The coronavirus nsp14 exoribonuclease interface with the cofactor nsp10 is essential for efficient virus replication and enzymatic activity.

Coronaviruses (CoVs) encode non-structural proteins (nsp's) 1-16, which assemble to form replication-transcription complexes that function in viral RNA synthesis. All CoVs encode a proofreading 3'-5' exoribonuclease in non-structural protein 14 (nsp14-ExoN) that mediates proofreading and high-fidelity replication and is critical for other roles in replication and pathogenesis. The enzymatic activity of nsp14-ExoN is enhanced in the presence of the cofactor nsp10.

Anticoagulation therapy for the prevention of subclinical leaflet thrombosis after transcatheter aortic valve replacement: A comprehensive literature review and future directions.

Leaflet thrombosis after transcatheter aortic valve replacement (TAVR) presents a significant challenge, leading to adverse clinical outcomes. Subclinical leaflet thrombosis (SLT) is increasingly recognized, and there is a growing concern about its role in clinical events and hemodynamic valve deterioration. Current recommendations for prophylactic anticoagulation or antiplatelet therapy following TAVR are primarily based on expert consensus rather than definitive evidence from randomized trials, resulting in a variety of antithrombotic strategies in clinical practice.

A review of clopidogrel resistance in lower extremity arterial disease.

Objective: Lower extremity arterial disease (LEAD) is a prevalent condition that produces a significant burden on health care systems. Patients with LEAD have an increased risk of major adverse cardiovascular events as well as major adverse limb events. Despite significant variation in guidance on antiplatelet therapy for LEAD worldwide, many governing bodies recommend clopidogrel as the preferred single anti-platelet agent.

Associations between fecal glucocorticoid levels and social bonds vary with relatedness in juvenile rhesus macaques.

Strong social bonds in gregarious adult animals have been associated with lower levels of glucocorticoids. However, similar research is lacking for juvenile primates. We examined relationships between social bonds and mean concentrations of fecal glucocorticoid metabolites (fGCMs) in 44 free-ranging juvenile rhesus macaques (Macaca mulatta) on Cayo Santiago, Puerto Rico.

Feasibility of Mental Health Triage Call Priority Prediction Using Machine Learning.

Background: Optimum efficiency and responsiveness to callers of mental health helplines can only be achieved if call priority is accurately identified. Currently, call operators making a triage assessment rely heavily on their clinical judgment and experience. Due to the significant morbidity and mortality associated with mental illness, there is an urgent need to identify callers to helplines who have a high level of distress and need to be seen by a clinician who can offer interventions for treatment.

Development and Validation of a Rapid Point-of-Care CYP2C19 Genotyping Platform.

Pharmacogenetic-guided prescribing can lead to more accurate medicine selection and dosing, improving patient outcomes and leading to better use of health care budgets. Loss-of-function variants in CYP2C19 influence an individual's ability to metabolize clopidogrel, increasing the risk of secondary vascular events following ischemic stroke and percutaneous coronary intervention. In acute clinical contexts, centralized laboratory-based testing is too slow to inform timely clinical decision-making.

Molecular Profiling Identifies CD49d and CD79b as Predictive Markers for Acquired Acalabrutinib Resistance in Patients With Chronic Lymphocytic Leukemia.

Contemporary studies of Bruton tyrosine kinase inhibitor (BTKi) resistance focus on mutations in the B-cell receptor (BCR) pathway, but alternative mechanisms of resistance remain undefined. Here, we sought to identify novel predictive markers of acquired resistance to acalabrutinib, a second-generation BTKi, in patients with chronic lymphocytic leukemia (CLL). Clinical samples from 41 patients with relapsed/refractory or treatment-naive CLL receiving acalabrutinib as part of a clinical trial (NCT02029443) were divided into two groups: those who continued to respond to treatment (NP, n = 23) and those who developed progressive disease on acalabrutinib therapy (PD, n = 18).

Free-living monitoring of ALS progression in upper limbs using wearable accelerometers.

Background: Wearable technology offers objective and remote quantification of disease progression in neurological diseases such as amyotrophic lateral sclerosis (ALS). Large population studies are needed to determine generalization and reproducibility of findings from pilot studies.

Methods: A large cohort of patients with ALS (N = 202) wore wearable accelerometers on their dominant and non-dominant wrists for a week every two to four weeks and self-entered the ALS Functional Rating Scale-Revised (ALSFRS-RSE) in similar time intervals.

Exploring Determinants of Effective Implementation of an Innovation Within Health Care: Qualitative Insights from Program Champions on Implementing One-at-a-Time Therapy Within Addictions and Mental Health Services in New Brunswick.

