Vestibular disease in dogs under UK primary veterinary care: Epidemiology and clinical management

Background Vestibular disease (VD), central or peripheral, can be a dramatic primary‐care presentation. Current literature describes mostly dogs examined in referral centers. Hypothesis/Objectives Describe the prevalence, presentation, clinical management, and outcomes of VD in dogs under primary veterinary care at UK practices participating in VetCompass. Animals Seven hundred and fifty‐nine vestibular cases identified out of 905 544 study dogs. Methods Retrospective cohort study. Potential VD cases clinically examined during 2016 were verified by reviewing clinical records for signalment, presenting clinical signs, treatments, and outcomes. Multivariable logistic regression was used to evaluate factors associated with VD. Results The overall prevalence of VD was 8 per 10 000 dogs (95% CI = 7‐9). Median age at first diagnosis was 12.68 years (interquartile range [IQR], 11.28‐14.64). Compared with crossbreeds, breeds with the highest odds of VD diagnosis included French Bulldogs (odds ratio [OR] = 9.25, 95% CI = 4.81‐17.76, P  < .001), Bulldogs (OR = 6.53, 95% CI = 2.66‐16.15, P  < .001), King Charles Spaniels (OR = 4.96, 95% CI = 2.52‐9.78, P  < .001), Cavalier King Charles Spaniels (OR = 3.56, 95% CI = 2.50‐5.06, P  < .001), and Springer Spaniels (OR = 3.37, 95% CI = 2.52‐4.52, P  < .001). The most common presenting signs were head tilt (69.8%), nystagmus (68.1%), and ataxia (64.5%). The most frequently used treatments were antiemetics (43.2%), systemic glucocorticoids (33.1%), antimicrobials (25%), and propentofylline (23.25%). There were 3.6% of cases referred. Improvement was recorded in 41.8% cases after a median of 4 days (IQR, 2‐10.25). Conclusions Our study identifies strong breed predispositions for VD. The low referral rates suggest that primary‐care data sources offer more generalizable information for benchmarking to help clinicians review their own clinical activities

Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1

Peer reviewedPublisher PD

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

The role of economic evaluation in the decision-making process of family physicians: design and methods of a qualitative embedded multiple-case study

<p>Abstract</p> <p>Background</p> <p>A considerable amount of resource allocation decisions take place daily at the point of the clinical encounter; especially in primary care, where 80 percent of health problems are managed. Ignoring economic evaluation evidence in individual clinical decision-making may have a broad impact on the efficiency of health services. To date, almost all studies on the use of economic evaluation in decision-making used a quantitative approach, and few investigated decision-making at the clinical level. An important question is whether economic evaluations affect clinical practice. The project is an intervention research study designed to understand the role of economic evaluation in the decision-making process of family physicians (FPs). The contributions of the project will be from the perspective of Pierre Bourdieu's sociological theory.</p> <p>Methods/design</p> <p>A qualitative research strategy is proposed. We will conduct an embedded multiple-case study design. Ten case studies will be performed. The FPs will be the unit of analysis. The sampling strategies will be directed towards theoretical generalization. The 10 selected cases will be intended to reflect a diversity of FPs. There will be two embedded units of analysis: FPs (micro-level of analysis) and field of family medicine (macro-level of analysis). The division of the determinants of practice/behaviour into two groups, corresponding to the macro-structural level and the micro-individual level, is the basis for Bourdieu's mode of analysis. The sources of data collection for the micro-level analysis will be 10 life history interviews with FPs, documents and observational evidence. The sources of data collection for the macro-level analysis will be documents and 9 open-ended, focused interviews with key informants from medical associations and academic institutions. The analytic induction approach to data analysis will be used. A list of codes will be generated based on both the original framework and new themes introduced by the participants. We will conduct within-case and cross-case analyses of the data.</p> <p>Discussion</p> <p>The question of the role of economic evaluation in FPs' decision-making is of great interest to scientists, health care practitioners, managers and policy-makers, as well as to consultants, industry, and society. It is believed that the proposed research approach will make an original contribution to the development of knowledge, both empirical and theoretical.</p

B Cell Depletion in HIV-1 Subtype A Infected Ugandan Adults: Relationship to CD4 T Cell Count, Viral Load and Humoral Immune Responses

To better understand the nature of B cell dysfunctions in subjects infected with HIV-1 subtype A, a rural cohort of 50 treatment-naïve Ugandan patients chronically infected with HIV-1 subtype A was studied, and the relationship between B cell depletion and HIV disease was assessed. B cell absolute counts were found to be significantly lower in HIV-1+ patients, when compared to community matched negative controls (p<0.0001). HIV-1-infected patients displayed variable functional and binding antibody titers that showed no correlation with viral load or CD4+ T cell count. However, B cell absolute counts were found to correlate inversely with neutralizing antibody (NAb) titers against subtype A (p = 0.05) and subtype CRF02_AG (p = 0.02) viruses. A positive correlation was observed between subtype A gp120 binding antibody titers and NAb breadth (p = 0.02) and mean titer against the 10 viruses (p = 0.0002). In addition, HIV-1 subtype A sera showed preferential neutralization of the 5 subtype A or CRF02_AG pseudoviruses, as compared with 5 pseudoviruses from subtypes B, C or D (p<0.001). These data demonstrate that in patients with chronic HIV-1 subtype A infection, significant B cell depletion can be observed, the degree of which does not appear to be associated with a decrease in functional antibodies. These findings also highlight the potential importance of subtype in the specificity of cross-clade neutralization in HIV-1 infection

