Genome-wide association study for calving performance using high-density genotypes in dairy and beef cattle

peer-reviewedBackground Calving difficulty and perinatal mortality are prevalent in modern-day cattle production systems. It is well-established that there is a genetic component to both traits, yet little is known about their underlying genomic architecture, particularly in beef breeds. Therefore, we performed a genome-wide association study using high-density genotypes to elucidate the genomic architecture of these traits and to identify regions of the bovine genome associated with them. Results Genomic regions associated with calving difficulty (direct and maternal) and perinatal mortality were detected using two statistical approaches: (1) single-SNP (single nucleotide polymorphism) regression and (2) a Bayesian approach. Data included high-density genotypes on 770 Holstein-Friesian, 927 Charolais and 963 Limousin bulls. Several novel or previously identified genomic regions were detected but associations differed by breed. For example, two genomic associations, one each on chromosomes 18 and 2 explained 2.49 % and 3.13 % of the genetic variance in direct calving difficulty in the Holstein-Friesian and Charolais populations, respectively. Imputed Holstein-Friesian sequence data was used to refine the genomic regions responsible for significant associations. Several candidate genes on chromosome 18 were identified and four highly significant missense variants were detected within three of these genes (SIGLEC12, CTU1, and ZNF615). Nevertheless, only CTU1 contained a missense variant with a putative impact on direct calving difficulty based on SIFT (0.06) and Polyphen (0.95) scores. Using imputed sequence data, we refined a genomic region on chromosome 4 associated with maternal calving difficulty in the Holstein-Friesian population and found the strongest association with an intronic variant in the PCLO gene. A meta-analysis was performed across the three breeds for each calving performance trait to identify common variants associated with these traits in the three breeds. Our results suggest that a portion of the genetic variation in calving performance is common to all three breeds. Conclusion The genomic architecture of calving performance is complex and mainly influenced by many polymorphisms of small effect. We identified several associations of moderate effect size but the majority were breed-specific, indicating that breed-specific alleles exist for calving performance or that the linkage phase between genotyped allele and causal mutation varies between breeds

Assembly and Maturation of a T = 4 Quasi-Equivalent Virus Is Guided by Electrostatic and Mechanical Forces

Nudaurelia capensis w virus (NωV) is a eukaryotic RNA virus that is well suited for the study of virus maturation. The virus initially assembles at pH 7.6 into a marginally stable 480-Å procapsid formed by 240 copies of a single type of protein subunit. During maturation, which occurs during apoptosis at pH 5.0, electrostatic forces guide subunit trajectories into a robust 410-Å virion that is buttressed by subunit associated molecular switches. We discuss the competing factors in the virus capsid of requiring near-reversible interactions during initial assembly to avoid kinetic traps, while requiring robust stability to survive in the extra-cellular environment. In addition, viruses have a variety of mechanisms to deliver the genome, which must remain off while still inside the infected cell, yet turn on under the proper conditions of infection. We conclude that maturation is the process that provides a solution to these conflicting requirements through a program that is encoded in the procapsid and that leads to stability and infectivity

Medium-Term Prospects for Ireland: An Update. Quarterly Economic Commentary Special Article, April 1990

The Institute publishes its Medium-Term Review approximately every eighteen months. The Review attempts to project likely prospects for the Irish economy, predicated on trends in the world economy and the stance of domestic policy. Since we published our last Review in June 1989, some important and unexpected political events have taken place in Eastern Europe which could have substantial political and economic implications for developments within the EC and Ireland over the next few years. These events were not foreseen when we wrote the Review last June, although many of the other forces determining our future growth have developed as we expected ( e.g., the impending slow-down of the UK economy, relatively buoyant growth in the rest of the EC and the implementation of the EC Structural Fund projects, albeit at a lower level and different timing than envisaged in the National Development Plan 1989-1993)

Does contact with a podiatrist prevent the occurrence of a lower extremity amputation in people with diabetes? A systematic review and meta-analysis

Objective To determine the effect of contact with a podiatrist on the occurrence of Lower Extremity Amputation (LEA) in people with diabetes.Design and data sources We conducted a systematic review of available literature on the effect of contact with a podiatrist on the risk of LEA in people with diabetes. Eligible studies, published in English, were identified through searches of PubMed, CINAHL, EMBASE and Cochrane databases. The key terms, ‘podiatry’, ‘amputation’ and ‘diabetes’, were searched as Medical Subject Heading terms. Reference lists of selected papers were hand-searched for additional articles. No date restrictions were imposed.Study selection Published randomised and analytical observational studies of the effect of contact with a podiatrist on the risk of LEA in people with diabetes were included. Cross-sectional studies, review articles, chart reviews and case series were excluded. Two reviewers independently assessed titles, abstracts and full articles to identify eligible studies and extracted data related to the study design, characteristics of participants, interventions, outcomes, control for confounding factors and risk estimates.Analysis Meta-analysis was performed separately for randomised and non-randomised studies. Relative risks (RRs) with 95% CIs were estimated with fixed and random effects models as appropriate.Results Six studies met the inclusion criteria and five provided data included in meta-analysis. The identified studies were heterogenous in design and included people with diabetes at both low and high risk of amputation. Contact with a podiatrist did not significantly affect the RR of LEA in a meta-analysis of available data from randomised controlled trials (RCTs); (1.41, 95% CI 0.20 to 9.78, 2 RCTs) or from cohort studies; (0.73, 95% CI 0.39 to 1.33, 3 Cohort studies with four substudies in one cohort). Conclusions There are very limited data available on the effect of contact with a podiatrist on the risk of LEA in people with diabetes

