The Potential Impact of Displacing Sedentary Time in Adults with Type 2 Diabetes.

This is the final published version. Available from Lippincott, Williams & Wilkins via the DOI in this record.PURPOSE: Sedentary time, in particular, prolonged unbroken sedentary time, is detrimental to health and displaces time spent in either light or moderate intensity physical activity. This cross-sectional study aimed to identify the potential impact of reallocating time from sedentary behaviors to more active behaviors on measures of body composition and metabolic health in people with type 2 diabetes. METHODS: Participants were 519 adults with newly diagnosed type 2 diabetes who had been recruited to the Early Activity in Diabetes (Early ACTID) randomized controlled trial. Waist-worn accelerometers were used to obtain objective measurement of sedentary time, light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) at baseline alongside clinical measurements and fasting blood samples to determine cholesterol, triglycerides, HOMA-IR, and glucose. Isotemporal substitution modeling was performed to determine the potential impact of reallocating 30 min of sedentary time accumulated in a single bout (long bout) with 30 min of interrupted sedentary time, LPA, or MVPA. RESULTS: Sedentary time accounted for 65% of the waking day, of which 45% was accumulated in prolonged (≥30 min) bouts. Reallocation of 30 min of long-bout sedentary time with 30 min of short-bout sedentary time was associated with lower body mass index (BMI) (adjusted β, -0.60; 95% confidence interval [CI], -1.00, -0.21) and waist circumference (WC) (adjusted β, -1.16; 95% CI, -2.08, -0.25). Stronger effects were seen for LPA and MVPA. Reallocation of 30 min of long-bout sedentary time with LPA was associated with higher HDL-cholesterol (adjusted β, 0.02; 95% CI, 0.00-0.03 mmol·L). CONCLUSIONS: Encouraging adults with newly diagnosed type 2 diabetes to break up prolonged periods of sedentary time may be an effective strategy for improving body composition and metabolic health.National Institute for Health Research (NIHR

Development of a brief, reliable and valid diet assessment tool for impaired glucose tolerance and diabetes: the UK Diabetes and Diet Questionnaire.

This is the final published version. Available from Cambridge University Press via the DOI in this record.OBJECTIVE: Dietary advice is fundamental in the prevention and management of type 2 diabetes (T2DM). Advice is improved by individual assessment but existing methods are time-consuming and require expertise. We developed a twenty-five-item questionnaire, the UK Diabetes and Diet Questionnaire (UKDDQ), for quick assessment of an individual's diet. The present study examined the UKDDQ's repeatability and relative validity compared with 4 d food diaries. DESIGN: The UKDDQ was completed twice with a median 3 d gap (interquartile range=1-7 d) between tests. A 4 d food diary was completed after the second UKDDQ. Diaries were analysed and food groups were mapped on to the UKDDQ. Absolute agreement between total scores was examined using intra-class correlation (ICC). Agreement for individual items was tested with Cohen's weighted kappa (κ w). SETTING: South West of England. SUBJECTS: Adults (n 177, 50·3 % women) with, or at high risk for, T2DM; mean age 55·8 (sd 8·6) years, mean BMI 34·4 (sd 7·3) kg/m2; participants were 91 % White British. RESULTS: The UKDDQ showed excellent repeatability (ICC=0·90 (0·82, 0·94)). For individual items, κ w ranged from 0·43 ('savoury pastries') to 0·87 ('vegetables'). Total scores from the UKDDQ and food diaries compared well (ICC=0·54 (0·27, 0·70)). Agreement for individual items varied and was good for 'alcohol' (κ w=0·71) and 'breakfast cereals' (κ w=0·70), with no agreement for 'vegetables' (κ w=0·08) or 'savoury pastries' (κ w=0·09). CONCLUSIONS: The UKDDQ is a new British dietary questionnaire with excellent repeatability. Comparisons with food diaries found agreements similar to those for international dietary questionnaires currently in use. It targets foods and habits important in diabetes prevention and management.National Institute for Health Research (NIHR)Avon Primary Care Research CollaborativeNational Institute for Health Research (NIHR

Dietary changes and associations with metabolic improvements in adults with type 2 diabetes during a patient-centred dietary intervention: an exploratory analysis.

This is the final published version. Available from BMJ Publishing Group via the DOI in this record.OBJECTIVES: Describe dietary intake of participants enrolled in a non-prescriptive dietary intervention and dietary changes at 6 months and explore whether these changes had a role in observed improvements in glycated haemoglobin (HbA1c), weight, lipids and blood pressure. DESIGN: Secondary analysis of data from the Early ACTivity in Diabetes randomised controlled trial. PARTICIPANTS: 262 patients with newly diagnosed type 2 diabetes randomised to the dietary intervention. OUTCOMES AND ANALYSIS: Changes in energy intake, macronutrients, fibre and alcohol and in weight, waist circumference, lipids, HbA1c and blood pressure at baseline and 6 months. Multivariate models were used to examine associations between dietary changes and metabolic variables. RESULTS: Men reported reducing mean energy intake from 1903±462 kcal to 1685 kcal±439 kcal (p<0.001), increasing carbohydrate intake from 42.4±6.6% to 43.8±6.6% (p=0.002) and reducing median alcohol intake from 13 (0-27) g to 5 (0-18) g (p<0.001). Women reported reducing mean energy intake from 1582±379 kcal to 1459±326 kcal (p<0.001) with no change to macronutrient distribution and alcohol. Fibre intake was maintained. In men (n=148), weak and clinically insignificant associations were found between increased carbohydrates and reduction in HbA1c (β=-0.003 (-0.006, -0.001); p=0.009), increased fibre and reduction in total cholesterol (β=-0.023 (-0.044, -0.002); p=0.033), decreased total fat and reduction in low-density lipoprotein (LDL)-cholesterol (β=0.024 (0.006, 0.001); p=0.011), and decreased alcohol and reduction in diastolic blood pressure (β=0.276 (0.055, 0.497); p=0.015). In women (n=75), associations were found between a decrease in transfats and reductions in waist circumference (β=-0.029 (0.006, 0.052); p=0.015), total cholesterol (β=0.399 (0.028, 0.770); p=0.036) and LDL cholesterol (β=0.365 (0.042, 0.668); p=0.028). CONCLUSIONS: Clinically important metabolic improvements observed in a patient-centred dietary intervention were not explained by changes in macronutrients. However, a non-prescriptive approach may promote a reduction in total energy intake while maintaining fibre consumption. TRIAL REGISTRATION NUMBER: The Early ACTID trial number ISRCTN92162869.Diabetes UKUK Department of HealthWestern Comprehensive Local Research NetworkNational Institute for Health Research (NIHR

Selective Inhibitors of Kv11.1 Regulate IL-6 Expression by Macrophages in Response to TLR/IL-1R Ligands

The mechanism by which the platelet-endothelial cell adhesion molecule PECAM-1 regulates leukodiapedesis, vascular endothelial integrity, and proinflammatory cytokine expression in vivo is not known. We recently identified PECAM-1 as a negative regulator of Kv11.1, a specific voltage-gated potassium channel that functioned in human macrophages to reset a resting membrane potential following depolarization. We demonstrate here that dofetilide (DOF), a selective inhibitor of the Kv11.1 current, had a profound inhibitory effect on neutrophil recruitment in mice following TLR/IL-1R–elicited peritonitis or intrascrotal injection of IL-1β, but had no effect on responses seen with TNFα. Furthermore, inhibitors of Kv11.1 (DOF, E4031, and astemizole), but not Kv1.3 (margatoxin), suppressed the expression of IL-6 and MCP-1 cytokines by murine resident peritoneal macrophages, while again having no effect on TNFα. In contrast, IL-6 expression by peritoneal mesothelial cells was unaffected. Using murine P388 cells, which lack endogenous C/EBPβexpression and are unresponsive to LPS for the expression of both IL-6 and MCP-1, we observed that DOF inhibited LPS-induced expression of IL-6 mRNA following ectopic expression of wild-type C/EBPβ, but not a serine-64 point mutant. Finally, DOF inhibited the constitutive activation of cdk2 in murine peritoneal macrophages; cdk2 is known to phosphorylate C/EBPβ at serine-64. Taken together, our results implicate a potential role for Kv11.1 in regulating cdk2 and C/EBPβ activity, where robust transactivation of both IL-6 and MCP-1 transcription is known to be dependent on serine-64 of C/EBPβ. Our data might also explain the altered phenotypes displayed by PECAM-1 knockout mice in several disease models

"I've made this my lifestyle now": a prospective qualitative study of motivation for lifestyle change among people with newly diagnosed type two diabetes mellitus

This is the final published version. Available from BMC via the DOI in this record.The datasets generated and/or analysed during the current study are not publicly available due to the level of personal information that is contained in the qualitative transcripts.Background: Diagnosis with Type 2 Diabetes is an opportunity for individuals to change their physical activity and dietary behaviours. Diabetes treatment guidelines recommend theory-based, patient-centred care and advocate the provision of support for patient motivation but the motivational experiences of people newly diagnosed with diabetes have not been well studied. Framed in self-determination theory, this study aimed to qualitatively explore how this patient group articulate and experience different types of motivation when attempting lifestyle change. Methods: A secondary analysis of semi-structured interview data collected with 30 (n female = 18, n male = 12) adults who had been newly diagnosed with type two diabetes and were participants in the Early ACTID trial was undertaken. Deductive directed content analysis was performed using NVivo V10 and researcher triangulation to identify and describe patient experiences and narratives that reflected the motivation types outlined in selfdetermination theory and if/how these changed over time. Results: The findings revealed the diversity in motivation quality both between and within individuals over time and that patients with newly-diagnosed diabetes have multifaceted often competing motivations for lifestyle behaviour change. Applying self-determination theory, we identified that many participants reported relatively dominant controlled motivation to comply with lifestyle recommendations, avoid their non-compliance being “found out” or supress guilt following lapses in behaviour change attempts. Such narratives were accompanied by experiences of frustrating slow behaviour change progress. More autonomous motivation was expressed as something often achieved over time and reflected goals to improve health, quality of life or family time. Motivational internalisation was evident and some participants had integrated their behaviour change to a new way of life which they found resilient to common barriers. Conclusions: Motivation for lifestyle change following diagnosis with type two diabetes is complex and can be relatively low in self-determination. To achieve the patient empowerment aspirations of current national health care plans, intervention developers, and clinicians would do well to consider the quality not just quantity of their patients’ motivation.National Institute for Health Research (NIHR

A methodology pruning the search space of six compiler transformations by addressing them together as one problem and by exploiting the hardware architecture details

Today’s compilers have a plethora of optimizations-transformations to choose from, and the correct choice, order as well parameters of transformations have a significant/large impact on performance; choosing the correct order and parameters of optimizations has been a long standing problem in compilation research, which until now remains unsolved; the separate sub-problems optimization gives a different schedule/binary for each sub-problem and these schedules cannot coexist, as by refining one degrades the other. Researchers try to solve this problem by using iterative compilation techniques but the search space is so big that it cannot be searched even by using modern supercomputers. Moreover, compiler transformations do not take into account the hardware architecture details and data reuse in an efficient way. In this paper, a new iterative compilation methodology is presented which reduces the search space of six compiler transformations by addressing the above problems; the search space is reduced by many orders of magnitude and thus an efficient solution is now capable to be found. The transformations are the following: loop tiling (including the number of the levels of tiling), loop unroll, register allocation, scalar replacement, loop interchange and data array layouts. The search space is reduced (a) by addressing the aforementioned transformations together as one problem and not separately, (b) by taking into account the custom hardware architecture details (e.g., cache size and associativity) and algorithm characteristics (e.g., data reuse). The proposed methodology has been evaluated over iterative compilation and gcc/icc compilers, on both embedded and general purpose processors; it achieves significant performance gains at many orders of magnitude lower compilation time

Sedentary time and markers of inflammation in people with newly diagnosed type 2 diabetes

This is the final version. Available on open access from Elsevier via the DOI in this recordBACKGROUND AND AIMS: We investigated whether objectively measured sedentary time was associated with markers of inflammation in adults with newly diagnosed type 2 diabetes. METHODS AND RESULTS: We studied 285 adults (184 men, 101 women, mean age 59.0 ± 9.7) who had been recruited to the Early ACTivity in Diabetes (Early ACTID) randomised controlled trial. C-reactive protein (CRP), adiponectin, soluble intracellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), and accelerometer-determined sedentary time and moderate-vigorous physical activity (MVPA) were measured at baseline and after six-months. Linear regression analysis was used to investigate the independent cross-sectional and longitudinal associations of sedentary time with markers of inflammation. At baseline, associations between sedentary time and IL-6 were observed in men and women, an association that was attenuated following adjustment for waist circumference. After 6 months of follow-up, sedentary time was reduced by 0.4 ± 1.2 h per day in women, with the change in sedentary time predicting CRP at follow-up. Every hour decrease in sedentary time between baseline and six-months was associated with 24% (1, 48) lower CRP. No changes in sedentary time between baseline and 6 months were seen in men. CONCLUSIONS: Higher sedentary time is associated with IL-6 in men and women with type 2 diabetes, and reducing sedentary time is associated with improved levels of CRP in women. Interventions to reduce sedentary time may help to reduce inflammation in women with type 2 diabetes.National Institute for Health Research (NIHR

The diagnosis of mental disorders: the problem of reification

A pressing need for interrater reliability in the diagnosis of mental disorders emerged during the mid-twentieth century, prompted in part by the development of diverse new treatments. The Diagnostic and Statistical Manual of Mental Disorders (DSM), third edition answered this need by introducing operationalized diagnostic criteria that were field-tested for interrater reliability. Unfortunately, the focus on reliability came at a time when the scientific understanding of mental disorders was embryonic and could not yield valid disease definitions. Based on accreting problems with the current DSM-fourth edition (DSM-IV) classification, it is apparent that validity will not be achieved simply by refining criteria for existing disorders or by the addition of new disorders. Yet DSM-IV diagnostic criteria dominate thinking about mental disorders in clinical practice, research, treatment development, and law. As a result, the modernDSMsystem, intended to create a shared language, also creates epistemic blinders that impede progress toward valid diagnoses. Insights that are beginning to emerge from psychology, neuroscience, and genetics suggest possible strategies for moving forward

The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology

The role of endomyocardial biopsy (EMB) in the diagnosis and treatment of adult and pediatric cardiovascular disease remains controversial, and the practice varies widely even among cardiovascular centers of excellence. A need for EMB exists because specific myocardial disorders that have unique prognoses and treatment are seldom diagnosed by noninvasive testing.1 Informed clinical decision making that weighs the risks of EMB against the incremental diagnostic, prognostic, and therapeutic value of the procedure is especially challenging for nonspecialists because the relevant published literature is usually cited according to specific cardiac diseases, which are only diagnosed after EM

Molecular Genetics of T Cell Development

T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. The transcriptional regulation of T cell development is contrasted with that of B cell development, in terms of their different degrees of overlap with the stem-cell program and the different roles of key transcription factors in gene regulatory networks leading to lineage commitment