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

Peer reviewed

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)'.

Interface of the Environment and Occurrence of Botrytis cinerea in Pre-symptomatic Tomato Crops

Botrytis cinerea (Grey mould) is a necrotrophic fungus infecting over 230 plant species worldwide. It can cause major pre- and post-harvest diseases of many agronomic and horticultural crops. Botrytis cinerea causes annual economic losses of 10–100 billion US dollars worldwide and instability in the food supply (Jin and Wu, 2015). Grey mould losses, either at the farm gate or later in the food chain, could be reduced with improved knowledge of inoculum availability during production. In this paper, we report on the ability to monitor Botrytis spore concentration in glasshouse tomato production ahead of symptom development on plants. Using a light weight and portable air sampler (microtitre immunospore trap) it was possible to quantify inoculum availability within hours. Also, this study investigated the spatial aspect of the pathogen with an increase of B. cinerea concentration in bio-aerosols collected in the lower part of the glasshouse (0.5 m) and adjacent to the trained stems of the tomato plants. No obvious relationship was observed between B. cinerea concentration and the internal glasshouse environmental parameters of temperature and relative humidity. However the occurrence of higher outside wind speeds did increase the prevalence of B. cinerea conidia in the cropping environment of a vented glasshouse. Knowledge of inoculum availability at time periods when the environmental risk of pathogen infection is high should improve the targeted use and effectiveness of control inputs.

Psychosocial impact of breast/ovarian (BRCA 1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort

This multi-centre UK study assesses the impact of predictive testing for breast and ovarian cancer predisposition genes (BRCA 1/2) in the clinical context. In the year following predictive testing, 261 adults (59 male) from nine UK genetics centres participated; 9 I gene mutation carriers and 170 noncarriers. Self-report questionnaires were completed at baseline (pre-genetic testing) and 1, 4 and 12 months following the genetic test result. Men were assessed for general mental health (by general health questionnaire (GHQ)) and women for general mental health, cancer-related worry, intrusive and avoidant thoughts, perception of risk and risk management behaviour. Main comparisons were between female carriers and noncarriers on all measures and men and women for general mental health. Female noncarriers benefited psychologically, with significant reductions in cancer-related worry following testing (P

Simulation and development of a mock circulation loop with variable compliance

Heart disease is attributed as the highest cause of death in the world. Although this could be alleviated by heart transplantation, there is a chronic shortage of donor hearts and so mechanical solutions are being considered. Currently, many Ventricular Assist Devices (VADs) are being developed worldwide in an effort to increase life expectancy and quality of life for end stage heart failure patients. Current pre-clinical testing methods for VADs involve laboratory testing using Mock Circulation Loops (MCLs), and in vivo testing in animal models. The research and development of highly accurate MCLs is vital to the continuous improvement of VAD performance. The first objective of this study was to develop and validate a mathematical model of a MCL. This model could then be used in the design and construction of a variable compliance chamber to improve the performance of an existing MCL as well as form the basis for a new miniaturised MCL. An extensive review of literature was carried out on MCLs and mathematical modelling of their function. A mathematical model of a MCL was then created in the MATLAB/SIMULINK environment. This model included variable features such as resistance, fluid inertia and volumes (resulting from the pipe lengths and diameters); compliance of Windkessel chambers, atria and ventricles; density of both fluid and compressed air applied to the system; gravitational effects on vertical columns of fluid; and accurately modelled actuators controlling the ventricle contraction. This model was then validated using the physical properties and pressure and flow traces produced from a previously developed MCL. A variable compliance chamber was designed to reproduce parameters determined by the mathematical model. The function of the variability was achieved by controlling the transmural pressure across a diaphragm to alter the compliance of the system. An initial prototype was tested in a previously developed MCL, and a variable level of arterial compliance was successfully produced; however, the complete range of compliance values required for accurate physiological representation was not able to be produced with this initial design. The mathematical model was then used to design a smaller physical mock circulation loop, with the tubing sizes adjusted to produce accurate pressure and flow traces whilst having an appropriate frequency response characteristic. The development of the mathematical model greatly assisted the general design of an in vitro cardiovascular device test rig, while the variable compliance chamber allowed simple and real-time manipulation of MCL compliance to allow accurate transition between a variety of physiological conditions. The newly developed MCL produced an accurate design of a mechanical representation of the human circulatory system for in vitro cardiovascular device testing and education purposes. The continued improvement of VAD test rigs is essential if VAD design is to improve, and hence improve quality of life and life expectancy for heart failure patients.

