Biomechanical comparison of titanium alloy additively manufactured and conventionally manufactured plate-screw constructs.

AIM: To biomechanically compare the bending stiffness, strength, and cyclic fatigue of titanium additively manufactured (AM) and conventionally manufactured (CM) limited contact plates (LCP) of equivalent dimensions using plate-screw constructs. METHODS: Twenty-four 1.5/2.0-mm plate constructs (CM: n = 12; AM: n = 12) were placed under 4-point bending conditions. Data were collected during quasi-static single cycle to failure and cyclic fatigue testing until implants plastically deformed or failed. Bending stiffness, bending structural stiffness, and bending strength were determined from load-displacement curves. Fatigue life was determined as number of cycles to failure. Median test variables for each method were compared using the Wilcoxon rank sum test within each group. Fatigue data was also analysed by the Kaplan-Meier estimator of survival function. RESULTS: There was no evidence for a difference in bending stiffness and bending structural stiffness between AM and CM constructs. However, AM constructs exhibited greater bending strength (median 3.07 (min 3.0, max 3.4) Nm) under quasi-static 4-point bending than the CM constructs (median 2.57 (min 2.5, max 2.6) Nm, p = 0.006). Number of cycles to failure under dynamic 4-point bending was higher for the CM constructs (median 164,272 (min 73,557, max 250,000) cycles) than the AM constructs (median 18,704 (min 14,427, max 33,228) cycles; p = 0.02). Survival analysis showed that 50% of AM plates failed by 18,842 cycles, while 50% CM plates failed by 78,543 cycles. CONCLUSION AND CLINICAL RELEVANCE: Additively manufactured titanium implants, printed to replicate a conventional titanium orthopaedic plate, were more prone to failure in a shorter fatigue period despite being stronger in single cycle to failure. Patient-specific implants made using this process may be brittle and therefore not comparable to CM orthopaedic implants. Careful selection of their use on a case/patient-specific basis is recommended.

Disseminated Rasamsonia argillacea infection in a dog.

CASE HISTORY: A 4-year-old, male neutered Borzoi presented for unlocalised pain and frequent episodes of vocalisation. CLINICAL FINDINGS: Pain was localised to the lumbar spine and radiographs revealed a L3-L4 lesion consistent with discospondylitis. The dog was treated for presumptive bacterial discospondylitis with surgical debridement, spinal stabilisation, and cephalexin. Samples collected from the affected intervertebral disc at the time of surgery revealed lymphoplasmacytic inflammation with no causative agent identified on histopathology or bacterial culture. After an initial period of improvement, signs recurred despite an 8-week antibiotic course, with the development of inappetence, weight loss, polydipsia, and polyuria. Repeat radiographs revealed a new cervical intervertebral lesion, and concurrent pyelonephritis was diagnosed based on blood and urine results. Fungal culture of urine resulted in growth of Rasamsonia argillacea species complex and disseminated fungal disease was clinically diagnosed. Antifungal treatment was commenced, however the dog deteriorated, and euthanasia was performed. PATHOLOGICAL FINDINGS: Multifocal white plaques were grossly visualised in the spleen, mesenteric lymph nodes, cervical vertebrae, and kidneys. Periodic acid-Schiff-positive, fine, parallel-walled, occasionally branching, septate hyphae 5-10 µm in diameter, and conidia 5-7 µm in diameter were found on sectioning all organs. R. argillacea species complex was identified by fungal culture of urine and was considered the species of fungal organism seen histologically. The isolate was subsequently confirmed as R. argillacea by DNA sequencing. DIAGNOSIS: Disseminated Rasamsonia argillacea infection. CLINICAL RELEVANCE: Rasamsonia argillacea species complex is a recognised invasive mycosis in veterinary medicine, with disseminated disease causing significant clinical complications and death. This is believed to be the first report of infection caused by R. argillacea in a dog in Australasia and highlights the importance of awareness of a potential fungal aetiology in dogs with discospondylitis.Abbreviations: CLSI: Clinical and Laboratory Standards Institute; CRI: Constant rate infusion; MEC: Minimum effective concentration; MIC: Minimum inhibitory concentration; PAS: Periodic acid-Schiff.

Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

COSMOS next generation - A public knowledge base leveraging chemical and biological data to support the regulatory assessment of chemicals.

