Noncoding RNAs and Duchenne muscular dystrophy

Noncoding RNAs (ncRNAs) such as miRNAs and long noncoding RNAs modulate gene transcription in response to environmental stressors and other stimuli. A role for ncRNAs in muscle pathologies has been demonstrated and further evidence suggests that ncRNAs also play a role in Duchenne muscular dystrophy (DMD). Studies investigating the differential expression of miRNAs in biological fluids between DMD patients and models of dystrophin deficiency (the MDX mouse model, canine models of DMD) and controls have been published, as these have a role in fibrosis. Long noncoding RNAs are differentially expressed in DMD patients and may, in part, have a mechanism of action via targeting of miRNAs. Although many of these recent findings need to be confirmed, ncRNAs may prove to be useful as potential biomarkers of disease. However, their use as therapeutic targets in DMD remains unclear

Towards an Efficient Finite Element Method for the Integral Fractional Laplacian on Polygonal Domains

We explore the connection between fractional order partial differential equations in two or more spatial dimensions with boundary integral operators to develop techniques that enable one to efficiently tackle the integral fractional Laplacian. In particular, we develop techniques for the treatment of the dense stiffness matrix including the computation of the entries, the efficient assembly and storage of a sparse approximation and the efficient solution of the resulting equations. The main idea consists of generalising proven techniques for the treatment of boundary integral equations to general fractional orders. Importantly, the approximation does not make any strong assumptions on the shape of the underlying domain and does not rely on any special structure of the matrix that could be exploited by fast transforms. We demonstrate the flexibility and performance of this approach in a couple of two-dimensional numerical examples

Big data analyses reveal patterns and drivers of the movements of southern elephant seals

The growing number of large databases of animal tracking provides an opportunity for analyses of movement patterns at the scales of populations and even species. We used analytical approaches, developed to cope with big data, that require no a priori assumptions about the behaviour of the target agents, to analyse a pooled tracking dataset of 272 elephant seals (Mirounga leonina) in the Southern Ocean, that was comprised of >500,000 location estimates collected over more than a decade. Our analyses showed that the displacements of these seals were described by a truncated power law distribution across several spatial and temporal scales, with a clear signature of directed movement. This pattern was evident when analysing the aggregated tracks despite a wide diversity of individual trajectories. We also identified marine provinces that described the migratory and foraging habitats of these seals. Our analysis provides evidence for the presence of intrinsic drivers of movement, such as memory, that cannot be detected using common models of movement behaviour. These results highlight the potential for big data techniques to provide new insights into movement behaviour when applied to large datasets of animal tracking.Comment: 18 pages, 5 figures, 6 supplementary figure

Anticarbamylated protein antibodies are associated with long-term disability and increased disease activity in patients with early inflammatory arthritis:Results from the Norfolk Arthritis Register

Objectives: Anticarbamylated protein (anti-CarP) antibodies are a novel family of autoantibodies recently identified in patients with inflammatory arthritis. The aim of this study was to investigate their association with long-term outcomes of disability and disease activity over 20 years’ follow-up in a cohort of patients with inflammatory polyarthritis (IP).  Methods: Norfolk Arthritis Register recruited adults with recent-onset swelling of ≥2 joints for ≥4 weeks from 1990 to 2009. At baseline, Health Assessment Questionnaire (HAQ) and 28 joint disease activity scores (DAS28) were obtained, and C reactive protein, rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA) and anti-CarP antibodies were measured. Further HAQ scores and DAS28 were obtained at regular intervals over 20 years. Generalised estimating equations were used to test the association between anti-CarP antibody status and longitudinal HAQ and DAS28 scores; adjusting for age, gender, smoking status, year of inclusion and ACPA status. Analyses were repeated in subgroups stratified by ACPA status. The relative association of RF, ACPA and anti-CarP antibodies with HAQ and DAS28 scores was investigated using a random effects model.  Results: 1995 patients were included; 1310 (66%) were female. Anti-CarP antibodies were significantly associated with more disability and higher disease activity, HAQ multivariate β-coefficient (95% CI) 0.12 (0.02 to 0.21), and these associations remained significant in the ACPA-negative subgroups. The associations of RF, ACPA and anti-CarP antibodies were found to be additive in the random effects model.  Conclusions: Anti-CarP antibodies are associated with increased disability and higher disease activity in patients with IP. Our results suggest that measurement of anti-CarP antibodies may be useful in identifying ACPA-negative patients with worse long-term outcomes. Further, anti-CarP antibody status provided additional information about RF and ACPA

An evaluation of enteral nutrition practices and nutritional provision in children during the entire length of stay in critical care

<b>Background</b> Provision of optimal nutrition in children in critical care is often challenging. This study evaluated exclusive enteral nutrition (EN) provision practices and explored predictors of energy intake and delay of EN advancement in critically ill children.<p></p> <b>Methods</b> Data on intake and EN practices were collected on a daily basis and compared against predefined targets and dietary reference values in a paediatric intensive care unit. Factors associated with intake and advancement of EN were explored.<p></p> <b>Results</b> Data were collected from 130 patients and 887 nutritional support days (NSDs). Delay to initiate EN was longer in patients from both the General Surgical and congenital heart defect (CHD) Surgical groups [Median (IQR); CHD Surgical group: 20.3 (16.4) vs General Surgical group: 11.4 (53.5) vs Medical group: 6.5 (10.9) hours; p <= 0.001]. Daily fasting time per patient was significantly longer in patients from the General Surgical and CHD Surgical groups than those from the Medical group [% of 24 h, Median (IQR); CHD Surgical group: 24.0 (29.2) vs General Surgical group: 41.7 (66.7) vs Medical group: 9.4 (21.9); p <= 0.001]. A lower proportion of fluids was delivered as EN per patient (45% vs 73%) or per NSD (56% vs 73%) in those from the CHD Surgical group compared with those with medical conditions. Protein and energy requirements were achieved in 38% and 33% of the NSDs. In a substantial proportion of NSDs, minimum micronutrient recommendations were not met particularly in those patients from the CHD Surgical group. A higher delivery of fluid requirements (p < 0.05) and a greater proportion of these delivered as EN (p < 0.001) were associated with median energy intake during stay and delay of EN advancement. Fasting (31%), fluid restriction (39%) for clinical reasons, procedures requiring feed cessation and establishing EN (22%) were the most common reasons why target energy requirements were not met.<p></p> <b>Conclusions</b> Provision of optimal EN support remains challenging and varies during hospitalisation and among patients. Delivery of EN should be prioritized over other "non-nutritional" fluids whenever this is possible.<p></p&gt

Multiple uncontrolled conditions and blood pressure medication intensification: an observational study

Abstract Background Multiple uncontrolled medical conditions may act as competing demands for clinical decision making. We hypothesized that multiple uncontrolled cardiovascular risk factors would decrease blood pressure (BP) medication intensification among uncontrolled hypertensive patients. Methods We observed 946 encounters at two VA primary care clinics from May through August 2006. After each encounter, clinicians recorded BP medication intensification (BP medication was added or titrated). Demographic, clinical, and laboratory information were collected from the medical record. We examined BP medication intensification by presence and control of diabetes and/or hyperlipidemia. 'Uncontrolled' was defined as hemoglobin A1c ≥ for diabetes, BP ≥ 140/90 mmHg (≥ 130/80 mmHg if diabetes present) for hypertension, and low density lipoprotein cholesterol (LDL-c) ≥ 130 mg/dl (≥ 100 mg/dl if diabetes present) for hyperlipidemia. Hierarchical regression models accounted for patient clustering and adjusted medication intensification for age, systolic BP, and number of medications. Results Among 387 patients with uncontrolled hypertension, 51.4% had diabetes (25.3% were uncontrolled) and 73.4% had hyperlipidemia (22.7% were uncontrolled). The BP medication intensification rate was 34.9% overall, but higher in individuals with uncontrolled diabetes and uncontrolled hyperlipidemia: 52.8% overall and 70.6% if systolic BP ≥ 10 mmHg above goal. Intensification rates were lowest if diabetes or hyperlipidemia were controlled, lower than if diabetes or hyperlipidemia were not present. Multivariable adjustment yielded similar results. Conclusions The presence of uncontrolled diabetes and hyperlipidemia was associated with more guideline-concordant hypertension care, particularly if BP was far from goal. Efforts to understand and improve BP medication intensification in patients with controlled diabetes and/or hyperlipidemia are warranted.http://deepblue.lib.umich.edu/bitstream/2027.42/78266/1/1748-5908-5-55.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78266/2/1748-5908-5-55.pdfPeer Reviewe

Prevalence and Correlates of Common Mental Disorders among Mothers of Young Children in Kilimanjaro Region of Tanzania.

Although poor maternal mental health is a major public health problem, with detrimental effects on the individual, her children and society, information on its correlates in low-income countries is sparse. This study investigates the prevalence of common mental disorders (CMD) among at-risk mothers, and explores its associations with sociodemographic factors. This population-based survey of mothers of children aged 0-36 months used the 14-item Shona Symptom Questionnaire (SSQ). Mothers whose response was "yes" to 8 or more items on the scale were defined as "at risk of CMD." Of the 1,922 mothers (15-48 years), 28.8% were at risk of CMD. Risk of CMD was associated with verbal abuse, physical abuse, a partner who did not help with the care of the child, being in a polygamous relationship, a partner with low levels of education, and a partner who smoked cigarettes. Cohabiting appeared to be protective. Taken together, our results indicate the significance of the quality of relations with one's partner in shaping maternal mental health. The high proportion of mothers who are at risk of CMD emphasizes the importance of developing evidence-based mental health programmes as part of the care package aimed at improving maternal well-being in Tanzania and other similar settings

Can programme theory be used as a 'translational tool’ to optimise health service delivery in a national early years’ initiative in Scotland: a case study

Background Theory-based evaluation (TBE) approaches are heralded as supporting formative evaluation by facilitating increased use of evaluative findings to guide programme improvement. It is essential that learning from programme implementation is better used to improve delivery and to inform other initiatives, if interventions are to be as effective as they have the potential to be. Nonetheless, few studies describe formative feedback methods, or report direct instrumental use of findings resulting from TBE. This paper uses the case of Scotland’s, National Health Service, early years’, oral health improvement initiative (Childsmile) to describe the use of TBE as a framework for providing feedback on delivery to programme staff and to assess its impact on programmatic action.<p></p> Methods In-depth, semi-structured interviews and focus groups with key stakeholders explored perceived deviations between the Childsmile programme 'as delivered’ and its Programme Theory (PT). The data was thematically analysed using constant comparative methods. Findings were shared with key programme stakeholders and discussions around likely impact and necessary actions were facilitated by the authors. Documentary review and ongoing observations of programme meetings were undertaken to assess the extent to which learning was acted upon.<p></p> Results On the whole, the activities documented in Childsmile’s PT were implemented as intended. This paper purposefully focuses on those activities where variation in delivery was evident. Differences resulted from the stage of roll-out reached and the flexibility given to individual NHS boards to tailor local implementation. Some adaptations were thought to have diverged from the central features of Childsmile’s PT, to the extent that there was a risk to achieving outcomes. The methods employed prompted national service improvement action, and proposals for local action by individual NHS boards to address this.<p></p> Conclusions The TBE approach provided a platform, to direct attention to areas of risk within a national health initiative, and to agree which intervention components were 'core’ to its hypothesised success. The study demonstrates that PT can be used as a 'translational tool’ to facilitate instrumental use of evaluative findings to optimise implementation within a complex health improvement programme.<p></p&gt

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Control of hyperglycaemia in paediatric intensive care (CHiP): study protocol.

BACKGROUND: There is increasing evidence that tight blood glucose (BG) control improves outcomes in critically ill adults. Children show similar hyperglycaemic responses to surgery or critical illness. However it is not known whether tight control will benefit children given maturational differences and different disease spectrum. METHODS/DESIGN: The study is an randomised open trial with two parallel groups to assess whether, for children undergoing intensive care in the UK aged <or= 16 years who are ventilated, have an arterial line in-situ and are receiving vasoactive support following injury, major surgery or in association with critical illness in whom it is anticipated such treatment will be required to continue for at least 12 hours, tight control will increase the numbers of days alive and free of mechanical ventilation at 30 days, and lead to improvement in a range of complications associated with intensive care treatment and be cost effective. Children in the tight control group will receive insulin by intravenous infusion titrated to maintain BG between 4 and 7.0 mmol/l. Children in the control group will be treated according to a standard current approach to BG management. Children will be followed up to determine vital status and healthcare resources usage between discharge and 12 months post-randomisation. Information regarding overall health status, global neurological outcome, attention and behavioural status will be sought from a subgroup with traumatic brain injury (TBI). A difference of 2 days in the number of ventilator-free days within the first 30 days post-randomisation is considered clinically important. Conservatively assuming a standard deviation of a week across both trial arms, a type I error of 1% (2-sided test), and allowing for non-compliance, a total sample size of 1000 patients would have 90% power to detect this difference. To detect effect differences between cardiac and non-cardiac patients, a target sample size of 1500 is required. An economic evaluation will assess whether the costs of achieving tight BG control are justified by subsequent reductions in hospitalisation costs. DISCUSSION: The relevance of tight glycaemic control in this population needs to be assessed formally before being accepted into standard practice