Developing the embedded researcher role: Learning from the first year of the National Institute for Health and Care Research (NIHR), Health Determinants Research Collaboration (HDRC), Doncaster, UK.

Background: Strategies to embed research knowledge into decision making contexts include the Embedded Research (ER) model, which involves the collocation of academic researchers in non-academic organisations such as hospitals and local authorities. A local authority in Doncaster, United Kingdom (UK) has adopted an embedded researcher model within the National Institute for Health and Care Research (NIHR), Health Determinants Research Collaboration (HDRC). This five-year collaboration enables universities and local authorities to work together to reduce health inequalities and target the social determinants of health. Building on previous embedded research models, this approach is unique due to its significant scale and long-term investment. In this opinion paper Embedded Researchers (ERs) reflect on their experiences of the first year of the collaboration. Study design: A reflective consultation exercise. Methods: Observation of HDRC delivery meetings, as well as informal discussions and a short proforma with ERs (N = 8). Results: ERs valued the five-year timeframe which provided a unique opportunity for strengthened relationships and to apply formative learning as the programme progressed. However, differences in knowledge of undertaking research across the HDRC team and between practitioners and academics require each to respect different professional experiences and to avoid potential power imbalances. Diverse projects required researchers to be generalists, applying their expertise to multiple topics. This requires careful priority setting alongside workload and expectation management. Conclusions: The significant scale and investment of the HDRC provides a unique opportunity for developing the ER role by applying formative learning as the programme progresses. However, success will require careful management of workload allocation and relationships between ERs and practitioners. Further learning on how to embed ERs within local authority contexts will emerge as the programme matures.

The association between obesity and quality of life: a retrospective analysis of a large-scale population-based cohort study.

BACKGROUND: The relationship between obesity and health-related quality of life (HRQoL) may be confounded by factors such as multimorbidity. The aim of the study was to explore this relationship, controlling for long-term conditions and other health, lifestyle and demographic factors in a general adult population. There was specific interest in the impact of high weight status, measured by body mass index (BMI) levels (obesity, morbid obesity) compared with individuals of normal weight. METHODS: Health, lifestyle and demographic data were collected from 64,631 individuals aged 16 years and over registered in the Yorkshire Health Study; a long-term cohort study. Data were collected in 2 waves: from patients attending GP surgeries in the South Yorkshire region; and using online recruitment across the entire Yorkshire and Humber area. Univariable and multivariable regression methods were utilised to identify factors associated with HRQoL as measured by the EQ-5D summary score. Long-term conditions were tested as both covariates and mediating factors on the causal pathway between obesity and HRQoL. RESULTS: Increasing levels of obesity are associated with reduced HRQoL, although this difference is negligible between those of normal weight and those who are overweight. Individuals with obesity and morbid obesity score 4.9 and 11.3 percentage points less on the EQ-5D summary scale respectively than those of normal weight. Concurrent physical, and particularly mental health-related long-term conditions are substantively related to HRQoL: those with 3 or more reported mental or physical health conditions score 29.8 and 14.6 percentage points less on the EQ-5D summary scale respectively than those with fewer conditions. Long-term conditions can be conceptualised as lying on the causal path between obesity and HRQoL, but there is weak evidence for a partial mediating relationship only. CONCLUSIONS: To conclude, in agreement with the established literature we have found a clear inverse relationship between increasing weight status and decreasing HRQoL and confirmed the mediating role of long-term conditions in the reduction of HRQoL in people with obesity. Nevertheless, a high BMI remains independently related to HRQoL, suggesting that 'healthy people with obesity' may be in transition to an unhealthy future.

Pliocene and Eocene provide best analogs for near-future climates.

As the world warms due to rising greenhouse gas concentrations, the Earth system moves toward climate states without societal precedent, challenging adaptation. Past Earth system states offer possible model systems for the warming world of the coming decades. These include the climate states of the Early Eocene (ca. 50 Ma), the Mid-Pliocene (3.3-3.0 Ma), the Last Interglacial (129-116 ka), the Mid-Holocene (6 ka), preindustrial (ca. 1850 CE), and the 20th century. Here, we quantitatively assess the similarity of future projected climate states to these six geohistorical benchmarks using simulations from the Hadley Centre Coupled Model Version 3 (HadCM3), the Goddard Institute for Space Studies Model E2-R (GISS), and the Community Climate System Model, Versions 3 and 4 (CCSM) Earth system models. Under the Representative Concentration Pathway 8.5 (RCP8.5) emission scenario, by 2030 CE, future climates most closely resemble Mid-Pliocene climates, and by 2150 CE, they most closely resemble Eocene climates. Under RCP4.5, climate stabilizes at Pliocene-like conditions by 2040 CE. Pliocene-like and Eocene-like climates emerge first in continental interiors and then expand outward. Geologically novel climates are uncommon in RCP4.5 (<1%) but reach 8.7% of the globe under RCP8.5, characterized by high temperatures and precipitation. Hence, RCP4.5 is roughly equivalent to stabilizing at Pliocene-like climates, while unmitigated emission trajectories, such as RCP8.5, are similar to reversing millions of years of long-term cooling on the scale of a few human generations. Both the emergence of geologically novel climates and the rapid reversion to Eocene-like climates may be outside the range of evolutionary adaptive capacity.

Icebergs in the Nordic Seas Throughout the Late Pliocene.

The Arctic cryosphere is changing and making a significant contribution to sea level rise. The Late Pliocene had similar CO2 levels to the present and a warming comparable to model predictions for the end of this century. However, the state of the Arctic cryosphere during the Pliocene remains poorly constrained. For the first time we combine outputs from a climate model with a thermodynamic iceberg model to simulate likely source regions for ice-rafted debris (IRD) found in the Nordic Seas from Marine Isotope Stage M2 to the mid-Piacenzian Warm Period and what this implies about the nature of the Arctic cryosphere at this time. We compare the fraction of melt given by the model scenarios with IRD data from four Ocean Drilling Program sites in the Nordic Seas. Sites 911A, 909C, and 907A show a persistent occurrence of IRD that model results suggest is consistent with permanent ice on Svalbard. Our results indicate that icebergs sourced from the east coast of Greenland do not reach the Nordic Seas sites during the warm Late Pliocene but instead travel south into the North Atlantic. In conclusion, we suggest a continuous occurrence of marine-terminating glaciers on Svalbard and on East Greenland (due to the elevation of the East Greenland Mountains during the Late Pliocene). The study has highlighted the usefulness of coupled climate model-iceberg trajectory modeling for understanding ice sheet behavior when proximal geological records for Pliocene ice presence or absence are absent or are inconclusive.

A quantification of the relationship between neuronal responses in the rat rostral ventromedial medulla and noxious stimulation-evoked withdrawal reflexes.

The rostral ventromedial medulla (RVM) regulates a range of involuntary behaviours but is most often associated with nociception via the action of pronociceptive ON cells and antinociceptive OFF cells. The phasic responses of ON and OFF cells determine whether or not incoming noxious signals provoke a withdrawal reflex, and previous studies have suggested that reflex RVM activity patterns actively shape motor output. Here we challenged the model by using juvenile rats, which are known to exhibit markedly different reflex responses compared with adults. By recording single-cell activity in the RVM and the electromyography responses of hindlimb flexor muscles to noxious thermal stimulation we found that the juvenile reflex had a shorter onset latency, was larger in amplitude and exhibited a decreased rise time compared with the adult reflex. The responses of ON and OFF cells faithfully tracked the shorter onset latency of the reflex by also responding earlier and, thus, still preceded the reflex. However, neither the reflex amplitude nor the ongoing response profile was predicted by the firing rate of RVM cells in either age group. Instead we found a close correspondence between RVM activity and the reflex only during the initiation of the response. Furthermore, the short rise time of the juvenile reflex was reflected in higher rates of change of both ON and OFF cell firing. Our data suggest that the RVM is associated only with the initiation of reflexes and does not shape ongoing muscle activity, which is more likely to be subserved by downstream spinal processes.

Macroevolutionary consequences of profound climate change on niche evolution in marine molluscs over the past three million years.