The COSMOS Database (DB) was originally established to provide reliable data for cosmetics-related chemicals within the COSMOS Project funded as part of the SEURAT-1 Research Initiative. The database has subsequently been maintained and developed further into COSMOS Next Generation (NG), a combination of database and in silico tools, essential components of a knowledge base. COSMOS DB provided a cosmetics inventory as well as other regulatory inventories, accompanied by assessment results and in vitro and in vivo toxicity data. In addition to data content curation, much effort was dedicated to data governance - data authorisation, characterisation of quality, documentation of meta information, and control of data use. Through this effort, COSMOS DB was able to merge and fuse data of various types from different sources. Building on the previous effort, the COSMOS Minimum Inclusion (MINIS) criteria for a toxicity database were further expanded to quantify the reliability of studies. COSMOS NG features multiple fingerprints for analysing structure similarity, and new tools to calculate molecular properties and screen chemicals with endpoint-related public profilers, such as DNA and protein binders, liver alerts and genotoxic alerts. The publicly available COSMOS NG enables users to compile information and execute analyses such as category formation and read-across. This paper provides a step-by-step guided workflow for a simple read-across case, starting from a target structure and culminating in an estimation of a NOAEL confidence interval. Given its strong technical foundation, inclusion of quality-reviewed data, and provision of tools designed to facilitate communication between users, COSMOS NG is a first step towards building a toxicological knowledge hub leveraging many public data systems for chemical safety evaluation. We continue to monitor the feedback from the user community at support@mn-am.com.

The effect of pearl spacing on single-cycle load-to-failure and cyclic loading parameters of 2.0†mm pearl locking plates.

AIMS: To compare the mechanical performance and mode of failure in four-point bending of two different 2.0 mm "string of pearls" locking plates that differ in dimensions. METHODS: Ten *2.0 mm, 82 mm long, 10-hole (Plate A) and ten 2.0 mm, 69 mm long, 12-hole (Plate B) Cortical Pearl Systems were secured to plate extenders and centred beneath an Instron tensile tester in four-point bending. In all constructs, a simulated fracture gap was maintained at 33 mm. Due to differences in plate dimensions, 33 mm corresponded to four pearls (Plate A) and six pearls (Plate B). Following an initial preload of 10 N, ramped single-cycle load-to-failure at 0.1 mm/second was performed in five Plate A and five Plate B constructs. Load and displacement were recorded. Constant frequency sinusoidal cyclic loading (33 N) at 20 mm/minute was performed on five Plate A and five Plate B constructs following 10 N of preload. Maximum moment and cycle count were recorded. Testing and data analysis were completed in accordance with the American Society for Testing and Materials F382-14 guidelines. Differences in performance and mode of failure were compared. RESULTS: : Plate A constructs produced higher mean values for bending stiffness (19.8 (SD 2.0) N/mm vs. 10.1 (SD 0.6) N/mm; p < 0.001), bending structural stiffness (0.77 (SD 0.08) Nm2 vs. 0.39 (SD 0.02) Nm2; p < 0.001), yield point (64.1 (SD 4.2) N vs. 54.6 (SD 3.9) N; p = 0.01), proof load (65.4 (SD 3.2) N vs. 55.6 (SD 4.0) N; p = 0.005), and bending strength (1.3 (SD 0.1) Nm vs. 1.1 (SD 0.08) Nm; p = 0.005) when compared to Plate B constructs in single cycle load-to-failure. Plate A constructs had a greater (p = 0.001) mean cycle count to failure (26,178 (SD 4,061) cycles) when compared with Plate B constructs (15,550 (SD 1,291) cycles). All plates failed by non-catastrophic plastic deformation. CONCLUSIONS: Plate A, which is wider, thicker and has a greater spacing between pearls, was mechanically superior to Plate B in four-point bending under single-cycle load-to-failure and sinusoidal cyclic loading. CLINICAL RELEVANCE: Although mechanical differences were identified in four-point bending, in vivo biomechanical performance remains undetermined. By selecting Plate B, the clinician may gain bone purchase through a greater number of pearls and thus screws per unit length, however, the inferior mechanical characteristics, as evaluated in four-point bending, should also be considered. Further research into the mechanical and biomechanical performance of these plating systems is warranted.

Calcaneotibial screws for immobilisation of the tarsocrural joint of dogs in extension: effect of the angle of screw placement on the force to failure in a canine cadaveric model.

