Cardiac Effects of a Single Dose of Pimobendan in Cats With Hypertrophic Cardiomyopathy; A Randomized, Placebo-Controlled, Crossover Study

Background: Pimobendan has been shown to impart a significant survival benefit in cardiomyopathic cats who receive it as part of heart failure therapy. However, use of pimobendan remains controversial in cats with hypertrophic cardiomyopathy (HCM) due to lack of pharmacodynamic data for pimobendan in cats with HCM and due to theoretical concerns for exacerbating left ventricular outflow tract obstructions. Hypothesis/Objectives: Our objective was to investigate the cardiac effects of pimobendan in cats with HCM. We hypothesized that pimobendan would not exacerbate left ventricular outflow tract obstructions and that it would improve echocardiographic measures of diastolic function. Animals: Thirteen purpose-bred cats were studied from a research colony with naturally-occurring HCM due to a variant in myosin binding protein C. Methods: Cats underwent two examinations 24 h apart with complete standard echocardiography. On their first day of evaluation, they were randomized to receive oral placebo or 1.25 mg pimobendan 1 h prior to exam. On their second examination, they were crossed over and received the remaining treatment. Investigators were blinded to all treatments. Results: The pimobendan group had a significant increase in left atrial fractional shortening (pimobendan group 41.7% ± 5.9; placebo group 36.1% ± 6.0; p = 0.04). There was no significant difference in left ventricular outflow tract (LVOT) velocities between the groups (pimobendan group 2.8 m/s ± 0.8; placebo group 2.6 m/s ± 1.0). There were no significant differences between the number of cats with LVOT obstructions between groups (12 in pimobendan group; 11 in placebo group; p = 1.00). There were no detectable differences in any systolic measures, including left ventricular fractional shortening, mitral annular plane systolic excursion, and tricuspid annular plane systolic excursion. Doppler-based diastolic function assessment was precluded by persistent tachycardia. Conclusions: Improved left atrial function in the pimobendan group could explain some of the reported survival benefit for HCM cats in CHF. Pimobendan did not exacerbate LVOT obstructions and thus may not be contraindicated in HCM cats with LVOT obstructions. Future studies are needed to better characterize other physiologic effects, particularly regarding diastolic function assessment, and to better assess safety of pimobendan over a longer time-course.Center for Companion Animal Health at the University of California Davis, School of Veterinary Medicine [2016-15-F]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

A Machine Learning Outlook: Post-processing of Global Medium-range Forecasts

Post-processing typically takes the outputs of a Numerical Weather Prediction (NWP) model and applies linear statistical techniques to produce improve localized forecasts, by including additional observations, or determining systematic errors at a finer scale. In this pilot study, we investigate the benefits and challenges of using non-linear neural network (NN) based methods to post-process multiple weather features -- temperature, moisture, wind, geopotential height, precipitable water -- at 30 vertical levels, globally and at lead times up to 7 days. We show that we can achieve accuracy improvements of up to 12% (RMSE) in a field such as temperature at 850hPa for a 7 day forecast. However, we recognize the need to strengthen foundational work on objectively measuring a sharp and correct forecast. We discuss the challenges of using standard metrics such as root mean squared error (RMSE) or anomaly correlation coefficient (ACC) as we move from linear statistical models to more complex non-linear machine learning approaches for post-processing global weather forecasts.Comment: 9 pages, 4 figures, 1 tabl

Congenital Cardiac Outflow Tract Abnormalities in Dogs: Prevalence and Pattern of Inheritance From 2008 to 2017

Subvalvular aortic stenosis (SAS) and valvular pulmonic stenosis (PS) are two of the most common congenital heart diseases of dogs. The aim of this study was to determine the prevalence and mode of inheritance of these congenital heart diseases in a large veterinary teaching hospital population. Case records of dogs presented to the University of California Davis, Veterinary Medical Teaching Hospital (UCD VMTH) between January 2008 to December 2017 were reviewed retrospectively and pedigree information was obtained when available. There were 259 unique SAS and 336 unique PS cases diagnosed during the study period. The prevalence of SAS was 0.3% of overall hospital admissions and 4.7% for all dogs seen by the cardiology service. The prevalence for PS was 0.41% of overall hospital admissions and 6.1% of dogs seen by the cardiology service. Bullmastiffs and Newfoundlands had the greatest prevalence (6.59 and 4.46%, respectively) and odds ratio (52.43 and 34.73, respectively) for SAS. Bulldogs and French Bulldogs had the greatest prevalence (4.8 and 2.7%, respectively) and odds ratio (13.32 and 7.52, respectively) for PS. The identified prevalence of SAS and PS is higher than previously reported. Pedigree analysis in SAS affected Bullmastiffs, Golden Retrievers, and Rottweilers suggested an autosomal recessive pattern of inheritance. The mode of inheritance for PS in Bulldogs, also appears to be autosomal recessive. The results of this study can be used to inform future selection of breeding pairs and genetic studies aimed at reducing the prevalence of these common congenital heart diseases

