SARS CoV-2 (Delta Variant) Infection Kinetics and Immunopathogenesis in Domestic Cats

Continued emergence of SARS-CoV-2 variants highlights the critical need for adaptable and translational animal models for acute COVID-19. Limitations to current animal models for SARS CoV-2 (e.g., transgenic mice, non-human primates, ferrets) include subclinical to mild lower respiratory disease, divergence from clinical COVID-19 disease course, and/or the need for host genetic modifications to permit infection. We therefore established a feline model to study COVID-19 disease progression and utilized this model to evaluate infection kinetics and immunopathology of the rapidly circulating Delta variant (B.1.617.2) of SARS-CoV-2. In this study, specific-pathogen-free domestic cats (n = 24) were inoculated intranasally and/or intratracheally with SARS CoV-2 (B.1.617.2). Infected cats developed severe clinical respiratory disease and pulmonary lesions at 4- and 12-days post-infection (dpi), even at 1/10 the dose of previously studied wild-type SARS-CoV-2. Infectious virus was isolated from nasal secretions of delta-variant infected cats in high amounts at multiple timepoints, and viral antigen was co-localized in ACE2-expressing cells of the lungs (pneumocytes, vascular endothelium, peribronchial glandular epithelium) and strongly associated with severe pulmonary inflammation and vasculitis that were more pronounced than in wild-type SARS-CoV-2 infection. RNA sequencing of infected feline lung tissues identified upregulation of multiple gene pathways associated with cytokine receptor interactions, chemokine signaling, and viral protein–cytokine interactions during acute infection with SARS-CoV-2. Weighted correlation network analysis (WGCNA) of differentially expressed genes identified several distinct clusters of dysregulated hub genes that are significantly correlated with both clinical signs and lesions during acute infection. Collectively, the results of these studies help to delineate the role of domestic cats in disease transmission and response to variant emergence, establish a flexible translational model to develop strategies to prevent the spread of SARS-CoV-2, and identify potential targets for downstream therapeutic development.     

Changes in the prevalence of comorbidity of mental and physical disorders in Singapore between 2010 and 2016

INTRODUCTIONFew studies have examined the changes in the prevalence of comorbidity of mental and physical disorders in recent years. The present study sought to examine whether the prevalence of comorbidity of mental and physical disorders in Singapore showed any changes between 2010 and 2016.METHODSWe extracted data from two repeated nationally representative cross-sectional surveys conducted among resident adults aged ≥ 18 years in Singapore. Significant changes were tested using pooled multinomial logistic regression analyses.RESULTSThe prevalence of comorbid mental and physical disorders increased significantly from 5.8% in 2010 to 6.7% in 2016. Among those with physical disorders, there were significant increases over time in the prevalence of comorbid generalised anxiety disorder (GAD) (0.1% vs. 0.4%) and obsessive-compulsive disorder (OCD) (1.4% vs. 3.9%) in diabetes mellitus, and alcohol dependence in cardiovascular disorders (0.1% vs. 1.3%). Among those with mental disorders, there were significant increases over time in the prevalence of comorbid diabetes mellitus in OCD (4.1% vs. 10.9%), cancer in major depressive disorder (0.4% vs. 2.4%), and cardiovascular disorders in GAD (0.4% vs. 6.7%) and alcohol dependence (0.9% vs. 11.8%). Significant changes in the overall prevalence of comorbid mental and physical disorders were also observed across age group, education and employment status.CONCLUSIONThe prevalence of comorbid mental and physical disorders increased significantly over time. This finding supports the need for more appropriate clinical management with better integration between mental health and general medical care professionals across all aspects of the healthcare system to treat this comorbidity in Singapore.     

Do cultural and linguistic competence matter in Latinos' completion of mandated substance abuse treatment?

ABSTRACT: BACKGROUND: Increasing evidence suggests that culturally and linguistically responsive programs may improve substance abuse treatment outcomes among Latinos. However, little is known about whether individual practices or culturally and linguistically responsive contexts support efforts by first-time Latino clients to successfully complete mandated treatment. METHODS: We analyzed client and program data from publicly funded treatment programs contracted through the criminal justice system in California. A sample of 5,150 first-time Latino clients nested within 48 treatment programs was analyzed using multilevel logistic regressions. RESULTS: Outpatient treatment, homelessness, and a high frequency of drug use at intake were associated with decreased odds of treatment completion among Latinos. Programs that routinely offered a culturally and linguistically responsive practice---namely, Spanish-language translation---were associated with increased odds of completion of mandated treatment. CONCLUSIONS: These preliminary findings suggest that concrete practices such as offering Spanish translation improve treatment adherence within a population that is at high risk of treatment dropout.     

Insulinotropic and Muscle Protein Synthetic Effects of Branched-Chain Amino Acids: Potential Therapy for Type 2 Diabetes and Sarcopenia

The loss of muscle mass and strength with aging (i.e., sarcopenia) has a negative effect on functional independence and overall quality of life. One main contributing factor to sarcopenia is the reduced ability to increase skeletal muscle protein synthesis in response to habitual feeding, possibly due to a reduction in postprandial insulin release and an increase in insulin resistance. Branched-chain amino acids (BCAA), primarily leucine, increases the activation of pathways involved in muscle protein synthesis through insulin-dependent and independent mechanisms, which may help counteract the “anabolic resistance” to feeding in older adults. Leucine exhibits strong insulinotropic characteristics, which may increase amino acid availability for muscle protein synthesis, reduce muscle protein breakdown, and enhance glucose disposal to help maintain blood glucose homeostasis.     

Advances in Predicting and Manipulating the Immunogenicity of Biotherapeutics and Vaccines

Therapeutic proteins are vital to the future of human health provision and the survival and profitability of the global pharmaceutical industry. Returns from protein therapeutics are experiencing unprecedented growth: both their number and their economic dividend have increased by an order of magnitude in the last 10 years. The potential immunogenicity of protein therapeutics raises many clinical and safety concerns. Many poorly understood factors relating to both product and host affect immune responses. Available laboratory measurement of immunogenicity is of little utility for predicting the clinical properties of biotherapeutics. Coupled with assay variability and standardization issues, this precludes adequate prediction of the biological or clinical responses of therapeutic proteins, arguing for the utilization of informatic strategies in the analysis and prediction of protein immunogenicity. Currently, many unresolved issues must be addressed and thus circumvented before effective prediction can become routine.