AIMS: To compare the force to failure under axial loading of a calcaneotibial screw placed approximately perpendicular to the tibia with that of a screw placed perpendicular to the calcaneus, when used to immobilise the tarsus in an ex vivo canine model. METHODS: Twelve pairs of cadaveric hindlimbs from large breed dogs, without orthopaedic or soft tissue disease, were prepared by transecting the limb at the level of the stifle and stripping the limbs of all musculature from the stifle to mid-metatarsus, including removal of the common calcaneal tendon from all limbs. The limbs in each pair were randomly assigned to receive a calcaneotibial screw placed perpendicular to the long axis of either the calcaneus (C group) or the tibia (T group) with the tarsus in full extension. The distal limb was potted in resin and the proximal tibia was pinned to allow biomechanical testing in compressive loading. Testing was performed to apply an axial load using a material testing machine in a proximodistal direction through the tibia, advancing at a rate of 10 mm/second. The force to failure was recorded in kN and compared between groups. RESULTS: The median force to failure of the C group was 0.86 (min 0.50; max 1.64) kN which was higher than the T group which had a median force to failure of 0.74 (min 0.26, max1.05) kN (p = 0.004). All modes of failure were by screw pull-out. CONCLUSIONS: A calcaneotibial screw placed at an angle approximately perpendicular to the long axis of the calcaneus, has a higher force to failure under axial loading than a calcaneotibial screw that is placed at an angle approximately perpendicular to the tibia, in a canine cadaveric model. CLINICAL RELEVANCE: A temporary calcaneotibial screw is a common method of immobilising the tarsus in extension to protect primary repair of a common calcaneal tendon injury. Placing a calcaneotibial screw perpendicular to the calcaneus may be a more reliable option for immobilisation of the tarsus to protect a common calcaneal tendon repair compared to screws placed perpendicular to the tibia. However extrapolation of these results into a clinical setting requires caution.

Animal medical genetics: a historical perspective on more than 50 years of research into genetic disorders of animals at Massey University.

Over the last 50 years, there have been major advances in knowledge and technology regarding genetic diseases, and the subsequent ability to control them in a cost-effective manner. This review traces these advances through research into genetic diseases of animals at Massey University (Palmerston North, NZ), and briefly discusses the disorders investigated during that time, with additional detail for disorders of major importance such as bovine α-mannosidosis, ovine ceroid-lipofuscinosis, canine mucopolysaccharidosis IIIA and feline hyperchylomicronaemia. The overall research has made a significant contribution to veterinary medicine, has provided new biological knowledge and advanced our understanding of similar disorders in human patients, including testing various specific therapies prior to human clinical trials.

Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making.

The fields of toxicology and chemical risk assessment seek to reduce, and eventually replace, the use of animals for the prediction of toxicity in humans. In this context, physiologically based kinetic (PBK) modelling based on in vitro and in silico kinetic data has the potential to a play significant role in reducing animal testing, by providing a methodology capable of incorporating in vitro human data to facilitate the development of in vitro to in vivo extrapolation of hazard information. In the present article, we discuss the challenges in: 1) applying PBK modelling to support regulatory decision making under the toxicology and risk-assessment paradigm shift towards animal replacement; 2) constructing PBK models without in vivo animal kinetic data, while relying solely on in vitro or in silico methods for model parameterization; and 3) assessing the validity and credibility of PBK models built largely using non-animal data. The strengths, uncertainties, and limitations of PBK models developed using in vitro or in silico data are discussed in an effort to establish a higher degree of confidence in the application of such models in a regulatory context. The article summarises the outcome of an expert workshop hosted by the European Commission Joint Research Centre (EC-JRC) - European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), on "Physiologically-Based Kinetic modelling in risk assessment - reaching a whole new level in regulatory decision-making" held in Ispra, Italy, in November 2016, along with results from an international survey conducted in 2017 and recently reported activities occurring within the PBK modelling field. The discussions presented herein highlight the potential applications of next generation (NG)-PBK modelling, based on new data streams.

Physiologically based mathematical models of nanomaterials for regulatory toxicology: A review.

