Interpreting genetic risks

Prof. Peter Beighton has given a professional lifetime to helping patients and their families who have been afflicted by inherited disease. His clinical skills have brought certainty, confidence and support to those confronted with some of the most difficult decisions in life’s progress. Prof. Beighton’s research has led to the discovery of new syndromes and the elucidation of accurate genetic risks in many diseases. This in turn has empowered patients and their families to make informed decisions and has provided doctors with the scientific knowledge to help patients. On the occasion of this festschrift, I join with so many members of Peter’s international professional family to pay tribute to his leadership and service – not only in medical genetics – but also in the broadest domains of healthcare.

Analysis of the 2007/8 Defra Farm Business Survey Energy Module

Key points This study has delivered an invaluable baseline estimate of energy use and greenhouse gas (GHG) emissions on commercial farms in England. Energy use and GHG emissions associated with particular commodities were quantified and results broadly agreed with those derived by Life Cycle Assessment, but with much scatter in the environmental performance of farms.Direct energy use on farms was generally less that indirect (embedded) energy use, except for horticulture, which is dominated by heating fuel use. In contrast, most GHG emissions are incurred on farms, rather than as embedded emissions.Scatter in both environmental and economic performance underlies the somewhat disappointing finding of no clear positive link between farm financial performance and energy use or GHG emissions. However, the mere existence of these ranges shows that there is scope for improvement in both financial and environmental performance and that there is no apparent barrier for both to be achievable in harmony. The recording of such farm-level energy data is essential for the future, as it should enable improvements to be made in efficiency of energy use. The improved UK agricultural GHG inventory will depend on high quality energy data on agricultural activities. This study will be invaluable in identifying the level of detail needed. Future data requirements include: contractor work rates and fuel use per unit area and per unit time, fertiliser and pesticide use by brand name, enhanced output data, especially animal live weights, and horticultural produce recorded by weight rather than by value

Parameterized Directed kk-Chinese Postman Problem and kk Arc-Disjoint Cycles Problem on Euler Digraphs

In the Directed $k$-Chinese Postman Problem ($k$-DCPP), we are given a connected weighted digraph $G$ and asked to find $k$ non-empty closed directed walks covering all arcs of $G$ such that the total weight of the walks is minimum. Gutin, Muciaccia and Yeo (Theor. Comput. Sci. 513 (2013) 124--128) asked for the parameterized complexity of $k$-DCPP when $k$ is the parameter. We prove that the $k$-DCPP is fixed-parameter tractable. We also consider a related problem of finding $k$ arc-disjoint directed cycles in an Euler digraph, parameterized by $k$. Slivkins (ESA 2003) showed that this problem is W[1]-hard for general digraphs. Generalizing another result by Slivkins, we prove that the problem is fixed-parameter tractable for Euler digraphs. The corresponding problem on vertex-disjoint cycles in Euler digraphs remains W[1]-hard even for Euler digraphs

Fatal, unintentional drowning in older people: an assessment of the role of preexisting medical conditions

Background: The number of older people (aged 65 y and over) is increasing in Australia and chronic medical conditions are common. Aquatic activities provide physical and social benefits; however, understanding the risks related to aquatic activity is important for ongoing health and wellbeing. We explore the impact of preexisting medical conditions on unintentional fatal drowning among older people in Australia. Methods: Using coronial, forensic, and medical histories from the Australian National Coronial Information System, all cases of unintentional death by drowning (or where drowning was a factor) among older people in Australia between July 1, 2002 and June 30, 2012 were investigated. Preexisting medical conditions were reviewed to determine whether they were contributory to drowning. Results: Of the 506 older people who drowned, 69.0% had a preexisting medical condition. The leading contributory medical condition was cardiovascular disease, followed by dementia, depression, epilepsy, and Parkinson disease. All conditions except cardiovascular disease and depression were overrepresented compared with the proportion of the disease in the population. Falling into water was the most common activity immediately before drowning, especially among those with dementia, whereas those with cardiovascular disease were most likely to drown while swimming. Conclusions: Preexisting medical conditions contribute to drowning in older people but with unequal contributions. With the prevalence of medical conditions expected to increase as the population ages, targeted education for older people will be important. Risk management will enable older people to safely participate in aquatic activities

A compilation of observations from moored current meters and associated oceanographic observations : POLYMODE Array III Cluster C, May 1977 - May 1978

A summary of the observations taken from moored stations and hydrographic surveys in POLYMODE Array III Cluster C is presented. Currents and water temperatures were measured at various depths, including: 150, 225, 300, 500, 750, 1500, 2500, and 4000 meters. Hydrographic surveys were made during the deployment and recovery cruises. Currents and water temperature data series cover the period from mid May, 1977 to early May, 1978. Cluster C contained 4 moorings, centered about 16°N, 54°W. Basic statistics of the raw time series data are tabulated. Low passed (3.9 day cutoff) daily time series are used to display: water temperature data, velocity stick diagrams, progressive vector diagrams, zonal and meridional eddy heat flux, eddy kinetic energy, a pseudo eddy potential energy, empirical orthogonal modes, and auto-correlations. Hourly data (low pass cutoff at 2 hours) is used to display spectral quantities. Hydrographic data, including 1600 stations from the N0DC archives, are used to display T-S diagrams, horizontal and vertical structure of temperature, salinity, and density, Brunt-Viasala frequency versus depth, and dynamic topography

Dopamine Augmented Rehabilitation in Stroke (DARS): a multicentre double-blind, randomised controlled trial of co-careldopa compared with placebo, in addition to routine NHS occupational and physical therapy, delivered early after stroke on functional recovery

