[Prevalence of claw disorders in swiss cattle farms].

INTRODUCTION The project «Healthy claws - the foundation for the future» aims to establish a Swiss national claw health monitoring based on digital recordings by claw trimmers during claw trimming. To assess claw health on the participating farms, between-herd prevalence, within-herd prevalence and cow prevalence of all claw disorders based on the «ICAR Claw Health Atlas» were calculated during this study. Claw trimmers underwent an intensive training and examination in order to ensure data quality. To guarantee the representativity of the prevalences, only farm claw trimmings were considered, where ≥ 80 % of the cows in a herd were trimmed. The calculations were based on 7108 cows and 403 heifers from 238 farms, during the period from February 2020 to February 2021. At least one claw disorder was present in 99,2 % of the farms, with 49,6 % of the heifers and 77,7 % of the cows having at least one claw disorder. The high prevalence is seen as a result of all ICAR claw disorders being considered, whereas not all of them are painful and consequently not all of them cause lameness. The absence of lameness assessment limits the evaluation of existing herd problems. High between-herd and cow prevalences were observed for the following claw disorders: heel horn erosion (92,9 %/64,7 %), digital dermatitis (55,9 %/20,7 %), white line disease (81,5 %/17,7 %) and sole hemorrhage (66,4 %/11,6 %). Asymmetric claws, corkscrew claws, scissor claws, horn fissure, interdigital phlegmon, swelling of the coronet and/or bulb and toe necrosis had low prevalences. The proportion of cows treated with a hoof block (0,5 %) was comparatively small in regard of the cows suffering from ulcers (5,6 %) and white line abscesses (2,5 %). The median within-herd prevalence of digital dermatitis was 5,6 %, with a maximal within-herd prevalence of 87,5 %. Despite the contagious nature of digital dermatitis, no increase of between-herd and cow prevalence has been observed in the past ten years throughout Switzerland. Based on this data, the Swiss claw health situation can be monitored, compared over time and improved in the future

[Risk factors for infectious foot disorders on two Swiss cattle mountain pastures].

In the present study, risk groups for infectious foot disorders were identified on two large Swiss cattle mountain pastures by analyzing animal and treatment data of a total of 3256 animals of the bovine species. Both mountain pastures were part of the Federal Office for Agriculture (FOAG) consultancy project «Healthy animals, attractive herdsmen positions and less medication on large cattle mountain pastures». The project was launched in 2020 following the increased incidence of lameness on these mountain pastures. Bacteriological and histological analyses were to provide information as to whether the most common foot disorder was interdigital phlegmon (IP) or whether digital dermatitis also occurred. Further, the temporal distribution of cases over the mountain pasture season and the influence of mountain pasture and year were investigated and interpreted for the project years 2020 to 2022, and treatment incidences were compared between years. Multiple treatment cycles in the same individual were classified into persistent infections and new infections. Nineteen of 394 first-treated cattle were clinically examined, 12 of them were additionally sampled for bacteriological and histological analyses. All cases examined showed, both clinically and following laboratory analyses, typical characteristics for IP. In contrast, there was no specific evidence for the presence of digital dermatitis. No persistent infections occurred during treatment with benzylpenicillin. Multivariate logistic regression analyses identified > 365-730-day-old cattle (odds ratio OR 8,29), as well as inseminated (OR 5,30) and non-inseminated (OR 7,85) heifers as risk groups for the disease studied (p < 0,05). Association with the oestrus activity of non-inseminated heifers and a generally higher locomotor activity in heifers compared to cows - with a correspondingly increased risk of injury - is conceivable. Meat breeds had a reduced risk compared to dairy breeds (OR 0,29). Breed differences in behavior and/or the effectiveness of the local immune response might have an impact. Knowing about these risk groups can be put to use in the future when selecting animals to be taken to the mountain pastures and/or when planning pasture management in order to reduce the prevalence of infectious foot disorders and thereby the use of antibiotics

Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy

HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the β-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1. This so-called allelic imbalance was detected in whole tissue samples but also in individual cells. There is evidence that the severity of HCM not only depends on the functional effect of the mutation itself, but also on the fraction of mutant protein in the myocardial tissue. Allelic imbalance has been shown to occur in a broad range of genes. Therefore, we aimed to examine whether the MYH7-alleles are intrinsically expressed imbalanced or whether the allelic imbalance is solely associated with the disease. We compared the expression of MYH7-alleles in non-HCM donors and in HCM-patients with different MYH7-missense mutations. In the HCM-patients, we identified imbalanced as well as equal expression of both alleles. Also at the protein level, allelic imbalance was determined. Most interestingly, we also discovered allelic imbalance and balance in non-HCM donors. Our findings therefore strongly indicate that apart from mutation-specific mechanisms, also non-HCM associated allelic-mRNA expression regulation may account for the allelic imbalance of the MYH7 gene in HCM-patients. Since the relative amount of mutant mRNA and protein or the extent of allelic imbalance has been associated with the severity of HCM, individual analysis of the MYH7-allelic expression may provide valuable information for the prognosis of each patient

User-Centered Development of a Patient Decision Aid for Choice of Early Abortion Method: Multi-Cycle Mixed Methods Study.

BACKGROUND: People seeking abortion in early pregnancy have the choice between medication and procedural options for care. The choice is preference-sensitive-there is no clinically superior option and the choice depends on what matters most to the individual patient. Patient decision aids (PtDAs) are shared decision-making tools that support people in making informed, values-aligned health care choices. OBJECTIVE: We aimed to develop and evaluate the usability of a web-based PtDA for the Canadian context, where abortion care is publicly funded and available without legal restriction. METHODS: We used a systematic, user-centered design approach guided by principles of integrated knowledge translation. We first developed a prototype using available evidence for abortion seekers' decisional needs and the risks, benefits, and consequences of each option. We then refined the prototype through think-aloud interviews with participants at risk of unintended pregnancy ("patient" participants). Interviews were audio-recorded and documented through field notes. Finally, we conducted a web-based survey of patients and health care professionals involved with abortion care, which included the System Usability Scale. We used content analysis to identify usability issues described in the field notes and open-ended survey questions, and descriptive statistics to summarize participant characteristics and close-ended survey responses. RESULTS: A total of 61 individuals participated in this study. Further, 11 patients participated in think-aloud interviews. Overall, the response to the PtDA was positive; however, the content analysis identified issues related to the design, language, and information about the process and experience of obtaining abortion care. In response, we adapted the PtDA into an interactive website and revised it to include consistent and plain language, additional information (eg, pain experience narratives), and links to additional resources on how to find an abortion health care professional. In total, 25 patients and 25 health care professionals completed the survey. The mean System Usability Scale score met the threshold for good usability among both patient and health care professional participants. Most participants felt that the PtDA was user-friendly (patients: n=25, 100%; health care professionals: n=22, 88%), was not missing information (patients: n=21, 84%; health care professionals: n=18, 72%), and that it was appropriate for patients to complete the PtDA before a consultation (patients: n=23, 92%; health care professionals: n=23, 92%). Open-ended responses focused on improving usability by reducing the length of the PtDA and making the website more mobile-friendly. CONCLUSIONS: We systematically designed the PtDA to address an unmet need to support informed, values-aligned decision-making about the method of abortion. The design process responded to a need identified by potential users and addressed unique sensitivities related to reproductive health decision-making

Inference of reticulate evolutionary histories by maximum likelihood: the performance of information criteria

Background: Maximum likelihood has been widely used for over three decades to infer phylogenetic trees from molecular data. When reticulate evolutionary events occur, several genomic regions may have conflicting evolutionary histories, and a phylogenetic network may provide a more adequate model for representing the evolutionary history of the genomes or species. A maximum likelihood (ML) model has been proposed for this case and accounts for both mutation within a genomic region and reticulation across the regions. However, the performance of this model in terms of inferring information about reticulate evolution and properties that affect this performance have not been studied. Results: In this paper, we study the effect of the evolutionary diameter and height of a reticulation event on its identifiability under ML. We find both of them, particularly the diameter, have a significant effect. Further, we find that the number of genes (which can be generalized to the concept of "non-recombining genomic regions") that are transferred across a reticulation edge affects its detectability. Last but not least, a fundamental challenge with phylogenetic networks is that they allow an arbitrary level of complexity, giving rise to the model selection problem. We investigate the performance of two information criteria, the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC), for addressing this problem. We find that BIC performs well in general for controlling the model complexity and preventing ML from grossly overestimating the number of reticulation events. Conclusion: Our results demonstrate that BIC provides a good framework for inferring reticulate evolutionary histories. Nevertheless, the results call for caution when interpreting the accuracy of the inference particularly for data sets with particular evolutionary features