The development of physiologically based (PB) models to support safety assessments in the field of nanotechnology has grown steadily during the last decade. This review reports on the availability of PB models for toxicokinetic (TK) and toxicodynamic (TD) processes, including in vitro and in vivo dosimetry models applied to manufactured nanomaterials (MNs). In addition to reporting on the state-of-the-art in the scientific literature concerning the availability of physiologically based kinetic (PBK) models, we evaluate their relevance for regulatory applications, mainly considering the EU REACH regulation. First, we performed a literature search to identify all available PBK models. Then, we systematically reported the content of the identified papers in a tailored template to build a consistent inventory, thereby supporting model comparison. We also described model availability for physiologically based dynamic (PBD) and in vitro and in vivo dosimetry models according to the same template. For completeness, a number of classical toxicokinetic (CTK) models were also included in the inventory. The review describes the PBK model landscape applied to MNs on the basis of the type of MNs covered by the models, their stated applicability domain, the type of (nano-specific) inputs required, and the type of outputs generated. We identify the main assumptions made during model development that may influence the uncertainty in the final assessment, and we assess the REACH relevance of the available models within each model category. Finally, we compare the state of PB model acceptance for chemicals and for MNs. In general, PB model acceptance is limited by the absence of standardised reporting formats, psychological factors such as the complexity of the models, and technical considerations such as lack of blood:tissue partitioning data for model calibration/validation.

Computational models for the assessment of manufactured nanomaterials: Development of model reporting standards and mapping of the model landscape.

Different types of computational models have been developed for predicting the biokinetics, environmental fate, exposure levels and toxicological effects of chemicals and manufactured nanomaterials (MNs). However, these models are not described in a consistent manner in the scientific literature, which is one of the barriers to their broader use and acceptance, especially for regulatory purposes. Quantitative structure-activity relationships (QSARs) are in silico models based on the assumption that the activity of a substance is related to its chemical structure. These models can be used to provide information on (eco)toxicological effects in hazard assessment. In an environmental risk assessment, environmental exposure models can be used to estimate the predicted environmental concentration (PEC). In addition, physiologically based kinetic (PBK) models can be used in various ways to support a human health risk assessment. In this paper, we first propose model reporting templates for systematically and transparently describing models that could potentially be used to support regulatory risk assessments of MNs, for example under the REACH regulation. The model reporting templates include (a) the adaptation of the QSAR Model Reporting Format (QMRF) to report models for MNs, and (b) the development of a model reporting template for PBK and environmental exposure models applicable to MNs. Second, we show the usefulness of these templates to report different models, resulting in an overview of the landscape of available computational models for MNs.

Grouping of nanomaterials to read-across hazard endpoints: a review.

The use of non-testing strategies like read-across in the hazard assessment of chemicals and nanomaterials (NMs) is deemed essential to perform the safety assessment of all NMs in due time and at lower costs. The identification of physicochemical (PC) properties affecting the hazard potential of NMs is crucial, as it could enable to predict impacts from similar NMs and outcomes of similar assays, reducing the need for experimental (and in particular animal) testing. This manuscript presents a review of approaches and available case studies on the grouping of NMs to read-across hazard endpoints. We include in this review grouping frameworks aimed at identifying hazard classes depending on PC properties, hazard classification modules in control banding (CB) approaches, and computational methods that can be used for grouping for read-across. The existing frameworks and case studies are systematically reported. Relevant nanospecific PC properties taken into account in the reviewed frameworks to support grouping are shape and surface properties (surface chemistry or reactivity) and hazard classes are identified on the basis of biopersistence, morphology, reactivity, and solubility.

Grouping of nanomaterials to read-across hazard endpoints: from data collection to assessment of the grouping hypothesis by application of chemoinformatic techniques.

BACKGROUND: An increasing number of manufactured nanomaterials (NMs) are being used in industrial products and need to be registered under the REACH legislation. The hazard characterisation of all these forms is not only technically challenging but resource and time demanding. The use of non-testing strategies like read-across is deemed essential to assure the assessment of all NMs in due time and at lower cost. The fact that read-across is based on the structural similarity of substances represents an additional difficulty for NMs as in general their structure is not unequivocally defined. In such a scenario, the identification of physicochemical properties affecting the hazard potential of NMs is crucial to define a grouping hypothesis and predict the toxicological hazards of similar NMs. In order to promote the read-across of NMs, ECHA has recently published "Recommendations for nanomaterials applicable to the guidance on QSARs and Grouping", but no practical examples were provided in the document. Due to the lack of publicly available data and the inherent difficulties of reading-across NMs, only a few examples of read-across of NMs can be found in the literature. This manuscript presents the first case study of the practical process of grouping and read-across of NMs following the workflow proposed by ECHA. METHODS: The workflow proposed by ECHA was used and slightly modified to present the read-across case study. The Read-Across Assessment Framework (RAAF) was used to evaluate the uncertainties of a read-across within NMs. Chemoinformatic techniques were used to support the grouping hypothesis and identify key physicochemical properties. RESULTS: A dataset of 6 nanoforms of TiO2 with more than 100 physicochemical properties each was collected. In vitro comet assay result was selected as the endpoint to read-across due to data availability. A correlation between the presence of coating or large amounts of impurities and negative comet assay results was observed. CONCLUSION: The workflow proposed by ECHA to read-across NMs was applied successfully. Chemoinformatic techniques were shown to provide key evidence for the assessment of the grouping hypothesis and the definition of similar NMs. The RAAF was found to be applicable to NMs.

