The handling of missing data in trial-based economic evaluations: should data be multiply imputed prior to longitudinal linear mixed-model analyses?

INTRODUCTION: For the analysis of clinical effects, multiple imputation (MI) of missing data were shown to be unnecessary when using longitudinal linear mixed-models (LLM). It remains unclear whether this also applies to trial-based economic evaluations. Therefore, this study aimed to assess whether MI is required prior to LLM when analyzing longitudinal cost and effect data. METHODS: Two-thousand complete datasets were simulated containing five time points. Incomplete datasets were generated with 10, 25, and 50% missing data in follow-up costs and effects, assuming a Missing At Random (MAR) mechanism. Six different strategies were compared using empirical bias (EB), root-mean-squared error (RMSE), and coverage rate (CR). These strategies were: LLM alone (LLM) and MI with LLM (MI-LLM), and, as reference strategies, mean imputation with LLM (M-LLM), seemingly unrelated regression alone (SUR-CCA), MI with SUR (MI-SUR), and mean imputation with SUR (M-SUR). RESULTS: For costs and effects, LLM, MI-LLM, and MI-SUR performed better than M-LLM, SUR-CCA, and M-SUR, with smaller EBs and RMSEs as well as CRs closers to nominal levels. However, even though LLM, MI-LLM and MI-SUR performed equally well for effects, MI-LLM and MI-SUR were found to perform better than LLM for costs at 10 and 25% missing data. At 50% missing data, all strategies resulted in relatively high EBs and RMSEs for costs. CONCLUSION: LLM should be combined with MI when analyzing trial-based economic evaluation data. MI-SUR is more efficient and can also be used, but then an average intervention effect over time cannot be estimated.

Batch-effect detection, correction and characterisation in Illumina HumanMethylation450 and MethylationEPIC BeadChip array data.

BACKGROUND: Genomic technologies can be subject to significant batch-effects which are known to reduce experimental power and to potentially create false positive results. The Illumina Infinium Methylation BeadChip is a popular technology choice for epigenome-wide association studies (EWAS), but presently, little is known about the nature of batch-effects on these designs. Given the subtlety of biological phenotypes in many EWAS, control for batch-effects should be a consideration. RESULTS: Using the batch-effect removal approaches in the ComBat and Harman software, we examined two in-house datasets and compared results with three large publicly available datasets, (1214 HumanMethylation450 and 1094 MethylationEPIC BeadChips in total), and find that despite various forms of preprocessing, some batch-effects persist. This residual batch-effect is associated with the day of processing, the individual glass slide and the position of the array on the slide. Consistently across all datasets, 4649 probes required high amounts of correction. To understand the impact of this set to EWAS studies, we explored the literature and found three instances where persistently batch-effect prone probes have been reported in abstracts as key sites of differential methylation. As well as batch-effect susceptible probes, we also discover a set of probes which are erroneously corrected. We provide batch-effect workflows for Infinium Methylation data and provide reference matrices of batch-effect prone and erroneously corrected features across the five datasets spanning regionally diverse populations and three commonly collected biosamples (blood, buccal and saliva). CONCLUSIONS: Batch-effects are ever present, even in high-quality data, and a strategy to deal with them should be part of experimental design, particularly for EWAS. Batch-effect removal tools are useful to reduce technical variance in Infinium Methylation data, but they need to be applied with care and make use of post hoc diagnostic measures.

Comparing the EQ-5D-5L crosswalks and value sets for England, the Netherlands and Spain: Exploring their impact on cost-utility results.

This study compares the five-level EuroQol five-dimension questionnaire (EQ-5D-5L) crosswalks and the 5L value sets for England, the Netherlands, and Spain and explores the implication of using one or the other for the results of cost-utility analyses. Data from two randomized controlled trials in depression and diabetes were used. Utility value distributions were compared, and mean differences in utility values between the EQ-5D-5L crosswalk and the 5L value set were described by country. Quality-adjusted life years (QALYs) were calculated using the area-under-the-curve method. Incremental cost-effectiveness ratios (ICERs) were calculated, and uncertainty around ICERs was estimated using bootstrapping and graphically shown in cost-effectiveness acceptability curves. For all countries investigated, utility value distributions differed between the EQ-5D-5L crosswalk and 5L value set. In both case studies, mean utility values were lower for the EQ-5D-5L crosswalk compared with the 5L value set in England and Spain, but higher in the Netherlands. However, these differences in utility values did not translate into relevant differences across utility estimation methods in incremental QALYs and the interventions' probability of cost-effectiveness. Thus, our results suggest that EQ-5D-5L crosswalks and 5L value sets can be used interchangeably in patients affected by mild or moderate conditions. Further research is needed to establish whether these findings are generalizable to economic evaluations among severely ill patients.

Methylome and transcriptome maps of human visceral and subcutaneous adipocytes reveal key epigenetic differences at developmental genes.

Adipocytes support key metabolic and endocrine functions of adipose tissue. Lipid is stored in two major classes of depots, namely visceral adipose (VA) and subcutaneous adipose (SA) depots. Increased visceral adiposity is associated with adverse health outcomes, whereas the impact of SA tissue is relatively metabolically benign. The precise molecular features associated with the functional differences between the adipose depots are still not well understood. Here, we characterised transcriptomes and methylomes of isolated adipocytes from matched SA and VA tissues of individuals with normal BMI to identify epigenetic differences and their contribution to cell type and depot-specific function. We found that DNA methylomes were notably distinct between different adipocyte depots and were associated with differential gene expression within pathways fundamental to adipocyte function. Most striking differential methylation was found at transcription factor and developmental genes. Our findings highlight the importance of developmental origins in the function of different fat depots.

