Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Manuscripts

The aim of this chapter is three-fold: first, to explain systematically the multiple disciplines that have to be employed in the study of manuscripts; second, to review the evolution and development of methodologies used by the scholars who have shaped the present form of scholarship, and to chart outstanding problems that have yet to be resolved; and third, to offer some ideas of what future research might entail and in what way scholarship might unfold. Since numerous and disparate methodologies are employed in the study of Bach manuscripts, the discussions that follow will take nothing for granted, but will describe and define each one as it relates to understanding and reproducing, with as much accuracy as possible, Bach’s intentions in the manuscripts that contain his music.

2D Monolayer MoS2–Carbon Interoverlapped Superstructure: Engineering Ideal Atomic Interface for Lithium Ion Storage: Engineering Ideal Atomic Interface for Lithium Ion Storage

A novel strategy for the controlled synthesis of 2D MoS<inf>2</inf>/C hybrid nanosheets consisting of the alternative layer-by-layer interoverlapped single-layer MoS<inf>2</inf> and mesoporous carbon (m-C) is demonstrated. Such special hybrid nanosheets with a maximized MoS<inf>2</inf>/m-C interface contact show very good performance for lithium-ion batteries in terms of high reversible capacity, excellent rate capability, and outstanding cycling stability.

Towards a Mourne National Park?Emergent prospects and pitfalls fromarticulating needs in a local context

This paper examines the prospects for sustainable rural tourism within a rural development paradigm. Specifically, an adaptive management approach is proposed as a means of understanding and accommodating the different goals and interests that exist within multi-functional rural areas. This model allows priorities to change in line with particular situations while remaining sensitive to economic, environmental, social and cultural impacts. The proposed Mourne National Park in Northern Ireland, also designated an Area of Outstanding Natural Beauty (AONB), forms the backdrop for this study. Through a critique of a consultation process that was undertaken with the community the question is posed: can a sustainable rural tourism approach achieve meaningful community engagement and thereby reflect the needs of the community? Central to the analysis are the power differentials between the various partners participating in this model of governance. The conclusions consider implications for rural communities, revealing how trusting and meaningful relationships are central to facilitating collaboration, cooperation and adaptation.

Spatio-Temporal Rich Model For Motion Vector Steganalysis

We propose a spatio-temporal rich model of motion vector planes as a part of a full steganalytic system against motion vector based steganography. Superior detection accuracy of the rich model over the previous methods has been lately demonstrated for digital images in both spatial and DCT domain. It has not been heretofore used for detection of motion vector steganography. We also introduced a transformation so as to extend the feature set with temporal residuals. We carried out the tests along with most recent motion vector steganalysis and steganography methods. Test results show that the proposed model delivers an outstanding performance compared to the previous methods.

Examining Participatory Governance in a Devolving UK: insights from national parks policy development in Northern Ireland

This paper provides a contemporary examination of policy making and participatory practice in the context of devolving governance in the UK. The paper takes Northern Ireland as its focus and is particularly timely considering the context of devolved governance, the ongoing transition from conflict to relative peace and the potential for rejuvenating democracy through participatory
governance. The paper concentrates on one particular policy process, namely the attempted designation of a national park in the Mournes Area of Outstanding Natural Beauty. A thematic analysis of qualitative data is drawn upon to analyse the structural factors that framed the policymaking process, in particular the role of power in determining how consultation processes were 2 initiated, designed and undertaken. Using Lukes’ model) as an analytical framework, power is shown to manifest at multiple levels within the policy-making process to influence policy outcomes. The paper reveals how the persistence of a top-down approach to policy development combined with a highly parochial political outlook undermined attempts to designate a Mourne National Park. The paper concludes that, given the immaturity of recently devolved government in
Northern Ireland, in this instance, the democratising intentions of devolved governance have not been met. This has implications for Northern Ireland’s recent reform of public administration which devolves certain planning powers to local authority level and the management of the internationally significant Mournes landscape.