Government of New Brunswick implemented One-at-a-Time (OAAT) therapy, a single-session approach to care, within Addiction and Mental Health (A&MH) services. We conducted interviews to understand determinants of implementation from program champions. Champions of the OAAT therapy implementation (N = 19; Child/Youth n = 8, Adult n = 11) working within A&MH services and school districts were recruited through the provincial implementation team.

Genome sequences of five bacteriophages that belong to the genus .

We describe the genomes of five lytic myophages, therapeutic candidates, that belong to the family and genus . The genomes ranged from 165,574 to 169,768 bp, with ca. 40% GC content, contained 289-300 coding sequences, had 15-16 tRNA genes, and no terminal repeats.

Stratified analysis identifies HIF-2 as a therapeutic target for highly immune-infiltrated melanomas.

While immune-checkpoint blockade (ICB) has revolutionized treatment of metastatic melanoma over the last decade, the identification of broadly applicable robust biomarkers has been challenging, driven in large part by the heterogeneity of ICB regimens and patient and tumor characteristics. To disentangle these features, we performed a standardized meta-analysis of eight cohorts of patients treated with anti-PD-1 (n=290), anti-CTLA-4 (n=175), and combination anti-PD-1/anti-CTLA-4 (n=51) with RNA sequencing of pre-treatment tumor and clinical annotations. Stratifying by immune-high vs -low tumors, we found that surprisingly, high immune infiltrate was a biomarker for response to combination ICB, but not anti-PD-1 alone.

Client and program-level factors associated with planned use of medications for opioid use disorder in specialty substance use treatment programs: Evidence from linked administrative data and survey data.

Background: Most patients in specialty drug treatment programs that are not federally licensed Opioid Treatment Programs (OTPs) programs do not receive medications for opioid use disorder (MOUD).

Methods: We linked results from a survey of non-OTP treatment program directors in New Jersey (n = 81) to statewide administrative records of admissions for opioid use to those programs between July 2021-June 2022. Using multi-level regression, we examined the association of three types of factors with planned MOUD use: program survey responses, client-level factors, and program-level client characteristic mix.

Pre-Emptive Pharmacogenetic Testing in the Acute Hospital Setting: A Cross-Sectional Study.

Background: Pharmacogenetic guided prescribing can be used to improve the safety and effectiveness of medicines. There are several approaches by which this intervention might be implemented in clinical practice, which will vary depending on the health system and clinical context.

Aim: To understand the clinical utility of panel-based pharmacogenetic testing in patients admitted acutely to hospital and to establish variables which predict if an individual might benefit from the intervention.

Improved influenza vaccine responses after expression of multiple viral glycoproteins from a single mRNA.

Influenza viruses cause substantial morbidity and mortality every year despite seasonal vaccination. mRNA-based vaccines have the potential to elicit more protective immune responses, but for maximal breadth and durability, it is desirable to deliver both the viral hemagglutinin and neuraminidase glycoproteins. Delivering multiple antigens individually, however, complicates manufacturing and increases cost, thus it would be beneficial to express both proteins from a single mRNA.

A cross-sectional study of the relative availability and prominence of shelf space allocated to healthy and unhealthy foods in supermarkets in urban Ireland, by area-level deprivation.

Background: Diet-related noncommunicable diseases (NCDs) are a leading cause of ill-health and death across Europe. In Ireland, dietary intakes of saturated fat, free sugar and salt exceed World Health Organization recommendations, and excess consumption follows a social gradient increasing population risk of diet-related NCDs. The retail food environment can influence consumer food choice and subsequent dietary intakes.

Headless hemagglutinin-containing influenza viral particles direct immune responses toward more conserved epitopes.

Seasonal influenza vaccines provide mostly strain-specific protection due to the elicitation of antibody responses focused on evolutionarily plastic antigenic sites in the hemagglutinin head domain. To direct the humoral response toward more conserved epitopes, we generated an influenza virus particle where the full-length hemagglutinin protein was replaced with a membrane-anchored, "headless" variant while retaining the normal complement of other viral structural proteins such as the neuraminidase as well as viral RNAs. We found that a single administration of a headless virus particle-based vaccine elicited high titers of antibodies that recognized more conserved epitopes on the major viral glycoproteins.

Characterizing social networks and influence of early-life social housing in weaned heifers on pasture.

Dairy cattle are gregarious animals that are commonly managed in social groups, yet group-level social dynamics remain underexplored in weaned heifers. We characterized activity and social networks after weaned heifers had been raised in social groups on pasture for approximately 2 mo and examined effects of preweaning social housing. Holstein heifers raised in individual pens (n = 17) or paired pens (n = 20; 10 pens of 2) were mingled between treatments and grouped (10-11 heifers/group; total of 4 groups observed) on pasture following weaning (8.