22 years of Predictive Testing for Huntington’s Disease : The Experience of the UK Huntington’s Prediction Consortium

Corrigendum European Journal of Human Genetics (2016) 24, 1515; doi:10.1038/ejhg.2016.81 22 Years of predictive testing for Huntington’s disease: the experience of the UK Huntington’s Prediction Consortium Sheharyar S Baig, Mark Strong, Elisabeth Rosser, Nicola V Taverner, Ruth Glew, Zosia Miedzybrodzka, Angus Clarke, David Craufurd, UK Huntington's Disease Prediction Consortium and Oliver W Quarrell Correction to: European Journal of Human Genetics advance online publication, 11 May 2016; doi: 10.1038/ejhg.2016.36 Post online publication the authors realised that they had made an error: The sentence on page 2: 'In the first 5-year period........but this changed significantly in the last 5-year period with 51% positive and 49% negative (χ2=20.6, P<0.0001)' should read: 'In the first 5-year period........but this changed significantly in the last 5-year period with 49% positive and 51% negative (χ2=20.6, P<0.0001)'.

Variability of the IFN-γ ELISpot assay in the context of proficiency testing and bridging studies.

Assays that assess cellular mediated immune responses performed under Good Clinical Laboratory Practice (GCLP) guidelines are required to provide specific and reproducible results. Defined validation procedures are required to establish the Standard Operating Procedure (SOP), include pass and fail criteria, as well as implement positivity criteria. However, little to no guidance is provided on how to perform longitudinal assessment of the key reagents utilized in the assay. Through the External Quality Assurance Program Oversight Laboratory (EQAPOL), an Interferon-gamma (IFN-γ) Enzyme-linked immunosorbent spot (ELISpot) assay proficiency testing program is administered. A limit of acceptable within site variability was estimated after six rounds of proficiency testing (PT). Previously, a PT send-out specific within site variability limit was calculated based on the dispersion (variance/mean) of the nine replicate wells of data. Now an overall 'dispersion limit' for the ELISpot PT program within site variability has been calculated as a dispersion of 3.3. The utility of this metric was assessed using a control sample to calculate the within (precision) and between (accuracy) experiment variability to determine if the dispersion limit could be applied to bridging studies (studies that assess lot-to-lot variations of key reagents) for comparing the accuracy of results with new lots to results with old lots. Finally, simulations were conducted to explore how this dispersion limit could provide guidance in the number of replicate wells needed for within and between experiment variability and the appropriate donor reactivity (number of antigen-specific cells) to be used for the evaluation of new reagents. Our bridging study simulations indicate using a minimum of six replicate wells of a control donor sample with reactivity of at least 150 spot forming cells per well is optimal. To determine significant lot-to-lot variations use the 3.3 dispersion limit for between and within experiment variability.

Impact of Genetic Testing and Family Health History Based Risk Counseling on Behavior Change and Cognitive Precursors for Type 2 Diabetes.

Family health history (FHH) in the context of risk assessment has been shown to positively impact risk perception and behavior change. The added value of genetic risk testing is less certain. The aim of this study was to determine the impact of Type 2 Diabetes (T2D) FHH and genetic risk counseling on behavior and its cognitive precursors. Subjects were non-diabetic patients randomized to counseling that included FHH +/- T2D genetic testing. Measurements included weight, BMI, fasting glucose at baseline and 12 months and behavioral and cognitive precursor (T2D risk perception and control over disease development) surveys at baseline, 3, and 12 months. 391 subjects enrolled of which 312 completed the study. Behavioral and clinical outcomes did not differ across FHH or genetic risk but cognitive precursors did. Higher FHH risk was associated with a stronger perceived T2D risk (pKendall < 0.001) and with a perception of "serious" risk (pKendall < 0.001). Genetic risk did not influence risk perception, but was correlated with an increase in perception of "serious" risk for moderate (pKendall = 0.04) and average FHH risk subjects (pKendall = 0.01), though not for the high FHH risk group. Perceived control over T2D risk was high and not affected by FHH or genetic risk. FHH appears to have a strong impact on cognitive precursors of behavior change, suggesting it could be leveraged to enhance risk counseling, particularly when lifestyle change is desirable. Genetic risk was able to alter perceptions about the seriousness of T2D risk in those with moderate and average FHH risk, suggesting that FHH could be used to selectively identify individuals who may benefit from genetic risk testing.

Design, fabrication and characterization of resonant waveguide grating based optical biosensors

The absence of rapid, low cost and highly sensitive biodetection platform has hindered the implementation of next generation cheap and early stage clinical or home based point-of-care diagnostics. Label-free optical biosensing with high sensitivity, throughput, compactness, and low cost, plays an important role to resolve these diagnostic challenges and pushes the detection limit down to single molecule. Optical nanostructures, specifically the resonant waveguide grating (RWG) and nano-ribbon cavity based biodetection are promising in this context. The main element of this dissertation is design, fabrication and characterization of RWG sensors for different spectral regions (e.g. visible, near infrared) for use in label-free optical biosensing and also to explore different RWG parameters to maximize sensitivity and increase detection accuracy. Design and fabrication of the waveguide embedded resonant nano-cavity are also studied. Multi-parametric analyses were done using customized optical simulator to understand the operational principle of these sensors and more important the relationship between the physical design parameters and sensor sensitivities. Silicon nitride (SixNy) is a useful waveguide material because of its wide transparency across the whole infrared, visible and part of UV spectrum, and comparatively higher refractive index than glass substrate. SixNy based RWGs on glass substrate are designed and fabricated applying both electron beam lithography and low cost nano-imprint lithography techniques. A Chromium hard mask aided nano-fabrication technique is developed for making very high aspect ratio optical nano-structure on glass substrate. An aspect ratio of 10 for very narrow (~60 nm wide) grating lines is achieved which is the highest presented so far. The fabricated RWG sensors are characterized for both bulk (183.3 nm/RIU) and surface sensitivity (0.21nm/nm-layer), and then used for successful detection of Immunoglobulin-G (IgG) antibodies and antigen (~1μg/ml) both in buffer and serum. Widely used optical biosensors like surface plasmon resonance and optical microcavities are limited in the separation of bulk response from the surface binding events which is crucial for ultralow biosensing application with thermal or other perturbations. A RWG based dual resonance approach is proposed and verified by controlled experiments for separating the response of bulk and surface sensitivity. The dual resonance approach gives sensitivity ratio of 9.4 whereas the competitive polarization based approach can offer only 2.5. The improved performance of the dual resonance approach would help reducing probability of false reading in precise bio-assay experiments where thermal variations are probable like portable diagnostics.

Paternalism and Competent Patient Choice in the Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People

In 2016 physicians in Ontario will be granted the authority to refer patients with gender dysphoria for sex reassignment surgery. In order to be granted this authority physicians must be trained in the World Professional Association for Transgender Health’s Standards of Care, which outlines healthcare procedures for the treatment of gender dysphoria and provides background information concerning transgender health. The Standards of Care require that patients undergo a process of 12 months of continuous living in a gender role that is congruent with their gender identity prior to being given access to sex reassignment surgery. While this requirement can sometimes be helpful it can also cause more harm than benefit. This paper argues that the requirement is strongly paternalistic in its current form and should no longer be mandatory in most cases.

Design, analysis and evaluation of sigma-delta based beamformers for medical ultrasound imaging applications

The inherent analogue nature of medical ultrasound signals in conjunction with the abundant merits provided by digital image acquisition, together with the increasing use of relatively simple front-end circuitries, have created considerable demand for single-bit  beamformers in digital ultrasound imaging systems. Furthermore, the increasing need to design lightweight ultrasound systems with low power consumption and low noise, provide ample justification for development and innovation in the use of single-bit  beamformers in ultrasound imaging systems. The overall aim of this research program is to investigate, establish, develop and confirm through a combination of theoretical analysis and detailed simulations, that utilize raw phantom data sets, suitable techniques for the design of simple-to-implement hardware efficient  digital ultrasound beamformers to address the requirements for 3D scanners with large channel counts, as well as portable and lightweight ultrasound scanners for point-of-care applications and intravascular imaging systems. In addition, the stability boundaries of higher-order High-Pass (HP) and Band-Pass (BP) Σ−Δ modulators for single- and dual- sinusoidal inputs are determined using quasi-linear modeling together with the describing-function method, to more accurately model the  modulator quantizer. The theoretical results are shown to be in good agreement with the simulation results for a variety of input amplitudes, bandwidths, and modulator orders. The proposed mathematical models of the quantizer will immensely help speed up the design of higher order HP and BP Σ−Δ modulators to be applicable for digital ultrasound beamformers. Finally, a user friendly design and performance evaluation tool for LP, BP and HP  modulators is developed. This toolbox, which uses various design methodologies and covers an assortment of  modulators topologies, is intended to accelerate the design process and evaluation of  modulators. This design tool is further developed to enable the design, analysis and evaluation of  beamformer structures including the noise analyses of the final B-scan images. Thus, this tool will allow researchers and practitioners to design and verify different reconstruction filters and analyze the results directly on the B-scan ultrasound images thereby saving considerable time and effort.

