Mechanisms of Action Underlying Conductance-Modifying Positive Allosteric Modulators of the NMDA Receptor.

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate a slow, Ca-permeable component of excitatory neurotransmission. Modulation of NMDAR function has the potential for disease modification as NMDAR dysfunction has been implicated in neurodevelopment, neuropsychiatric, neurologic, and neurodegenerative disorders. We recently described the thieno[2,3-day]pyrimidin-4-one (EU1622) class of positive allosteric modulators, including several potent and efficacious analogs.

A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies.

The clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy.

Indoor Air Quality Assessments in 10 Long-Term Care Facilities during the COVID-19 Pandemic, California, 2021-2023.

Objectives: This study aimed to assess indoor air quality (IAQ) in long-term care facilities (LTCFs) in California during the COVID-19 pandemic and evaluate their implementation of IAQ best practices described by public health authorities to control respiratory pathogen transmission via inhalation.

Design: This observational study conducted IAQ assessments in a convenience sample of LTCFs to gather qualitative data on the implementation of IAQ best practices. The design included 5 pilot visits to develop a standardized method of data collection and then systematic data collection at 10 facilities.

Molecular mechanism of ligand gating and opening of NMDA receptor.

Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity. The N-methyl-D-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands-glutamate and glycine-for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively.

A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants.

The receptor tyrosine kinase FGFR3 is frequently mutated in bladder cancer and is a validated therapeutic target. Although pan-FGFR tyrosine kinase inhibitors (TKI) have shown clinical efficacy, toxicity and acquired resistance limit the benefit of these agents. While antibody-based therapeutics can offer superior selectivity than TKIs, conventional ligand-blocking antibodies are usually ineffective inhibitors of constitutively active receptor tyrosine kinases.

Development of a Dihydroquinoline-Pyrazoline GluN2C/2D-Selective Negative Allosteric Modulator of the -Methyl-d-aspartate Receptor.

Subunit-selective inhibition of -methyl-d-aspartate receptors (NMDARs) is a promising therapeutic strategy for several neurological disorders, including epilepsy, Alzheimer's and Parkinson's disease, depression, and acute brain injury. We previously described the dihydroquinoline-pyrazoline (DQP) analogue () as a potent NMDAR negative allosteric modulator with selectivity for GluN2C/D over GluN2A/B. However, moderate (<100-fold) subunit selectivity, inadequate cell-membrane permeability, and poor brain penetration complicated the use of as an probe.

VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.

V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remains elusive.

Racial disparities in emergency medicine: Implementation of a novel educational module in the emergency medicine clerkship.

Objectives: Despite decades of literature recognizing racial disparities (RDs) in emergency medicine (EM), published curricula dedicated to addressing them are sparse. We present details of our novel RD curriculum for EM clerkships and its educational outcomes.

Methods: We created a 30-min interactive didactic module on the topic designed for third- and fourth-year medical students enrolled in our EM clerkships.

CD22-targeted CD28 bispecific antibody enhances antitumor efficacy of odronextamab in refractory diffuse large B cell lymphoma models.

Although many patients with diffuse large B cell lymphoma (DLBCL) may achieve a complete response to frontline chemoimmunotherapy, patients with relapsed/refractory disease typically have poor outcomes. Odronextamab, a CD20xCD3 bispecific antibody that provides "signal 1" through the activation of the T cell receptor/CD3 complex, has exhibited early, promising activity for patients with highly refractory DLBCL in phase 1 trials. However, not all patients achieve complete responses, and many relapse, thus representing a high unmet medical need.

Design and Evaluation of a Curriculum on Intimate Partner Violence for Medical Students in an Emergency Medicine Clerkship.

Purpose: Intimate partner violence (IPV) is a widespread public health issue that is relevant to all areas of medicine. Patients who suffer from IPV often contact the health care system via the emergency department, making this a particularly important but too often overlooked issue in this setting. Education on IPV varies in medical schools and emergency medicine (EM) educational programs, and evidence suggests that a barrier to assessing for IPV is a lack of adequate training of clinicians.

Immuno-PET Monitoring of Lymphocytes Using the CD8-Specific Antibody REGN5054.

Assessment of immune-cell subsets within the tumor immune microenvironment is a powerful approach to better understand cancer immunotherapy responses. However, the use of biopsies to assess the tumor immune microenvironment poses challenges, including the potential for sampling error, restricted sampling over time, and inaccessibility of some tissues/organs, as well as the fact that single biopsy analyses do not reflect discordance across multiple intrapatient tumor lesions. Immuno-positron emission tomography (PET) presents a promising translational imaging approach to address the limitations and assess changes in the tumor microenvironment.

Interference in a Neutralizing Antibody Assay for Odronextamab, a CD20xCD3 Bispecific mAb, from Prior Rituximab Therapy and Possible Mitigation Strategy.