A veterinary perspective on preventing injuries and other problems that shorten the life of working dogs.

Domesticated dogs are widely used for farm work, law enforcement, military service and in assistance roles. Farm dogs assist farmers by guarding or moving stock, reducing the requirement for human workers and enabling steep terrain to be productive. Working and service dogs are subject to illness and injury, depending on their breed characteristics, activities and the environment in which they work. There are limited data in the veterinary literature on the causes of loss and early retirement of working dogs, and targeted research is required to better determine factors that affect their incidence. Many breeds of working dog suffer from inherited forms of musculoskeletal disease; most importantly, elbow and hip dysplasia. The effectiveness of traditional radiographic (phenotypic) scoring schemes at reducing the prevalence of hip and elbow dysplasia has been variable. The selection of breeding stock should preferably be based on estimated breeding values, rather than on an individual phenotypic score/grade. Nutrition can affect physical and mental performance, disease risk and susceptibility, and recovery from injury, age-associated decline and longevity. The dietary proportions of fat, protein and carbohydrate influence fuel selection during exercise. A common concern among farmers is the difficulty of maintaining body condition in their dogs during periods of heavy work with current feeding practices. Additionally, maintaining a positive calcium balance is necessary for adaptive remodelling in response to exercise. Research strategies should include improved treatment options, the development of more specific means of genetic selection for inherited diseases, investigation into specific nutritional requirements and the dissemination of this knowledge.

Les chiens domestiqués sont très largement utilisés pour travailler dans les fermes, ainsi qu'en tant que chiens policiers, chiens militaires ou chiens d'assistance. Les chiens de ferme aident les éleveurs à garder ou à déplacer leurs troupeaux, ce qui réduit les besoins en main d'oeuvre et permet d'exploiter des terrains escarpés. Les chiens de travail et aidants sont plus ou moins exposés à la maladie et aux blessures, en fonction des caractéristiques de leur race, des tâches qui leur sont confiées et de l'environnement dans lequel ils travaillent. Il n'existe pas beaucoup d'études vétérinaires publiées sur les causes des morts et des mises à la retraite prématurées des chiens de travail, thème qu'il conviendrait d'explorer plus précisément afin de mieux déterminer les facteurs affectant l'incidence de ces problèmes. Plusieurs races canines sont atteintes de troubles musculo-squelettiques héréditaires, dont le plus important est la dysplasie du coude et de la hanche. Les méthodes traditionnelles d'interprétation radiologique (mesure des phénotypes) ont contribué à réduire la prévalence de la dysplasie du coude et de la hanche, avec des résultats variables. La sélection des reproducteurs devrait reposer sur l'estimation de leur potentiel génétique (valeur d'élevage) plutôt que sur le score ou l'échelle de mesure du phénotype d'un individu. L'alimentation joue un rôle sur les performances physiques et mentales, la sensibilité aux maladies et le risque sanitaire, les capacités de rétablissement après une blessure, le processus de vieillissement et la longévité. La proportion relative des lipides, protéines et glucides dans l'alimentation donnée aux chiens détermine les sources d'énergie utilisées durant l'effort. Une préoccupation courante parmi les éleveurs concerne la difficulté de maintenir leurs chiens en bonne condition physique pendant les périodes où le travail est le plus dur, compte tenu des pratiques d'alimentation actuelles. Il est également important de maintenir un bon équilibre en calcium afin de soutenir les capacités d'adaptation à l'effort et de récupération. Les stratégies de recherche devraient explorer les pistes d'amélioration des traitements, mettre au point des méthodes de sélection génétique axées spécifiquement sur les maladies héréditaires et mieux élucider les besoins nutritionnels des chiens, sans oublier de diffuser par la suite les connaissances ainsi obtenues.

