Prevalence of Disorders Recorded in Dogs Attending Primary-Care Veterinary Practices in England

Purebred dog health is thought to be compromised by an increasing occurence of inherited diseases but inadequate prevalence data on common disorders have hampered efforts to prioritise health reforms. Analysis of primary veterinary practice clinical data has been proposed for reliable estimation of disorder prevalence in dogs. Electronic patient record (EPR) data were collected on 148,741 dogs attending 93 clinics across central and south-eastern England. Analysis in detail of a random sample of EPRs relating to 3,884 dogs from 89 clinics identified the most frequently recorded disorders as otitis externa (prevalence 10.2%, 95% CI: 9.1-11.3), periodontal disease (9.3%, 95% CI: 8.3-10.3) and anal sac impaction (7.1%, 95% CI: 6.1-8.1). Using syndromic classification, the most prevalent body location affected was the head-and-neck (32.8%, 95% CI: 30.7-34.9), the most prevalent organ system affected was the integument (36.3%, 95% CI: 33.9-38.6) and the most prevalent pathophysiologic process diagnosed was inflammation (32.1%, 95% CI: 29.8-34.3). Among the twenty most-frequently recorded disorders, purebred dogs had a significantly higher prevalence compared with crossbreds for three: otitis externa (P = 0.001), obesity (P = 0.006) and skin mass lesion (P = 0.033), and popular breeds differed significantly from each other in their prevalence for five: periodontal disease (P = 0.002), overgrown nails (P = 0.004), degenerative joint disease (P = 0.005), obesity (P = 0.001) and lipoma (P = 0.003). These results fill a crucial data gap in disorder prevalence information and assist with disorder prioritisation. The results suggest that, for maximal impact, breeding reforms should target commonly-diagnosed complex disorders that are amenable to genetic improvement and should place special focus on at-risk breeds. Future studies evaluating disorder severity and duration will augment the usefulness of the disorder prevalence information reported herein

Evolutionary distances in the twilight zone -- a rational kernel approach

Phylogenetic tree reconstruction is traditionally based on multiple sequence alignments (MSAs) and heavily depends on the validity of this information bottleneck. With increasing sequence divergence, the quality of MSAs decays quickly. Alignment-free methods, on the other hand, are based on abstract string comparisons and avoid potential alignment problems. However, in general they are not biologically motivated and ignore our knowledge about the evolution of sequences. Thus, it is still a major open question how to define an evolutionary distance metric between divergent sequences that makes use of indel information and known substitution models without the need for a multiple alignment. Here we propose a new evolutionary distance metric to close this gap. It uses finite-state transducers to create a biologically motivated similarity score which models substitutions and indels, and does not depend on a multiple sequence alignment. The sequence similarity score is defined in analogy to pairwise alignments and additionally has the positive semi-definite property. We describe its derivation and show in simulation studies and real-world examples that it is more accurate in reconstructing phylogenies than competing methods. The result is a new and accurate way of determining evolutionary distances in and beyond the twilight zone of sequence alignments that is suitable for large datasets.Comment: to appear in PLoS ON

Are C-Reactive Protein Associated Genetic Variants Associated with Serum Levels and Retinal Markers of Microvascular Pathology in Asian Populations from Singapore?

Introduction:C-reactive protein (CRP) levels are associated with cardiovascular disease and systemic inflammation. We assessed whether CRP-associated loci were associated with serum CRP and retinal markers of microvascular disease, in Asian populations.Methods:Genome-wide association analysis (GWAS) for serum CRP was performed in East-Asian Chinese (N = 2,434) and Malays (N = 2,542) and South-Asian Indians (N = 2,538) from Singapore. Leveraging on GWAS data, we assessed, in silico, association levels among the Singaporean datasets for 22 recently identified CRP-associated loci. At loci where directional inconsistencies were observed, quantification of inter-ethnic linkage disequilibrium (LD) difference was determined. Next, we assessed association for a variant at CRP and retinal vessel traits [central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE)] in a total of 24,132 subjects of East-Asian, South-Asian and European ancestry.Results:Serum CRP was associated with SNPs in/near APOE, CRP, HNF1A and LEPR (p-values ≤4.7×10-8) after meta-analysis of Singaporean populations. Using a candidate-SNP approach, we further replicated SNPs at 4 additional loci that had been recently identified to be associated with serum CRP (IL6R, GCKR, IL6 and IL1F10) (p-values ≤0.009), in the Singaporean datasets. SNPs from these 8 loci explained 4.05% of variance in serum CRP. Two SNPs (rs2847281 and rs6901250) were detected to be significant (p-value ≤0.036) but with opposite effect directions in the Singaporean populations as compared to original European studies. At these loci we did not detect significant inter-population LD differences. We further did not observe a significant association between CRP variant and CRVE or CRAE levels after meta-analysis of all Singaporean and European datasets (p-value >0.058).Conclusions:Common variants associated with serum CRP, first detected in primarily European studies, are also associated with CRP levels in East-Asian and South-Asian populations. We did not find a causal link between CRP and retinal measures of microvascular disease

