Predictors of social participation: evidence from repeated cross-sectional population surveys in England.

BACKGROUND: Social participation is linked to better health and well-being. However, there is limited research on the individual and area-level predictors of participation. This study aims to determine the characteristics associated with participation, particularly the impact of community asset availability. METHODS: We used data from 34 582 adult respondents to the nationally representative Community Life Survey from 2013 to 2018. We measured social participation by reported participation in 15 types of groups. We used probit and negative binomial regression models and included a wide range of individual, household and area characteristics, and availability of 14 types of community assets. RESULTS: The following characteristics were associated with higher levels of participation: being female (+3.0 percentage points (p.p.) (95% CI 1.8 to 4.1p.p.), Black, Asian or Minority Ethnicity (+3.7p.p. (1.9 to 5.5p.p.)), homeownership (+4.1 p.p. (2.7 to 5.6p.p.)) and living in a rural area (+2.1p.p. (0.5 to 3.6p.p)). Respondents from the most deprived areas were less likely to participate than those in average deprivation areas (-3.9p.p. (-5.9 to -1.99p.p.)). Higher availability of community assets was associated with increased participation in groups. The effect of availability on participation varied by type of asset. CONCLUSION: Improving community assets infrastructure in high deprivation and urban areas would encourage more social participation in these areas.

NNLO interpolation grids for jet production at the LHC.

Fast interpolation-grid frameworks facilitate an efficient and flexible evaluation of higher-order predictions for any choice of parton distribution functions or value of the strong coupling α s . They constitute an essential tool for the extraction of parton distribution functions and Standard Model parameters, as well as studies of the dependence of cross sections on the renormalisation and factorisation scales. The APPLfast project provides a generic interface between the parton-level Monte Carlo generator and both the APPLgrid and the fastNLO libraries for the grid interpolation. The extension of the project to include hadron-hadron collider processes at next-to-next-to-leading order in perturbative QCD is presented, together with an application for jet production at the LHC.

Universal dynamics of coarsening during polymer-polymer thin-film spinodal dewetting kinetics.

The dewetting dynamics of a supported bilayer polymer thin film on a solid substrate is investigated using grazing incidence x-ray photon correlation spectroscopy. We find that the top layer dewets via the spinodal mechanism. The kinetics of the dewetting is studied by monitoring the time evolution of the surface diffuse x-ray scattering intensity. We study the time evolution of fluctuations about the average surface structure by measuring the two-time x-ray intensity fluctuation correlation functions. Using these two-time correlation functions we quantify the crossover from early-time diffusive dynamics to hydrodynamics. The early diffusive regime satisfies dynamic universality. The two-time correlation functions also quantify the onset of hydrodynamic effects. The hydrodynamic regime is observed during the spinodal dewetting process as these interactions are not screened.

Recruitment and Consent in an observational study.

OBJECTIVE: The study sought to explore the consent rate and associated potential bias across a cohort in a large longitudinal population based study. RESEARCH DESIGN: Data were taken from a study designed to examine the effects of the reintroduction of community water fluoridation on children's oral health over a five-year period. Children were recruited from a fluoridated and non-fluoridated area in Cumbria, referred to as Group 1 and Group 2. RESULTS: Data were available for 3138 individuals. The consent rate was 12.91 percentage points lower in Group 2 than Group 1 (95% CI -16.27 to -9.56, p⟨0.001). The population in Group 2 was more deprived (higher Index of Multiple Deprivation (IMD)) than Group 1 before consent was taken. Consent was not associated with deprivation in either group. CONCLUSION: The cohort appeared to be unaffected by IMD-related non-consent. However there was a difference in consent rate between the two groups. With the population in Group 1 being more deprived than Group 2, it will be important to incorporate these differences into the analysis at the end of this longitudinal study.

Sociodemographic disparities in non-diabetic hyperglycaemia and the transition to type 2 diabetes: evidence from the English Longitudinal Study of Ageing.