El uso del perro doméstico en tareas agrícolas, policiales, militares y de socorro o ayuda está muy extendido. Los perros pastores ayudan al granjero vigilando o conduciendo el ganado, lo que reduce la necesidad de personal humano y permite aprovechar las tierras situadas en terrenos escarpados. Los perros de trabajo y de servicio están sujetos a enfermedades y lesiones que dependen de las características de la raza, la actividad de que se trate y el medio en que esta discurra. En la bibliografía veterinaria hay escasa información sobre las causas que subyacen a la pérdida o la jubilación anticipada de perros de trabajo. De ahí la necesidad de investigar específicamente este aspecto para determinar con más precisión los factores que influyen en ello. Muchas razas de perros de trabajo padecen formas hereditarias de enfermedad musculoesquelética, la más importante de ellas la displasia de codo o cadera. Los tradicionales sistemas de puntuación radiológica (fenotípica) han resultado de eficacia variable para reducir la prevalencia de estas dos displasias. La selección de ejemplares reproductores debería basarse no tanto en la puntuación o grado fenotípico de cada individuo como en los valores estimados de cría. La alimentación puede influir en el rendimiento físico y mental, el riesgo de enfermedades y la sensibilidad a ellas, la recuperación tras una lesión y la longevidad o la decadencia ligada a la edad. Las proporciones de grasas, proteínas y carbohidratos presentes en el régimen alimentario influyen en la selección de combustible metabólico durante la actividad física. Uno de los aspectos que preocupa a todos los granjeros es la dificultad de mantener el cuerpo del perro en condiciones en los periodos de mucho trabajo con las actuales prácticas de alimentación. Además, también es necesario mantener un saldo positivo de calcio para que tenga lugar la remodelación adaptativa del cuerpo en respuesta al ejercicio físico. Los planes de investigación deben incluir aspectos como la búsqueda de mejores alternativas de tratamiento, la obtención de medios más específicos de selección genética respecto de las enfermedades hereditarias, el estudio de necesidades nutricionales específicas y la difusión de cuanto conocimiento resulte de estas investigaciones.

Provisional heritability estimates of four distraction index traits in a breeding population of German Shepherd dogs.

AIM To obtain provisional estimates of the heritability (h2 ) of passive laxity of the coxofemoral joints of a breeding colony of German Shepherd dogs, measured using the PennHIP distraction index (DI). METHODS Records were obtained of the PennHIP DI of right and left hips of 195 German Shepherd dogs (377 DI records) from the dog breeding colony of the New Zealand Police Dog Breeding Centre between 2003 and 2016, as well as pedigree records of 884 animals over four generations. Estimates of h2 and variance components for the log transformed DI data were obtained using restricted maximum likelihood procedures with a single trait sire model. Four DI traits for each dog were analysed: left hip, right hip, mean and worse-hip DI. The model included the fixed effects of sex and year of birth, with the age at scoring as a covariable, the random sire effect and residual error for each observation. RESULTS The h2 of the DI of the left hip (0.81, SE 0.40) was higher than the h2 of the DI of the right hip (0.35, SE 0.36). The h2 for the worse-hip DI (0.15, SE 0.28) in each dog was lower than the h2 of the individual hip DI, or the h2 for the mean of the two hips (0.53, SE 0.36) in each dog. The low number of generations prevented a meaningful analysis of the genetic trend. CONCLUSIONS AND CLINICAL RELEVANCE The h2 estimates for the left, right and mean DI traits were moderate to high, whereas the h2 estimates for the worse-hip DI (as used by the PennHIP programme for ranking of dogs) was low, but all estimates had large SE due to the small sample size. This provisional estimate of the h2 of four distraction index traits suggests that the mean DI could be useful as a selection tool against canine hip dysplasia in German Shepherd dogs, whereas the worse-hip DI may be less effective. Heritability estimates from a population with a greater number of DI measures is needed to validate this finding given the large SE in our study.

The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017.

This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.

Mechanical testing of a steel-reinforced epoxy resin bar and clamp for external skeletal fixation of long-bone fractures in cats.