Analysis of Binding Site Hot Spots on the Surface of Ras GTPase

We have recently discovered an allosteric switch in Ras, bringing an additional level of complexity to this GTPase whose mutants are involved in nearly 30% of cancers. Upon activation of the allosteric switch, there is a shift in helix 3/loop 7 associated with a disorder to order transition in the active site. Here, we use a combination of multiple solvent crystal structures and computational solvent mapping (FTMap) to determine binding site hot spots in the “off” and “on” allosteric states of the GTP-bound form of H-Ras. Thirteen sites are revealed, expanding possible target sites for ligand binding well beyond the active site. Comparison of FTMaps for the H and K isoforms reveals essentially identical hot spots. Furthermore, using NMR measurements of spin relaxation, we determined that K-Ras exhibits global conformational dynamics very similar to those we previously reported for H-Ras. We thus hypothesize that the global conformational rearrangement serves as a mechanism for allosteric coupling between the effector interface and remote hot spots in all Ras isoforms. At least with respect to the binding sites involving the G domain, H-Ras is an excellent model for K-Ras and probably N-Ras as well. Ras has so far been elusive as a target for drug design. The present work identifies various unexplored hot spots throughout the entire surface of Ras, extending the focus from the disordered active site to well-ordered locations that should be easier to target

Concordance studies between hospital discharge data and medical records for the recording of lower extremity amputation and diabetes in the Republic of Ireland.

Background Hospital discharge data have been used to study trends in Lower Extremity Amputation (LEA) rates in people with and without diabetes. The aim of this study was to assess the reliability of routine hospital discharge data in the Republic of Ireland (RoI) for this purpose by determining the level of agreement between hospital discharge data and medical records for both the occurrence of LEA and diagnosis of diabetes. Methods Two concordance studies between hospital discharge data (HIPE) and medical records were performed. To determine the level of agreement for LEA occurrence, HIPE records were compared to theatre logbooks in 9 hospitals utilising HIPE over a two-year period in a defined study area. To determine the level of agreement for diabetes diagnosis, HIPE records were compared to laboratory records in each of the 4 largest hospitals utilising HIPE over a one week period in the same study area. The proportions of positive and negative agreement and Cohen’s kappa statistic of agreement were calculated. Results During a two-year study period in 9 hospitals, 216 LEAs were recorded in both data sources. Sixteen LEAs were recorded in medical records alone and 25 LEAs were recorded in hospital discharge records alone. The proportion of positive agreement was 0.91 (95% CI 0.88-0.94), the proportion of negative agreement was 0.99 (95% CI 0.98-0.99) and the kappa statistic was 0.91 (95% CI 0.88-0.94). During a one-week study period in 4 hospitals, 49 patients with diabetes and 716 patients without diabetes were recorded in both data sources. Eighteen patients had diabetes in medical records alone and 2 patients had diabetes in hospital discharge records alone. The proportion of positive agreement was 0.83 (95% CI 0.76-0.9), the proportion of negative agreement was 0.99 (95% CI 0.98-0.99) and the kappa statistic was 0.82 (95% CI 0.75-0.89). Conclusions This study detected high levels of agreement between hospital discharge data and medical records for LEA and diabetes in a defined study area. Based on these findings, we suggest that HIPE is sufficiently reliable to monitor trends in LEAs in people with and without diabetes in the RoI

Exploring obstetricians', midwives' and general practitioners' approach to weight management in pregnant women with a BMI >= 25 kg/m(2): a qualitative study

Objective: The aim of this study was to explore healthcare professionals’ (HCPs) beliefs and attitudes towards weight management for pregnant women with a body mass index (BMI) ≥25 kg/m2. Design: Qualitative study. Setting: A public antenatal clinic in a large academic maternity hospital in Cork, Ireland, and general practice clinics in the same region. Participants: HCPs such as hospital-based midwives and consultant obstetricians and general practitioners (GPs). Method: Semistructured interviews were conducted with a purposive sample of hospital-based HCPs and a sample of GPs working in the same region. Interviews were recorded, transcribed and thematically analysed using NVivo software. Results: Seventeen HCPs were interviewed (hospital based=10; GPs=7). Four themes identified the complexity of weight management in pregnancy and the challenges HCPs faced when trying to balance the medical and psychosocial needs of the women. HCPs acknowledged weight as a sensitive conversation topic, leading to a ‘softly-softly approach’ to weight management. HCPs tried to strike a balance between being woman centred and empathetic and medicalising the conversation. HCPs described ‘doing what you can with what you have’ and shifting the focus to managing obstetric complications. Furthermore, there were unclear roles and responsibilities in terms of weight management. Conclusion: HCPs need to have standardised approaches and evidence-based guidelines that support the consistent monitoring and management of weight during pregnancy