Waged domestic work in Argentina: the regulation of care provision

This paper addresses the condition of domestic work in Argentina, in a perspective that draws from the literature on care work. In this approach, domestic work can be interpreted as one of the mercantile forms in which care work is socially organized, due to the persistence of the traditional sexual division of labor and the weakness of public policies. From these considerations, I develop a quantitative study on the levels of informality, precarity, and wage inequality that characterize domestic work in that country. Thereafter, I discuss the main measures adopted by the Argentine government since 2003, with the goal of reducing legal discrimination of domestic workers and promoting their formalization. On this basis, the paper highlights the advances in the recognition of domestic workers’ labor rights, while emphasizing how social and cultural restraints still permeate labor relations in this sector.

What is the Point of Copyright History?:Reflections on Copyright at Common law in 1774 by H. Tomás Gómez-Arostegui

Copyright history has long been a subject of intense and contested enquiry. Historical narratives about the early development of copyright were first prominently mobilised in eighteenth century British legal discourse, during the so-called Battle of the Booksellers between Scottish and London publishers. The two landmark copyright decisions of that time – Millar v. Taylor (1769) and Donaldson v. Becket (1774) – continue to provoke debate today. The orthodox reading of Millar and Donaldson presents copyright as a natural proprietary right at common law inherent in authors. Revisionist accounts dispute that traditional analysis. These conflicting perspectives have, once again, become the subject of critical scrutiny with the publication of Copyright at Common Law in 1774 by Prof Tomas Gomez-Arostegui in 2014, in the Connecticut Law Review ((2014) 47 Conn. L. Rev. 1) and as a CREATe Working Paper (No. 2014/16, 3 November 2014).

Taking Prof Gomez-Arostegui’s extraordinary work in this area as a point of departure, Dr Elena Cooper and Professor Ronan Deazley (then both academics at CREATe) organised an event, held at the University of Glasgow on 26th and 27th March 2015, to consider the interplay between copyright history and contemporary copyright policy. Is Donaldson still relevant, and, if so, why? What justificatory goals are served by historical investigation, and what might be learned from the history of the history of copyright? Does the study of copyright history still have any currency within an evidence-based policy context that is increasingly preoccupied with economic impact analysis?

This paper provides a lasting record of these discussions, including an editorial introduction, written comments by each of the panelists and Prof. Gomez-Arostegui and an edited transcript of the Symposium debate.

Influence of diabetes on natriuretic peptide thresholds in screening for Stage B heart failure

CONTEXT: Natriuretic peptide (NP) has been shown to be an effective screening tool to identify patients with Stage B heart failure and to have clinical value in preventing heart failure progression. The impact of associated metabolic confounders on the screening utility of NP needs clarification.

OBJECTIVE: To assess the impact of diabetes mellitus (DM) on NP screening for asymptomatic Stage B heart failure.

MATERIALS AND METHODS: The study population consisted of 1368 asymptomatic patients with cardiovascular risk factors recruited from general practice as part of the STOP-HF trial. B-type NP (BNP) was quantified at point-of-care.

RESULTS: BNP was found to be as accurate for detecting Stage B heart failure in DM patients compared to non-DM patients (AUC 0.75 [0.71,0.78] and 0.77 [0.72,0.82], respectively). However, different BNP thresholds are required to achieve the same level of diagnostic sensitivity in DM compared with non-DM patients. To achieve 80% sensitivity a difference of 5-ng/L lower is required for patients with DM.