In order to predict the fate of biodiversity in a rapidly changing world, we must first understand how species adapt to new environmental conditions. The long-term evolutionary dynamics of species' physiological tolerances to differing climatic regimes remain obscure. Here, we unite palaeontological and neontological data to analyse whether species' environmental tolerances remain stable across 3 Myr of profound climatic changes using 10 phylogenetically, ecologically and developmentally diverse mollusc species from the Atlantic and Gulf Coastal Plains, USA. We additionally investigate whether these species' upper and lower thermal tolerances are constrained across this interval. We find that these species' environmental preferences are stable across the duration of their lifetimes, even when faced with significant environmental perturbations. The results suggest that species will respond to current and future warming either by altering distributions to track suitable habitat or, if the pace of change is too rapid, by going extinct. Our findings also support methods that project species' present-day environmental requirements to future climatic landscapes to assess conservation risks.

Non-Fickian diffusion and the accumulation of methane bubbles in deep-water sediments.

In the absence of fractures, methane bubbles in deep-water sediments can be immovably trapped within a porous matrix by surface tension. The dominant mechanism of transfer of gas mass therefore becomes the diffusion of gas molecules through porewater. The accurate description of this process requires non-Fickian diffusion to be accounted for, including both thermal diffusion and gravitational action. We evaluate the diffusive flux of aqueous methane considering non-Fickian diffusion and predict the existence of extensive bubble mass accumulation zones within deep-water sediments. The limitation on the hydrate deposit capacity is revealed; too weak deposits cannot reach the base of the hydrate stability zone and form any bubbly horizon.

Warm climates of the past--a lesson for the future?

This Discussion Meeting Issue of the Philosophical Transactions A had its genesis in a Discussion Meeting of the Royal Society which took place on 10-11 October 2011. The Discussion Meeting, entitled 'Warm climates of the past: a lesson for the future?', brought together 16 eminent international speakers from the field of palaeoclimate, and was attended by over 280 scientists and members of the public. Many of the speakers have contributed to the papers compiled in this Discussion Meeting Issue. The papers summarize the talks at the meeting, and present further or related work. This Discussion Meeting Issue asks to what extent information gleaned from the study of past climates can aid our understanding of future climate change. Climate change is currently an issue at the forefront of environmental science, and also has important sociological and political implications. Most future predictions are carried out by complex numerical models; however, these models cannot be rigorously tested for scenarios outside of the modern, without making use of past climate data. Furthermore, past climate data can inform our understanding of how the Earth system operates, and can provide important contextual information related to environmental change. All past time periods can be useful in this context; here, we focus on past climates that were warmer than the modern climate, as these are likely to be the most similar to the future. This introductory paper is not meant as a comprehensive overview of all work in this field. Instead, it gives an introduction to the important issues therein, using the papers in this Discussion Meeting Issue, and other works from all the Discussion Meeting speakers, as exemplars of the various ways in which past climates can inform projections of future climate. Furthermore, we present new work that uses a palaeo constraint to quantitatively inform projections of future equilibrium ice sheet change.

Extemporaneous compounding in veterinary practice: a New Zealand perspective.

AIMS: The aims of this study were to explore the extent of extemporaneous compounding in veterinary centres throughout New Zealand and to determine whether pharmacists could collaborate with veterinarians to improve this service in New Zealand. METHODS: Questionnaires were sent to 200 randomly selected veterinarians in New Zealand. Semi-structured interviews were also conducted with selected participants from four animal facilities (zoos, research facilities and animal shelters) and two compounding pharmacies. RESULTS: Of the 200 veterinarian questionnaire recipients, 99 responded. Ten replies were withdrawn from the study giving a response rate of 44.5%. Of these 89, 33 (37%) compounded in their practice. Of the 33 compounding professionals, 3 (9%) compounded daily for animals under their care; 11 (34%) weekly, 18 (54%) monthly and 1 (3%) compounded yearly. Compounding was done by 29/33 (88%) veterinarians, 16/33 (48%) veterinary nurses or 6/33 (18%) others. It was carried out due to the unavailability of commercial products, or the need for dose adjustment to ease administration or improve compliance. The animals most commonly requiring veterinary compounding were dogs (21/33; 64%), cats (19/33; 58%) or cattle (15/33; 46%). Products which were commonly compounded included cyclosporin eye drops, methimazole gels and potassium bromide solutions. Issues commonly faced when compounding included unavailability of dosage forms (18/33; 55%) or appropriate ingredients (14/33; 42%), stability (12/33; 36%), time constraints (10/33; 30%) or unavailability of equipment (9/33; 27%). Reasons given for not compounding included medicines being commercially available (38/56; 68%), pharmacy compounding for those particular practices (24/56; 43%), lack of training (21/56; 38%), ingredients (16/56; 29%) or equipment (15/56; 11%). All participants who worked with a pharmacist (11/33; 33%) described this relationship as beneficial and indicated they would continue to do so in the future. CONCLUSIONS: Veterinary extemporaneous compounding exists in New Zealand. As pharmacists have extensive knowledge in formulating medications and compounding they could be of greater value to veterinarians and their patients. Educating both professions on the opportunities available to them from this collaboration could be an important step forward. CLINICAL RELEVANCE: This study provides new information regarding extemporaneous compounding for veterinary patients in New Zealand.