AIM: To explore whether there are social inequalities in non-diabetic hyperglycaemia (NDH) and in transitions to type 2 diabetes mellitus and NDH low-risk status in England. METHODS: Some 9143 men and women aged over 50 years were analysed from waves 2, 4, 6 and 8 (2004-2016) of the English Longitudinal Study of Ageing (ELSA). Participants were categorized as: NDH 'low-risk' [HbA1c < 42 mmol/mol (< 6.0%)], NDH [HbA1c 42-47 mmol/mol (6.0-6.4%)] and type 2 diabetes [HbA1c > 47 mmol/mol (> 6.4%)]. Logistic regression models estimated the association between sociodemographic characteristics and NDH, and the transitions from NDH to diagnosed or undiagnosed type 2 diabetes and low-risk status in future waves. RESULTS: NDH was more prevalent in older participants, those reporting a disability, those living in deprived areas and in more disadvantaged social classes. Older participants with NDH were less likely to progress to undiagnosed type 2 diabetes [odds ratio (OR) 0.27, 95% confidence interval (CI) 0.08, 0.96]. NDH individuals with limiting long-standing illness (OR 1.72, 95% CI 1.16, 2.53), who were economically inactive (OR 1.60, 95% CI 1.02, 2.51) or from disadvantaged social classes (OR 1.63, 95% CI 1.02, 2.61) were more likely to progress to type 2 diabetes. Socially disadvantaged individuals were less likely (OR 0.64, 95% CI 0.41, 0.98) to progress to NDH low-risk status. CONCLUSIONS: There were socio-economic differences in NDH prevalence, transition to type 2 diabetes and transition to NDH low-risk status. Disparities in transitions included the greater likelihood of disadvantaged social groups with NDH developing type 2 diabetes and greater likelihood of advantaged social groups with NDH becoming low-risk. These socio-economic differences should be taken into account when targeting prevention initiatives.

Calculations for deep inelastic scattering using fast interpolation grid techniques at NNLO in QCD and the extraction of α s from HERA data.

The extension of interpolation-grid frameworks for perturbative QCD calculations at next-to-next-to-leading order (NNLO) is presented for deep inelastic scattering (DIS) processes. A fast and flexible evaluation of higher-order predictions for any a posteriori choice of parton distribution functions (PDFs) or value of the strong coupling constant is essential in iterative fitting procedures to extract PDFs and Standard Model parameters as well as for a detailed study of the scale dependence. The APPLfast project, described here, provides a generic interface between the parton-level Monte Carlo program NNLOjet and both the APPLgrid and fastNLO libraries for the production of interpolation grids at NNLO accuracy. Details of the interface for DIS processes are presented together with the required interpolation grids at NNLO, which are made available. They cover numerous inclusive jet measurements by the H1 and ZEUS experiments at HERA. An extraction of the strong coupling constant is performed as an application of the use of such grids and a best-fit value of α s ( M Z ) = 0.1170 ( 15 ) exp ( 25 ) th is obtained using the HERA inclusive jet cross section data.

How the past impacts the future: modelling the performance of evolutionarily distinct mammals through time.

How does past evolutionary performance impact future evolutionary performance? This is an important question not just for macroevolutionary biologists who wish to chart the phenomena that describe deep-time changes in biodiversity but also for conservation biologists, as evolutionarily distinct species-which may be deemed 'low-performing' in our current era-are increasingly the focus of conservation efforts. Contrasting hypotheses exist to account for the history and future of evolutionarily distinct species: on the one hand, they may be relicts of large radiations, potentially 'doomed' to extinction; or they may be slow-evolving, 'living fossils', likely neither to speciate nor go extinct; or they may be seeds of future radiations. Here, we attempt to test these hypotheses in Mammalia by combining a molecular phylogenetic supertree with fossil record occurrences and measuring change in evolutionary distinctness (ED) at different time slices. With these time slices, we modelled future ED as a function of past ED. We find that past evolutionary performance does indeed have an impact on future evolutionary performance: the most evolutionarily isolated clades tend to become more evolutionarily distinct with time, indicating that low-performing clades tend to remain low-performing throughout their evolutionary history. This article is part of a discussion meeting issue 'The past is a foreign country: how much can the fossil record actually inform conservation?'

Accelerometer activity tracking in horses and the effect of pasture management on time budget.