Genome-wide associations for milk production and somatic cell score in Holstein-Friesian cattle in Ireland

<p>Abstract</p> <p>Background</p> <p>Contemporary dairy breeding goals have broadened to include, along with milk production traits, a number of non-production-related traits in an effort to improve the overall functionality of the dairy cow. Increased indirect selection for resistance to mastitis, one of the most important production-related diseases in the dairy sector, via selection for reduced somatic cell count has been part of these broadened goals. A number of genome-wide association studies have identified genetic variants associated with milk production traits and mastitis resistance, however the majority of these studies have been based on animals which were predominantly kept in confinement and fed a concentrate-based diet (i.e. high-input production systems). This genome-wide association study aims to detect associations using genotypic and phenotypic data from Irish Holstein-Friesian cattle fed predominantly grazed grass in a pasture-based production system (low-input).</p> <p>Results</p> <p>Significant associations were detected for milk yield, fat yield, protein yield, fat percentage, protein percentage and somatic cell score using separate single-locus, frequentist and multi-locus, Bayesian approaches. These associations were detected using two separate populations of Holstein-Friesian sires and cows. In total, 1,529 and 37 associations were detected in the sires using a single SNP regression and a Bayesian method, respectively. There were 103 associations in common between the sires and cows across all the traits. As well as detecting associations within known QTL regions, a number of novel associations were detected; the most notable of these was a region of chromosome 13 associated with milk yield in the population of Holstein-Friesian sires.</p> <p>Conclusions</p> <p>A total of 276 of novel SNPs were detected in the sires using a single SNP regression approach. Although obvious candidate genes may not be initially forthcoming, this study provides a preliminary framework upon which to identify the causal mechanisms underlying the various milk production traits and somatic cell score. Consequently this will deepen our understanding of how these traits are expressed.</p

Exploring patient information needs in type 2 diabetes: A cross sectional study of questions

This study set out to analyze questions about type 2 diabetes mellitus (T2DM) from patients and the public. The aim was to better understand people's information needs by starting with what they do not know, discovered through their own questions, rather than starting with what we know about T2DM and subsequently finding ways to communicate that information to people affected by or at risk of the disease. One hundred and sixty-four questions were collected from 120 patients attending outpatient diabetes clinics and 300 questions from 100 members of the public through the Amazon Mechanical Turk crowdsourcing platform. Twenty-three general and diabetes-specific topics and five phases of disease progression were identified; these were used to manually categorize the questions. Analyses were performed to determine which topics, if any, were significant predictors of a question's being asked by a patient or the public, and similarly for questions from a woman or a man. Further analysis identified the individual topics that were assigned significantly more often to the crowdsourced or clinic questions. These were Causes (CI: [-0.07, -0.03], p < .001), Risk Factors ([-0.08, -0.03], p < .001), Prevention ([-0.06, -0.02], p < .001), Diagnosis ([-0.05, -0.02], p < .001), and Distribution of a Disease in a Population ([-0.05,-0.01], p = .0016) for the crowdsourced questions and Treatment ([0.03, 0.01], p = .0019), Disease Complications ([0.02, 0.07], p < .001), and Psychosocial ([0.05, 0.1], p < .001) for the clinic questions. No highly significant gender-specific topics emerged in our study, but questions about Weight were more likely to come from women and Psychosocial questions from men. There were significantly more crowdsourced questions about the time Prior to any Diagnosis ([(-0.11, -0.04], p = .0013) and significantly more clinic questions about Health Maintenance and Prevention after diagnosis ([0.07. 0.17], p < .001). A descriptive analysis pointed to the value provided by the specificity of questions, their potential to disclose emotions behind questions, and the as-yet unrecognized information needs they can reveal. Large-scale collection of questions from patients across the spectrum of T2DM progression and from the public-a significant percentage of whom are likely to be as yet undiagnosed-is expected to yield further valuable insights

Hypertension, Diabetes Mellitus and Task Shifting in Their Management in Sub-Saharan Africa

Chronic diseases are becoming increasingly important in sub-Saharan Africa (SSA). The current density and distribution of health workforce suggest that SSA cannot respond to the growing demand for chronic disease care, together with the frequent infectious diseases. Innovative approaches are therefore needed to rapidly expand the health workforce. In this article, we discuss the evidences in support of nurse-led strategies for chronic disease management in SSA, with a focus on hypertension and diabetes mellitus