Feasibility of a stepped wedge cluster RCT and concurrent observational sub-study to evaluate the effects of modified ward night lighting on inpatient fall rates and sleep quality: A protocol for a pilot trial

Background: Falls among hospitalised patients impose a considerable burden on health systems globally and prevention is a priority. Some patient-level interventions have been effective in reducing falls, but others have not. An alternative and promising approach to reducing inpatient falls is through the modification of the hospital physical environment and the night lighting of hospital wards is a leading candidate for investigation. In this pilot trial, we will determine the feasibility of conducting a main trial to evaluate the effects of modified night lighting on inpatient ward level fall rates. We will test also the feasibility of collecting novel forms of patient level data through a concurrent observational sub-study. Methods/design: A stepped wedge, cluster randomised controlled trial will be conducted in six inpatient wards over 14 months in a metropolitan teaching hospital in Brisbane (Australia). The intervention will consist of supplementary night lighting installed across all patient rooms within study wards. The planned placement of luminaires, configurations and spectral characteristics are based on prior published research and pre-trial testing and modification. We will collect data on rates of falls on study wards (falls per 1000 patient days), the proportion of patients who fall once or more, and average length of stay. We will recruit two patients per ward per month to a concurrent observational sub-study aimed at understanding potential impacts on a range of patient sleep and mobility behaviour. The effect on the environment will be monitored with sensors to detect variation in light levels and night-time room activity. We will also collect data on possible patient-level confounders including demographics, pre-admission sleep quality, reported vision, hearing impairment and functional status. Discussion: This pragmatic pilot trial will assess the feasibility of conducting a main trial to investigate the effects of modified night lighting on inpatient fall rates using several new methods previously untested in the context of environmental modifications and patient safety. Pilot data collected through both parts of the trial will be utilised to inform sample size calculations, trial design and final data collection methods for a subsequent main trial.

Soil nitrogen—crop response calibration relationships and criteria for winter cereal crops grown in Australia

More than 1200 wheat and 120 barley experiments conducted in Australia to examine yield responses to applied nitrogen (N) fertiliser are contained in a national database of field crops nutrient research (BFDC National Database). The yield responses are accompanied by various pre-plant soil test data to quantify plant-available N and other indicators of soil fertility status or mineralisable N. A web application (BFDC Interrogator), developed to access the database, enables construction of calibrations between relative crop yield ((Y0/Ymax) × 100) and N soil test value. In this paper we report the critical soil test values for 90% RY (CV90) and the associated critical ranges (CR90, defined as the 70% confidence interval around that CV90) derived from analysis of various subsets of these winter cereal experiments. Experimental programs were conducted throughout Australia’s main grain-production regions in different eras, starting from the 1960s in Queensland through to Victoria during 2000s. Improved management practices adopted during the period were reflected in increasing potential yields with research era, increasing from an average Ymax of 2.2 t/ha in Queensland in the 1960s and 1970s, to 3.4 t/ha in South Australia (SA) in the 1980s, to 4.3 t/ha in New South Wales (NSW) in the 1990s, and 4.2 t/ha in Victoria in the 2000s. Various sampling depths (0.1–1.2 m) and methods of quantifying available N (nitrate-N or mineral-N) from pre-planting soil samples were used and provided useful guides to the need for supplementary N. The most regionally consistent relationships were established using nitrate-N (kg/ha) in the top 0.6 m of the soil profile, with regional and seasonal variation in CV90 largely accounted for through impacts on experimental Ymax. The CV90 for nitrate-N within the top 0.6 m of the soil profile for wheat crops increased from 36 to 110 kg nitrate-N/ha as Ymax increased over the range 1 to >5 t/ha. Apparent variation in CV90 with seasonal moisture availability was entirely consistent with impacts on experimental Ymax. Further analyses of wheat trials with available grain protein (~45% of all experiments) established that grain yield and not grain N content was the major driver of crop N demand and CV90. Subsets of data explored the impact of crop management practices such as crop rotation or fallow length on both pre-planting profile mineral-N and CV90. Analyses showed that while management practices influenced profile mineral-N at planting and the likelihood and size of yield response to applied N fertiliser, they had no significant impact on CV90. A level of risk is involved with the use of pre-plant testing to determine the need for supplementary N application in all Australian dryland systems. In southern and western regions, where crop performance is based almost entirely on in-crop rainfall, this risk is offset by the management opportunity to split N applications during crop growth in response to changing crop yield potential. In northern cropping systems, where stored soil moisture at sowing is indicative of minimum yield potential, erratic winter rainfall increases uncertainty about actual yield potential as well as reducing the opportunity for effective in-season applications.

High quality assembly of phase-only liquid crystal on silicon ((LCOS) devices

Liquid crystal on silicon (LCOS) for phase-only holography is ideally made to better optical tolerance than that for conventional amplitude modulating applications. Die-level assembly is suited to custom devices and pre-production prototypes because of its flexibility and efficiency in conserving the silicon backplane. Combined with automated assembly, it will allow high reproducibility and fast turnaround time, paving the way for pre-production testing and customer sampling before mass production. Pre-assembly optical testing is the key element in the process. By taking into account the flatness of both the backplane and the front glass plate, we have assembled high quality LCOS devices. We have reached our aim of less than one quarter wavelength phase distortion across the active area. © 2011 IEEE.

