Polyglutamine diseases

Polyglutamine diseases are a collection of nine CAG trinucleotide expansion disorders, presenting with a spectrum of neurological and clinical phenotypes. Recent human, mouse and cell studies of Huntington's disease have highlighted the role of DNA repair genes in somatic expansion of the CAG repeat region, modifying disease pathogenesis. Incomplete splicing of the HTT gene has also been shown to occur in humans, with the resulting exon 1 fragment most probably contributing to the Huntington's disease phenotype. In the spinocerebellar ataxias, studies have converged on transcriptional dysregulation of ion channels as a key disease modifier. In addition, advances have been made in understanding how increased levels of toxic, polyglutamine-expanded proteins can arise in the spinocerebellar ataxias through post-transcriptional and -translational modifications and autophagic mechanisms. Recent studies in spinal and bulbar muscular atrophy implicate similar pathogenic pathways to the more common polyglutamine diseases, highlighting autophagy stimulation as a potential therapeutic target. Finally, the therapeutic use of antisense oligonucleotides in several polyglutamine diseases has shown preclinical benefits and serves as potential future therapies in humans

Water intoxication presenting as maternal and neonatal seizures: a case report.

Introduction We present an unusual case of fitting in the mother and newborn child, and the challenges faced in the management of their hyponatraemia due to water intoxication. Case presentation A previously well 37-year-old, primigravid Caucasian woman presented with features mimicking eclampsia during labour. These included confusion, reduced consciousness and seizures but without a significant history of hypertension, proteinuria or other features of pre-eclampsia. Her serum sodium was noted to be low at 111 mmol/litre as was that of her newborn baby. She needed anti-convulsants with subsequent intubation to stop the fitting and was commenced on a hypertonic saline infusion with frequent monitoring of serum sodium. There is a risk of long-term neurological damage from central pontine myelinolysis if the hyponatraemia is corrected too rapidly. Mother and baby went on to make a full recovery without any long-term neurological complications. Conclusion There is little consensus on the treatment of life-threatening hyponatraemia. Previous articles have outlined several possible management strategies as well as their risks. After literature review, an increase in serum sodium concentration of no more than 8–10 mmol/litre in 24 hours is felt to be safe but can be exceeded with extreme caution if life-threatening symptoms do not resolve. Formulae exist to calculate the amount of sodium needed and how much hypertonic intravenous fluid will be required to allow safer correction. We hypothesise the possible causes of hyponatraemia in this patient and underline its similarity in symptom presentation to eclampsia

Availability of cancer decision-support tools: A cross-sectional survey of UK primary care

This is the author accepted manuscript. The final version is available from Royal College of General Practitioners via the DOI in this record.Background Decision-support tools quantify the risk of undiagnosed cancer in symptomatic patients, and may help general practitioners (GPs) when making referrals. Aims: To quantify the availability and use of cancer decision-support tools (QCancer® and Risk Assessment Tools). To explore the association between tool availability and two-week-wait referrals for suspected cancer. Design and setting: Cross-sectional postal survey in UK primary care. Methods: 4,600 GPs from a random sample of 975 UK general practices were invited to participate. Outcome measures included the proportions of UK general practices where: (1) cancer decision-support tools are available, and (2) at least one GP uses the tool. Weighted least-squares linear regression with robust errors tested the association between tool availability and number of two-week-wait referrals, adjusting for practice size, sex, age and index of multiple deprivation. Results: 476 GPs in 227 practices responded (response rates: practitioner, 10.3%; practice, 23.3%). Cancer decision-support tools were available in 83/227 (36.6%, 95% confidence interval 30.3% to 43.1%) practices. Tools were available and likely to be used in 38/227 (16.7%, 12.1% to 22.2%) practices. In sub-group analyses of 172 English practices, there was no difference in mean two-week-wait referral rate between practices with tools and those without (mean adjusted difference in referrals per 100,000: 3.1, -5.5 to +11.7). Conclusions: This is the first survey of cancer decision-support tool availability and use. It suggests that the tools are an underused resource in the UK. Given the cost of cancer investigation, a randomised controlled trial of such clinical decision-support aids would be appropriate.National Institute for Health Research (NIHR

Is omission of free text records a possible source of data loss and bias in Clinical Practice Research Datalink studies? A case-control study.

This is the final version of the article. Available from the publisher via the DOI in this record.OBJECTIVES: To estimate data loss and bias in studies of Clinical Practice Research Datalink (CPRD) data that restrict analyses to Read codes, omitting anything recorded as text. DESIGN: Matched case-control study. SETTING: Patients contributing data to the CPRD. PARTICIPANTS: 4915 bladder and 3635 pancreatic, cancer cases diagnosed between 1 January 2000 and 31 December 2009, matched on age, sex and general practitioner practice to up to 5 controls (bladder: n=21 718; pancreas: n=16 459). The analysis period was the year before cancer diagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: Frequency of haematuria, jaundice and abdominal pain, grouped by recording style: Read code or text-only (ie, hidden text). The association between recording style and case-control status (χ(2) test). For each feature, the odds ratio (OR; conditional logistic regression) and positive predictive value (PPV; Bayes' theorem) for cancer, before and after addition of hidden text records. RESULTS: Of the 20 958 total records of the features, 7951 (38%) were recorded in hidden text. Hidden text recording was more strongly associated with controls than with cases for haematuria (140/336=42% vs 556/3147=18%) in bladder cancer (χ(2) test, p<0.001), and for jaundice (21/31=67% vs 463/1565=30%, p<0.0001) and abdominal pain (323/1126=29% vs 397/1789=22%, p<0.001) in pancreatic cancer. Adding hidden text records corrected PPVs of haematuria for bladder cancer from 4.0% (95% CI 3.5% to 4.6%) to 2.9% (2.6% to 3.2%), and of jaundice for pancreatic cancer from 12.8% (7.3% to 21.6%) to 6.3% (4.5% to 8.7%). Adding hidden text records did not alter the PPV of abdominal pain for bladder (codes: 0.14%, 0.13% to 0.16% vs codes plus hidden text: 0.14%, 0.13% to 0.15%) or pancreatic (0.23%, 0.21% to 0.25% vs 0.21%, 0.20% to 0.22%) cancer. CONCLUSIONS: Omission of text records from CPRD studies introduces bias that inflates outcome measures for recognised alarm symptoms. This potentially reinforces clinicians' views of the known importance of these symptoms, marginalising the significance of 'low-risk but not no-risk' symptoms.SJP is funded by a University of Exeter PhD studentship. This report presents independent research part funded by the National Institute for Health Research Programme Grants for Applied Research programme (RP-PG-0608- 10045). The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health

Risk prediction tools for cancer in primary care.

This is the final version of the article. Available from the publisher via the DOI in this record.Numerous risk tools are now available, which predict either current or future risk of a cancer diagnosis. In theory, these tools have the potential to improve patient outcomes through enhancing the consistency and quality of clinical decision-making, facilitating equitable and cost-effective distribution of finite resources such as screening tests or preventive interventions, and encouraging behaviour change. These potential uses have been recognised by the National Cancer Institute as an 'area of extraordinary opportunity' and an increasing number of risk prediction models continue to be developed. The data on predictive utility (discrimination and calibration) of these models suggest that some have potential for clinical application; however, the focus on implementation and impact is much more recent and there remains considerable uncertainty about their clinical utility and how to implement them in order to maximise benefits and minimise harms such as over-medicalisation, anxiety and false reassurance. If the potential benefits of risk prediction models are to be realised in clinical practice, further validation of the underlying risk models and research to assess the acceptability, clinical impact and economic implications of incorporating them in practice are needed

Reflected Light from Sand Grains in the Terrestrial Zone of a Protoplanetary Disk

We show that grains have grown to ~mm size (sand sized) or larger in the terrestrial zone (within ~3 AU) of the protoplanetary disk surrounding the 3 Myr old binary star KH 15D. We also argue that the reflected light in the system reaches us by back scattering off the far side of the same ring whose near side causes the obscuration.Comment: 22 pages, 5 figures. To be published in Nature, March 13, 2008. Contains a Supplemen

Effect Threshold for Selenium Toxicity in Juvenile Splittail, Pogonichthys macrolepidotus A

In fish, selenium can bioaccumulate and cause adverse impacts. One of the fish species potentially at risk from selenium in the San Francisco Bay (California, USA) is the splittail (Pogonichthys macrolepidotus). Previous studies have derived a whole body NOAEL and LOAEL of 9.0 and 12.9 mg/kg-dw, respectively, for selenium in juveniles. However, the NOAEL/LOAEL approach leaves some uncertainty regarding the threshold of toxicity. Therefore, the raw data from the original experiment was re-analyzed using a logistic regression to derive EC10 values of 0.9 mg/kg-dw in feed, 7.9 mg/kg-dw in muscle, 18.6 mg/kg-dw in liver for juvenile splittail. Selenium concentrations in the dietary items of wild splittail exceed the EC10 values derived here. Thus, deformities previously reported in wild splittail may have resulted from selenium exposures via the food chain

The effect of food type on the portion size effect in children aged 2-12 years: A systematic review and meta-analysis.

