SNPs for parentage testing and traceability in globally diverse breeds of sheep

DNA-based parentage determination accelerates genetic improvement in sheep by increasing pedigree accuracy. Single nucleotide polymorphism (SNP) markers can be used for determining parentage and to provide unique molecular identifiers for tracing sheep products to their source. However, the utility of a particular "parentage SNP" varies by breed depending on its minor allele frequency (MAF) and its sequence context. Our aims were to identify parentage SNPs with exceptional qualities for use in globally diverse breeds and to develop a subset for use in North American sheep. Starting with genotypes from 2,915 sheep and 74 breed groups provided by the International Sheep Genomics Consortium (ISGC), we analyzed 47,693 autosomal SNPs by multiple criteria and selected 163 with desirable properties for parentage testing. On average, each of the 163 SNPs was highly informative (MAF≥0.3) in 48±5 breed groups. Nearby polymorphisms that could otherwise confound genetic testing were identified by whole genome and Sanger sequencing of 166 sheep from 54 breed groups. A genetic test with 109 of the 163 parentage SNPs was developed for matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. The scoring rates and accuracies for these 109 SNPs were greater than 99% in a panel of North American sheep. In a blinded set of 96 families (sire, dam, and non-identical twin lambs), each parent of every lamb was identified without using the other parent's genotype. In 74 ISGC breed groups, the median estimates for probability of a coincidental match between two animals (PI), and the fraction of potential adults excluded from parentage (PE) were 1.1×10(-39) and 0.999987, respectively, for the 109 SNPs combined. The availability of a well-characterized set of 163 parentage SNPs facilitates the development of high-throughput genetic technologies for implementing accurate and economical parentage testing and traceability in many of the world's sheep breeds.

Service level agreements-driven management of distributed applications in cloud computing environments

Advancements in cloud computing have enabled the proliferation of distributed applications, which require management and control of multiple services. However, without an efficient mechanism for scaling services in response to changing workload conditions, such as number of connected users, application performance might suffer, leading to violations of Service Level Agreements (SLA) and possible inefficient use of hardware resources. Combining dynamic application requirements with the increased use of virtualised computing resources creates a challenging resource Management context for application and cloud-infrastructure owners. In such complex environments, business entities use SLAs as a means for specifying quantitative and qualitative requirements of services. There are several challenges in running distributed enterprise applications in cloud environments, ranging from the instantiation of service VMs in the correct order using an adequate quantity of computing resources, to adapting the number of running services in response to varying external loads, such as number of users. The application owner is interested in finding the optimum amount of computing and network resources to use for ensuring that the performance requirements of all her/his applications are met. She/he is also interested in appropriately scaling the distributed services so that application performance guarantees are maintained even under dynamic workload conditions. Similarly, the infrastructure Providers are interested in optimally provisioning the virtual resources onto the available physical infrastructure so that her/his operational costs are minimized, while maximizing the performance of tenants’ applications. Motivated by the complexities associated with the management and scaling of distributed applications, while satisfying multiple objectives (related to both consumers and providers of cloud resources), this thesis proposes a cloud resource management platform able to dynamically provision and coordinate the various lifecycle actions on both virtual and physical cloud resources using semantically enriched SLAs. The system focuses on dynamic sizing (scaling) of virtual infrastructures composed of virtual machines (VM) bounded application services. We describe several algorithms for adapting the number of VMs allocated to the distributed application in response to changing workload conditions, based on SLA-defined performance guarantees. We also present a framework for dynamic composition of scaling rules for distributed service, which used benchmark-generated application Monitoring traces. We show how these scaling rules can be combined and included into semantic SLAs for controlling allocation of services. We also provide a detailed description of the multi-objective infrastructure resource allocation problem and various approaches to satisfying this problem. We present a resource management system based on a genetic algorithm, which performs allocation of virtual resources, while considering the optimization of multiple criteria. We prove that our approach significantly outperforms reactive VM-scaling algorithms as well as heuristic-based VM-allocation approaches.

Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review

OBJECTIVE: To determine the accuracy of magnetic resonance imaging criteria for the early diagnosis of multiple sclerosis in patients with suspected disease. DESIGN: Systematic review. DATA SOURCES: 12 electronic databases, citation searches, and reference lists of included studies. Review methods Studies on accuracy of diagnosis that compared magnetic resonance imaging, or diagnostic criteria incorporating such imaging, to a reference standard for the diagnosis of multiple sclerosis. RESULTS: 29 studies (18 cohort studies, 11 other designs) were included. On average, studies of other designs (mainly diagnostic case-control studies) produced higher estimated diagnostic odds ratios than did cohort studies. Among 15 studies of higher methodological quality (cohort design, clinical follow-up as reference standard), those with longer follow-up produced higher estimates of specificity and lower estimates of sensitivity. Only two such studies followed patients for more than 10 years. Even in the presence of many lesions (> 10 or > 8), magnetic resonance imaging could not accurately rule multiple sclerosis in (likelihood ratio of a positive test result 3.0 and 2.0, respectively). Similarly, the absence of lesions was of limited utility in ruling out a diagnosis of multiple sclerosis (likelihood ratio of a negative test result 0.1 and 0.5). CONCLUSIONS: Many evaluations of the accuracy of magnetic resonance imaging for the early detection of multiple sclerosis have produced inflated estimates of test performance owing to methodological weaknesses. Use of magnetic resonance imaging to confirm multiple sclerosis on the basis of a single attack of neurological dysfunction may lead to over-diagnosis and over-treatment.

Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria.

BACKGROUND Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.

Do multiple true-false items beat the commonly used one-best-answers questions regarding to the Ottawa Criteria for Good Assessment? Results of a literature review

Background: Multiple True-False-Items (MTF-Items) might offer some advantages compared to one-best-answer-questions (TypeA) as they allow more than one correct answer and may better represent clinical decisions. However, in medical education assessment MTF-Items are seldom used. Summary of Work: With this literature review existing findings on MTF-items and on TypeA were compared along the Ottawa Criteria for Good Assessment, i.e. (1) reproducibility, (2) feasibility, (3) validity, (4) acceptance, (5) educational effect, (6) catalytic effects, and (7) equivalence. We conducted a literature research on ERIC and Google Scholar including papers from the years 1935 to 2014. We used the search terms “multiple true-false”, “true-false”, “true/false”, and “Kprim” combined with “exam”, “test”, and “assessment”. Summary of Results: We included 29 out of 33 studies. Four of them were carried out in the medical field Compared to TypeA, MTF-Items are associated with (1) higher reproducibility (2) lower feasibility (3) similar validity (4) higher acceptance (5) higher educational effect (6) no studies on catalytic effects or (7) equivalence. Discussion and Conclusions: While studies show overall good characteristics of MTF items according to the Ottawa criteria, this type of question seems to be rather seldom used. One reason might be the reported lower feasibility. Overall the literature base is still weak. Furthermore, only 14 % of literature is from the medical domain. Further studies to better understand the characteristics of MTF-Items in the medical domain are warranted. Take-home messages: Overall the literature base is weak and therefore further studies are needed. Existing studies show that: MTF-Items show higher reliability, acceptance and educational effect; MTF-Items are more difficult to produce

How valuable are multiple treatment comparison methods in evidence-based health-care evaluation?

Objectives To compare the use of pair-wise meta-analysis methods to multiple treatment comparison (MTC) methods for evidence-based health-care evaluation to estimate the effectiveness and cost-effectiveness of alternative health-care interventions based on the available evidence. Methods Pair-wise meta-analysis and more complex evidence syntheses, incorporating an MTC component, are applied to three examples: 1) clinical effectiveness of interventions for preventing strokes in people with atrial fibrillation; 2) clinical and cost-effectiveness of using drug-eluting stents in percutaneous coronary intervention in patients with coronary artery disease; and 3) clinical and cost-effectiveness of using neuraminidase inhibitors in the treatment of influenza. We compare the two synthesis approaches with respect to the assumptions made, empirical estimates produced, and conclusions drawn. Results The difference between point estimates of effectiveness produced by the pair-wise and MTC approaches was generally unpredictable—sometimes agreeing closely whereas in other instances differing considerably. In all three examples, the MTC approach allowed the inclusion of randomized controlled trial evidence ignored in the pair-wise meta-analysis approach. This generally increased the precision of the effectiveness estimates from the MTC model. Conclusions The MTC approach to synthesis allows the evidence base on clinical effectiveness to be treated as a coherent whole, include more data, and sometimes relax the assumptions made in the pair-wise approaches. However, MTC models are necessarily more complex than those developed for pair-wise meta-analysis and thus could be seen as less transparent. Therefore, it is important that model details and the assumptions made are carefully reported alongside the results.