Promotion of a healthy lifestyle among 5-year-old overweight children: Health behavior outcomes of the 'Be active, eat right' study

Background: This study evaluates the effects of an intervention performed by youth health care professionals on child health behaviors. The intervention consisted of offering healthy lifestyle counseling to parents of overweight (not obese) 5-year-old children. Effects of the intervention on the child having breakfast, drinking sweet beverages, watching television and playing outside were evaluated. Methods. Data were collected with the 'Be active, eat right' study, a cluster randomized controlled trial among nine youth health care centers in the Netherlands. Parents of overweight children received lifestyle counseling according to the intervention protocol in the intervention condition (n = 349) and usual care in the control condition (n = 288). Parents completed questionnaires regarding demographic characteristics, health behaviors and the home environment at baseline and at 2-year follow-up. Cluster adjusted regression models were applied; interaction terms were explored. Results: The population for analysis consisted of 38.1% boys; mean age 5.8 [sd 0.4] years; mean BMI SDS 1.9 [sd 0.4]. There were no significant differences in the number of minutes of outside play or television viewing a day between children in the intervention and the control condition. Also, the odds ratio for having breakfast daily or drinking two or less glasses of sweet beverages a day showed no significant differences between the two conditions. Additional analyses showed that the odds ratio for drinking less than two glasses of sweet beverages at follow-up compared with baseline was significantly higher for children in both the intervention (p < 0.001) and the control condition (p = 0.029). Conclusions: Comparison of the children in the two conditions showed that the intervention does not contribute to a change in health behaviors. Further studies are needed to investigate opportunities to adjust the intervention protocol, such as integration of elements in the regular well-child visit. The intervention protocol for youth health care may become part of a broader approach to tackle childhood overweight and obesity. Trial registration. Current Controlled Trials ISRCTN04965410

Expression and function of G-protein-coupled receptorsin the male reproductive tract

This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.Esta revisão enfatiza a expressão e a função dos receptores muscarínicos, adrenoceptores α1 e receptores para relaxina no sistema reprodutor masculino. A expressão dos receptores muscarínicos e adrenoceptores α1 em compartimentos específicos de dúctulos eferentes, epidídimo, ductos deferentes, vesícula seminal e próstata de várias espécies indica o envolvimento destes receptores na modulação da composição do fluido luminal e na contração do músculo liso, incluindo efeitos na fertilidade masculina. Além disso, a ativação dos receptores muscarínicos leva à transativação do receptor para o fator crescimento epidermal e proliferação das células de Sertoli. Os receptores para relaxina estão presentes no testículo, RXFP1 nas espermátides alongadas e células de Sertoli de rato e RXFP2 nas células de Leydig e germinativas de ratos e humano, sugerindo o envolvimento destes receptores no processo espermatogênico. A localização de ambos os receptores na porção apical das células epiteliais e no músculo liso dos ductos deferentes de rato sugere um papel na contração e na regulação da secreção.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de FarmacologiaUNIFESP, EPM, Depto. de FarmacologiaSciEL

Association of Autistic Traits With Depression From Childhood to Age 18 Years.

ImportancePopulation-based studies following trajectories of depression in autism spectrum disorders (ASD) from childhood into early adulthood are rare. The role of genetic confounding and of potential environmental intermediaries, such as bullying, in any associations is unclear.ObjectivesTo compare trajectories of depressive symptoms from ages 10 to 18 years for children with or without ASD and autistic traits, to assess associations between ASD and autistic traits and an International Statistical Classification of Diseases, 10th Revision (ICD-10) depression diagnosis at age 18 years, and to explore the importance of genetic confounding and bullying.Design, setting, and participantsLongitudinal study of participants in the Avon Longitudinal Study of Parents and Children birth cohort in Bristol, United Kingdom, followed up through age 18 years. Data analysis was conducted from January to November 2017.Main outcomes and measuresDepressive symptoms were assessed using the Short Mood and Feelings Questionnaire (SMFQ) at 6 time points between ages 10 and 18 years. An ICD-10 depression diagnosis at age 18 years was established using the Clinical Interview Schedule-Revised. Exposures were ASD diagnosis and 4 dichotomized autistic traits (social communication, coherence, repetitive behavior, and sociability). An autism polygenic risk score was derived using the Psychiatric Genomics Consortium autism discovery genome-wide association study summary data. Bullying was assessed at ages 8, 10, and 13 years.ResultsThe maximum sample with complete data was 6091 for the trajectory analysis (48.8% male) and 3168 for analysis of depression diagnosis at age 18 years (44.4% male). Children with ASD and autistic traits had higher average SMFQ depressive symptom scores than the general population at age 10 years (eg, for social communication 5.55 [95% CI, 5.16-5.95] vs 3.73 [95% CI, 3.61-3.85], for ASD 7.31 [95% CI, 6.22-8.40] vs 3.94 [95% CI, 3.83-4.05], remaining elevated in an upward trajectory until age 18 years (eg, for social communication 7.65 [95% CI, 6.92-8.37] vs 6.50 [95% CI, 6.29-6.71], for ASD 7.66 [95% CI, 5.96-9.35] vs 6.62 [95% CI, 6.43-6.81]). Social communication impairments were associated with depression at age 18 years (adjusted relative risk, 1.68; 95% CI, 1.05-2.70), and bullying explained a substantial proportion of this risk. There was no evidence of confounding by the autism polygenic risk score. Analysis in larger samples using multiple imputation led to similar but more precise results.Conclusions and relevanceChildren with ASD and ASD traits have higher depressive symptom scores than the general population by age 10 years, which persist to age 18 years, particularly in the context of bullying. Social communication impairments are an important autistic trait in relation to depression. Bullying, as an environmental intermediary, could be a target for interventions