Visual cues such as plate size, amount of food served and packaging are known to influence the effects of portion size on food intake. Unit bias is a well characterised heuristic and helps to determine consumption norms. In an obesogenic environment where large portions are common place, the unit or segmentation bias may be overridden promoting overconsumption of both amorphous or unit foods. The aim of this review was to investigate the impact of offering unit or amorphous food on the portion size effect (PSE) in children aged 2–12 years. A systematic search for literature was conducted in Medline, PsycInfo and Web of Science in February 2018. A total of 1197 papers were retrieved following the searches. Twenty-one papers were included in the systematic review, of which 15 provided requisite statistical information for inclusion in a random effects meta-analysis. Increasing children's food portion size by 51–100% led to a significant increase in intake (SMD = 0.47, 95% CI: 0.39–0.55). There was no evidence to suggest that increases in consumption were related to food type (p = 0.33), child age (p = 0.47) or initial portion size served (p=0.14). Residual heterogeneity was not significant (p=0.24). The PSE was demonstrated in children aged 2–12 years when offered both unit and amorphous food items. The effect was not restricted by food type, child age or influenced by initial portion size served. Of the studies included in the meta-analysis between study heterogeneity was low suggesting minimal variation in treatment effects between studies, however, more research is required to understand the mechanisms of the PSE in preschool children. Future research should determine feasible methods to downsize portion sizes served to children

Adopting a Whole Systems Approach to Transport Decarbonisation, Air Quality and Health: An Online Participatory Systems Mapping Case Study in the UK

In a drive to achieve net zero emissions, U.K. transport decarbonisation policies are predominantly focussed on measures to promote the uptake and use of electric vehicles (EVs). This is reflected in the COP26 Transport Declaration signed by 38 national governments, alongside city region governments, vehicle manufacturers and investors. However, emerging evidence suggests that EVs present multiple challenges for air quality, mobility and health, including risks from non-exhaust emissions (NEEs) and increasing reliance on vehicles for short trips. Understanding the interconnected links between electric mobility, human health and the environment, including synergies and trade-offs, requires a whole systems approach to transport policymaking. In the present paper, we describe the use of Participatory Systems Mapping (PSM) in which a diverse group of stakeholders collaboratively constructed a causal model of the U.K. surface transport system through a series of interactive online workshops. We present the map and its analysis, with our findings illustrating how unintended consequences of EV-focussed transport policies may have an impact on air quality, human health and important social functions of the transport system. We conclude by considering how online participatory causal modelling techniques could be effectively integrated with empirical metrics to facilitate effective policy design and appraisal in the transport sector

Hybrid architecture for shallow accumulation mode AlGaAs/GaAs heterostructures with epitaxial gates

Accumulation mode devices with epitaxially grown gates have excellent electrical stability due to the absence of dopant impurities and surface states. We overcome typical fabrication issues associated with epitaxially gated structures (e.g., gate leakage and high contact resistance) by using separate gates to control the electron densities in the Ohmic and Hall bar regions. This hybrid gate architecture opens up a way to make ultrastable nanoscale devices where the separation between the surface gates and the 2D electron gas is small. In this work, we demonstrate that the hybrid devices made from the same wafer have reproducible electrical characteristics, with identical mobility and density traces over a large range of 2D densities. In addition, thermal cycling does not influence the measured electrical characteristics. As a demonstration of concept, we have fabricated a hybrid single-electron transistor on a shallow (50 nm) AlGaAs/GaAs heterostructure that shows clear Coulomb blockade oscillations in the low temperature conductance.This project was supported by the Australian Government under the Australia-India Strategic Research Fund and by the Australian Research Council (ARC) DP scheme. A.R.H. acknowledges an ARC Outstanding Researcher Award. Devices were fabricated using the facilities at the NSW Node of the Australian National Fabrication Facility (ANFF). J.R., A.L., and A.D.W. acknowledge support from Mercur Pr-2013-0001, BMBF-Q.com-H 16KIS0109, and DFH/UFA CDFA-05-06.Copyright (2015) American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in MacLeod SJ, See AM, Hamilton AR, Farrer I, Ritchie DA, Ritzmann J, Ludwig A, Wieck AD, Applied Physics Letters 106, 012105 (2015) and may be found at http://dx.doi.org/10.1063/1.4905210