A cell-based assay was developed to detect neutralizing anti-drug antibodies (NAbs) against odronextamab, a CD20xCD3 bispecific monoclonal antibody (mAb) under investigation for treatment of CD20+ B cell malignancies. In this assay, odronextamab bridges between two cell types, CD20-expressing HEK293 cells and CD3-expressing Jurkat T cells that generate a luciferase signal upon CD3 clustering. Patient samples containing NAbs directed to either arm of the bispecific drug block the odronextamab bridge formation between the cell lines thus preventing the generation of the luciferase signal.

Correlation of attending and patient assessment of resident communication skills in the emergency department.

Background: Communication and interpersonal skills are one of the Accreditation Council for Graduate Medical Education's six core competencies. Validated methods for assessing these among trainees are lacking. Educators have developed various communication assessment tools from both the supervising attending and the patient perspectives.

Impact of an end-of-fourth-year emergency medicine bootcamp.

Background: The final months of the fourth-year of medical school are variable in educational and clinical experience, and the effect on clinical knowledge and preparedness for residency is unclear. Specialty-specific "bootcamps" are a growing trend in medical education aimed at increasing clinical knowledge, procedural skills, and confidence prior to the start of residency.

Methods: We developed a 4-week Emergency Medicine (EM) bootcamp offered during the final month of medical school.

Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning.

T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear.

T-wave heterogeneity in standard resting 12-lead ECGs is associated with 90-day cardiac mortality in women following emergency department admission: A nested case-control study.

Background: We investigated whether T-wave heterogeneity (TWH) can identify patients who are at risk for near-term cardiac mortality.

Methods: A nested case-control analysis was performed in the 888 patients admitted to the Emergency Department (ED) of our medical center in July through September 2018 who had ≥2 serial troponin measurement tests within 6 hr for acute coronary syndrome evaluation to rule-in or rule-out the presence of acute myocardial infarction. Patients who died from cardiac causes during 90 days after ED admission were considered cases (n = 20; 10 women) and were matched 1:4 on sex and age with patients who survived during this period (n = 80, 40 women).

Hearing loss as a predictor for hearing protection attenuation among miners.

Objective: This study investigated risk factors for poor earplug fit, with a focus on the association between hearing loss and personal attenuation ratings (PARs).

Methods: Earplug fit was assessed by obtaining PARs using a real ear at attenuation threshold (REAT) system. Hearing loss was assessed using the unoccluded hearing thresholds measured during the REAT testing and the results of a speech-in-noise test.

A Simulation-Based Prospective Cohort Study on Teaching Best Practices in Firearms Safety.

Background: Gun violence in the United States is a significant public health concern. The high rate of weapons carriage by Americans places medical providers at risk for exposure to firearms in the workplace and provides an opportunity for patient safety counseling. Few curricular interventions have been published on teaching firearms safety principles to medical providers.

Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy.

Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti-PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T cells by cross-linking the TCR/CD3 complex with a tumor-specific antigen (TSA).

Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail.

Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola-one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure.

A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies.

T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide-major histocompatibility complexes ("signal 1"); activation is enhanced by engagement of a second "costimulatory" receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell ("signal 2"). CD3-based bispecific antibodies act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific and bridging to TCR/CD3 with the other. Although some of these so-called TSAxCD3 bispecifics have demonstrated promising antitumor efficacy in patients with cancer, their activity remains to be optimized.

A Multimodal Curriculum With Patient Feedback to Improve Medical Student Communication: Pilot Study.

Introduction: Despite the extraordinary amount of time physicians spend communicating with patients, dedicated education strategies on this topic are lacking. The objective of this study was to develop a multimodal curriculum including direct patient feedback and assess whether it improves communication skills as measured by the Communication Assessment Tool (CAT) in fourth-year medical students during an emergency medicine (EM) clerkship.

Methods: This was a prospective, randomized trial of fourth-year students in an EM clerkship at an academic medical center from 2016-2017.

Derivation and validation of a machine learning record linkage algorithm between emergency medical services and the emergency department.

Objective: Linking emergency medical services (EMS) electronic patient care reports (ePCRs) to emergency department (ED) records can provide clinicians access to vital information that can alter management. It can also create rich databases for research and quality improvement. Unfortunately, previous attempts at ePCR and ED record linkage have had limited success.

Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human -Knockin Mice.

In the tumor microenvironment, multiple inhibitory checkpoint receptors can suppress T-cell function, thereby enabling tumor immune evasion. Blockade of one of these checkpoint receptors, PD-1, with therapeutic antibodies has produced positive clinical responses in various cancers; however, the efficacy of this approach can be further improved. Simultaneously targeting multiple inhibitory checkpoint receptors has emerged as a promising therapeutic strategy.

A combined care model using early access to specialists off-hours to reduce cardiac admissions.

Despite the implementation of diagnostic and treatment algorithms for many common cardiovascular (CV) complaints, identifying low- and intermediate-risk cardiac patients presenting to the emergency department (ED) who could be managed without hospital admission remains difficult. We hypothesized that the presence of an attending cardiologist in the ED after normal working hours would decrease the proportion of these patients admitted to the hospital. We conducted a retrospective study of patients seen in the ED with cardiac diagnoses identified by ICD-9 codes during the time period when the cardiologist was available (6 p.