Heart Rate and Heart Rate Variability of Rhesus Macaques (Macaca mulatta) Affected by Left Ventricular Hypertrophy

Hypertrophic cardiomyopathy (HCM) is frequently associated with sudden cardiac death, presumably due to the development of malignant arrhythmias. The risk of sudden cardiac death due to HCM has been reported to be predicted by assessing electrocardiographic (ECG) changes including frequencies and complexities of arrhythmias as well as heart rate variability (HRV) as an assessment of autonomic balance. Sudden cardiac death in association with naturally-occurring left ventricular hypertrophy (LVH) has been reported in a colony of rhesus macaques and is under investigation as a potential non-human primate model of human HCM. In the present study, 10 rhesus macaques with LVH and 10 without the signs of LVH confirmed by an echocardiographic examination were recruited for assessing ECG and HRV parameters. ECG morphology on 10-s, 6-lead ECG analysis, and the frequency and complexity of arrhythmias as well as HRV on 20-h ambulatory ECG Holter analyses were assessed. On the standard 10-s 6-lead ECG analysis, P wave and QRS complex duration as well as the QRS complex amplitude were significantly increased in the LVH-affected rhesus macaques compared to control rhesus macaques. Analysis of 20-h Holter monitoring revealed no statistically significant differences in the frequency or the complexity of arrhythmias between the LVH and the control groups. Several HRV parameters were smaller in the LVH group than the control group throughout the majority of Holter recordings showing periods of reduced variability, however, no statistically significant differences were achieved across groups and/or time points. These findings indicate that ECG analysis and Holter monitoring of rhesus macaques are feasible and that ECG morphological changes in association with LVH could be used as a possible component of an antemortem screening tool. The rhesus macaques of this study did not reveal clear indications of risk for sudden cardiac death. Further studies are necessary to determine the etiology of sudden cardiac death due in LVH affected rhesus macaques and identify if any parameters of arrhythmia assessment or HRV can be used to predict the development of sudden cardiac death

Development of a broadly active influenza intranasal vaccine adjuvanted with self-assembled particles composed of mastoparan-7 and CpG

Currently licensed vaccine adjuvants offer limited mucosal immunity, which is needed to better combat respiratory infections such as influenza. Mast cells (MCs) are emerging as a target for a new class of mucosal vaccine adjuvants. Here, we developed and characterized a nanoparticulate adjuvant composed of an MC activator [mastoparan-7 (M7)] and a TLR ligand (CpG). This novel nanoparticle (NP) adjuvant was co-formulated with a computationally optimized broadly reactive antigen (COBRA) for hemagglutinin (HA), which is broadly reactive against influenza strains. M7 was combined at different ratios with CpG and tested for in vitro immune responses and cytotoxicity. We observed significantly higher cytokine production in dendritic cells and MCs with the lowest cytotoxicity at a charge-neutralizing ratio of nitrogen/phosphate = 1 for M7 and CpG. This combination formed spherical NPs approximately 200 nm in diameter with self-assembling capacity. Mice were vaccinated intranasally with COBRA HA and M7-CpG NPs in a prime–boost–boost schedule. Vaccinated mice had significantly higher antigen-specific antibody responses (IgG and IgA) in serum and mucosa compared with controls. Splenocytes from vaccinated mice had significantly increased cytokine production upon antigen recall and the presence of central and effector memory T cells in draining lymph nodes. Finally, co-immunization with NPs and COBRA HA induced influenza H3N2-specific HA inhibition antibody titers across multiple strains and partially protected mice from a challenge against an H3N2 virus. These results illustrate that the M7-CpG NP adjuvant combination can induce a protective immune response with a broadly reactive influenza antigen via mucosal vaccination

Computational strategies to combat COVID-19: useful tools to accelerate SARS-CoV-2 and coronavirus research

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel virus of the family Coronaviridae. The virus causes the infectious disease COVID-19. The biology of coronaviruses has been studied for many years. However, bioinformatics tools designed explicitly for SARS-CoV-2 have only recently been developed as a rapid reaction to the need for fast detection, understanding and treatment of COVID-19. To control the ongoing COVID-19 pandemic, it is of utmost importance to get insight into the evolution and pathogenesis of the virus. In this review, we cover bioinformatics workflows and tools for the routine detection of SARS-CoV-2 infection, the reliable analysis of sequencing data, the tracking of the COVID-19 pandemic and evaluation of containment measures, the study of coronavirus evolution, the discovery of potential drug targets and development of therapeutic strategies. For each tool, we briefly describe its use case and how it advances research specifically for SARS-CoV-2. All tools are free to use and available online, either through web applications or public code repositories.Peer Reviewe