovarian cancer.

an epigenetic tumor suppressor, is the most common gene mutation in clear-cell ovarian cancers (CCOCs). CCOCs are often resistant to standard chemotherapy and lack effective therapies. We hypothesized that loss would increase CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival.

Applied physiologically-based pharmacokinetic modeling to assess uridine diphosphate-glucuronosyltransferase-mediated drug-drug interactions for Vericiguat.

Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate-glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug-drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically.