Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution.

Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the diverse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.

Altered DNA Methylation in the Developing Brains of Rats Genetically Prone to High versus Low Anxiety.

There is growing evidence of abnormal epigenetic processes playing a role in the neurobiology of psychiatric disorders, although the precise nature of these anomalies remains largely unknown. To study neurobiological (including epigenetic) factors that influence emotionality, we use rats bred for distinct behavioral responses to novelty. Rats bred for low novelty response (low responder [LR]) exhibit high levels of anxiety- and depressive-like behavior compared with high novelty responder (HR) rats. Prior work revealed distinct limbic brain development in HR versus LR rats, including altered expression of genes involved in DNA methylation. This led us to hypothesize that DNA methylation differences in the developing brain drive the disparate HR/LR neurobehavioral phenotypes. Here we report altered DNA methylation markers (altered DNA methyltransferase protein levels and increased global DNA methylation levels) in the early postnatal amygdala of LR versus HR male rats. Next-generation sequencing methylome profiling identified numerous differentially methylated regions across the genome in the early postnatal HR/LR amygdala. We also contrasted methylation profiles of male HRs and LRs with a control rat strain that displays an intermediate behavioral phenotype relative to the HR/LR extremes; this revealed that the LR amygdalar methylome was abnormal, with the HR profile more closely resembling that of the control group. Finally, through two methylation manipulations in early life, we found that decreasing DNA methylation in the developing male and female amygdala improves adult anxiety- and depression-like behavior. These findings suggest that inborn DNA methylation differences play important roles in shaping brain development and lifelong emotional behavior.SIGNIFICANCE STATEMENT Epigenetic changes are biological mechanisms that regulate the expression and function of genes throughout the brain and body. DNA methylation, one type of epigenetic mechanism, is known to be altered in brains of psychiatric patients, which suggests a role for DNA methylation in the pathogenesis of psychiatric disorders, such as depression and anxiety. The present study examines brains of rats that display high versus low levels of anxiety- and depression-like behavior to investigate how neural DNA methylation levels differ in these animals and how such differences shape their emotional behavioral differences. Studying how epigenetic processes affect emotional behavior may improve our understanding of the neurobiology of psychiatric disorders and lead to improved treatments.

Effect of familial diabetes status and age at diagnosis on type 2 diabetes risk: a nation-wide register-based study from Denmark.

AIMS/HYPOTHESIS: We assessed whether the risk of developing type 2 diabetes and the age of onset varied with the age at diabetes diagnosis of affected family members. METHODS: We performed a national register-based open cohort study of individuals living in Denmark between 1995 and 2012. The population under study consisted of all individuals aged 30 years or older without diagnosed diabetes at the start date of the cohort (1 January 1995) and who had information about their parents' identity. Individuals who turned 30 years of age during the observation period and had available parental identity information were also added to the cohort from that date (open cohort design). These criteria restricted the study population mostly to people born between 1960 and 1982. Multivariable Poisson regression models adjusted for current age and highest educational attainment were used to estimate incidence rate ratios (IRRs) of type 2 diabetes. RESULTS: We followed 2,000,552 individuals for a median of 14 years (24,034,059 person-years) and observed 76,633 new cases of type 2 diabetes. Compared with individuals of the same age and sex who did not have a parent or full sibling with diabetes, the highest risk of developing type 2 diabetes was observed in individuals with family members diagnosed at an early age. The IRR was progressively lower with a higher age at diabetes diagnosis in family members: 3.9 vs 1.4 for those with a parental age at diagnosis of 50 or 80 years, respectively; and 3.3 vs 2.0 for those with a full sibling's age at diagnosis of 30 or 60 years, respectively. CONCLUSIONS/INTERPRETATION: People with a family member diagnosed with diabetes at an earlier age are more likely to develop diabetes and also to develop it at an earlier age than those with a family member diagnosed in later life. This finding highlights the importance of expanding our understanding of the interplay between genetic diabetes determinants and the social, behavioural and environmental diabetes determinants that track in families across generations. Accurate registration of age at diagnosis should form an integral part of recording a diabetes family history, as it provides easily obtainable and highly relevant detail that may improve identification of individuals at increased risk of younger onset of type 2 diabetes. In particular, these individuals may benefit from closer risk factor assessment and follow-up, as well as prevention strategies that may involve the family.

Effect of screening for type 2 diabetes on healthcare costs: a register-based study among 139,075 individuals diagnosed with diabetes in Denmark between 2001 and 2009.

AIMS/HYPOTHESIS: Trials have not demonstrated benefits to the population of screening for type 2 diabetes. However, there may be cost savings for those found to have diabetes. We therefore aimed to compare healthcare costs among individuals with incident type 2 diabetes in a screened group with those in an unscreened group. METHODS: In this register-based, non-randomised controlled trial, eligible individuals were men and women aged 40-69 years without known diabetes who were registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes risk-score questionnaire. Individuals with a moderate-to-high risk were invited to visit their family doctor for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other practices in Denmark constituted the retrospectively constructed no-screening (control) group. In this post hoc analysis, we identified individuals from the screening and no-screening groups who were diagnosed with diabetes between 2001 and 2009 (n = 139,075). Using national registry data, we quantified the cost of healthcare services in these two groups between 2001 and 2012. From a healthcare sector perspective, we estimated the potential healthcare cost savings for individuals with diabetes that were attributable to the screening programme. RESULTS: In the screening group, 27,177 of 153,107 individuals (18% of those sent a risk-score questionnaire) attended for screening, 1533 of whom were diagnosed with diabetes. Between 2001 and 2009, 13,992 people were newly diagnosed with diabetes in the screening group (including those diagnosed by screening) and 125,083 in the no-screening group. Healthcare costs were significantly lower in the screening group compared with the no-screening group (difference in mean total annual healthcare costs -€889 per individual with incident diabetes; 95% CI -€1196, -€581). The screening programme was associated with a cost saving per person with incident diabetes over a 5-year period of €2688 (95% CI €1421, €3995). CONCLUSIONS/INTERPRETATION: Healthcare costs were lower among individuals with incident type 2 diabetes in the screened group compared with the unscreened group. The relatively modest cost of screening per person discovered to have developed diabetes was offset within 2 years by savings in the healthcare system.

Effect of screening for type 2 diabetes on risk of cardiovascular disease and mortality: a controlled trial among 139,075 individuals diagnosed with diabetes in Denmark between 2001 and 2009.

AIMS/HYPOTHESIS: There is continuing debate about the net benefits of population screening for type 2 diabetes. We compared the risk of cardiovascular disease (CVD) and mortality among incident cases of type 2 diabetes in a screened group with those in an unscreened group. METHODS: In this register-based non-randomised controlled trial, eligible individuals were all men and women aged 40-69 years without known diabetes, registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes-risk-score questionnaire. Individuals at moderate-to-high risk were invited to visit their family doctor for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other practices in Denmark constituted the retrospectively constructed no-screening (control) group. In this post hoc analysis, we identified individuals from the screening and no-screening groups who were diagnosed with diabetes between 2001 and 2009 (n = 139,075), and compared risk of CVD and mortality in these groups between 2001 and 2012. RESULTS: In the screening group, 27,177/153,107 (18%) individuals attended for screening, of whom 1533 were diagnosed with diabetes. Between 2001 and 2009, 13,992 people were newly diagnosed with diabetes in the screening group (including those diagnosed by screening) and 125,083 in the no-screening group. Between 2001 and 2012, the risks of CVD and mortality were lower among individuals with diabetes in the screening group compared with individuals with diabetes in the no-screening (control) group (CVD HR 0.84, 95% CI 0.80, 0.89; mortality HR 0.79, 95% CI 0.74, 0.84). CONCLUSIONS/INTERPRETATION: A single round of diabetes screening and cardiovascular risk assessment in middle-aged Danish adults in general practice was associated with a significant reduction in risk of all-cause mortality and CVD events in those diagnosed with diabetes.

Effect of population screening for type 2 diabetes and cardiovascular risk factors on mortality rate and cardiovascular events: a controlled trial among 1,912,392 Danish adults.

AIMS/HYPOTHESIS: Health check programmes for chronic disease have been introduced in a number of countries. However, there are few trials assessing the benefits and harms of these screening programmes at the population level. In a post hoc analysis, we evaluated the effect of population-based screening for type 2 diabetes and cardiovascular risk factors on mortality rates and cardiovascular events. METHODS: This register-based, non-randomised, controlled trial included men and women aged 40-69 years without known diabetes who were registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes risk score questionnaire. Individuals at moderate-to-high risk were invited to visit their GP for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other general practices in Denmark constituted the retrospectively constructed no-screening (control) group. Outcomes were mortality rate and cardiovascular events (cardiovascular disease death, non-fatal ischaemic heart disease or stroke). The analysis was performed according to the intention-to-screen principle. RESULTS: Among the screening group, 27,177 (18%) individuals attended for assessment of diabetes status and cardiovascular risk. Of these, 1,533 were diagnosed with diabetes. During a median follow-up of 9.5 years, there were 11,826 deaths in the screening group and 141,719 in the no-screening group (HR 0.99 [95% CI 0.96, 1.02], p = 0.66). There were 17,941 cardiovascular events in the screening group and 208,476 in the no-screening group (HR 0.99 [0.96, 1.02], p = 0.49). CONCLUSIONS/INTERPRETATION: A population-based stepwise screening programme for type 2 diabetes and cardiovascular risk factors among all middle-aged adults in Denmark was not associated with a reduction in rate of mortality or cardiovascular events between 2001 and 2012.

Does training of general practitioners for intensive treatment of people with screen-detected diabetes have a spillover effect on mortality and cardiovascular morbidity in 'at risk' individuals with normoglycaemia? Results from the ADDITION-Denmark cluster-randomised controlled trial.

AIMS/HYPOTHESIS: Within a trial of intensive treatment of people with screen-detected diabetes, we aimed to assess a potential spillover effect of the trial intervention on incident cardiovascular disease (CVD) and all-cause mortality among people who screened positive on a diabetes risk questionnaire but who were normoglycaemic. METHODS: In the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark trial, 175 general practices were cluster-randomised into: (1) screening plus routine care of individuals with screen-detected diabetes (control group); or (2) screening plus training and support in intensive multifactorial treatment of individuals with screen-detected diabetes (intervention group). We identified all individuals who screened positive on a diabetes risk questionnaire in ADDITION-Denmark but were normoglycaemic following biochemical testing for use in this secondary analysis. After a median 8.9 years follow-up, we used data from national registers to compare rates of first CVD events and all-cause mortality in individuals in the routine care group with those in the intensive treatment group. RESULTS: In total, 21,513 individuals screened positive for high risk of diabetes but were normoglycaemic on biochemical testing in ADDITION-Denmark practices between 2001 and 2006 (10,289 in the routine care group and 11,224 in the intensive treatment group). During 9 years of follow-up, there were 3784 first CVD events and 1748 deaths. The incidence of CVD was lower among the intensive treatment group compared with the routine care group (HR 0.92 [95% CI 0.85, 0.99]). This association was stronger among individuals at highest CVD risk (heart SCORE ≥ 10; HR 0.85 [95% CI 0.75, 0.96]). There was no difference in mortality between the two treatment groups (HR 1.02 [95% CI 0.92, 1.14]). CONCLUSIONS/INTERPRETATION: Training of general practitioners to provide target-driven intensive management of blood glucose levels and other cardiovascular risk factors showed some evidence of a spillover effect on the risk of CVD over a 9 year period among individuals at high risk of diabetes. The effect was particularly pronounced among those at highest risk of CVD. There was no effect on mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT00237549.

Trajectories of glycaemia, insulin sensitivity and insulin secretion in South Asian and white individuals before diagnosis of type 2 diabetes: a longitudinal analysis from the Whitehall II cohort study.

AIMS/HYPOTHESIS: South Asian individuals have reduced insulin sensitivity and increased risk of type 2 diabetes compared with white individuals. Temporal changes in glycaemic traits during middle age suggest that impaired insulin secretion is a particular feature of diabetes development among South Asians. We therefore aimed to examine ethnic differences in early changes in glucose metabolism prior to incident type 2 diabetes. METHODS: In a prospective British occupational cohort, subject to 5 yearly clinical examinations, we examined ethnic differences in trajectories of fasting plasma glucose (FPG), 2 h post-load plasma glucose (2hPG), fasting serum insulin (FSI), 2 h post-load serum insulin (2hSI), HOMA of insulin sensitivity (HOMA2-S) and secretion (HOMA2-B), and the Gutt insulin sensitivity index (ISI0,120) among 120 South Asian and 867 white participants who developed diabetes during follow-up (1991-2013). We fitted cubic mixed-effects models to longitudinal data with adjustment for a wide range of covariates. RESULTS: Compared with white individuals, South Asians had a faster increase in FPG before diagnosis (slope difference 0.22 mmol/l per decade; 95% CI 0.02, 0.42; p = 0.03) and a higher FPG level at diagnosis (0.27 mmol/l; 95% CI 0.06, 0.48; p = 0.01). They also had higher FSI and 2hSI levels before and at diabetes diagnosis. South Asians had a faster decline and lower HOMA2-S (log e -transformed) at diagnosis compared with white individuals (0.33; 95% CI 0.21, 0.46; p < 0.001). HOMA2-B increased in both ethnic groups until 7 years before diagnosis and then declined; the initial increase was faster in white individuals. ISI0,120 declined steeply in both groups before diagnosis; levels were lower among South Asians before and at diagnosis. There were no ethnic differences in 2hPG trajectories. CONCLUSIONS/INTERPRETATION: We observed different trajectories of plasma glucose, insulin sensitivity and secretion prior to diabetes diagnosis in South Asian and white individuals. This might be due to ethnic differences in the natural history of diabetes. South Asian individuals experienced a more rapid decrease in insulin sensitivity and faster increases in FPG compared with white individuals. These findings suggest more marked disturbance in beta cell compensation prior to diabetes diagnosis in South Asian individuals.

Prospective associations between sedentary time, physical activity, fitness and cardiometabolic risk factors in people with type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to examine the prospective associations between objectively measured physical activity energy expenditure (PAEE), sedentary time, moderate-to-vigorous-intensity physical activity (MVPA), cardiorespiratory fitness (CRF) and cardiometabolic risk factors over 4 years in individuals with recently diagnosed diabetes. METHODS: Among 308 adults (mean age 61.0 [SD 7.2] years; 34% female) with type 2 diabetes from the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION)-Plus study, we measured physical activity using individually calibrated combined heart rate and movement sensing. Multivariable linear regression models were constructed to examine the associations between baseline PAEE, sedentary time, MVPA, CRF and cardiometabolic risk factors and clustered cardiometabolic risk (CCMR) at follow-up, and change in these exposures and change in CCMR and its components over 4 years of follow-up. RESULTS: Individuals who increased their PAEE between baseline and follow-up had a greater reduction in waist circumference (-2.84 cm, 95% CI -4.84, -0.85) and CCMR (-0.17, 95% CI -0.29, -0.04) compared with those who decreased their PAEE. Compared with individuals who decreased their sedentary time, those who increased their sedentary time had a greater increase in waist circumference (3.20 cm, 95% CI 0.84, 5.56). Increases in MVPA were associated with reductions in systolic blood pressure (-6.30 mmHg, 95% CI -11.58, -1.03), while increases in CRF were associated with reductions in CCMR (-0.23, 95% CI -0.40,-0.05) and waist circumference (-3.79 cm, 95% CI -6.62, -0.96). Baseline measures were generally not predictive of cardiometabolic risk at follow-up. CONCLUSIONS/INTERPRETATION: Encouraging people with recently diagnosed diabetes to increase their physical activity and decrease their sedentary time may have beneficial effects on their waist circumference, blood pressure and CCMR.

Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety.

The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high versus low behavioral response to novelty and found that high-reactive (bred high-responder, bHR) rats displayed greater risk-taking, impulsivity and aggression relative to low-reactive (bred low-responder, bLR) rats, which showed high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable, but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior to the brain development and emotional behavior of bLR offspring. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine the effects on the following: (1) developmental gene expression in the hippocampus and amygdala and (2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain's developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations. © 2015 S. Karger AG, Basel.

Which behavior change techniques are associated with changes in physical activity, diet and body mass index in people with recently diagnosed diabetes?

BACKGROUND: Meta-analyses have identified promising behavior change techniques (BCTs) in changing obesity-related behaviors from intervention descriptions. However, it is unclear whether these BCTs are used by intervention participants and are related to outcomes. PURPOSE: The purpose of this study is to investigate BCT use by participants of an intervention targeting physical activity and diet and whether BCT use was related to behavior change and weight loss. METHODS: Intervention participants (N = 239; 40-69 years) with recently diagnosed type 2 diabetes in the ADDITION-Plus trial received a theory-based intervention which taught them a range of BCTs. BCT usage was reported at 1 year. RESULTS: Thirty-six percent of the participants reported using all 16 intervention BCTs. Use of a higher number of BCTs and specific BCTs (e.g., goal setting) were associated with a reduction in body mass index (BMI). CONCLUSIONS: BCT use was associated with weight loss. Future research should identify strategies to promote BCT use in daily life. ( TRIAL REGISTRATION: ISRCTN99175498.).

Long-term effect of population screening for diabetes on cardiovascular morbidity, self-rated health, and health behavior.

PURPOSE: There is limited trial evidence concerning the long-term effects of screening for type 2 diabetes on population morbidity. We examined the effect of a population-based diabetes screening program on cardiovascular morbidity, self-rated health, and health-related behaviors. METHODS: We conducted a pragmatic, parallel-group, cluster-randomized controlled trial of diabetes screening (the ADDITION-Cambridge study) including 18,875 individuals aged 40 to 69 years at high risk of diabetes in 32 general practices in eastern England (27 practices randomly allocated to screening, 5 to no-screening for control). Of those eligible for screening, 466 (2.9%) were diagnosed with diabetes. Seven years after randomization, a random sample of patients was sent a postal questionnaire: 15% from the screening group (including diabetes screening visit attenders and non-attenders) and 40% from the no-screening control group. Self-reported cardiovascular morbidity, self-rated health (using the SF-8 Health Survey and EQ-5D instrument), and health behaviors were compared between trial groups using an intention-to-screen analysis. RESULTS: Of the 3,286 questionnaires mailed out, 1,995 (61%) were returned, with 1,945 included in the analysis (screening: 1,373; control: 572). At 7 years, there were no significant differences between the screening and control groups in the proportion of participants reporting heart attack or stroke (OR = 0.90, 95% CI, 0.71-1.15); SF-8 physical health summary score as an indicator of self-rated health status (ß -0.33, 95% CI, -1.80 to 1.14); EQ-5D visual analogue score (ß: 0.80, 95% CI, -1.28 to 2.87); total physical activity (ß 0.50, 95% CI, -4.08 to 5.07); current smoking (OR 0.97, 95% CI, 0.72 to 1.32); and alcohol consumption (ß 0.14, 95% CI, -1.07 to 1.35). CONCLUSIONS: Invitation to screening for type 2 diabetes appears to have limited impact on population levels of cardiovascular morbidity, self-rated health status, and health behavior after 7 years.

Increasing objectively measured sedentary time increases clustered cardiometabolic risk: a 6 year analysis of the ProActive study.

AIMS/HYPOTHESIS: We aimed to quantify the associations between change in objectively measured sedentary and moderate-to-vigorous physical activity (MVPA) times and self-reported television viewing over 6 years and change in a clustered cardiometabolic risk score (CCMR), including and excluding waist circumference (CCMR without adiposity component, CCMR no adip ), and its individual components, among the adult children of people with type 2 diabetes. METHODS: In 171 adults (mean ± SD age 42.52 ± 6.30 years; 46% men) with a parental history of diabetes (ProActive UK), physical activity accelerometer measures and self-reported television viewing were assessed at baseline and a mean ± SD of 6.27 ± 0.46 years later. Associations between change in sedentary time, MVPA time and television viewing and cardiometabolic risk and mediation by adiposity change were examined by multiple linear regression and the product of coefficients method, respectively. RESULTS: Greater increases in sedentary time (h/day) were associated with larger increases in clustered cardiometabolic risk (CCMR: 0.08 [95% CI 0.01, 0.15]; CCMR no adip : 0.08 [0.01, 0.16]) and triacylglycerol (0.15 [0.01, 0.29]), independent of baseline sedentary and MVPA times, change in MVPA time and other confounders. No evidence was found for mediation by change in waist circumference and BMI for the associations with CCMR no adip and triacylglycerol. Greater increases in MVPA time (h/day) were associated with larger decreases in waist circumference (-3.86 [-7.58, -0.14]), independently of baseline MVPA and sedentary times, change in sedentary time and other confounders. Television viewing was not independently associated with any of the cardiometabolic outcomes. CONCLUSIONS/INTERPRETATION: Increasing sedentary time is independently related to increasing clustered cardiometabolic risk and triacylglycerol in adults at high risk of developing diabetes. Strategies to prevent diabetes might target reducing sedentary time. Trial registration ISRCTN61323766.

Association between objectively assessed sedentary time and physical activity with metabolic risk factors among people with recently diagnosed type 2 diabetes.

AIMS/HYPOTHESIS: The aim of our study was to examine the associations between sedentary time (SED-time), time spent in moderate-to-vigorous-intensity physical activity (MVPA), total physical activity energy expenditure (PAEE) and cardiorespiratory fitness with metabolic risk among individuals with recently diagnosed type 2 diabetes. METHODS: Individuals participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION)-Plus trial underwent measurement of SED-time, MVPA and PAEE using a combined activity and movement sensor (n = 394), and evaluation of cardiorespiratory fitness (n = 291) and anthropometric and metabolic status. Clustered metabolic risk was calculated by summing standardised values for waist circumference, triacylglycerol, HbA1c, systolic blood pressure and the inverse of HDL-cholesterol. Multivariate linear regression analyses were used to quantify the associations between SED-time, MVPA, PAEE and cardiorespiratory fitness with individual metabolic risk factors and clustered metabolic risk. RESULTS: Each additional 1 h of SED-time was positively associated with clustered metabolic risk, independently of sleep duration and MVPA (ß = 0.16 [95% CI 0.03, 0.29]). After accounting for SED-time, MVPA was associated with systolic blood pressure (ß = -2.07 [-4.03, -0.11]) but not with clustered metabolic risk (ß = 0.01 [-0.28, 0.30]). PAEE and cardiorespiratory fitness were significantly and independently inversely associated with clustered metabolic risk (ß = -0.03 [-0.05, -0.02] and ß = -0.06 [-0.10, -0.03], respectively). Associations between SED-time and metabolic risk were generally stronger in the low compared with the high fitness group. CONCLUSIONS/INTERPRETATION: PAEE was inversely associated with metabolic risk, whereas SED-time was positively associated with metabolic risk. MVPA was not associated with clustered metabolic risk after accounting for SED-time. Encouraging this high-risk group to decrease SED-time, particularly those with low cardiorespiratory fitness, and increase their overall physical activity may have beneficial effects on disease progression and reduction of cardiovascular risk. TRIAL REGISTRATION: ISRCTN99175498.

Multiple behaviour change intervention and outcomes in recently diagnosed type 2 diabetes: the ADDITION-Plus randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to assess whether or not a theory-based behaviour change intervention delivered by trained and quality-assured lifestyle facilitators can achieve and maintain improvements in physical activity, dietary change, medication adherence and smoking cessation in people with recently diagnosed type 2 diabetes. METHODS: An explanatory randomised controlled trial was conducted in 34 general practices in Eastern England (Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care-Plus [ADDITION-Plus]). In all, 478 patients meeting eligibility criteria (age 40 to 69 years with recently diagnosed screen or clinically detected diabetes) were individually randomised to receive either intensive treatment (n = 239) or intensive treatment plus a theory-based behaviour change intervention led by a facilitator external to the general practice team (n = 239). Randomisation was central and independent using a partial minimisation procedure to balance stratifiers between treatment arms. Facilitators taught patients skills to facilitate change in and maintenance of key health behaviours, including goal setting, self-monitoring and building habits. Primary outcomes included physical activity energy expenditure (individually calibrated heart rate monitoring and movement sensing), change in objectively measured fruit and vegetable intake (plasma vitamin C), medication adherence (plasma drug levels) and smoking status (plasma cotinine levels) at 1 year. Measurements, data entry and laboratory analysis were conducted with staff unaware of participants' study group allocation. RESULTS: Of 475 participants still alive, 444 (93%; intervention group 95%, comparison group 92%) attended 1-year follow-up. There were no significant differences between groups in physical activity (difference: +1.50 kJ kg(-1) day(-1); 95% CI -1.74, 4.74), plasma vitamin C (difference: -3.84 µmol/l; 95% CI -8.07, 0.38), smoking (OR 1.37; 95% CI 0.77, 2.43) and plasma drug levels (difference in metformin levels: -119.5 µmol/l; 95% CI -335.0, 95.9). Cardiovascular risk factors and self-reported behaviour improved in both groups with no significant differences between groups. CONCLUSIONS/INTERPRETATION: For patients with recently diagnosed type 2 diabetes receiving intensive treatment in UK primary care, a facilitator-led individually tailored behaviour change intervention did not improve objectively measured health behaviours or cardiovascular risk factors over 1 year. TRIAL REGISTRATION: ISRCTN99175498 FUNDING: The trial is supported by the Medical Research Council, the Wellcome Trust, National Health Service R&D support funding (including the Primary Care Research and Diabetes Research Networks) and National Institute of Health Research under its Programme Grants for Applied Research scheme. The Primary Care Unit is supported by NIHR Research funds. Bio-Rad provided equipment for HbA1c testing during the screening phase.

Effect of early intensive multifactorial therapy compared with routine care on self-reported health status, general well-being, diabetes-specific quality of life and treatment satisfaction in screen-detected type 2 diabetes mellitus patients (ADDITION-Europe): a cluster-randomised trial.

AIMS/HYPOTHESIS: The study aimed to examine the effects of intensive treatment (IT) vs routine care (RC) on patient-reported outcomes after 5 years in screen-detected diabetic patients. METHODS: In a pragmatic, cluster-randomised, parallel-group trial, 343 general practices in Denmark, Cambridge and Leicester (UK) and the Netherlands were randomised to screening for type 2 diabetes mellitus plus IT of multiple risk factors in people 40-69 years without known diabetes (n = 1,678 patients) or screening plus RC (n = 1,379 patients). Practices were randomised in a 1:1 ratio according to a computer-generated list. Diabetes mellitus was diagnosed according to WHO criteria. Exclusions were: life expectancy <1 year, housebound, pregnant or lactating, or psychological or psychiatric problems. Treatment targets for IT were: HbA1c <7.0% (53 mmol/mol), BP ≤135/85 mmHg, cholesterol <5 mmol/l in the absence of a history of coronary heart disease and <4.5 mmol/l in patients with cardiovascular (CV) disease; prescription of aspirin to people taking antihypertensive medication and, in cases of CV disease or BP >120/80 mmHg, ACE inhibitors were recommended. After 2003, the treatment algorithm recommended statins to all patients with cholesterol of ≥3.5 mmol/l. Outcome measures were: health status (Euroqol 5 Dimensions [EQ-5D]) at baseline and at follow-up; and health status (36-item Short Form Health Survey [SF-36] and Euroquol Visual Analogue Scale [EQ-VAS]), well-being (12-item Short Form of the Well-Being Questionnaire), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life) and satisfaction with diabetes treatment (Diabetes Treatment Satisfaction Questionnaire) at follow-up. At baseline, standardised self-report questionnaires were used to collect information. Questionnaires were completed at the same health assessment visit as the anthropometric and biochemical measurements. The patients and the staff assessing the outcomes were unaware of the group assignments. Participants were followed for a mean of 5.7 years. Outcome data were available for 1,250 participants in the intensive treatment group (74%) and 967 participants in the routine care group (70%). The estimated differences in means from the four centres were pooled using random effects meta-analysis. Baseline EQ-5D level was used as a covariate in all analyses. RESULTS: EQ-5D values did not change between diagnosis and follow-up, with a median (interquartile range) of 0.85 (0.73-1.00) at baseline and 0.85 (0.73-1.00) at 5 year follow-up. Health status, well-being, diabetes-specific quality of life and treatment satisfaction did not differ between the intensive treatment and routine care groups. There was some heterogeneity between centres (I 2 being between 13% [SF-36 physical functioning] and 73% [EQ-VAS]). CONCLUSIONS/INTERPRETATION: There were no differences in health status, well-being, quality of life and treatment satisfaction between screen-detected type 2 diabetes mellitus patients receiving intensive treatment and those receiving routine care. These results suggest that intensive treatment does not adversely affect patient-reported outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00237549 FUNDING: ADDITION-Denmark was supported by the National Health Services, the Danish Council for Strategic Research, the Danish Research Foundation for General Practice, Novo Nordisk Foundation, the Danish Centre for Evaluation and Health Technology Assessment, the Diabetes Fund of the National Board of Health, the Danish Medical Research Council and the Aarhus University Research Foundation. In addition, unrestricted grants from pharmaceutical companies were received. ADDITION-Cambridge was supported by the Wellcome Trust, the Medical Research Council, the NIHR Health Technology Assessment Programme, National Health Service R&D support funding and the National Institute for Health Research. SJG received support from the Department of Health NIHR grant funding scheme. ADDITION-Leicester was supported by Department of Health, the NIHR Health Technology Assessment Programme, National Health Service R&D support funding and the National Institute for Health Research. ADDITION-Netherlands was supported by unrestricted grants from Novo Nordisk, Glaxo Smith Kline and Merck, and by the Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht.

Screening for type 2 diabetes and population mortality over 10 years (ADDITION-Cambridge): a cluster-randomised controlled trial.

BACKGROUND: The increasing prevalence of type 2 diabetes poses a major public health challenge. Population-based screening and early treatment for type 2 diabetes could reduce this growing burden. However, uncertainty persists around the benefits of screening for type 2 diabetes. We assessed the effect of a population-based stepwise screening programme on mortality. METHODS: In a pragmatic parallel group, cluster-randomised trial, 33 general practices in eastern England were randomly assigned by the method of minimisation in an unbalanced design to: screening followed by intensive multifactorial treatment for people diagnosed with diabetes (n=15); screening plus routine care of diabetes according to national guidelines (n=13); and a no-screening control group (n=5). The study population consisted of 20,184 individuals aged 40-69 years (mean 58 years), at high risk of prevalent undiagnosed diabetes, on the basis of a previously validated risk score. In screening practices, individuals were invited to a stepwise programme including random capillary blood glucose and glycated haemoglobin (HbA(1c)) tests, a fasting capillary blood glucose test, and a confirmatory oral glucose tolerance test. The primary outcome was all-cause mortality. All participants were flagged for mortality surveillance by the England and Wales Office of National Statistics. Analysis was by intention-to-screen and compared all-cause mortality rates between screening and control groups. This study is registered, number ISRCTN86769081. FINDINGS: Of 16,047 high-risk individuals in screening practices, 15,089 (94%) were invited for screening during 2001-06, 11,737 (73%) attended, and 466 (3%) were diagnosed with diabetes. 4137 control individuals were followed up. During 184,057 person-years of follow up (median duration 9·6 years [IQR 8·9-9·9]), there were 1532 deaths in the screening practices and 377 in control practices (mortality hazard ratio [HR] 1·06, 95% CI 0·90-1·25). We noted no significant reduction in cardiovascular (HR 1·02, 95% CI 0·75-1·38), cancer (1·08, 0·90-1·30), or diabetes-related mortality (1·26, 0·75-2·10) associated with invitation to screening. INTERPRETATION: In this large UK sample, screening for type 2 diabetes in patients at increased risk was not associated with a reduction in all-cause, cardiovascular, or diabetes-related mortality within 10 years. The benefits of screening might be smaller than expected and restricted to individuals with detectable disease. FUNDING: Wellcome Trust; UK Medical Research Council; National Health Service research and development support; UK National Institute for Health Research; University of Aarhus, Denmark; Bio-Rad.

Predictors of change in objectively measured and self-reported health behaviours among individuals with recently diagnosed type 2 diabetes: longitudinal results from the ADDITION-Plus trial cohort.

BACKGROUND: There is limited evidence about predictors of health behaviour change in people with type 2 diabetes. The aim of this study was to assess change in health behaviours over one year and to identify predictors of behaviour change among adults with screen-detected and recently clinically diagnosed diabetes. METHODS: ADDITION-Plus was a randomised controlled trial of a behaviour change intervention among 478 patients (40-69 years). Physical activity and diet were measured objectively (physical activity at 1 year) and by self-report at baseline and one year. Associations between baseline predictors and behaviour change were quantified using multivariable linear regression. RESULTS: Participants increased their plasma vitamin C and fruit intake, reduced energy and fat intake from baseline to follow-up. Younger age, male sex, a smaller waist circumference, and a lower systolic blood pressure at baseline were associated with higher levels of objectively measured physical activity at one year. Greater increases in plasma vitamin C were observed in women (beta-coefficient [95% CI]: beta = -5.52 [-9.81, -1.22]) and in those with screen-detected diabetes (beta = 6.09 [1.74, 10.43]). Younger age predicted a greater reduction in fat (beta = -0.43 [-0.72, -0.13]) and energy intake (beta = -6.62 [-13.2, -0.05]). Patients with screen-detected diabetes (beta = 74.2 [27.92, 120.41]) reported a greater increase in fruit intake. There were no significant predictors of change in self-reported physical activity. Beliefs about behaviour change and diabetes did not predict behaviour change. CONCLUSIONS: Older patients, men and those with a longer duration of diabetes may need more intensive support for dietary change. We recommend that future studies use objective measurement of health behaviours and that researchers add predictors beyond the individual level. Our results support a focus on establishing healthy lifestyle changes early in the diabetes disease trajectory.

Is wearing a pedometer associated with higher physical activity among adolescents?

OBJECTIVE: To examine whether wearing a pedometer was associated with higher objectively-measured physical activity (PA) among adolescents independent of other behavior change strategies, and whether this association differed by sex or day of wear. METHOD: In a parallel-group population-based cohort study, 892 adolescents (43.4% male, mean±SD age, 14.5±0.5years) from Eastern England were recruited. PA was measured (in 2005-2006) by accelerometry over four days; a sub-group (n=345) wore a pedometer coterminously with the accelerometer. Three-level (individual, day of wear and school level) multiple linear regression was used to examine the association between accelerometry (counts/min, cpm) and pedometer wear, stratified by sex and adjusted for weekday/weekend. RESULTS: For the entire cohort, there was a significant decline in cpm over four days (p<0.01). Girls wearing pedometers had higher mean cpm than those not wearing a pedometer, independent of BMI z-score, socio-economic status, weekday/weekend, and school clustering (ß=5.1; 95% CI: 0.8 to 9.5, p=0.02). This association was not seen in boys. CONCLUSION: Pedometer wear was associated with higher PA among adolescent girls, but not boys. Findings may support sex-specific intervention strategies. In addition to pedometer monitoring, additional strategies may be required to promote PA levels, especially among boys.

Performance of the UKPDS outcomes model for prediction of myocardial infarction and stroke in the ADDITION-Europe trial cohort.

OBJECTIVES: We assessed the performance of the UK Prospective Diabetes Study (UKPDS) outcomes model in predicting the risk of myocardial infarction (MI) and stroke in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION-Europe) a trial cohort of patients with screen-detected type 2 diabetes from the United Kingdom, Denmark, and The Netherlands. METHODS: We estimated the 5-year accumulated risk of MI and stroke for 2899 screen-detected people with type 2 diabetes by using the UKPDS outcomes model (version 1.3). We compared the predicted and actual risks by country and by intervention group (routine care; intensive multifactorial treatment). We assessed discrimination and goodness of fit by using area under receiver operating characteristic curves and the Hosmer-Lemeshow chi-square test. Multiple imputations were used to overcome missing data. RESULTS: The UKPDS outcomes model overestimated the risk of MI and stroke. Mean predicted/actual ratios of 5-year accumulated risk were 2.31 for MI in the routine care group and 3.97 in the intensive multifactorial treatment group and 1.59 and 1.48 for stroke, respectively. The differences in absolute risk between the intervention groups were underestimated for MI (observed vs. predicted: 0.0127 vs. 0.0009) and slightly overestimated for stroke (-0.0013 vs. -0.0004). The area under the receiver operating characteristic curve was 0.72 (95% confidence interval 0.66-0.79) for MI and 0.70 (95% confidence interval 0.64-0.77) for stroke. The Hosmer-Lemeshow test statistic was nonsignificant in all groups. The model performed better in absolute risk prediction in Denmark and the United Kingdom than in The Netherlands. CONCLUSIONS: The UKPDS outcomes model has moderate discriminatory ability in the ADDITION-Europe trial cohort but overestimated absolute risk. The model may need updating for cardiovascular disease risk prediction in contemporary diabetes populations where patients may be diagnosed earlier in the disease trajectory and in whom cardiovascular risk is therefore lower.