A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours

Background:The current biomarkers alpha-fetoprotein and human chorionic gonadotropin have limited sensitivity and specificity for diagnosing malignant germ-cell tumours (GCTs). MicroRNAs (miRNAs) from the miR-371-373 and miR-302/367 clusters are overexpressed in all malignant GCTs, and some of these miRNAs show elevated serum levels at diagnosis. Here, we developed a robust technical pipeline to quantify these miRNAs in the serum and cerebrospinal fluid (CSF). The pipeline was used in samples from a cohort of exclusively paediatric patients with gonadal and extragonadal malignant GCTs, compared with appropriate tumour and non-tumour control groups.Methods:We developed a method for miRNA quantification that enabled sample adequacy assessment and reliable data normalisation. We performed qRT-PCR profiling for miR-371-373 and miR-302/367 cluster miRNAs in a total of 45 serum and CSF samples, obtained from 25 paediatric patients.Results:The exogenous non-human spike-in cel-miR-39-3p and the endogenous housekeeper miR-30b-5p were optimal for obtaining robust serum and CSF qRT-PCR quantification. A four-serum miRNA panel (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p): (i) showed high sensitivity/specificity for diagnosing paediatric extracranial malignant GCT; (ii) allowed early detection of relapse of a testicular mixed malignant GCT; and (iii) distinguished intracranial malignant GCT from intracranial non-GCT tumours at diagnosis, using CSF and serum samples.Conclusions:The pipeline we have developed is robust, scalable and transferable. It potentially promises to improve clinical management of paediatric (and adult) malignant GCTs

The present and future of serum diagnostic tests for testicular germ cell tumours.

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371-373 and miR-302-367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17

Universal Artifacts Affect the Branching of Phylogenetic Trees, Not Universal Scaling Laws

The superficial resemblance of phylogenetic trees to other branching structures allows searching for macroevolutionary patterns. However, such trees are just statistical inferences of particular historical events. Recent meta-analyses report finding regularities in the branching pattern of phylogenetic trees. But is this supported by evidence, or are such regularities just methodological artifacts? If so, is there any signal in a phylogeny?In order to evaluate the impact of polytomies and imbalance on tree shape, the distribution of all binary and polytomic trees of up to 7 taxa was assessed in tree-shape space. The relationship between the proportion of outgroups and the amount of imbalance introduced with them was assessed applying four different tree-building methods to 100 combinations from a set of 10 ingroup and 9 outgroup species, and performing covariance analyses. The relevance of this analysis was explored taking 61 published phylogenies, based on nucleic acid sequences and involving various taxa, taxonomic levels, and tree-building methods.All methods of phylogenetic inference are quite sensitive to the artifacts introduced by outgroups. However, published phylogenies appear to be subject to a rather effective, albeit rather intuitive control against such artifacts. The data and methods used to build phylogenetic trees are varied, so any meta-analysis is subject to pitfalls due to their uneven intrinsic merits, which translate into artifacts in tree shape. The binary branching pattern is an imposition of methods, and seldom reflects true relationships in intraspecific analyses, yielding artifactual polytomies in short trees. Above the species level, the departure of real trees from simplistic random models is caused at least by two natural factors--uneven speciation and extinction rates; and artifacts such as choice of taxa included in the analysis, and imbalance introduced by outgroups and basal paraphyletic taxa. This artifactual imbalance accounts for tree shape convergence of large trees.There is no evidence for any universal scaling in the tree of life. Instead, there is a need for improved methods of tree analysis that can be used to discriminate the noise due to outgroups from the phylogenetic signal within the taxon of interest, and to evaluate realistic models of evolution, correcting the retrospective perspective and explicitly recognizing extinction as a driving force. Artifacts are pervasive, and can only be overcome through understanding the structure and biological meaning of phylogenetic trees. Catalan Abstract in Translation S1