AIMS: To provide veterinarians with confidence when using a commercially available epoxy resin in external skeletal fixators (ESF), testing was conducted to determine exothermia during curing of the epoxy resin compared to polymethylmethacrylate (PMMA), the hardness of the epoxy resin as a bar over 16 weeks, and the strength of the epoxy resin bar compared with metal clamps in similarly constructed Type 1a ESF constructs simulating the repair of feline long bone fractures. METHODS: Exothermia of the epoxy resin during curing was tested against PMMA with surface temperatures recorded over the first 15 minutes of curing, using four samples of each product. The hardness of 90 identical epoxy resin bars was tested by subjecting them to cyclic loads (1,000 cycles of 20.5 N, every 7 days) over a 16-week period and impact testing 10 bars every 2 weeks. Ten bars that were not subjected to cyclic loads were impact tested at 0 weeks and another 10 at 16 weeks. Strength of the epoxy resin product, as a bar and clamp composite, was tested against metal SK and Kirschner-Ehmer (KE) clamps and bars in Type 1a, tied-in intramedullary pin, ESF constructs with either 90° or 75° pin placement, subjected to compressive and bending loads to 75 N. RESULTS: The maximum temperature during curing of the epoxy resin (min 39.8, max 43.0)°C was less than the PMMA (min 85.2, max 98.5)°C (p<0.001). There was no change in hardness of the epoxy resin bars over the 16 weeks of cyclic loading (p=0.58). There were no differences between the median strength of the epoxy resin, SK or KE ESF constructs in compression or bending when tested to 75 N (p>0.05). Stiffness of constructs with 75° pin placement was greater for SK than epoxy resin constructs in compression (p=0.046), and was greater for KE than epoxy resin constructs in bending (p=0.033). CONCLUSIONS: The epoxy resin tested was found to be less exothermic than PMMA; bars made from the epoxy resin showed durability over an expected fracture healing timeframe and had mechanical strength characteristics comparable to metal bar and clamp ESF constructs. CLINICAL RELEVANCE: The epoxy resin ESF construct tested in this study can be considered a suitable replacement for SK or KE ESF constructs in the treatment of feline long-bone fractures, in terms of mechanical strength.

Heritabilities and genetic trends for elbow score as recorded by the New Zealand Veterinary Association Elbow Dysplasia Scheme (1992-2013) in four breeds of dog.

AIM: To estimate the heritability of the New Zealand Veterinary Association (NZVA) elbow phenotype, obtain estimated breeding values (EBV) for the worst-elbow score and estimate the genetic trends for this trait in four populous breeds of dogs, using the records from the NZVA Canine Elbow Dysplasia Scheme database (1992-2013). METHODS: Overall, 4,070 elbow records from a pedigree of 11,311 dogs were available for animals scored between 1992 and 2013. The worst elbow score between the left and right elbows was identified for each dog and used for EBV analysis. Estimates of heritability and EBV for the elbow score of dogs from German Shepherd dog, Labrador Retriever, Golden Retriever and Rottweiler breeds were obtained using restricted maximum likelihood procedures with a within-breed linear animal model. The model included the fixed effects of sex and birth year, with age at scoring as a covariable, and the random effect of animal. Genetic trends for the worst-elbow score were calculated as the regression coefficient of the EBV, weighted by reliabilities, on year of birth. RESULTS: The estimates of heritability for worst-elbow score were 0.25 (SE 0.06) in German Shepherd dogs, 0.46 (SE 0.06) in Labrador Retrievers, 0.18 (SE 0.07) in Golden Retrievers and 0.29 (SE 0.11) in Rottweilers. The genetic trend for German Shepherd dogs was -0.0082 (SE 0.0015), for Labrador Retrievers was -0.0016 (SE 0.0016), for Golden Retrievers was -0.0033 (SE 0.0010) and for Rottweilers was -0.0070 (SE 0.0023) units per annum, which were different from zero (p<0.01) in all breeds except Labrador Retrievers. CONCLUSIONS AND CLINICAL RELEVANCE: A small but favourable response to selection was achieved by three of the four breeds in the study period; during which selection for elbow traits has been largely voluntary. While the magnitude of genetic change in terms of elbow units per annum may appear small, it must be remembered that elbow scoring grades only range from 0-3. Greater improvement may be possible if compulsory screening was a requirement for pedigree breeding stock, and if greater selection pressure were applied on the basis on an individual's EBV, rather than the worst-elbow score alone. The maintenance of an open registry, with transparency of EBV information made available to all breeders, may enhance selection intensity opportunities and potentially assist with the process and progress of breeding selection.

Nonstructural protein 5A resistance profile in patients with chronic hepatitis C treated with ledipasvir-containing regimens without sofosbuvir.