Multiple small "imaging" branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?

Most screening programs for familial pancreatic cancer are currently based on endoscopic ultrasonography and/or magnetic resonance imaging (MRI). Cystic lesions, especially those suspicious for small intraductal pancreatic mucinous neoplasms (IPMNs) of the branch ducts, can be visualized in up to 40 % of individuals at risk, but their pathological importance in the setting of FPC is yet not well established. Individuals at risk from a prospective screening program for familial pancreatic cancer with small "imaging" IPMNs of the branch-duct type (BD-IPMN) who underwent pancreatic resection were analysed regarding clinico-pathological data and the locations of pancreatic lesions. Five of 125 individuals at risk who underwent screening had multiple small (size 2-10 mm) unicystic lesions and/or multicystic single lesions in the pancreatic body and tail suspicious for BD-IPMNs upon MRI imaging and decided to undergo surgical resection after interdisciplinary counselling, although none fulfilled the consensus criteria for IPMN resection. Histological examination revealed BD-IPMNs with low or moderate dysplasia of the gastric type in combination with multifocal PanIN2 and PanIN3 lesions in 4 individuals. The remaining patient had only tiny ductectasias in the pancreatic tail with multifocal PanIN 2 lesions in the entire gland and one PanIN3 lesion in the pancreatic head. Intriguingly, the location of the most dysplastic histological lesions (PanIN3) did not correspond to the preoperatively detected lesions and were not visible in preoperative imaging. In the setting of FPC, the presence of multiple small "imaging" BD-IPMNs may indicate the presence of high-grade PanIN lesions elsewhere in the pancreas.

The role of admission blood glucose in outcome prediction of surviving patients with multiple injuries

BACKGROUND: Recent literature demonstrates hyperglycemia to be common in patients with trauma and associated with poor outcome in patients with traumatic brain injury and critically ill patients. The goal of this study was to analyze the impact of admission blood glucose on the outcome of surviving patients with multiple injuries. METHODS: Patients' charts (age >16) admitted to the emergency room of the University Hospital of Berne, Switzerland, between January 1, 2002, and December 31, 2004, with an Injury Severity Score >or=17 and more than one severely injured organ system were reviewed retrospectively. Outcome measurements included morbidity, intensive care unit, and hospital length of stay. RESULTS: The inclusion criteria were met by 555 patients, of which 108 (19.5%) patients died. After multiple regression analysis, admission blood glucose proved to be an independent predictor of posttraumatic morbidity (p < 0.0001), intensive care unit, and hospital length of stay (p < 0.0001), despite intensified insulin therapy on the intensive care unit. CONCLUSIONS: In this population of patients with multiple injuries, hyperglycemia on admission was strongly associated with increased morbidity, especially infections, prolonged intensive care unit, and hospital length of stay independent of injury severity, gender, age, and various biochemical parameters.

A generalized anisotropic quadric yield criterion and its application to bone tissue at multiple length scales

Nonlinear computational analysis of materials showing elasto-plasticity or damage relies on knowledge of their yield behavior and strengths under complex stress states. In this work, a generalized anisotropic quadric yield criterion is proposed that is homogeneous of degree one and takes a convex quadric shape with a smooth transition from ellipsoidal to cylindrical or conical surfaces. If in the case of material identification, the shape of the yield function is not known a priori, a minimization using the quadric criterion will result in the optimal shape among the convex quadrics. The convexity limits of the criterion and the transition points between the different shapes are identified. Several special cases of the criterion for distinct material symmetries such as isotropy, cubic symmetry, fabric-based orthotropy and general orthotropy are presented and discussed. The generality of the formulation is demonstrated by showing its degeneration to several classical yield surfaces like the von Mises, Drucker–Prager, Tsai–Wu, Liu, generalized Hill and classical Hill criteria under appropriate conditions. Applicability of the formulation for micromechanical analyses was shown by transformation of a criterion for porous cohesive-frictional materials by Maghous et al. In order to demonstrate the advantages of the generalized formulation, bone is chosen as an example material, since it features yield envelopes with different shapes depending on the considered length scale. A fabric- and density-based quadric criterion for the description of homogenized material behavior of trabecular bone is identified from uniaxial, multiaxial and torsional experimental data. Also, a fabric- and density-based Tsai–Wu yield criterion for homogenized trabecular bone from in silico data is converted to an equivalent quadric criterion by introduction of a transformation of the interaction parameters. Finally, a quadric yield criterion for lamellar bone at the microscale is identified from a nanoindentation study reported in the literature, thus demonstrating the applicability of the generalized formulation to the description of the yield envelope of bone at multiple length scales.

Characterization of microcirculation in multiple sclerosis lesions by dynamic texture parameter analysis (DTPA)

OBJECTIVE Texture analysis is an alternative method to quantitatively assess MR-images. In this study, we introduce dynamic texture parameter analysis (DTPA), a novel technique to investigate the temporal evolution of texture parameters using dynamic susceptibility contrast enhanced (DSCE) imaging. Here, we aim to introduce the method and its application on enhancing lesions (EL), non-enhancing lesions (NEL) and normal appearing white matter (NAWM) in multiple sclerosis (MS). METHODS We investigated 18 patients with MS and clinical isolated syndrome (CIS), according to the 2010 McDonald's criteria using DSCE imaging at different field strengths (1.5 and 3 Tesla). Tissues of interest (TOIs) were defined within 27 EL, 29 NEL and 37 NAWM areas after normalization and eight histogram-based texture parameter maps (TPMs) were computed. TPMs quantify the heterogeneity of the TOI. For every TOI, the average, variance, skewness, kurtosis and variance-of-the-variance statistical parameters were calculated. These TOI parameters were further analyzed using one-way ANOVA followed by multiple Wilcoxon sum rank testing corrected for multiple comparisons. RESULTS Tissue- and time-dependent differences were observed in the dynamics of computed texture parameters. Sixteen parameters discriminated between EL, NEL and NAWM (pAVG = 0.0005). Significant differences in the DTPA texture maps were found during inflow (52 parameters), outflow (40 parameters) and reperfusion (62 parameters). The strongest discriminators among the TPMs were observed in the variance-related parameters, while skewness and kurtosis TPMs were in general less sensitive to detect differences between the tissues. CONCLUSION DTPA of DSCE image time series revealed characteristic time responses for ELs, NELs and NAWM. This may be further used for a refined quantitative grading of MS lesions during their evolution from acute to chronic state. DTPA discriminates lesions beyond features of enhancement or T2-hypersignal, on a numeric scale allowing for a more subtle grading of MS-lesions.

Northern Hemisphere temperature reconstruction during the last millennium using multiple annual proxies

Previous studies have either exclusively used annual tree-ring data or have combined tree-ring series with other, lower temporal resolution proxy series. Both approaches can lead to significant uncertainties, as tree-rings may underestimate the amplitude of past temperature variations, and the validity of non-annual records cannot be clearly assessed. In this study, we assembled 45 published Northern Hemisphere (NH) temperature proxy records covering the past millennium, each of which satisfied 3 essential criteria: the series must be of annual resolution, span at least a thousand years, and represent an explicit temperature signal. Suitable climate archives included ice cores, varved lake sediments, tree-rings and speleothems. We reconstructed the average annual land temperature series for the NH over the last millennium by applying 3 different reconstruction techniques: (1) principal components (PC) plus second-order autoregressive model (AR2), (2) composite plus scale (CPS) and (3) regularized errors-in-variables approach (EIV). Our reconstruction is in excellent agreement with 6 climate model simulations (including the first 5 models derived from the fifth phase of the Coupled Model Intercomparison Project (CMIP5) and an earth system model of intermediate complexity (LOVECLIM), showing similar temperatures at multi-decadal timescales; however, all simulations appear to underestimate the temperature during the Medieval Warm Period (MWP). A comparison with other NH reconstructions shows that our results are consistent with earlier studies. These results indicate that well-validated annual proxy series should be used to minimize proxy-based artifacts, and that these proxy series contain sufficient information to reconstruct the low-frequency climate variability over the past millennium.

Multiple Sclerosis: Current Knowledge and Future Outlook

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal loss. The etiology of MS is unknown; however, environmental and genetic factors play a key role in the development of MS. Diagnostic criteria have been adapted to facilitate earlier diagnosis with increased sensitivity and specificity. Our understanding of the pathophysiology of MS has deepened considerably in recent years, resulting in different therapies to modify the disease course. Furthermore, several drugs have lately shown efficacy in phase III studies and their approval is expected in the near future. As treatment options expand, a future challenge will be to find the optimal treatment for the individual patient. Summary: This mini-review gives an overview of the current knowledge of MS with emphasis on the latest diagnostic criteria and both current and upcoming treatment options. Key Messages: Treatment of MS changes rapidly as the knowledge and therapeutic options in MS expand. Clinical Impact: Diagnosis of MS is based on McDonald criteria. MS therapy can be divided into relapse, disease-modifying and symptomatic treatment. Relapses are commonly treated with intravenous methylprednisolone. First-line therapy consists of either interferon-β, glatiramer acetate or teriflunomide. In general, agents used as escalation therapies (natalizumab, fingolimod and mitoxantrone) are more potent than the agents used for first-line therapy; however, these have potentially serious side effects and should be used with care.