Evaluation of an early detection tool for social-emotional and behavioral problems in toddlers: The Brief Infant Toddler Social and Emotional Assessment - A cluster randomized trial

<p>Abstract</p> <p>Background</p> <p>The prevalence of social-emotional and behavioral problems is estimated to be 8 to 9% among preschool children. Effective early detection tools are needed to promote the provision of adequate care at an early stage. The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) was developed for this purpose. This study evaluates the effectiveness of the BITSEA to enhance social-emotional and behavioral health of preschool children.</p> <p>Methods and Design</p> <p>A cluster randomized controlled trial is set up in youth health care centers in the larger Rotterdam area in the Netherlands, to evaluate the BITSEA. The 31 youth health care centers are randomly allocated to either the control group or the intervention group. The intervention group uses the scores on the BITSEA and cut-off points to evaluate a child's social-emotional and behavioral health and to decide whether or not the child should be referred. The control group provides care as usual, which involves administering a questionnaire that structures the conversation between child health professionals and parents. At a one year follow-up measurement the social-emotional and behavioral health of all children included in the study population will be evaluated.</p> <p>Discussion</p> <p>It is hypothesized that better results will be found, in terms of social-emotional and behavioral health in the intervention group, compared to the control group, due to more adequate early detection, referral and more appropriate and timely care.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2035">NTR2035</a></p

Probabilistic Phylogenetic Inference with Insertions and Deletions

A fundamental task in sequence analysis is to calculate the probability of a multiple alignment given a phylogenetic tree relating the sequences and an evolutionary model describing how sequences change over time. However, the most widely used phylogenetic models only account for residue substitution events. We describe a probabilistic model of a multiple sequence alignment that accounts for insertion and deletion events in addition to substitutions, given a phylogenetic tree, using a rate matrix augmented by the gap character. Starting from a continuous Markov process, we construct a non-reversible generative (birth–death) evolutionary model for insertions and deletions. The model assumes that insertion and deletion events occur one residue at a time. We apply this model to phylogenetic tree inference by extending the program dnaml in phylip. Using standard benchmarking methods on simulated data and a new “concordance test” benchmark on real ribosomal RNA alignments, we show that the extended program dnamlε improves accuracy relative to the usual approach of ignoring gaps, while retaining the computational efficiency of the Felsenstein peeling algorithm

Accurate and fast methods to estimate the population mutation rate from error prone sequences

Abstract Background The population mutation rate (θ) remains one of the most fundamental parameters in genetics, ecology, and evolutionary biology. However, its accurate estimation can be seriously compromised when working with error prone data such as expressed sequence tags, low coverage draft sequences, and other such unfinished products. This study is premised on the simple idea that a random sequence error due to a chance accident during data collection or recording will be distributed within a population dataset as a singleton (i.e., as a polymorphic site where one sampled sequence exhibits a unique base relative to the common nucleotide of the others). Thus, one can avoid these random errors by ignoring the singletons within a dataset. Results This strategy is implemented under an infinite sites model that focuses on only the internal branches of the sample genealogy where a shared polymorphism can arise (i.e., a variable site where each alternative base is represented by at least two sequences). This approach is first used to derive independently the same new Watterson and Tajima estimators of θ, as recently reported by Achaz 1 for error prone sequences. It is then used to modify the recent, full, maximum-likelihood model of Knudsen and Miyamoto 2, which incorporates various factors for experimental error and design with those for coalescence and mutation. These new methods are all accurate and fast according to evolutionary simulations and analyses of a real complex population dataset for the California seahare. Conclusion In light of these results, we recommend the use of these three new methods for the determination of θ from error prone sequences. In particular, we advocate the new maximum likelihood model as a starting point for the further development of more complex coalescent/mutation models that also account for experimental error and design.</p