Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

This project was supported by Queen Mary Innovation Ltd Proof of Concept Fund (2012/13) and The William Harvey Research Foundation

Influence of Adiposity on Insulin Resistance and Glycemia Markers Among UK Children of South Asian, Black African-Caribbean, and White European Origin Child Heart and Health Study in England

OBJECTIVE: Ethnic differences in type 2 diabetes risk between South Asians and white Europeans originate before adult life and are not fully explained by higher adiposity levels in South Asians. Although metabolic sensitivity to adiposity may differ between ethnic groups, this has been little studied in childhood. We have therefore examined the associations among adiposity, insulin resistance, and glycemia markers in children of different ethnic origins. RESEARCH DESIGN AND METHODS: Cross-sectional study of 4,633 9- to 10-year-old children (response rate 68%) predominantly of South Asian, black African-Caribbean, and white European origin (n = 1,266, 1,176, and 1,109, respectively) who had homeostasis model assessments of insulin resistance (HOMA-IR), glycemia markers (HbA1c and fasting glucose), and adiposity (BMI, waist circumference, skinfold thicknesses, and bioimpedance [fat mass]). RESULTS: All adiposity measures were positively associated with HOMA-IR in all ethnic groups, but associations were stronger among South Asians compared to black African-Caribbeans and white Europeans. For a 1-SD increase in fat mass percentage, percentage differences in HOMA-IR were 37.5% (95% CI 33.3–41.7), 29.7% (25.8–33.8), and 27.0% (22.9–31.2), respectively (P interaction < 0.001). All adiposity markers were positively associated with HbA1c in South Asians and black African-Caribbeans but not in white Europeans; for a 1-SD increase in fat mass percentage, percentage differences in HbA1c were 0.04% (95% CI 0.03–0.06), 0.04% (0.02–0.05), and 0.02% (−0.00 to 0.04), respectively (P interaction < 0.001). Patterns for fasting glucose were less consistent. CONCLUSIONS: South Asian children are more metabolically sensitive to adiposity. Early prevention or treatment of childhood obesity may be critical for type 2 diabetes prevention, especially in South Asians

Awareness without learning: A preliminary study exploring the effects of beachgoer's experiences on risk taking behaviours

Most drowning deaths on Australian beaches occur in locations not patrolled by lifeguards. At patrolled locations, where lifeguards supervise flagged areas in which beachgoers are encouraged to swim between, the incidence of drowning is reduced. To date, risk prevention practices on coasts focus on patrolled beaches, deploying warning signs at unpatrolled locations with the aim of raising public awareness of risk. What remains unexplored is the potential for learning and behaviour change that can transfer from patrolled to unpatrolled beaches through beachgoer's experiences and interactions with lifeguards. The aim of this preliminary study is to explore the risk perceptions of beachgoers at a patrolled beach to establish if and how their experiences of beach risk and interactions with lifeguards affect their behaviours. Data was collected in Gerroa, Australia by engaging 49 beachgoers using a mixed survey-interview methodology. Results show that beachgoers are aware that they should ‘swim between the flags’, but many did not know the basis for the positioning of safety flags. A key finding is that beachgoer's express a clear desire for a skills-based model of community engagement that enables learning with lifeguards. This demonstrates a reflective public that desires skill-development, which may transfer from patrolled to unpatrolled beaches to affect broader risk reduction on the Australian coast. Learning how to avoid site-specific rip hazards with lifeguards at the beach presents a promising, and previously unexplored model for beach drowning risk prevention that has the potential to affect behaviour at unpatrolled beaches, providing an empirically-supported alternative to prevailing deficit-based awareness raising methods

Initiation of Psychotropic Medication after Partner Bereavement: A Matched Cohort Study

Background Recent changes to diagnostic criteria for depression in DSM-5 remove the bereavement exclusion, allowing earlier diagnosis following bereavement. Evaluation of the potential effect of this change requires an understanding of existing psychotropic medication prescribing by non-specialists after bereavement. Aims To describe initiation of psychotropic medication in the first year after partner bereavement. Methods In a UK primary care database, we identified 21,122 individuals aged 60 and over with partner bereavement and no psychotropic drug use in the previous year. Prescribing (anxiolytic/hypnotic, antidepressant, antipsychotic) after bereavement was compared to age, sex and practice matched controls. Results The risks of receiving a new psychotropic prescription within two and twelve months of bereavement were 9.5% (95% CI 9.1 to 9.9%) and 17.9% (17.3 to 18.4%) respectively; an excess risk of initiation in the first year of 12.4% compared to non-bereaved controls. Anxiolytic/hypnotic and antidepressant initiation rates were highest in the first two months. In this period, the hazard ratio for initiation of anxiolytics/hypnotics was 16.7 (95% CI 14.7 to 18.9) and for antidepressants was 5.6 (4.7 to 6.7) compared to non-bereaved controls. 13.3% of those started on anxiolytics/hypnotics within two months continued to receive this drug class at one year. The marked variation in background family practice prescribing of anxiolytics/hypnotics was the strongest determinant of their initiation in the first two months after bereavement. Conclusion Almost one in five older people received a new psychotropic drug prescription in the year after bereavement. The early increase and trend in antidepressant use after bereavement suggests some clinicians did not adhere to the bereavement exclusion, with implications for its recent removal in DSM-5. Family practice variation in use of anxiolytics/hypnotics suggests uncertainty over their role in bereavement with the potential for inappropriate long term use

Use of spatiotemporal analysis of laboratory submission data to identify potential outbreaks of new or emerging diseases in cattle in Great Britain

BACKGROUND: New and emerging diseases of livestock may impact animal welfare, trade and public health. Early detection of outbreaks can reduce the impact of these diseases by triggering control measures that limit the number of cases that occur. The aim of this study was to investigate whether prospective spatiotemporal methods could be used to identify outbreaks of new and emerging diseases in scanning surveillance data. SaTScan was used to identify clusters of unusually high levels of submissions where a diagnosis could not be reached (DNR) using different probability models and baselines. The clusters detected were subjected to a further selection process to reduce the number of false positives and a more detailed epidemiological analysis to ascertain whether they were likely to represent real outbreaks. RESULTS: 187,925 submissions of clinical material from cattle were made to the Regional Laboratory of the Veterinary Laboratories Agency (VLA) between 2002 and 2007, and the results were stored on the VLA FarmFile database. 16,925 of these were classified as DNRs and included in the analyses. Variation in the number and proportion of DNRs was found between syndromes and regions, so a spatiotemporal analysis for each DNR syndrome was done. Six clusters were identified using the Bernoulli model after applying selection criteria (e.g. size of cluster). The further epidemiological analysis revealed that one of the systemic clusters could plausibly have been due to Johne's disease. The remainder were either due to misclassification or not consistent with a single diagnosis. CONCLUSIONS: Our analyses have demonstrated that spatiotemporal methods can be used to detect clusters of new or emerging diseases, identify clusters of known diseases that may not have been diagnosed and identify misclassification in the data, and highlighted the impact of data quality on the ability to detect outbreaks. Spatiotemporal methods should be used alongside current temporal methods for analysis of scanning surveillance data. These statistical analyses should be followed by further investigation of possible outbreaks to determine whether cases have common features suggesting that these are likely to represent real outbreaks, or whether issues with the collection or processing of information have resulted in false positives

Unified force law for granular impact cratering

Experiments on the low-speed impact of solid objects into granular media have been used both to mimic geophysical events and to probe the unusual nature of the granular state of matter. Observations have been interpreted in terms of conflicting stopping forces: product of powers of projectile depth and speed; linear in speed; constant, proportional to the initial impact speed; and proportional to depth. This is reminiscent of high-speed ballistics impact in the 19th and 20th centuries, when a plethora of empirical rules were proposed. To make progress, we developed a means to measure projectile dynamics with 100 nm and 20 us precision. For a 1-inch diameter steel sphere dropped from a wide range of heights into non-cohesive glass beads, we reproduce prior observations either as reasonable approximations or as limiting behaviours. Furthermore, we demonstrate that the interaction between projectile and medium can be decomposed into the sum of velocity-dependent inertial drag plus depth-dependent friction. Thus we achieve a unified description of low-speed impact phenomena and show that the complex response of granular materials to impact, while fundamentally different from that of liquids and solids, can be simply understood

Age-related differences in adaptation during childhood: The influences of muscular power production and segmental energy flow caused by muscles

Acquisition of skillfulness is not only characterized by a task-appropriate application of muscular forces but also by the ability to adapt performance to changing task demands. Previous research suggests that there is a different developmental schedule for adaptation at the kinematic compared to the neuro-muscular level. The purpose of this study was to determine how age-related differences in neuro-muscular organization affect the mechanical construction of pedaling at different levels of the task. By quantifying the flow of segmental energy caused by muscles, we determined the muscular synergies that construct the movement outcome across movement speeds. Younger children (5-7 years; n = 11), older children (8-10 years; n = 8), and adults (22-31 years; n = 8) rode a stationary ergometer at five discrete cadences (60, 75, 90, 105, and 120 rpm) at 10% of their individually predicted peak power output. Using a forward dynamics simulation, we determined the muscular contributions to crank power, as well as muscular power delivered to the crank directly and indirectly (through energy absorption and transfer) during the downstroke and the upstroke of the crank cycle. We found significant age × cadence interactions for (1) peak muscular power at the hip joint [Wilks' Lambda = 0.441, F(8,42) = 2.65, p = 0.019] indicating that at high movement speeds children produced less peak power at the hip than adults, (2) muscular power delivered to the crank during the downstroke and the upstroke of the crank cycle [Wilks' Lambda = 0.399, F(8,42) = 3.07, p = 0.009] indicating that children delivered a greater proportion of the power to the crank during the upstroke when compared to adults, (3) hip power contribution to limb power [Wilks' Lambda = 0.454, F(8,42) = 2.54, p = 0.023] indicating a cadence-dependence of age-related differences in the muscular synergy between hip extensors and plantarflexors. The results demonstrate that in spite of a successful performance, children construct the task of pedaling differently when compared to adults, especially when they are pushed to their performance limits. The weaker synergy between hip extensors and plantarflexors suggests that a lack of inter-muscular coordination, rather than muscular power production per se, is a factor that limits children's performance ranges

How to find an attractive solution to the liar paradox

The general thesis of this paper is that metasemantic theories can play a central role in determining the correct solution to the liar paradox. I argue for the thesis by providing a specific example. I show how Lewis’s reference-magnetic metasemantic theory may decide between two of the most influential solutions to the liar paradox: Kripke’s minimal fixed point theory of truth and Gupta and Belnap’s revision theory of truth. In particular, I suggest that Lewis’s metasemantic theory favours Kripke’s solution to the paradox over Gupta and Belnap’s. I then sketch how other standard criteria for assessing solutions to the liar paradox, such as whether a solution faces a so-called revenge paradox, fit into this picture. While the discussion of the specific example is itself important, the underlying lesson is that we have an unused strategy for resolving one of the hardest problems in philosophy

The challenges faced in the design, conduct and analysis of surgical randomised controlled trials

Randomised evaluations of surgical interventions are rare; some interventions have been widely adopted without rigorous evaluation. Unlike other medical areas, the randomised controlled trial (RCT) design has not become the default study design for the evaluation of surgical interventions. Surgical trials are difficult to successfully undertake and pose particular practical and methodological challenges. However, RCTs have played a role in the assessment of surgical innovations and there is scope and need for greater use. This article will consider the design, conduct and analysis of an RCT of a surgical intervention. The issues will be reviewed under three headings: the timing of the evaluation, defining the research question and trial design issues. Recommendations on the conduct of future surgical RCTs are made. Collaboration between research and surgical communities is needed to address the distinct issues raised by the assessmentof surgical interventions and enable the conduct of appropriate and well-designed trials.The Health Services Research Unit is funded by the Scottish Government Health DirectoratesPeer reviewedPublisher PD