CONCLUSION: Although a significantly different BNP threshold is detected for patients with DM, the BNP concentration difference is small and unlikely to warrant a clinically different diagnostic threshold.

What is the Point of Copyright History?

Copyright history has long been a subject of intense and contested enquiry, and has once again become the subject of critical scrutiny with the publication of "Copyright at Common Law in 1774" by Prof Tomas Gomez-Arostegui in the Connecticut Law Review ((2014) 47 Conn. L. Rev. 1).
This online resource documents two events organised to explore the impact of "Copyright at Common Law in 1774". It incorporates a public lecture by Prof Gomez-Arostegui, and the full record of a one-day symposium of international experts debating the implications of Gomez-Arostegui's scholarship in this domain.

GPs’ and community pharmacists’ opinions on medication management at transitions of care in Ireland

Objective. The aim of this study was to survey GPs and community pharmacists (CPs) in Ireland regarding current practices of medication management, specifically medication reconciliation, communication between health care providers and medication errors as patients transition in care.
Methods. A national cross-sectional survey was distributed electronically to 2364 GPs, 311 GP Registrars and 2382 CPs. Multivariable associations comparing GPs to CPs were generated and content analysis of free text responses was undertaken.
Results. There was an overall response rate of 17.7% (897 respondents—554 GPs/Registrars and 343 CPs). More than 90% of GPs and CPs were positive about the effects of medication reconciliation on medication safety and adherence. Sixty per cent of GPs reported having no formal system of medication reconciliation. Communication between GPs and CPs was identified as good/very good by >90% of GPs and CPs. The majority (>80%) of both groups could clearly recall prescribing errors, following a transition of care, they had witnessed in the previous 6 months. Free text content analysis corroborated the positive relationship between GPs and CPs, a frustration with secondary care communication, with many examples given of prescribing errors.
Conclusions. While there is enthusiasm for the benefits of medication reconciliation there are limited formal structures in primary care to support it. Challenges in relation to systems that support inter-professional communication and reduce medication errors are features of the primary/secondary care transition. There is a need for an improved medication management system. Future research should focus on the identified barriers in implementing medication reconciliation and systems that can improve it.

Midwifery-led antenatal care models: mapping a systematic review to an evidence-based quality framework to identify key components and characteristics of care

Background: Implementing effective antenatal care models is a key global policy goal. However, the mechanisms of action of these multi-faceted models that would allow widespread implementation are seldom examined and poorly understood. In existing care model analyses there is little distinction between what is done, how it is done, and who does it. A new evidence-informed quality maternal and newborn care (QMNC) framework identifies key characteristics of quality care. This offers the opportunity to identify systematically the characteristics of care delivery that may be generalizable across contexts, thereby enhancing implementation. Our objective was to map the characteristics of antenatal care models tested in Randomised Controlled Trials (RCTs) to a new evidence-based framework for quality maternal and newborn care; thus facilitating the identification of characteristics of effective care.

Methods: A systematic review of RCTs of midwifery-led antenatal care models. Mapping and evaluation of these models’ characteristics to the QMNC framework using data extraction and scoring forms derived from the five framework components. Paired team members independently extracted data and conducted quality assessment using the QMNC framework and standard RCT criteria.

Results: From 13,050 citations initially retrieved we identified 17 RCTs of midwifery-led antenatal care models from Australia (7), the UK (4), China (2), and Sweden, Ireland, Mexico and Canada (1 each). QMNC framework scores ranged from 9 to 25 (possible range 0–32), with most models reporting fewer than half the characteristics associated with quality maternity care. Description of care model characteristics was lacking in many studies, but was better reported for the intervention arms. Organisation of care was the best-described component. Underlying values and philosophy of care were poorly reported.

Conclusions: The QMNC framework facilitates assessment of the characteristics of antenatal care models. It is vital to understand all the characteristics of multi-faceted interventions such as care models; not only what is done but why it is done, by whom, and how this differed from the standard care package. By applying the QMNC framework we have established a foundation for future reports of intervention studies so that the characteristics of individual models can be evaluated, and the impact of any differences appraised.