Publisher Correction: Novel immunotherapeutics against LGR5 to target multiple cancer types.

[Image: see text]

Novel immunotherapeutics against LGR5 to target multiple cancer types.

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5 cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment.

Immunogenicity and Safety of Heterologous Omicron BA.1 and Bivalent SARS-CoV-2 Recombinant Spike Protein Booster Vaccines: A Phase 3 Randomized Clinical Trial.

Background: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone or as a bivalent preparation with the prototype vaccine (NVX-CoV2373) to assess antibody responses to SARS-CoV-2.

Interleukin-1 blockade in patients with Wiskott-Aldrich syndrome: a retrospective multinational case series.

Up to 70% of patients with Wiskott-Aldrich syndrome (WAS) develop autoimmune and inflammatory manifestations. Dysregulation of interleukin 1 (IL-1) may be involved in their pathogenesis, yet there is little evidence on treatment with anti-IL-1 agents in these patients. We conducted a multicenter retrospective analysis of 9 patients with WAS treated with anti-IL-1 agents (anakinra or canakinumab).

Predicting the response of a long-distance migrant to changing environmental conditions in winter.

Access to high-quality food is critical for long-distance migrants to provide energy for migration and arrival at breeding grounds in good condition. We studied effects of changing abundance and availability of a marine food, common eelgrass ( L.), on an arctic-breeding, migratory goose, black brant ( Lawrence 1846), at a key non-breeding site, Bahía San Quintín, Mexico.

Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen.

Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55.

Identification of Novel Potent NSD2-PWWP1 Ligands Using Structure-Based Design and Computational Approaches.

Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity.

Enantioselective Phase-Transfer-Catalyzed Synthesis of Spirocyclic Azetidine Oxindoles.

Spiro-3,2'-azetidine oxindoles combine two independently important pharmacophores in an understudied spirocyclic motif that is attractive for medicinal chemistry. Here, the enantioselective synthesis of these structures is achieved in up to 2:98 er through intramolecular C-C bond formation, involving activation of the substrate with a novel SF-containing chiral cation phase-transfer (PT) catalyst. The products are readily elaborated/deprotected to afford medicinally relevant enantioenriched compounds.

Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein-Ligand Interactions and High Selectivity.

The DNA-encoded library (DEL) discovery platform has emerged as a powerful technology for hit identification in recent years. It has become one of the major parallel workstreams for small molecule drug discovery along with other strategies such as HTS and data mining. For many researchers working in the DEL field, it has become increasingly evident that many hits and leads discovered via DEL screening bind to target proteins with unique and unprecedented binding modes.

Cascaded Logic Gates Based on High-Performance Ambipolar Dual-Gate WSe Thin Film Transistors.

Ambipolar dual-gate transistors based on low-dimensional materials, such as graphene, carbon nanotubes, black phosphorus, and certain transition metal dichalcogenides (TMDs), enable reconfigurable logic circuits with a suppressed off-state current. These circuits achieve the same logical output as complementary metal-oxide semiconductor (CMOS) with fewer transistors and offer greater flexibility in design. The primary challenge lies in the cascadability and power consumption of these logic gates with static CMOS-like connections.

A roadmap for developing an emergency department based critical care consultation service: Building the early intervention team (EIT).

Emergency Department (ED) crowding and boarding impact safe and effective health care delivery. ED clinicians must balance caring for new arrivals who require stabilization and resuscitation as well as those who need longitudinal care and re-evaluation. These challenges are magnified in the setting of critically ill patients boarding for the intensive care unit.

CLINICAL, MOLECULAR, AND EXOSOMAL MECHANISMS OF CARDIAC AND BRAIN DYSFUNCTION IN SEPSIS.

Sepsis is a complex disease resulting from a dysregulated inflammatory response to an infection. Initiation of sepsis occurs from a localized infection that disseminates to the bloodstream placing all organ systems at risk. Septic shock is classically observed to manifest itself as systemic hypotension with hyporesponsiveness to vasopressor agents.

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial.

Background: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover.

Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection.

Importance: Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship.

Objective: To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI.

Climate Change and Physiatry: A Call to Proportional and Prospective Action.

Through increased temperature-related illness, exposure to wildfire smoke and air pollutants, and more frequent and intense natural disasters, climate change is disproportionately affecting the health of people with disabilities. Although the evidence behind the health effects of climate change is growing, there remain critical research gaps in the physiatric literature that must be addressed. Increased education throughout the medical-education continuum is also needed to prepare physiatrists to address the climate-related health effects impacting their patient populations.

Accelerated Critical Therapy Now in the Emergency Department Using an Early Intervention Team: The Impact of Early Critical Care Consultation for ICU Boarders.

Unlabelled: Evaluate the impact of an emergency department (ED)-based critical care consultation service, hypothesizing early consultation results in shorter hospital length of stay (LOS).

Design: Retrospective observational study from February 2018 to 2020.

Setting: An urban academic quaternary referral center.

Comparing the Diagnostic Accuracy of Clinician Judgment to a Novel Host Response Diagnostic for Acute Respiratory Illness.

Background: Difficulty discriminating bacterial from viral infections drives antibacterial misuse. Host gene expression tests discriminate bacterial and viral etiologies, but their clinical utility has not been evaluated.

Methods: Host gene expression and procalcitonin levels were measured in 582 emergency department participants with suspected infection.

Safety, immunogenicity, and efficacy of a COVID-19 vaccine (NVX-CoV2373) co-administered with seasonal influenza vaccines: an exploratory substudy of a randomised, observer-blinded, placebo-controlled, phase 3 trial.

Background: The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines.

Methods: We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK.

Optimization of an Imidazo[1,2-]pyridine Series to Afford Highly Selective Type I1/2 Dual Mer/Axl Kinase Inhibitors with Efficacy.

Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective probe compound .

Effects of Compliance With the Early Management Bundle (SEP-1) on Mortality Changes Among Medicare Beneficiaries With Sepsis: A Propensity Score Matched Cohort Study.

Background: US hospitals have reported compliance with the SEP-1 quality measure to Medicare since 2015. Finding an association between compliance and outcomes is essential to gauge measure effectiveness.

Research Question: What is the association between compliance with SEP-1 and 30-day mortality among Medicare beneficiaries?

Study Design And Methods: Studying patient-level data reported to Medicare by 3,241 hospitals from October 1, 2015, to March 31, 2017, we used propensity score matching and a hierarchical general linear model (HGLM) to estimate the treatment effects associated with compliance with SEP-1.

Trauma informed interventions: A systematic review.

Background: Health inequities remain a public health concern. Chronic adversity such as discrimination or racism as trauma may perpetuate health inequities in marginalized populations. There is a growing body of the literature on trauma informed and culturally competent care as essential elements of promoting health equity, yet no prior review has systematically addressed trauma informed interventions.

Is Dementia-Specific Caregiving Compared With Non-Dementia Caregiving Associated With Physical Difficulty Among Caregivers for Community-Dwelling Adults?

Objective: The purpose of this study is to identify whether dementia caregiving is associated with physical difficulty among informal caregivers.

Methods: This cross-sectional retrospective cohort study design used data from the 2015 National Health and Aging Trends Study and the National Study of Caregiving. Binary logistic regression was used to examine the association between substantial physical difficulty and dementia caregiving among 1,871 caregivers.