All-ceramic or metal-ceramic tooth-supported fixed dental prostheses (FDPs)? A systematic review of the survival and complication rates. Part II: Multiple-unit FDPs.

OBJECTIVE To assess the 5-year survival of metal-ceramic and all-ceramic tooth-supported fixed dental prostheses (FDPs) and to describe the incidence of biological, technical and esthetic complications. METHODS Medline (PubMed), Embase and Cochrane Central Register of Controlled Trials (CENTRAL) searches (2006-2013) were performed for clinical studies focusing on tooth-supported FDPs with a mean follow-up of at least 3 years. This was complemented by an additional hand search and the inclusion of 10 studies from a previous systematic review [1]. Survival and complication rates were analyzed using robust Poisson's regression models to obtain summary estimates of 5-year proportions. RESULTS Forty studies reporting on 1796 metal-ceramic and 1110 all-ceramic FDPs fulfilled the inclusion criteria. Meta-analysis of the included studies indicated an estimated 5-year survival rate of metal-ceramic FDPs of 94.4% (95% CI: 91.2-96.5%). The estimated survival rate of reinforced glass ceramic FDPs was 89.1% (95% CI: 80.4-94.0%), the survival rate of glass-infiltrated alumina FDPs was 86.2% (95% CI: 69.3-94.2%) and the survival rate of densely sintered zirconia FDPs was 90.4% (95% CI: 84.8-94.0%) in 5 years of function. Even though the survival rate of all-ceramic FDPs was lower than for metal-ceramic FDPs, the differences did not reach statistical significance except for the glass-infiltrated alumina FDPs (p=0.05). A significantly higher incidence of caries in abutment teeth was observed for densely sintered zirconia FDPs compared to metal-ceramic FDPs. Significantly more framework fractures were reported for reinforced glass ceramic FDPs (8.0%) and glass-infiltrated alumina FDPs (12.9%) compared to metal-ceramic FDPs (0.6%) and densely sintered zirconia FDPs (1.9%) in 5 years in function. However, the incidence of ceramic fractures and loss of retention was significantly (p=0.018 and 0.028 respectively) higher for densely sintered zirconia FDPs compared to all other types of FDPs. CONCLUSIONS Survival rates of all types of all-ceramic FDPs were lower than those reported for metal-ceramic FDPs. The incidence of framework fractures was significantly higher for reinforced glass ceramic FDPs and infiltrated glass ceramic FDPs, and the incidence for ceramic fractures and loss of retention was significantly higher for densely sintered zirconia FDPs compared to metal-ceramic FDPs.

Use of a modified Delphi panel to identify and weight criteria for prioritization of zoonotic diseases in Switzerland

Zoonotic diseases have a significant impact on public health globally. To prevent or reduce future zoonotic outbreaks, there is a constant need to invest in research and surveillance programs while updating risk management strategies. However, given the limited resources available, disease prioritization based on the need for their control and surveillance is important. This study was performed to identify and weight disease criteria for the prioritization of zoonotic diseases in Switzerland using a semi-quantitative research method based on expert opinion. Twenty-eight criteria relevant for disease control and surveillance, classified under five domains, were selected following a thorough literature review, and these were evaluated and weighted by seven experts from the Swiss Federal Veterinary Office using a modified Delphi panel. The median scores assigned to each criterion were then used to rank 16 notifiable and/or emerging zoonoses in Switzerland. The experts weighted the majority of the criteria similarly, and the top three criteria were Severity of disease in humans, incidence and prevalence of the disease in humans and treatment in humans. Based on these weightings, the three highest ranked diseases were Avian Influenza, Bovine Spongiform Encephalitis, and Bovine Tuberculosis. Overall, this study provided a preliminary list of criteria relevant for disease prioritization in Switzerland. These were further evaluated in a companion study which involved a quantitative prioritization method and multiple stakeholders.