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43.

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.

A stable-isotope HPLC-MS/MS method to simplify storage of human whole blood samples for glutathione assay.

BACKGROUND: Glutathione is the principal non-protein tripeptide thiol present in most mammalian cells and plays an important role in the redox status of biological systems. The accurate assessment of reduced glutathione (GSH) status as a reliable index of oxidative stress is of research and clinical significance. GSH undergoes rapid oxidation after sample collection and this presents a challenge. METHODS: Validation of an HPLC-MS/MS assay is reported. Storage stability using four variants of a methanolic precipitation with addition of stable isotope internal standard at collection is compared to L-serine borate/EDTA with perchloric acid precipitation (SBPE). RESULTS: Precipitation with methanol and addition of stable isotope on sample collection, combined with storage in solution at -70 °C showed superior storage stability to SBPE and other variants of the methanolic precipitation method up to 99 days. CONCLUSIONS: The combination of stable isotope with methanolic precipitation at collection, with assay by HPLC-MS/MS provides superior results after storage of whole blood samples for at least 99 days.

Prochlorperazine tablets repackaged into dose administration aids: can the patient be assured of quality?

BACKGROUND AND OBJECTIVE: Patients are increasingly requiring their medications to be repackaged into dose administration aids because of the positive outcomes associated with reduction in medication related hospitalization and adverse effects due to improved medicines management. Since the stability of these repackaged medications is not the responsibility of manufacturer, it is important that drug substances with potential stability issues be identified. Thus the objective of this study was to evaluate the stability of prochlorperazine, a light sensitive drug repackaged into dose administration aids (DAAs), in order to provide guidelines to the pharmacist and advice to the patient on appropriate storage. METHODS: Prochlorperazine tablets were stored repackaged in DAAs and in their original packaging for 8 weeks at ambient (25 +/- 1 degrees C; 60 +/- 1.5% RH), accelerated (40 +/- 1 degrees C; 75 +/- 1.5% RH) and in-use conditions encountered in situ both in a pharmacy and the patients' home. They were assessed for both chemical (using a validated HPLC method) and physical stability according to British Pharmacopoeial (BP) standards. In addition, photostability testing was undertaken under ICH conditions. RESULTS AND DISCUSSION: Chemical and physical stability was confirmed to be within BP Limits. There were, however, noticeable organoleptic changes in the tablets stored under in-use conditions with a progressive grey discolouration over the 8 weeks, starting in week 2. CONCLUSION: Despite the confirmation of physical and chemical stability within BP limits, the discoloration and the potential for photodegradants to cause adverse effects in patients must lead us to draw the conclusion that the quality of this medication has been compromised. Pharmacists thus need to take this into account in repackaging and storage of prochlorperazine in DAAs and advise patients to store their DAA protected from light, heat and humidity.

The past is a guide to the future? Comparing Middle Pliocene vegetation with predicted biome distributions for the twenty-first century.