Characterization of an Nmr Homolog That Modulates GATA Factor-Mediated Nitrogen Metabolite Repression in Cryptococcus neoformans

Nitrogen source utilization plays a critical role in fungal development, secondary metabolite production and pathogenesis. In both the Ascomycota and Basidiomycota, GATA transcription factors globally activate the expression of catabolic enzyme-encoding genes required to degrade complex nitrogenous compounds. However, in the presence of preferred nitrogen sources such as ammonium, GATA factor activity is inhibited in some species through interaction with co-repressor Nmr proteins. This regulatory phenomenon, nitrogen metabolite repression, enables preferential utilization of readily assimilated nitrogen sources. In the basidiomycete pathogen Cryptococcus neoformans, the GATA factor Gat1/Are1 has been co-opted into regulating multiple key virulence traits in addition to nitrogen catabolism. Here, we further characterize Gat1/Are1 function and investigate the regulatory role of the predicted Nmr homolog Tar1. While GAT1/ARE1 expression is induced during nitrogen limitation, TAR1 transcription is unaffected by nitrogen availability. Deletion of TAR1 leads to inappropriate derepression of non-preferred nitrogen catabolic pathways in the simultaneous presence of favoured sources. In addition to exhibiting its evolutionary conserved role of inhibiting GATA factor activity under repressing conditions, Tar1 also positively regulates GAT1/ARE1 transcription under non-repressing conditions. The molecular mechanism by which Tar1 modulates nitrogen metabolite repression, however, remains open to speculation. Interaction between Tar1 and Gat1/Are1 was undetectable in a yeast two-hybrid assay, consistent with Tar1 and Gat1/Are1 each lacking the conserved C-terminus regions present in ascomycete Nmr proteins and GATA factors that are known to interact with each other. Importantly, both Tar1 and Gat1/Are1 are suppressors of C. neoformans virulence, reiterating and highlighting the paradigm of nitrogen regulation of pathogenesis

Semi-Automated Image Analysis for the Assessment of Megafaunal Densities at the Arctic Deep-Sea Observatory HAUSGARTEN

Megafauna play an important role in benthic ecosystem function and are sensitive indicators of environmental change. Non-invasive monitoring of benthic communities can be accomplished by seafloor imaging. However, manual quantification of megafauna in images is labor-intensive and therefore, this organism size class is often neglected in ecosystem studies. Automated image analysis has been proposed as a possible approach to such analysis, but the heterogeneity of megafaunal communities poses a non-trivial challenge for such automated techniques. Here, the potential of a generalized object detection architecture, referred to as iSIS (intelligent Screening of underwater Image Sequences), for the quantification of a heterogenous group of megafauna taxa is investigated. The iSIS system is tuned for a particular image sequence (i.e. a transect) using a small subset of the images, in which megafauna taxa positions were previously marked by an expert. To investigate the potential of iSIS and compare its results with those obtained from human experts, a group of eight different taxa from one camera transect of seafloor images taken at the Arctic deep-sea observatory HAUSGARTEN is used. The results show that inter- and intra-observer agreements of human experts exhibit considerable variation between the species, with a similar degree of variation apparent in the automatically derived results obtained by iSIS. Whilst some taxa (e. g. Bathycrinus stalks, Kolga hyalina, small white sea anemone) were well detected by iSIS (i. e. overall Sensitivity: 87%, overall Positive Predictive Value: 67%), some taxa such as the small sea cucumber Elpidia heckeri remain challenging, for both human observers and iSIS

Semi-Automated Image Analysis for the Assessment of Megafaunal Densities at the Arctic Deep-Sea Observatory HAUSGARTEN

Megafauna play an important role in benthic ecosystem function and are sensitive indicators of environmental change. Non-invasive monitoring of benthic communities can be accomplished by seafloor imaging. However, manual quantification of megafauna in images is labor-intensive and therefore, this organism size class is often neglected in ecosystem studies. Automated image analysis has been proposed as a possible approach to such analysis, but the heterogeneity of megafaunal communities poses a non-trivial challenge for such automated techniques. Here, the potential of a generalized object detection architecture, referred to as iSIS (intelligent Screening of underwater Image Sequences), for the quantification of a heterogenous group of megafauna taxa is investigated. The iSIS system is tuned for a particular image sequence (i.e. a transect) using a small subset of the images, in which megafauna taxa positions were previously marked by an expert. To investigate the potential of iSIS and compare its results with those obtained from human experts, a group of eight different taxa from one camera transect of seafloor images taken at the Arctic deep-sea observatory HAUSGARTEN is used. The results show that inter- and intra-observer agreements of human experts exhibit considerable variation between the species, with a similar degree of variation apparent in the automatically derived results obtained by iSIS. Whilst some taxa (e. g. Bathycrinus stalks, Kolga hyalina, small white sea anemone) were well detected by iSIS (i. e. overall Sensitivity: 87%, overall Positive Predictive Value: 67%), some taxa such as the small sea cucumber Elpidia heckeri remain challenging, for both human observers and iSIS