The study aimed to evaluate the effects of baseline hepatitis C virus (HCV) nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) on sustained virologic response to ledipasvir (LDV)-containing regimens in the absence of sofosbuvir (SOF) in patients with HCV genotype (GT) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV + vedroprevir (NS3 protease inhibitor) + tegobuvir (NS5B inhibitor) ± ribavirin or LDV + ribavirin + pegylated interferon. Population sequencing of HCV NS5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT1a, and 298 (26.9%) had GT1b infection. The overall prevalence of NS5A RASs at baseline was 9.4%; 7.6% (57/747) and 13.8% (41/298) of patients with GT1a and GT1b infection, respectively. The majority of GT1a-infected patients with NS5A RASs at baseline had a single NS5A RAS (78.9%) at NS5A positions K24R, M28T, Q30H/L, L31M and Y93H/N/C/S. The spectrum of NS5A RASs detected in GT1b patients was much less diverse compared to GT1a patients, with all patients harbouring a single NS5A RAS either L31M or Y93H/C. For patients treated with LDV-containing regimens in the absence of SOF, the presence of baseline NS5A RASs was associated with low SVR rates. In patients with virologic failure, nearly all had either pre-existing and/or emergent NS5A RASs: 287/287 (100%) and 40/42 (95.2%) patients with GT1a and GT1b infection, respectively. Three novel NS5A substitutions were identified as emergent NS5A RASs: K26E and S38F in GT1a; and L31I in GT1b. In conclusion, the presence of NS5A RASs at baseline reduced the SVR rate in patients treated with LDV in combination vedroprevir + tegobuvir ± ribavirin or ribavirin + pegylated interferon. Virologic failure was associated with the detection of NS5A RASs in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV drug combination and may be more important than that of the individual DAAs.

Kinetics of Plasma Cell-Free DNA and Creatine Kinase in a Canine Model of Tissue Injury.

BACKGROUND: Cell-free DNA (cfDNA) comprises short, double-stranded circulating DNA sequences released from damaged cells. In people, cfDNA concentrations correlate well with disease severity and tissue damage. No reports are available regarding cfDNA kinetics in dogs. OBJECTIVES/HYPOTHESIS: Cell-free DNA will have a short biological half-life and would be able to stratify mild, moderate, and severe tissue injury. Our study aims were to determine the kinetics and biological half-life of cfDNA and to contrast them with those of creatine kinase (CK). ANIMALS: Three groups of 10 dogs undergoing open ovariohysterectomy, surgery for cranial cruciate ligament rupture (CCLR), or hemilaminectomy. METHODS: Plasma for cfDNA and CK analysis was collected at admission, at induction of anesthesia, postsurgery (time 0) and at 6, 12, 24, 36, 48, 60, and 72 hours after surgery. RESULTS: The biological half-life of plasma cfDNA and CK were 5.64 hours (95% confidence interval [CI 95], 4.36-7.98 hours) and 28.7 hours (CI95, 25.3-33.3 hours), respectively. In the hemilaminectomy group, cfDNA concentrations differed significantly from admission at 6-12 hours after surgery. Creatine kinase activity differed among the surgical groups and reached a peak 6 hours after surgery. In the ovariohysterectomy and CCLR groups, plasma CK activity 72 hours after surgery did not differ from admission activity of the ovariohysterectomy group. In contrast, in the hemilaminectomy group, plasma CK activity after 72 hours did not return to the ovariohysterectomy group admission activity. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma CK activity has a longer biological half-life than previously thought. In contrast to plasma CK activity, cfDNA has a short half-life and could be a useful marker for peracute severe tissue injury.

A pilot randomised controlled trial investigating a Mediterranean diet intervention in pregnant women for the primary prevention of allergic diseases in infants.

BACKGROUND: Observational studies suggest a potentially protective role of the Mediterranean diet (MD) in allergic diseases, including asthma. Large scale randomised controlled trials (RCTs) are needed to test the hypothesised allergy-prevention benefits of a MD during pregnancy. The present two-arm pilot RCT in pregnant women at high-risk of having a child who would develop allergic disease investigated maternal recruitment, retention and acceptability of an MD dietary intervention in the UK. The trial also assessed the effect of the intervention on MD adherence scores at 12 and at 24 weeks post-randomisation. METHODS: Thirty women were recruited at around 12 weeks of gestation. Retention was high (28 out of 30; 93%). The intervention was acceptable to participants. Mean (SD) adherence to the MD at baseline was 12.4 (2.9) in the intervention arm (n = 14) and 13.0 (1.9) in the control arm (n = 16), where 24 represents maximal adherence. There was a favourable short-term change in MD score: the adjusted mean difference (intervention - control) in the change in MD score from baseline to 12 weeks post-randomisation was 2.4 (95% confidence interval = 0.6-4.2, P = 0.012). CONCLUSIONS: The trial provides important insights into recruitment, retention and sustaining the dietary intervention, which will be used in the design of a large RCT.