Infographic: Dealing with the Past in Northern Ireland

Highlight the outstanding human rights issues in dealing with the past after the Stormont House Agreement

Enhancement of Wear and Corrosion Resistance of Beta Titanium Alloy by Laser Gas Alloying with Nitrogen

The relatively high elastic modulus coupled with the presence of toxic vanadium (V) in Ti6Al4 V alloy has long been a concern in orthopaedic applications. To solve the problem, a variety of non-toxic and low modulus beta-titanium (beta-Ti) alloys have been developed. Among the beta-Ti alloy family, the quaternary Ti-Nb-Zr-Ta (TNZT) alloys have received the highest attention as a promising replacement for Ti6Al4 V due to their lower elastic modulus and outstanding long term stability against corrosion in biological environments. However, the inferior wear resistance of TNZT is still a problem that must be resolved before commercialising in the orthopaedic market. In this work, a newly-developed laser surface treatment technique was employed to improve the surface properties of Ti-35.3Nb-7.3Zr-5.7Ta alloy. The surface structure and composition of the laser-treated TNZT surface were examined by grazing incidence x-ray diffraction (GI-XRD) and x-ray photoelectron spectroscopy (XPS). The wear and corrosion resistance were evaluated by pin-on-plate sliding test and anodic polarisation test in Hanks’ solution. The experimental results were compared with the untreated (or base) TNZT material. The research findings showed that the laser surface treatment technique reported in this work can effectively improve the wear and corrosion resistance of TNZT.

Abstract: Psychometric properties of two self-report clinical competence scales for nursing students.

Abstract: Psychometric properties of two self-report clinical competence scales for nursing students.
Background: It is important to assess the clinical competence of nursing students to gauge their professional development and educational needs. This can be measured by self-assessment tools. Anema and McCoy (2010) contended that the currently available measures need further psychometric testing.
Aim: To test the psychometric properties of Nursing Competencies Questionnaire (NCQ) and Self-Efficacy in Clinical Performance (SECP) clinical competence scales.

Method: A non-randomly selected sample of n=248 2nd year nursing students completed NCQ, SECP and demographic questionnaires (June and September 2013). Mokken Scaling Analysis (MSA) was used to test the structural validity and scale properties, convergent and discriminant validity and reliability were subsequently tested.

Results: The NCQ provided evidence of a unidimensional scale which had strong scale scalability coefficients Hs =0.581; but limited evidence of item rankability HT =0.367. MSA undertaken with the SECP scale identified two potential unidimensional scales the SECP28 and SECP7, each with adequate evidence of good/reasonable scalablity psychometric properties as a summed scale but no/very limited evidence of scale rankability (SECP28: Hs = 0.55, HT=0.211; SECP7: Hs = 0.61, HT=0.049). Analysis of between cohort differences and NCQ/ SECP scale scores produced evidence of convergent and discriminant validity and good internal reliability: NCQ α = 0.93, SECP28 α = 0.96, and SECP7 α=0.89.

Discussion: The NCQ was verified to have evidence of reliability and validity; however, as the SECP findings are new, and the sample small, with reference to Straat and colleagues (2014), the SECP results should be interpreted with caution and verified on a second sample.

Conclusions: Measurement of perceived self-competence could inform the development of nursing competence and could start early in a nursing programme. Further testing of the NCQ and SECP scales with larger samples and from different years is indicated.


References:
Anema, M., G and McCoy, JK. (2010) Competency-Based Nursing Education: Guide to Achieving Outstanding Learner Outcomes. New York: Springer.
Straat, JH., van der Ark, LA and Sijtsma, K. (2014) Minimum Sample Size Requirements for Mokken Scale Analysis Educational and Psychological Measurement 74 (5), 809-822.

Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer

: High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. Additionally, a better understanding of the toxicity profile is needed if PARP inhibitors are to be used in the curative, rather than the palliative, setting. We reviewed the development of PARP inhibitors in phase I-III clinical trials, including combination trials of PARP inhibitors and chemotherapy/antiangiogenics, the approval for these agents, the mechanisms of resistance, and the outstanding issues, including the development of biomarkers and the rate of long-term hematologic toxicities with these agents.

IMPLICATIONS FOR PRACTICE: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has recently received approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA), with a second agent (rucaparib) likely to be approved in the near future. However, the patient population with potential benefit from PARP inhibitors is likely wider than that of germline BRCA mutation-associated disease, and biomarkers are in development to enable the selection of patients with the potential for clinical benefit from these agents. Questions remain regarding the toxicities of PARP inhibitors, limiting the use of these agents in the prophylactic or adjuvant setting until more information is available. The indications for olaparib as indicated by the FDA and EMA are reviewed.