During the Middle Pliocene, the Earth experienced greater global warmth compared with today, coupled with higher atmospheric CO2 concentrations. To determine the extent to which the Middle Pliocene can be used as a 'test bed' for future warming, we compare data and model-based Middle Pliocene vegetation with simulated global biome distributions for the mid- and late twenty-first century. The best agreement is found when a Middle Pliocene biome reconstruction is compared with a future scenario using 560 ppmv atmospheric CO2. In accordance with palaeobotanical data, all model simulations indicate a generally warmer and wetter climate, resulting in a northward shift of the taiga-tundra boundary and a spread of tropical savannah and woodland in Africa and Australia at the expense of deserts. Our data-model comparison reveals differences in the distribution of polar vegetation, which indicate that the high latitudes during the Middle Pliocene were still warmer than its predicted modern analogue by several degrees. However, our future scenarios do not consider multipliers associated with 'long-term' climate sensitivity. Changes in global temperature, and thus biome distributions, at higher atmospheric CO2 levels will not have reached an equilibrium state (as is the case for the Middle Pliocene) by the end of this century.

Assessing the assessment measures for menstrual cycle symptoms: a guide for researchers and clinicians.

A review of measures of menstrual cycle symptoms is provided. This will enable researchers and clinicians to make the appropriate choice of method for their study requirements. In recent years, these measures have taken the form of retrospective questionnaires (rating severity of symptoms from memory) and prospective diaries (daily checklists of symptoms). Many of these draw on aspects of the well-known retrospective questionnaires, the Menstrual Distress Questionnaire and Premenstrual Assessment Form, in their development and validation. Each measure will be briefly described, followed by comments on its development, psychometric properties and finally an evaluation of its strengths and weaknesses. It concludes with an examination of the implications arising from the review, and some recommendations that menstrual cycle researchers and clinicians may wish to consider, as they decide upon the most appropriate measure for their needs.

Alcohol actions on GABA(A) receptors: from protein structure to mouse behavior.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were R. Adron Harris and Susumu Ueno. The presentations were (1) Protein kinase Cepsilon-regulated sensitivity of gamma-aminobutyric acid type A (GABAA) receptors to allosteric agonists, by Robert O. Messing, A. M. Sanchez-Perez, C. W. Hodge, T. McMahon, D. Wang, K. K. Mehmert, S. P. Kelley, A. Haywood, and M. F. Olive; (2) Genetic and functional analysis of a GABAA receptor gamma2 subunit variant: A candidate for quantitative trait loci involved in alcohol sensitivity and withdrawal, by Kari J. Buck and Heather M. Hood; (3) Tryptophan-scanning mutagenesis in GABAA receptor subunits: Channel gating and alcohol actions, by Susumu Ueno; and (4) Can a single binding site account for actions of alcohols on GABAA and glycine receptors? by R. Adron Harris, Yuri Blednov, Geoffrey Findlay, and Maria Paola Mascia.

Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKCepsilon.

Several of the actions of ethanol are mediated by gamma-aminobutyrate type A (GABA(A)) receptors. Here we demonstrated that mutant mice lacking protein kinase C epsilon (PKCepsilon) were more sensitive than wild-type littermates to the acute behavioral effects of ethanol and other drugs that allosterically activate GABA(A) receptors. GABA(A) receptors in membranes isolated from the frontal cortex of PKCepsilon null mice were also supersensitive to allosteric activation by ethanol and flunitrazepam. In addition, these mutant mice showed markedly reduced ethanol self-administration. These findings indicate that inhibition of PKCepsilon increases sensitivity of GABA(A) receptors to ethanol and allosteric modulators. Pharmacological agents that inhibit PKCepsilon may be useful for treatment of alcoholism and may provide a non-sedating alternative for enhancing GABA(A) receptor function to treat other disorders such as anxiety and epilepsy.

General anaesthesia: who decides, and why?

This study sought to determine the relative influence dentists and parents have on the decision to give a general anaesthetic to a child, and to identify the factors that influence that decision. The research involved group discussions and in-depth interviewing as a method of investigating attitudes and behaviour in greater detail. The results indicated that parents are not able to make informed choices about general anaesthesia being used on their child; the dentist has the greatest influence on the decision to use general anaesthesia; and that this decision is often influenced by non-clinical factors. These non-clinical factors were identified as: the norms of the dentist, overall attitudes to general anaesthesia and how general anaesthesia provision was structured locally. The findings suggest that any attempt to reduce the current levels of general anaesthesia further must address these factors, whilst taking into account the needs of patients and dentists.