BACKGROUND: Accelerometry is an accepted means of quantifying human physical activity. Quantitative physical activity tracking could be beneficial for studies into equine health and disease prevention, for example in relation to obesity management. OBJECTIVES: Validate accelerometer use in grazing horses, determine between-day repeatability, and assess the effects of pasture size on time budget (i.e. duration in each activity category). STUDY DESIGN: Proof of concept. METHODS: Accelerometers (ActiGraph) were positioned at the poll. Horses underwent 5 min of observed activity in three categories: standing, grazing and ambulating. Receiver-operating characteristic curve analysis, used on ten second data epochs, calculated cut points between the activities. A 20-day study was then undertaken on 6 horses at pasture. Time in each category (per day) was deduced; a Mann Whitney U test was performed to compare standard vs. small paddock and day vs. night turn out. RESULTS: Cut-off values with the optimum sensitivity (94.7-97.7%) and specificity (94.7-96.8%) were found to be <127.6 counts for standing, 127.6-702.7 counts for grazing and >702.7 counts for ambulating. Repeatability was analysed descriptively: Median (IQR) of the between-day difference in minutes standing, grazing and ambulating were 46.9 (21.3-87.9), 77.3 (40.2-124.5) and 15.6 (6.8-40.2) respectively. Median times standing and ambulating were significantly different between standard and small paddocks: standing: 8.7 vs. 10.3 h (P<0.001); ambulating: 55.7 vs. 39.6 min (P = 0.002). There was no significant difference in the median time spent grazing. There were significant differences between day and night: standing: 32.95% vs. 50.97% (P = 0.001), grazing: 60.81% vs. 46.77% (P<0.001) and ambulating: 4.57% vs. 2.40% (P<0.001). MAIN LIMITATIONS: Small sample size and lack of cross-validation of cut-off points on independent, 'unseen' data. CONCLUSIONS: Accelerometry can differentiate standing, grazing and ambulating in horses. Our proof-of-concept study demonstrates modifying pasture size influences activity budgets; opening avenues into studying obesity management.

δ15N of lichens reflects the isotopic signature of ammonia source.

Although it is generally accepted that δ15N in lichen reflects predominating N isotope sources in the environment, confirmation of the direct correlation between lichen δ15N and atmospheric δ15N is still missing, especially under field conditions with most confounding factors controlled. To fill this gap and investigate the response of lichens with different tolerance to atmospheric N deposition, thalli of the sensitive Evernia prunastri and the tolerant Xanthoria parietina were exposed for ten weeks to different forms and doses of N in a field manipulation experiment where confounding factors were minimized. During this period, several parameters, namely total N, δ15N and chlorophyll a fluorescence, were measured. Under the experimental conditions, δ15N in lichens quantitatively responded to the δ15N of released gaseous ammonia (NH3). Although a high correlation between the isotopic signatures in lichen tissue and supplied N was found both in tolerant and sensitive species, chlorophyll a fluorescence indicated that the sensitive species very soon lost its photosynthetic functionality with increasing N availability. The most damaging response to the different N chemical forms was observed with dry deposition of NH3, although wet deposition of ammonium ions had a significant observable physiological impact. Conversely, there was no significant effect of nitrate ions on chlorophyll a fluorescence, implying differential sensitivity to dry deposition versus wet deposition and to ammonium versus nitrate in wet deposition. Evernia prunastri was most sensitive to NH3, then NH4+, with lowest sensitivity to NO3-. Moreover, these results confirm that lichen δ15N can be used to indicate the δ15N of atmospheric ammonia, providing a suitable tool for the interpretation of the spatial distribution of NH3 sources in relation to their δ15N signal.

Uncertainties and implications of applying aggregated data for spatial modelling of atmospheric ammonia emissions.

Ammonia emissions vary greatly at a local scale, and effects (eutrophication, acidification) occur primarily close to sources. Therefore it is important that spatially distributed emission estimates are located as accurately as possible. The main source of ammonia emissions is agriculture, and therefore agricultural survey statistics are the most important input data to an ammonia emission inventory alongside per activity estimates of emission potential. In the UK, agricultural statistics are collected at farm level, but are aggregated to parish level, NUTS-3 level or regular grid resolution for distribution to users. In this study, the Modifiable Areal Unit Problem (MAUP), associated with such amalgamation, is investigated in the context of assessing the spatial distribution of ammonia sources for emission inventories. England was used as a test area to study the effects of the MAUP. Agricultural survey data at farm level (point data) were obtained under license and amalgamated to different areal units or zones: regular 1-km, 5-km, 10-km grids and parish level, before they were imported into the emission model. The results of using the survey data at different levels of amalgamation were assessed to estimate the effects of the MAUP on the spatial inventory. The analysis showed that the size and shape of aggregation zones applied to the farm-level agricultural statistics strongly affect the location of the emissions estimated by the model. If the zones are too small, this may result in false emission "hot spots", i.e., artificially high emission values that are in reality not confined to the zone to which they are allocated. Conversely, if the zones are too large, detail may be lost and emissions smoothed out, which may give a false impression of the spatial patterns and magnitude of emissions in those zones. The results of the study indicate that the MAUP has a significant effect on the location and local magnitude of emissions in spatial inventories where amalgamated, zonal data are used.

Towards ultrafast dynamics with split-pulse X-ray photon correlation spectroscopy at free electron laser sources.

One of the important challenges in condensed matter science is to understand ultrafast, atomic-scale fluctuations that dictate dynamic processes in equilibrium and non-equilibrium materials. Here, we report an important step towards reaching that goal by using a state-of-the-art perfect crystal based split-and-delay system, capable of splitting individual X-ray pulses and introducing femtosecond to nanosecond time delays. We show the results of an ultrafast hard X-ray photon correlation spectroscopy experiment at LCLS where split X-ray pulses were used to measure the dynamics of gold nanoparticles suspended in hexane. We show how reliable speckle contrast values can be extracted even from very low intensity free electron laser (FEL) speckle patterns by applying maximum likelihood fitting, thus demonstrating the potential of a split-and-delay approach for dynamics measurements at FEL sources. This will enable the characterization of equilibrium and, importantly also reversible non-equilibrium processes in atomically disordered materials.

Contemporary women's secure psychiatric services in the United Kingdom: A qualitative analysis of staff views.

WHAT IS KNOWN ON THE SUBJECT?: Three pilot UK-only Women's Enhanced Medium Secure Services (WEMSS) was opened in 2007 to support women's movement from high secure care and provide a bespoke, women-only service. Evidence suggests that women's secure services are particularly challenging environments to work in and staffing issues (e.g., high turnover) can cause difficulties in establishing a therapeutic environment. Research in this area has focused on the experiences of service users. Studies which have examined staff views have focused on their feelings towards women in their care and the emotional burden of working in women's secure services. No papers have made a direct comparison between staff working in different services. WHAT DOES THIS STUDY ADD TO EXISTING KNOWLEDGE?: This is the first study to explore the views and experiences of staff in the three UK WEMSS pilot services and contrast them with staff from women's medium secure services. Drawing upon data from eighteen semi-structured interviews (nine WEMSS, nine non-WEMSS), key themes cover staff perceptions of factors important for women's recovery and their views on operational aspects of services. This study extends our understanding of the experiences of staff working with women in secure care and bears relevance for staff working internationally, as well as in UK services. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The study reveals the importance of induction and training for bank and agency staff working in women's secure services. Further, regular clinical supervision should be mandatory for all staff so they are adequately supported. ABSTRACT: Introduction Women's Enhanced Medium Secure Services (WEMSS) is bespoke, gender-sensitive services which opened in the UK in 2007 at three pilot sites. This study is the first of its kind to explore the experiences of WEMSS staff, directly comparing them to staff in a standard medium secure service for women. The literature to date has focused on the experiences of service users or staff views on working with women in secure care. Aim This qualitative study, embedded in a multimethod evaluation of WEMSS, aimed to explore the views and experiences of staff in WEMSS and comparator medium secure services. Methods Qualitative interviews took place with nine WEMSS staff and nine comparator medium secure staff. Interviews focused on factors important for recovery, barriers to facilitating recovery and operational aspects of the service. Discussion This study provides a rare insight into the perspectives of staff working in UK women's secure services, an under-researched area in the UK and internationally. Findings suggest that the success of services, including WEMSS, is compromised by operational factors such as the use of bank staff. Implications for practice Comprehensive training and supervision should be mandatory for all staff, so best practice is met and staff adequately supported.

Long-term increases in soil carbon due to ecosystem fertilization by atmospheric nitrogen deposition demonstrated by regional-scale modelling and observations.

Fertilization of nitrogen (N)-limited ecosystems by anthropogenic atmospheric nitrogen deposition (Ndep) may promote CO2 removal from the atmosphere, thereby buffering human effects on global radiative forcing. We used the biogeochemical ecosystem model N14CP, which considers interactions among C (carbon), N and P (phosphorus), driven by a new reconstruction of historical Ndep, to assess the responses of soil organic carbon (SOC) stocks in British semi-natural landscapes to anthropogenic change. We calculate that increased net primary production due to Ndep has enhanced detrital inputs of C to soils, causing an average increase of 1.2 kgCm-2 (c. 10%) in soil SOC over the period 1750-2010. The simulation results are consistent with observed changes in topsoil SOC concentration in the late 20th Century, derived from sample-resample measurements at nearly 2000 field sites. More than half (57%) of the additional topsoil SOC is predicted to have a short turnover time (c. 20 years), and will therefore be sensitive to future changes in Ndep. The results are the first to validate model predictions of Ndep effects against observations of SOC at a regional field scale. They demonstrate the importance of long-term macronutrient interactions and the transitory nature of soil responses in the terrestrial C cycle.

Association between psychological health and wound complications after surgery.

BACKGROUND: Surgical wound complications remain a major cause of morbidity, leading to higher costs and reduced quality of life. Although psychological health is widely considered to affect wound healing, the evidence on wound outcomes after surgery is mixed. Studies generally focus on small samples of patients undergoing a specific procedure and have limited statistical power. METHODS: This study investigated the relationship between three different measures of anxiety and/or depression and seven adverse surgical outcomes using observational data collected before and after surgery between 2009 and 2011. A wide range of confounding factors was adjusted for, including patient demographics, physical co-morbidities, health-related behaviours, month of operation, procedure complexity and treating hospital. RESULTS: The estimation sample included 176 827 patients undergoing 59 410 hip replacements, 64 145 knee replacements, 38 328 hernia repairs and 14 944 varicose vein operations. Patients with moderate anxiety or depression had an increased probability of wound complications after a hip replacement (odds ratio (OR) 1·17, 95 per cent c.i. 1·11 to 1·24). They were more likely to be readmitted for a wound complication (OR 1·20, 1·02 to 1·41) and had an increased duration of hospital stay by 0·19 (95 per cent c.i. 0·15 to 0·24) days. Estimated associations were consistent across all four types of operation and for each measure of anxiety and/or depression. CONCLUSION: Preoperative psychological health is a significant risk factor for adverse wound outcomes after surgery for four of the procedures most commonly performed in England.

Evaluation of a minor eye conditions scheme delivered by community optometrists.

BACKGROUND: The establishment of minor eye conditions schemes (MECS) within community optometric practices provides a mechanism for the timely assessment of patients presenting with a range of acute eye conditions. This has the potential to reduce waiting times and avoid unnecessary referrals to hospital eye services (HES). OBJECTIVE: To evaluate the clinical effectiveness, impact on hospital attendances and patient satisfaction with a minor eye service provided by community optometrists. METHODS: Activity and outcome data were collected for 12 months in the Lambeth and Lewisham MECS. A patient satisfaction questionnaire was given to patients at the end of their MECS appointment. A retrospective difference-in-differences analysis of hospital activity compared changes in the volume of referrals by general practitioners (GPs) from a period before (April 2011-March 2013) to after (April 2013-March 2015) the introduction of the scheme in Lambeth and Lewisham relative to a neighbouring area (Southwark) where the scheme had not been commissioned. Appropriateness of case management was assessed by consensus using clinical members of the research team. RESULTS: A total of 2123 patients accessed the scheme. Approximately two-thirds of patients (67.5%) were referred by their GP. The commonest reasons for patients attending for a MECS assessment were 'red eye' (36.7% of patients), 'painful white eye' (11.1%) and 'flashes and floaters' (10.2%). A total of 64.1% of patients were managed in optometric practice and 18.9% were referred to the HES; of these, 89.2% had been appropriately referred. First attendances to HES referred by GPs reduced by 26.8% (95% CI -40.5% to -13.1%) in Lambeth and Lewisham compared to Southwark. CONCLUSIONS: The Lambeth and Lewisham MECS demonstrates clinical effectiveness, reduction in hospital attendances and high patient satisfaction and represents a successful collaboration between commissioners, local HES units and primary healthcare providers.

The potential for tree planting strategies to reduce local and regional ecosystem impacts of agricultural ammonia emissions.

Trees are very effective at capturing both gaseous and particulate pollutants from the atmosphere. But while studies have often focussed on PM and NOx in the urban environment, little research has been carried out on the tree effect of capturing gaseous emissions of ammonia in the rural landscape. To examine the removal or scavenging of ammonia by trees a long-range atmospheric model (FRAME) was used to compare two strategies that could be used in emission reduction policies anywhere in the world where nitrogen pollution from agriculture is a problem. One strategy was to reduce the emission source strength of livestock management systems by implementing two 'tree-capture' systems scenarios - tree belts downwind of housing and managing livestock under trees. This emission reduction can be described as an 'on-farm' emission reduction policy, as ammonia is 'stopped' from dispersion outside the farm boundaries. The second strategy was to apply an afforestation policy targeting areas of high ammonia emission through two planting scenarios of increasing afforestation by 25% and 50%. Both strategies use trees with the aim of intercepting NH3 emissions to protect semi-natural areas. Scenarios for on-farm emission reductions showed national reductions in nitrogen deposition to semi-natural areas of 0.14% (0.2 kt N-NHx) to 2.2% (3.15 kt N-NHx). Scenarios mitigating emissions from cattle and pig housing gave the highest reductions. The afforestation strategy showed national reductions of 6% (8.4 kt N-NHx) to 11% (15.7 kt N-NHx) for 25% and 50% afforestation scenarios respectively. Increased capture by the planted trees also showed an added benefit of reducing long range effects including a decrease in wet deposition up to 3.7 kt N-NHx (4.6%) and a decrease in export from the UK up to 8.3 kt N-NHx (6.8%).

ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts.

Autophagy can sustain or kill tumor cells depending upon the context. The mechanism of autophagy-associated cell death has not been well elucidated and autophagy has enhanced or inhibited sensitivity of cancer cells to cytotoxic chemotherapy in different models. ARHI (DIRAS3), an imprinted tumor suppressor gene, is downregulated in 60% of ovarian cancers. In cell culture, re-expression of ARHI induces autophagy and ovarian cancer cell death within 72 h. In xenografts, re-expression of ARHI arrests cell growth and induces autophagy, but does not kill engrafted cancer cells. When ARHI levels are reduced after 6 weeks, dormancy is broken and xenografts grow promptly. In this study, ARHI-induced ovarian cancer cell death in culture has been found to depend upon autophagy and has been linked to G1 cell-cycle arrest, enhanced reactive oxygen species (ROS) activity, RIP1/RIP3 activation and necrosis. Re-expression of ARHI enhanced the cytotoxic effect of cisplatin in cell culture, increasing caspase-3 activation and PARP cleavage by inhibiting ERK and HER2 activity and downregulating XIAP and Bcl-2. In xenografts, treatment with cisplatin significantly slowed the outgrowth of dormant autophagic cells after reduction of ARHI, but the addition of chloroquine did not further inhibit xenograft outgrowth. Taken together, we have found that autophagy-associated cancer cell death and autophagy-enhanced sensitivity to cisplatin depend upon different mechanisms and that dormant, autophagic cancer cells are still vulnerable to cisplatin-based chemotherapy.

Quantification of diastolic dysfunction via the age dependence of diastolic function - impact of insulin resistance with and without type 2 diabetes.

BACKGROUND: The alarming prevalence of heart failure with preserved ejection fraction requires quantification of diastolic dysfunction (DDF). Myocardial diastolic velocity E' implies that age is the most important determinant. We tested the hypothesis that age allows for quantification of DDF and assessment of the structural and metabolic determinants in patients with and without type 2 diabetes (D). METHODS: This prospective, cross-sectional study assessed cardiovascular, metabolic and ultrasound data in 409 consecutive patients (Diabetes Center, Bogenhausen-Munich) between 20 and 90 years without known cardiac disease and either with (n=204) or without D but with common prevalence of cardiovascular risk factors, including a subgroup of healthy individuals (H, n=94). RESULTS: In H, E' related to age as: E'norm=-0.163∗years+19.69 (R(2)=0.77, p<0.0001). According to this 1% reduction by annual physiologic aging, DDF was quantitated as E'-E' norm. Compared to nondiabetics, D patients were older, had greater BMI, lower E', more cardiovascular risk and greater DDF. In nondiabetics, grading of DDF by E-E'norm correlated with grading by filling pressure E/E'. Determinants of DDF by multivariate analysis included pulse wave velocity, diastolic blood pressure and the triglyceride/HDL ratio (a marker of insulin resistance) in nondiabetics and in D the same risk factors in reverse sequence and heart rate. Neither left atrial size nor left ventricular mass had significant impact. CONCLUSIONS: The physiological impact of age on myocardial function consists of a 1% annual reduction in E' and enables precise quantification of diastolic dysfunction thereby unmasking the importance of metabolic risk for DDF.

ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7.

The process of autophagy has been described in detail at the molecular level in normal cells, but less is known of its regulation in cancer cells. Aplasia Ras homolog member I (ARHI; DIRAS3) is an imprinted tumor suppressor gene that is downregulated in multiple malignancies including ovarian cancer. Re-expression of ARHI slows proliferation, inhibits motility, induces autophagy and produces tumor dormancy. Our previous studies have implicated autophagy in the survival of dormant ovarian cancer cells and have shown that ARHI is required for autophagy induced by starvation or rapamycin treatment. Re-expression of ARHI in ovarian cancer cells blocks signaling through the PI3K and Ras/MAP pathways, which, in turn, downregulates mTOR and initiates autophagy. Here we show that ARHI is required for autophagy-meditated cancer cell arrest and ARHI inhibits signaling through PI3K/AKT and Ras/MAP by enhancing internalization and degradation of the epidermal growth factor receptor. ARHI-mediated downregulation of PI3K/AKT and Ras/ERK signaling also decreases phosphorylation of FOXo3a, which sequesters this transcription factor in the nucleus. Nuclear retention of FOXo3a induces ATG4 and MAP-LC3-I, required for maturation of autophagosomes, and also increases the expression of Rab7, required for fusion of autophagosomes with lysosomes. Following the knockdown of FOXo3a or Rab7, autophagolysosome formation was observed but was markedly inhibited, resulting in numerous enlarged autophagosomes. ARHI expression correlates with LC3 expression and FOXo3a nuclear localization in surgical specimens of ovarian cancer. Thus, ARHI contributes to the induction of autophagy through multiple mechanisms in ovarian cancer cells.

Impaired sensorimotor gating in Fmr1 knock out and Fragile X premutation model mice.

Fragile X syndrome (FXS) is a common inherited cause of intellectual disability that results from a CGG repeat expansion in the FMR1 gene. Large repeat expansions trigger both transcriptional and translational suppression of Fragile X protein (FMRP) production. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an allelic neurodegenerative disease caused by smaller "pre-mutation" CGG repeat expansions that enhance FMR1 transcription but lead to translational inefficiency and reduced FMRP expression in animal models. Sensorimotor gating as measured by pre-pulse inhibition (PPI) is altered in both FXS patients and Fmr1 knock out (KO) mice. Similarly, FXTAS patients have demonstrated PPI deficits. Recent work suggests there may be overlapping synaptic defects between Fmr1 KO and CGG knock-in premutation mouse models (CGG KI). We therefore sought to interrogate PPI in CGG KI mice. Using a quiet PPI protocol more akin to human testing conditions, we find that Fmr1 KO animals have significantly impaired PPI. Using this same protocol, we find CGG KI mice demonstrate an age-dependent impairment in PPI compared to wild type (WT) controls. This study describes a novel phenotype in CGG KI mice that can be used in future therapeutic development targeting premutation associated symptoms.