Early Functional Deficit and Microglial Disturbances in a Mouse Model of Amyotrophic Lateral Sclerosis

11 p.

Evaluation of cement stresses in finite element analyses of cemented orthopaedic implants

Stress analysis of the cement fixation of orthopaedic implants to bone is frequently? carried out using finite element analysis. However, the stress distribution in the cement laver is usually intricate, and it is difficult to report it in a way that facilitates comparison of implants for pre-clinical testing. To study this problem, and make recommendations for stress reporting, a finite element analysis of a hip prosthesis implanted into a synthetic composite femur is developed. Three cases are analyzed: a fully bonded implant, a debonded implant, and a debonded implant where the cement is removed distal to the stein tip. In addition to peak stresses, and contour and vector plots, a stressed volume and probability-of-failure analysis is reported. It is predicted that the peak stress is highest for the debonded stem, and that removal of the distal cement more than halves this peak stress. This would suggest that omission of the distal cement is good for polished prostheses (as practiced for the Exeter design). However; if the percentage of cement stressed above a certain threshold (say 3 MPa) is considered, then the removal of distal cement is shown to be disadvantageous because a higher volume of cement is stressed to above the threshold. Vector plots clearly demonstrate the different load transfer for bonded and debonded prostheses: A bonded stein generates maximum tensile stresses in the longitudinal direction, whereas a debonded stem generates most tensile stresses in the hoop direction, except near the tip where tensile longitudinal stresses occur due to subsidence of the stein. Removal of the cement distal to the tip allows greater subsidence but alleviates these large stresses at the tip, albeit at the expense of increased hoop stresses throughout the mantle. It is concluded that a thorough analysis of cemented implants should not report peak stress, which can be misleading, but rather stressed volume, and that vector plots should be reported if a precise analysis of the load transfer mechanism is required.

Computer simulating a trial of a load-bearing implant: example of an intramedullary prosthesis

Computational modelling is becoming ever more important for obtaining regulatory approval for new medical devices. An accepted approach is to infer performance in a population from an analysis conducted for an idealised or ‘average’ patient; we present here a method for predicting the performance of an orthopaedic implant when released into a population—effectively simulating a clinical trial. Specifically we hypothesise that an analysis based on a method for predicting the performance in a population will lead to different conclusions than an analysis based on an idealised or ‘average’ patient. To test this hypothesis we use a finite element model of an intramedullary implant in a bone whose size and remodelling activity is different for each individual in the population. We compare the performance of a low Young’s modulus implant (View the MathML source) to one with a higher Young’s modulus (200 GPa). Cyclic loading is applied and failure is assumed when the migration of the implant relative to the bone exceeds a threshold magnitude. The analysis for an idealised of ‘average’ patient predicts that the lower modulus device survives longer whereas the analysis simulating a clinical trial predicts no statistically-significant tendency (p=0.77) for the low modulus device to perform better. It is concluded that population-based simulations of implant performance–simulating a clinical trial–present a very valuable opportunity for more realistic computational pre-clinical testing of medical devices.

Clinical trials in cystic fibrosis

In patients with cystic fibrosis (CF), clinical trials are of paramount importance. Here, the current status of drug development in CF is discussed and future directions highlighted. Methods for pre-clinical testing of drugs with potential activity in CF patients including relevant animal models are described. Study design options for phase II and phase III studies involving CF patients are provided, including required patient numbers, safety issues and surrogate end point parameters for drugs, tested for different disease manifestations. Finally, regulatory issues for licensing new therapies for CF patients are discussed, including new directives of the European Union and the structure of a European clinical trial network for clinical studies involving CF patients is proposed.

Tumorigenesis and peritoneal colonization from fallopian tube epithelium

Ovarian cancer is the most lethal gynecological malignancy, primarily because its origin and initiation factors are unknown. A secretory murine oviductal epithelial (MOE) model was generated to address the hypothesis that the fallopian tube is an origin for high-grade serous cancer. MOE cells were stably altered to express mutation in p53, silence PTEN, activate AKT, and amplify KRAS alone and in combination, to define if this cell type gives rise to tumors and what genetic alterations are required to drive malignancy. Cell lines were characterized in vitro and allografted into mice. Silencing PTEN formed high-grade carcinoma with wide spread tumor explants including metastasis into the ovary. Addition of p53 mutation to PTEN silencing did not enhance this phenotype, whereas addition of KRAS mutation reduced survival. Interestingly, PTEN silencing and KRAS mutation originating from ovarian surface epithelium generated endometrioid carcinoma, suggesting that different cellular origins with identical genetic manipulations can give rise to distinct cancer histotypes. Defining the roles of specific signaling modifications in tumorigenesis from the fallopian tube/oviduct is essential for early detection and development of targeted therapeutics. Further, syngeneic MOE allografts provide an ideal model for pre-clinical testing in an in vivo environment with an intact immune system.