BACKGROUND: Dopamine is a key modulator of striatal function and learning, and may improve motor recovery after stroke. Seven small trials of dopamine agonists after stroke have provided equivocal evidence of the clinical effectiveness of dopamine agonists in improving motor recovery. DESIGN: Dopamine Augmented Rehabilitation in Stroke was a multicentre, randomised, double-blind, placebo-controlled trial with stroke patients randomised to receive 6 weeks of co-careldopa (Sinemet®, Merck Sharp & Dohme Ltd) or placebo in combination with occupational and physical rehabilitation. METHODS: The primary outcome measure was the proportion of patients walking independently at 8 weeks [Rivermead Mobility Index (RMI) score of ≥ 7 points and ‘yes’ to item 7 on the RMI]. Secondary outcome measures assessed physical functioning, pain, cognition, mood, fatigue and carer burden at 8 weeks, 6 months and 12 months. RESULTS: Between May 2011 and March 2014, 593 patients (mean age 68.5 years) and 165 carers (mean age 59.7 years) were recruited from stroke rehabilitation units; 308 patients were randomised to co-careldopa and 285 to placebo at a median of 15 days following stroke onset. The study drug was to be taken 45–60 minutes before therapy, which included motor activities (mean 23.2 and 24.8 sessions in the co-careldopa and placebo groups, respectively). The mean number of investigational medicinal product doses taken was 20.6 in the co-careldopa group and 22.4 in the placebo group. Ability to walk independently was not improved at 8 weeks [40.6% (co-careldopa) vs. 44.6% (placebo); odds ratio 0.78, 95% confidence interval (CI) 0.53 to 1.15], 6 months [51.6% (co-careldopa) vs. 53.3% (placebo)] or 12 months [51.6% (co-careldopa) vs. 56.8% (placebo)]. There were no significant differences for Barthel Index, Nottingham Extended Activities of Daily Living, ABILHAND Manual Ability Measure or Modified Rankin Scale, pain or fatigue at any time point. Montreal Cognitive Assessment scores did not significantly differ; the majority of participants had cognitive impairment at baseline, which improved during 12 months’ follow-up. No difference was observed in General Health Questionnaire 12-item version scores between groups at 8 weeks and 12 months but, at 6 months, those in the co-careldopa group reported significantly better general health [mean difference (MD) –1.33, 95% CI –2.57 to –0.10]. Mortality at 12 months was not significantly different. Carers in the placebo group reported significantly greater burden at 6 months (MD 5.05, 95% CI 0.10 to 10.01) and 12 months (MD 7.52, 95% CI 1.87 to 13.18). CONCLUSION: Co-careldopa in addition to routine NHS occupational and physical therapy is not clinically effective or cost-effective in improving walking, physical functioning, mood or cognition following stroke. We recommend further research to develop imaging and clinical markers that would allow identification of promising drug therapies that would enhance motor therapy in improving walking ability and arm function. Further research is needed to compare strategies of giving drug therapy intermittently immediately prior to therapy sessions or as continuous background daily administration. LIMITATIONS: In total, 10.3% of patients were lost to follow-up at 8 weeks and < 10% of patients met the strict per-protocol definition. Despite this, the findings are robust and generalisable to patients with limited mobility in the first few weeks after stroke. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99643613. FUNDING: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership

Efficacy and safety of co-careldopa as an add-on therapy to occupational and physical therapy in patients after stroke (DARS): a randomised, double-blind, placebo controlled trial

Background Dopamine is a key modulator of striatal function and learning and might improve motor recovery after stroke. Previous small trials of dopamine agonists after stroke provide equivocal evidence of effectiveness on improving motor recovery. We aimed to assess the safety and efficacy of co-careldopa plus routine occupational and physical therapy during early rehabilitation after stroke. Methods This double-blind, multicentre, randomised controlled trial of co-careldopa versus placebo in addition to routine NHS occupational and physical therapy was done at 51 UK NHS acute inpatient stroke rehabilitation services. We recruited patients with new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke 5–42 days before randomisation, who were unable to walk 10 m or more, had a score of less than 7 points on the Rivermead Mobility Index, were expected to need rehabilitation, and were able to access rehabilitation after discharge from hospital. Participants were assigned (1:1) using stratified random blocks to receive 6 weeks of oral co-careldopa or matched placebo in addition to routine NHS physiotherapy and occupational therapy. The initial two doses of co-careldopa were 62·5 mg (50 mg of levodopa and 12·5 mg of carbidopa) and the remaining doses were 125 mg (100 mg of levodopa and 25 mg of carbidopa). Participants were required to take a single oral tablet 45–60 min before physiotherapy or occupational therapy session. The primary outcome was ability to walk independently, defined as a Rivermead Mobility Index score of 7 or more, at 8 weeks. Primary and safety analyses were done in the intention-to-treat population. The trial is registered on the ISRCTN registry, number ISRCTN99643613.Findings Between May 30, 2011, and March 28, 2014, of 1574 patients found eligible, 593 (mean age 68·5 years) were randomly assigned to either the co-careldopa group (n=308) or to the placebo group (n=285), on an average 18 days after stroke onset. Primary outcome data were available for all 593 patients. We found no evidence that the ability to walk independently improved with co-careldopa (125 [41%] of 308 patients) compared with placebo (127 [45%] of 285 patients; odds ratio 0·78 [95% CI 0·53–1·15]) at 8 weeks. Mortality at 12 months did not differ between the two groups (22 [7%] vs 17 [6%]). Serious adverse events were largely similar between groups. Vomiting during therapy sessions, after taking the study drug, was the most frequent adverse event and was more frequent in the co-careldopa group than the placebo group (19 [6·2%] vs 9 [3·2%]).Interpretation Co-careldopa in addition to routine occupational and physical therapy does not seem to improve walking after stroke. Further research might identify subgroups of patients with stroke who could benefit from dopaminergic therapy at different doses or times after stroke with more intensive motor therap

Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA