Validation of the ARIC prediction model for sudden cardiac death in the European population: The ESCAPE-NET project.

BACKGROUND: Sudden cardiac death is responsible for 10% to 20% of all deaths in Europe. The current study investigates how well the risk of sudden cardiac death can be predicted. To this end, we validated a previously developed prediction model for sudden cardiac death from the Atherosclerosis Risk in Communities study (USA). METHODS: Data from participants of the Copenhagen City Heart Study (CCHS) (n=9988) was used to externally validate the previously developed prediction model for sudden cardiac death. The model's performance was assessed through discrimination (C-statistic) and calibration by the Hosmer-Lemeshow goodness-of-fit (HL) statistics suited for censored data and visual inspection of calibration plots. Additional validation was performed using data from the Hoorn Study (N=2045), employing the same methods. RESULTS: During ten years of follow-up of CCHS participants (mean age: 58.7 years, 56.2% women), 425 experienced SCD (4.2%). The prediction model showed good discrimination for sudden cardiac death risk (C-statistic: 0.81, 95% CI: 0.79-0.83). Calibration was robust (HL statistic: P=0.8). Visual inspection of the calibration plot showed that the calibration could be improved. Sensitivity was 89.8%, and specificity was 60.6%. The positive and negative predictive values were 10.1% and 99.2%. Model performance was similar in the Hoorn Study (C-statistic: 0.81, 95% CI: 0.77-0.85 and the HL statistic: 1.00). CONCLUSION: Our study showed that the previously developed prediction model in North American adults performs equally well in identifying those at risk for sudden cardiac death in a general North-West European population. However, the positive predictive value is low.

Prolongation of the QTc interval is associated with an increased risk of cardiovascular diseases: The Hoorn study.

BACKGROUND/OBJECTIVE: Prolonged heart rate-corrected QT interval (QTc) on the electrocardiogram (ECG) is maybe associated with the occurrence of cardiovascular diseases (CVD), but the evidence is inconsistent. Therefore, we investigated whether baseline prolongation of the QTc interval is associated with CVD morbidity and mortality and its subtypes and whether glucose tolerance modifies this association in a population-based cohort study with a mean follow-up of 10.8 years. METHODS: We analyzed a glucose tolerance stratified sample (N = 487) from the longitudinal population-based Hoorn Study cohort (age 64 ± 7 years, 48% female). Cox regression was used to investigate the association between sex-specific baseline QTc quartiles and CVD morbidity and mortality. The risk was also estimated per 10 ms increase in QTc. All analyses were adjusted for age, sex, smoking status, systolic blood pressure, prevalent CVD, glucose tolerance status, hypertension and total cholesterol. In addition, stratified analyses were conducted for glucose tolerance status. RESULTS: During a mean follow-up of 10.8 years, 351 CVD events were observed. The adjusted hazard ratios (95% CI) for each 10 ms increase in QTc interval were 1.06 (95% CI: 1.02-1.10) for CVD, 1.06 (95% CI: 0.97-1.15) for acute myocardial infarction, 1.07 (95% CI: 1.01-1.13) for stroke, 1.12 (95% CI: 1.06-1.19) for heart failure, 1.04 (95% CI: 0.96-1.12) for peripheral arterial disease and 1.01 (95% CI:0.95-1.08) for coronary heart disease. Glucose tolerance status did not modify the association (P > 0.2). CONCLUSION/INTERPRETATION: Prolongation of the QTc interval is associated with morbidity and mortality due to general CVD. Glucose tolerance status did not modify these associations.

Diagnostic value of echocardiographic markers for diastolic dysfunction and heart failure with preserved ejection fraction.

This study aimed to evaluate the diagnostic performance of echocardiographic markers of heart failure with preserved ejection fraction (HFpEF) and left ventricular diastolic dysfunction (LVDD) in comparison with the gold standard of cardiac catheterization. Diagnosing HFpEF is challenging, as symptoms are non-specific and often absent at rest. A clear need exists for sensitive echocardiographic markers to diagnose HFpEF. We systematically searched for studies testing the diagnostic value of novel echocardiographic markers for HFpEF and LVDD. Two investigators independently reviewed the studies and assessed the risk of bias. Results were meta-analysed when four or more studies reported a similar diagnostic measure. Of 353 studies, 20 fulfilled the eligibility criteria. The risk of bias was high especially in the patients' selection domain. The highest diagnostic performance was demonstrated by a multivariable model combining echocardiographic, clinical and arterial function markers with an area under the curve of 0.95 (95% CI, 0.89-0.98). A meta-analysis of four studies indicated a reasonable diagnostic performance for left atrial strain with an AUC of 0.83 (0.70-0.95), a specificity of 93% (95% CI, 90-97%) and a sensitivity of 77% (95% CI, 59-96%). Moreover, the addition of exercise E/e' improved the sensitivity of HFpEF diagnostic algorithms up to 90%, compared with 60 and 34% of guidelines alone. Despite the heterogeneity of the included studies, this review supported the current multivariable-based approach for the diagnosis of HFpEF and LVDD and showed a potential diagnostic role for exercise echocardiography and left atrial strain. Larger well-designed studies are needed to evaluate the incremental value of novel diagnostic tools to current diagnostic algorithms.

Prognostic models for predicting the risk of foot ulcer or amputation in people with type 2 diabetes: a systematic review and external validation study.

AIMS/HYPOTHESIS: Approximately 25% of people with type 2 diabetes experience a foot ulcer and their risk of amputation is 10-20 times higher than that of people without type 2 diabetes. Prognostic models can aid in targeted monitoring but an overview of their performance is lacking. This study aimed to systematically review prognostic models for the risk of foot ulcer or amputation and quantify their predictive performance in an independent cohort. METHODS: A systematic review identified studies developing prognostic models for foot ulcer or amputation over minimal 1 year follow-up applicable to people with type 2 diabetes. After data extraction and risk of bias assessment (both in duplicate), selected models were externally validated in a prospective cohort with a 5 year follow-up in terms of discrimination (C statistics) and calibration (calibration plots). RESULTS: We identified 21 studies with 34 models predicting polyneuropathy, foot ulcer or amputation. Eleven models were validated in 7624 participants, of whom 485 developed an ulcer and 70 underwent amputation. The models for foot ulcer showed C statistics (95% CI) ranging from 0.54 (0.54, 0.54) to 0.81 (0.75, 0.86) and models for amputation showed C statistics (95% CI) ranging from 0.63 (0.55, 0.71) to 0.86 (0.78, 0.94). Most models underestimated the ulcer or amputation risk in the highest risk quintiles. Three models performed well to predict a combined endpoint of amputation and foot ulcer (C statistics >0.75). CONCLUSIONS/INTERPRETATION: Thirty-four prognostic models for the risk of foot ulcer or amputation were identified. Although the performance of the models varied considerably, three models performed well to predict foot ulcer or amputation and may be applicable to clinical practice.

A personalised screening strategy for diabetic retinopathy: a cost-effectiveness perspective.

AIMS/HYPOTHESIS: In this study we examined the cost-effectiveness of three different screening strategies for diabetic retinopathy: using a personalised adaptive model, annual screening (fixed intervals), and the current Dutch guideline (stratified based on previous retinopathy grade). METHODS: For each individual, optimal diabetic retinopathy screening intervals were determined, using a validated risk prediction model. Observational data (1998-2017) from the Hoorn Diabetes Care System cohort of people with type 2 diabetes were used (n = 5514). The missing values of retinopathy grades were imputed using two scenarios of slow and fast sight-threatening retinopathy (STR) progression. By comparing the model-based screening intervals to observed time to develop STR, the number of delayed STR diagnoses was determined. Costs were calculated using the healthcare perspective and the societal perspective. Finally, outcomes and costs were compared for the different screening strategies. RESULTS: For the fast STR progression scenario, personalised screening resulted in 11.6% more delayed STR diagnoses and €11.4 less costs per patient compared to annual screening from a healthcare perspective. The personalised screening model performed better in terms of timely diagnosis of STR (8.8% less delayed STR diagnosis) but it was slightly more expensive (€1.8 per patient from a healthcare perspective) than the Dutch guideline strategy. CONCLUSIONS/INTERPRETATION: The personalised diabetic retinopathy screening model is more cost-effective than the Dutch guideline screening strategy. Although the personalised screening strategy was less effective, in terms of timely diagnosis of STR patients, than annual screening, the number of delayed STR diagnoses is low and the cost saving is considerable. With around one million people with type 2 diabetes in the Netherlands, implementing this personalised model could save €11.4 million per year compared with annual screening, at the cost of 658 delayed STR diagnoses with a maximum delayed time to diagnosis of 48 months.

Prediction models for development of retinopathy in people with type 2 diabetes: systematic review and external validation in a Dutch primary care setting.

AIMS/HYPOTHESIS: The aims of this study were to identify all published prognostic models predicting retinopathy risk applicable to people with type 2 diabetes, to assess their quality and accuracy, and to validate their predictive accuracy in a head-to-head comparison using an independent type 2 diabetes cohort. METHODS: A systematic search was performed in PubMed and Embase in December 2019. Studies that met the following criteria were included: (1) the model was applicable in type 2 diabetes; (2) the outcome was retinopathy; and (3) follow-up was more than 1 year. Screening, data extraction (using the checklist for critical appraisal and data extraction for systemic reviews of prediction modelling studies [CHARMS]) and risk of bias assessment (by prediction model risk of bias assessment tool [PROBAST]) were performed independently by two reviewers. Selected models were externally validated in the large Hoorn Diabetes Care System (DCS) cohort in the Netherlands. Retinopathy risk was calculated using baseline data and compared with retinopathy incidence over 5 years. Calibration after intercept adjustment and discrimination (Harrell's C statistic) were assessed. RESULTS: Twelve studies were included in the systematic review, reporting on 16 models. Outcomes ranged from referable retinopathy to blindness. Discrimination was reported in seven studies with C statistics ranging from 0.55 (95% CI 0.54, 0.56) to 0.84 (95% CI 0.78, 0.88). Five studies reported on calibration. Eight models could be compared head-to-head in the DCS cohort (N = 10,715). Most of the models underestimated retinopathy risk. Validating the models against different severities of retinopathy, C statistics ranged from 0.51 (95% CI 0.49, 0.53) to 0.89 (95% CI 0.88, 0.91). CONCLUSIONS/INTERPRETATION: Several prognostic models can accurately predict retinopathy risk in a population-based type 2 diabetes cohort. Most of the models include easy-to-measure predictors enhancing their applicability. Tailoring retinopathy screening frequency based on accurate risk predictions may increase the efficiency and cost-effectiveness of diabetic retinopathy care. REGISTRATION: PROSPERO registration ID CRD42018089122.

Addressing safety risks in integrated care programs for older people living at home: a scoping review.

BACKGROUND: Many older people live at home, often with complex and chronic health and social care needs. Integrated care programs are increasingly being implemented as a way to better address these needs. To support older people living at home, it is also essential to maintain their safety. Integrated care programs have the potential to address a wide range of risks and problems that could undermine older people's ability to live independently at home. The aim of this scoping review is to provide insight into how integrated care programs address safety risks faced by older people living at home - an area that is rather underexplored. METHODS: Safety was conceptualised as preventing or reducing the risk of problems, associated with individual functioning and behaviour, social and physical environments, and health and social care management, which could undermine older people's ability to live independently at home. For this scoping review a systematic literature search was performed to identify papers describing integrated care programs where at least one intervention component addressed safety risks. Data were extracted on the programs' characteristics, safety risks addressed, and the activities and interventions used to address them. RESULTS: None of the 11 programs included in this review explicitly mentioned safety in their goals. Nevertheless, following the principles of our conceptual framework, the programs appeared to address risks in multiple domains. Most attention was paid to risks related to older people's functioning, behaviour, and the health and social care they receive. Risks related to people's physical and social environments received less attention. CONCLUSION: Even though prevention of safety risks is not an explicit goal of integrated care programs, the programs address a wide range of risks on multiple domains. The need to address social and environmental risks is becoming increasingly important given the growing number of people receiving care and support at home. Prioritising a multidimensional approach to safety in integrated care programs could enhance the ability of health and social care systems to support older people to live safely at home.

Advancing integrated care evaluation in shifting contexts: blending implementation research with case study design in project SUSTAIN.

BACKGROUND: Despite many studies evaluating the effectiveness of integrated care, evidence remains inconsistent. There is increasing commentary pointing out the mismatch between the ability to capture the somewhat 'illusive' impact of integrated care initiatives and programmes, and the most appropriate way to do this. Focusing on methodology, this paper describes and critically reviews the experiences of SUSTAIN, a Horizon 2020 funded project (2015-2019) with the purpose of advancing knowledge and understanding of cross-European integrated care evaluation. SUSTAIN sought to improve integrated care initiatives for older people in seven countries, and to maximise the potential for knowledge transfer and application across Europe. The methods approach drew from implementation research, employing the participative Evidence Integration Triangle (EIT) and incorporating a mixed method, multiple embedded case study design. A core set of qualitative and quantitative indicators, alongside context and process data, were created and tested within four key project domains (person-centredness, prevention-orientation, safety and efficiency). The paper critically discusses the overall approach, highlighting the value of the EIT and case study design, and signalling the challenges of data collection with frail older people and stakeholder involvement at the sites, as well as difficulties developing the core set of indicators. CONCLUSIONS: Lessons learned and recommendations for advancing integrated care evaluation are put forward that focus on the status of integrated care as a complex intervention and a process. The use of implementation research methods and case study design are recommended as an additional evaluation approach for researchers to consider, alongside suggested ways of improving methods of data collection with frail populations and cost analysis.

Visit-to-visit variability of glycemia and vascular complications: the Hoorn Diabetes Care System cohort.

BACKGROUND: Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration. MATERIALS AND METHODS: Individuals with type 2 diabetes (n = 6770) from the Hoorn Diabetes Care System cohort were included in this study. The coefficient of variation (CV) was calculated over 5-year sliding intervals. People divided in quintiles based on their CV. Cox proportional hazard models were used to investigate the role of glycemic CV as risk factor in diabetes-related complications and mortality. RESULTS: The coefficient of variation of glucose (FG-CV) increased with time, in contrast to HbA1c (HbA1c-CV). People with a high FG-CV were those with an early age of diabetes onset (ΔQ5-Q1 = - 2.39 years), a higher BMI (ΔQ5-Q1 = + 0.92 kg/m2), an unfavorable lipid profile, i.e. lower levels of HDL-C (ΔQ5-Q1 = - 0.06 mmol/mol) and higher triglycerides (ΔQ5-Q1 =+ 1.20 mmol/mol). People with the highest FG-CV in the first 5-year interval showed an increased risk of insulin initiation, retinopathy, macrovascular complications and mortality independent of mean glycemia, classical risk factors and medication use. For HbA1c, the associations were weaker and less consistent. CONCLUSIONS: Individuals with a higher FG-CV have an unfavorable metabolic profile and have an increased risk of developing micro- and macrovascular complications and mortality. The association of HbA1c-CV with metabolic outcomes and complications was less consistent in comparison to FG-CV.

Sex- and site-specific differences in colorectal cancer risk among people with type 2 diabetes.

PURPOSE: The prevalence of colorectal cancer is higher among patients with type 2 diabetes mellitus (T2D) than among patients without diabetes. Furthermore, men are at higher risk for developing colorectal cancer than women in the general population and also subsite-specific risks differ per sex. The aim was to evaluate the impact of T2D on these associations. METHODS: A population-based matched cohort study was performed using data from the PHARMO Database Network. Patients with T2D were selected and matched (1:4) to diabetes free controls. Cox proportional hazards models were used to estimate hazard ratios (HRs) for CRC and its subsites. HRs were determined per sex and adjusted for age and socioeconomic status. The ratio of distal versus proximal colon cancer was calculated for people with T2D and controls per sex and stratified by age. RESULTS: Over 55,000 people with T2D were matched to > 215,000 diabetes free controls. Men and women with T2D were 1.3 times more likely to develop colorectal cancer compared to controls. Men with T2D were at higher risk to develop distal colon cancer (hazard ratio (95% confidence interval), 1.42 (1.08-1.88)), and women with T2D were at higher risk for developing proximal colon cancer (hazard ratio (95% confidence interval), 1.58 (1.13-2.19)). For rectal cancer, no statistically significant risk was observed for both men and women. CONCLUSIONS: Sex-specific screening strategies and prevention protocols should be considered for people with T2D. More tailored screening strategies may optimize the effectiveness of colorectal cancer screening in terms of reducing incidence and mortality.

Factors Associated With Nonadherence to Cardiovascular Medications: A Cross-sectional Study.

BACKGROUND: Cardiovascular medications have well-established benefits in the primary and secondary prevention of cardiovascular diseases. Unfortunately, adherence to these medicines is often suboptimal. To develop interventions intended to enhance adherence to cardiovascular medications, more insight is needed into the complex character of medication nonadherence. OBJECTIVE: The aim of the present study was to identify which factors are associated with nonadherence to cardiovascular medications in a sample of patients from Dutch community pharmacies. METHODS: In this cross-sectional study, patients using cardiovascular medications from 23 community pharmacies were included. Patient demographics, medication and disease characteristics, knowledge, quality of life, attitude toward medicines, and satisfaction with information were assessed. Both an adherent sample (n = 146) and a sample of patients nonadherent to prescribed medications (n = 109) during the last 6 months as assessed with pharmacy refill data (proportion of days covered <80%) were selected. Associations with refill nonadherence were assessed using univariate and multivariate logistic regression analyses. RESULTS: In total, 255 patients participated (53.3% men, 71.6 ± 10.9 years). Factors associated with cardiovascular medication nonadherence in multivariate analyses included experiencing difficulties with medication use due to forgetting, having insufficient knowledge on what to do when a dose is forgotten, and having an ambivalent attitude toward medicines (beliefs of high necessity and high concerns). CONCLUSIONS: Intervention strategies to enhance cardiovascular medication nonadherence should be targeted mainly to the unintentional dimension of nonadherence and include information and tools to prevent forgetting. Conversely, the influence of factors that underlie intentional nonadherence, particularly patients' beliefs about medicines, should also be addressed.

HbA1c is associated with altered expression in blood of cell cycle- and immune response-related genes.

AIMS/HYPOTHESIS: Individuals with type 2 diabetes are heterogeneous in their glycaemic control as tracked by blood HbA1c levels. Here, we investigated the extent to which gene expression levels in blood reflect current and future HbA1c levels. METHODS: HbA1c levels at baseline and 1 and 2 year follow-up were compared with gene expression levels in 391 individuals with type 2 diabetes from the Hoorn Diabetes Care System Cohort (15,564 genes, RNA sequencing). The functions of associated baseline genes were investigated further using pathway enrichment analysis. Using publicly available data, we investigated whether the genes identified are also associated with HbA1c in the target tissues, muscle and pancreas. RESULTS: At baseline, 220 genes (1.4%) were associated with baseline HbA1c. Identified genes were enriched for cell cycle and complement system activation pathways. The association of 15 genes extended to the target tissues, muscle (n = 113) and pancreatic islets (n = 115). At follow-up, expression of 25 genes (0.16%) associated with 1 year HbA1c and nine genes (0.06%) with 2 year HbA1c. Five genes overlapped across all time points, and 18 additional genes between baseline and 1 year follow-up. After adjustment for baseline HbA1c, the number of significant genes at 1 and 2 years markedly decreased, suggesting that gene expression levels in whole blood reflect the current glycaemic state and but not necessarily the future glycaemic state. CONCLUSIONS/INTERPRETATION: HbA1c levels in individuals with type 2 diabetes are associated with expression levels of genes that link to the cell cycle and complement system activation.

Socio-economic status and HbA1c in type 2 diabetes: A systematic review and meta-analysis.

Up until now, differences in HbA1c levels by socio-economic status (SES) have been identified, but not yet quantified in people with type 2 diabetes. The aim of this study was therefore to assess the difference in HbA1c levels between people with type 2 diabetes of different SES in a systematic review and meta-analysis. A systematic literature search was conducted in MEDLINE, Embase, Ebsco, and the Cochrane Library until January 14, 2018. Included studies described adults with type 2 diabetes in whom the association between SES and HbA1c levels was studied. Studies were rated for methodological quality and data were synthesized quantitatively (meta-analysis) and qualitatively (levels of evidence), stratified for type of SES variable, i.e., education, income, deprivation, and employment. Fifty-one studies were included: 15 high, 27 moderate, and 9 of low methodological quality. Strong evidence was provided that people of low SES have higher HbA1c levels than people of high SES, for deprivation, education, and employment status. The pooled mean difference in HbA1c levels between people of low and high SES was 0.26% (95% CI, 0.09-0.43) or 3.12 mmol/mol (95% CI, 1.21-5.04) for education and 0.20% (95% CI, -0.05 to 0.46) or 2.36 mmol/mol (95%CI, -0.61 to 5.33) for income. In conclusion, our systematic review and meta-analysis showed that there was an inverse association between SES and HbA1c levels in people with type 2 diabetes. Future research should focus on finding SES-sensitive strategies to reduce HbA1c levels in people with type 2 diabetes.

Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: A systematic review and meta-analysis.

The long-term impact of dipeptidyl peptidase-4 (DPP-4) inhibition is unknown, and there are concerns about the influence of DPP-4 inhibition on carcinogenesis of the pancreas and thyroid. As DPP-4 is a rather unselective enzyme present in many tissues, we focused on all specific cancer types. PubMed and EMBASE were searched between January 2005 and April 2017 to identify studies comparing DPP-4 inhibitors with either placebo or active drugs on cancer risk. Studies were included if they reported on at least one specific cancer outcome and had a follow-up of at least 1 year after start of drug use. Methodological quality of the studies was assessed by the Cochrane Collaboration's tool and the Newcastle-Ottawa Scale. Twenty-five studies met the inclusion criteria (12 randomized controlled trials and 13 observational studies). Sample sizes of the DPP-4 inhibitor groups ranged from 29 to 8212 patients for randomized controlled trials and from 2422 to 71 137 patients for observational studies. Mean age ranged from 51 to 76 years, and mean follow-up was 1.5 years. None of the pooled (sensitivity) analyses, except the observational studies studying breast cancer (hazard ratio [95% CI]: 0.76 [0.60-0.96]), showed evidence for an association between DPP-4 inhibitors and site-specific cancer. Also for pancreatic and thyroid cancer, no statistically significant risk was found. Based on the current literature, it is not possible to conclude whether DPP-4 inhibitors were associated with an increased risk of site-specific cancer. Future studies should address the methodological limitations and follow patients for a longer period to determine the long-term cancer risk of DPP-4 inhibitors.

Association of changes in inflammation with variation in glycaemia, insulin resistance and secretion based on the KORA study.

AIMS: Subclinical systemic inflammation may contribute to the development of type 2 diabetes, but its association with early progression of glycaemic deterioration in persons without diabetes has not been fully investigated. Our primary aim was to assess longitudinal associations of changes in pro-inflammatory (leukocytes, high-sensitivity C-reactive protein (hsCRP)) and anti-inflammatory (adiponectin) markers with changes in markers that assessed glycaemia, insulin resistance, and secretion (HbA1c , HOMA-IR, and HOMA-ß). Furthermore, we aimed to directly compare longitudinal with cross-sectional associations. MATERIALS AND METHODS: This study includes 819 initially nondiabetic individuals with repeated measurements from the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 cohort study (median follow-up: 7.1 years). Longitudinal and cross-sectional associations were simultaneously examined using linear mixed growth models. Changes in markers of inflammation were used as independent and changes in markers of glycaemia/insulin resistance/insulin secretion as dependent variables. Models were adjusted for age, sex, major lifestyle and metabolic risk factors for diabetes using time-varying variables in the final model. RESULTS: Changes of leukocyte count were positively associated with changes in HbA1c and HOMA-ß while changes in adiponectin were inversely associated with changes in HbA1c . All examined cross-sectional associations were statistically significant; they were generally stronger and mostly directionally consistent to the longitudinal association estimates. CONCLUSIONS: Adverse changes in low-grade systemic inflammation go along with glycaemic deterioration and increased insulin secretion independently of changes in other risk factors, suggesting that low-grade inflammation may contribute to the development of hyperglycaemia and a compensatory increase in insulin secretion.

HbA1c response after insulin initiation in patients with type 2 diabetes mellitus in real life practice: Identifying distinct subgroups.

AIMS: To identify subgroups of patients with type 2 diabetes mellitus (T2DM) following distinct trajectories of HbA1c after insulin initiation and explore underlying differences in clinical characteristics. MATERIALS AND METHODS: A cohort study was conducted in patients with T2DM initiating insulin in 2007-2013 with a follow-up of 2 to 4 years. Data were collected from the Groningen Initiative to Analyze Type 2 Diabetes Treatment (GIANTT) database. The primary outcome was subgroups with different trajectories of HbA1c patterns after insulin initiation, as identified by latent class growth modeling. Differences between subgroups were tested using one-way ANOVA, Kruskal-Wallis or chi-square tests, where appropriate. RESULTS: From 1459 patients, three subgroups with distinct HbA1c patterns were identified. Group 1 (8%) initially showed a moderate decrease followed by an increase in HbA1c 2 years later, despite receiving more comedication. Group 2 (84%) showed a stable decrease. Group 3 (8%) had a high initial level of HbA1c and a rapid decline within the first year, followed by a slow increase thereafter. Group 1 patients were on average 6-7 years younger than patients in groups 2 and 3 and were more likely to receive sulfonylureas than Group 3 patients. Group 3 patients had a shorter diabetes duration and were less well-controlled for HbA1c, systolic blood pressure and LDL-cholesterol at insulin initiation. CONCLUSIONS: Most patients showed a stable HbA1c response, but one out of six patients showed either a poor response, or a rapid initial response only after insulin initiation. Response patterns were associated with age, diabetes duration and risk-factor controls at the time of insulin initiation.

The impact of greenspace and condition of the neighbourhood on child overweight.

Background: Childhood overweight/obesity has been associated with environmental, parenting and socioeconomic status (SES) factors. This paper assesses the influence of the amount of green space, accessibility to a garden and neighbourhood condition on being overweight/obese. It investigates whether parental behaviours moderate or mediate this influence and evaluates the interaction of SES with environmental context. Methods: 6467 children from the UK Millennium Cohort Study living in England were analysed. We estimated logistic regressions to examine the initial association between environment and overweight. Subsequently, parenting determinants comprising: food consumption, physical activity, rules and regularity were evaluated as moderators or mediators. Lastly SES related variables were tested as moderators or mediators of the associations. Results: Statistically significant associations were found between low levels of green space, no access to a garden, run down area and childhood overweight/obesity [odds ratio (OR) [95% confidence interval (CI)] respectively: 1.14 (1.02-1.27), 1.35 (1.16-1.58), 1.22 (1.05-1.42)]. None of the parental constructs mediated or moderated the relationships between environment and childhood overweight/obesity. Including SES, parental education moderated the effect of environmental context. Specifically, among lower educated households lack of garden access and less green space was associated with overweight/obesity; and among higher educated households poor neighbourhood condition influenced the probability of overweight/obesity respectively: 1.38 (1.12-1.70) OR 1.38, 95% CI (1.21-1.70). Conclusions: This study suggests that limits on access to outdoor space are associated with future childhood overweight/obesity although the ways in which this occurs are moderated by parental education level.

Estimated GFR, Albuminuria, and Cognitive Performance: The Maastricht Study.

BACKGROUND: Reduced estimated glomerular filtration rate (eGFR) and albuminuria have been associated with worse cognitive performance. However, few studies have examined whether these associations are confined to older individuals or may be extended to the middle-aged population. STUDY DESIGN: Cross-sectional analyses of a prospective population-based cohort study. SETTING & PARTICIPANTS: 2,987 individuals aged 40 to 75 years from the general population (The Maastricht Study). PREDICTOR: eGFR and urinary albumin excretion (UAE). OUTCOMES: Memory function, information processing speed, and executive function. MEASUREMENTS: Analyses were adjusted for demographic variables (age, sex, and educational level), lifestyle factors (smoking behavior and alcohol consumption), depression, and cardiovascular disease risk factors (glucose metabolism status, waist circumference, total to high-density lipoprotein cholesterol ratio, triglyceride level, use of lipid-modifying medication, systolic blood pressure, use of antihypertensive medication, and prevalent cardiovascular disease). RESULTS: UAE was <15mg/24 h in 2,439 (81.7%) participants, 15 to <30 mg/24 h in 309 (10.3%), and ≥30mg/24 h in 239 (8.0%). In the entire study population, UAE≥30mg/24 h was associated with lower information processing speed as compared to UAE<15mg/24 h (ß [SD difference] = -0.148; 95% CI, -0.263 to -0.033) after full adjustment, whereas continuous albuminuria was not. However, significant interaction terms (P for interaction < 0.05) suggested that albuminuria was most strongly and extensively associated with cognitive performance in older individuals. Mean (±SD) eGFR, estimated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine-cystatin C equation (eGFRcr-cys), was 88.4±14.6 mL/min/1.73m2. eGFRcr-cys was not associated with any of the domains of cognitive performance after full adjustment. However, significant interaction terms (P for interaction < 0.05) suggested that eGFRcr-cys was associated with cognitive performance in older individuals. LIMITATIONS: Cross-sectional design, which limited causal inferences. CONCLUSIONS: In the entire study population, albuminuria was independently associated with lower information processing speed, whereas eGFRcr-cys was not associated with cognitive performance. However, both were more strongly and extensively associated with cognitive performance in older individuals.

Extension of the association structure in joint models to include weighted cumulative effects.

Motivated by a study measuring diabetes-related risk factors and complications, we postulate an extension to the standard formulation of joint models for longitudinal and survival outcomes, wherein the longitudinal outcome has a cumulative effect on the hazard of the event, weighted by recency. We focus on the relationship between the biomarker HbA1c and the development of sight threatening retinopathy, since the impact of the HbA1c marker on the risk of sight threatening retinopathy is expected to be cumulative, with the evolution of the HbA1c marker over time contributing to progressively greater damage to the vascular structure of the retina. Opting for a parametric approach, we propose the use of the normal and skewed normal probability density functions as weight functions, estimating the relevant parameters directly from the data. The use of the recency-weighted cumulative effect specification allows us to incorporate differences in the development of the longitudinal profile over time in the calculation of hazard ratios between subjects. The proposed functions provide us with parameters with clinically relevant interpretations while retaining a degree of flexibility. In addition, they also allow answering of important clinical questions regarding the relative importance of various segments of the biomarkers history in the estimation of the risk of the event. Copyright © 2017 John Wiley & Sons, Ltd.

Circulating linoleic acid and alpha-linolenic acid and glucose metabolism: the Hoorn Study.

PURPOSE: Data on the relation between linoleic acid (LA) and alpha-linolenic acid (ALA) and type 2 diabetes mellitus (T2DM) risk are scarce and inconsistent. The aim of this study was to investigate the association of serum LA and ALA with fasting and 2 h post-load plasma glucose and glycated hemoglobin (HbA1c). METHOD: This study included 667 participants from third examination (2000) of the population-based Hoorn study in which individuals with glucose intolerance were overrepresented. Fatty acid profiles in serum total lipids were measured at baseline, in 2000. Diabetes risk markers were measured at baseline and follow-up in 2008. Linear regression models were used in cross-sectional and prospective analyses. RESULTS: In cross-sectional analyses (n = 667), serum LA was inversely associated with plasma glucose, both in fasting conditions (B = -0.024 [-0.045, -0.002]) and 2 h after glucose tolerance test (B = -0.099 [-0.158, -0.039]), but not with HbA1c (B = 0.000 [-0.014, 0.013]), after adjustment for relevant factors. In prospective analyses (n = 257), serum LA was not associated with fasting (B = 0.003 [-0.019, 0.025]) or post-load glucose (B = -0.026 [-0.100, 0.049]). Furthermore, no significant associations were found between serum ALA and glucose metabolism in cross-sectional or prospective analyses. CONCLUSIONS: In this study, serum LA was inversely associated with fasting and post-load glucose in cross-sectional, but not in prospective analyses. Further studies are needed to elucidate the exact role of serum LA and ALA levels and dietary polyunsaturated fatty acids in glucose metabolism.