Diagnostic accuracy of depression questionnaires in adult patients with diabetes: A systematic review and meta-analysis.

BACKGROUND: Comorbid depression is common among patients with diabetes and has severe health consequences, but often remains unrecognized. Several questionnaires are used to screen for depression. A systematic review and meta-analysis regarding the diagnostic accuracy of depression questionnaires in adults with diabetes is unavailable. Our aim was to conduct a systematic review and meta-analysis to evaluate the diagnostic accuracy of depression questionnaires in adults with type 1 or type 2 diabetes. METHODS: PubMed, Embase and PsycINFO were searched from inception to 28 February 2018. Studies were included when the diagnostic accuracy of depression questionnaires was assessed in a diabetes population and the reference standard was a clinical interview. Data extraction was performed by one reviewer and checked by another. Two reviewers independently conducted the quality assessment (QUADAS-2). Diagnostic accuracy was pooled in bivariate random effects models. The main outcome was diagnostic accuracy, expressed as sensitivity and specificity, of depression questionnaires in an adult diabetes population. This study is reported according to PRISMA-DTA and is registered with PROSPERO (CRD42018092950). RESULTS: A total 6,097 peer-reviewed articles were screened. Twenty-one studies (N = 5,703 patients) met the inclusion criteria for the systematic review. Twelve different depression questionnaires were identified, of which the CES-D (n = 6 studies) and PHQ-9 (n = 7 studies) were the most frequently evaluated. Risk of bias was unclear for multiple domains in the majority of studies. In the meta-analyses, five (N = 1,228) studies of the CES-D (≥16), five (N = 1,642) of the PHQ-9 (≥10) and four (N = 822) of the algorithm of the PHQ-9 were included in the pooled analysis. The CES-D (≥16) had a pooled sensitivity of 85.0% (95%CI, 71.3-92.8%) and a specificity of 71.6% (95%CI, 62.5-79.2%); the PHQ-9 (≥10) had a sensitivity of 81.5% (95%CI, 57.1-93.5%) and a specificity of 79.7% (95%CI, 62.1-90.4%). The algorithm for the PHQ-9 had a sensitivity of 60.9% (95%CI, 52.3-90.8%) and a specificity of 64.0% (95%CI, 53.0-93.9%). CONCLUSIONS: This review indicates that the CES-D had the highest sensitivity, whereas the PHQ-9 had the highest specificity, although confidence intervals were wide and overlapping. The algorithm for the PHQ-9 had the lowest sensitivity and specificity. Given the variance in results and suboptimal reporting of studies, further high quality studies are needed to confirm the diagnostic accuracy of these depression questionnaires in patients with diabetes.

Two-year effectiveness of a stepped-care depression prevention intervention and predictors of incident depression in primary care patients with diabetes type 2 and/or coronary heart disease and subthreshold depression: data from the Step-Dep cluster randomised controlled trial.

INTRODUCTION: Major depressive disorders (MDD), diabetes mellitus type 2 (DM2) and coronary heart disease (CHD) are leading contributors to the global burden of disease and often co-occur. OBJECTIVES: To evaluate the 2-year effectiveness of a stepped-care intervention to prevent MDD compared with usual care and to develop a prediction model for incident depression in patients with DM2 and/or CHD with subthreshold depression. METHODS: Data of 236 Dutch primary care patients with DM2/CHD with subthreshold depression (Patient Health Questionnaire 9 (PHQ-9) score ≥6, no current MDD according to the Mini International Neuropsychiatric Interview (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria)) who participated in the Step-Dep trial were used. A PHQ-9 score of ≥10 at minimally one measurement during follow-up (at 3, 6, 9, 12 and 24 months) was used to determine the cumulative incidence of MDD. Potential demographic and psychological predictors were measured at baseline via web-based self-reported questionnaires and evaluated using a multivariable logistic regression model. Model performance was assessed with the Hosmer-Lemeshow test, Nagelkerke's R2 explained variance and area under the receiver operating characteristic curve (AUC). Bootstrapping techniques were used to internally validate our model. RESULTS: 192 patients (81%) were available at 2-year follow-up. The cumulative incidence of MDD was 97/192 (51%). There was no statistically significant overall treatment effect over 24 months of the intervention (OR 1.37; 95% CI 0.52 to 3.55). Baseline levels of anxiety, depression, the presence of >3 chronic diseases and stressful life events predicted the incidence of MDD (AUC 0.80, IQR 0.79-0.80; Nagelkerke's R2 0.34, IQR 0.33-0.36). CONCLUSION: A model with 4 factors predicted depression incidence during 2-year follow-up in patients with DM2/CHD accurately, based on the AUC. The Step-Dep intervention did not influence the incidence of MDD. Future depression prevention programmes should target patients with these 4 predictors present, and aim to reduce both anxiety and depressive symptoms. TRIAL REGISTRATION NUMBER: NTR3715.

Measurement properties of depression questionnaires in patients with diabetes: a systematic review.

PURPOSE: To conduct a systematic review on measurement properties of questionnaires measuring depressive symptoms in adult patients with type 1 or type 2 diabetes. METHODS: A systematic review of the literature in MEDLINE, EMbase and PsycINFO was performed. Full text, original articles, published in any language up to October 2016 were included. Eligibility for inclusion was independently assessed by three reviewers who worked in pairs. Methodological quality of the studies was evaluated by two independent reviewers using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. Quality of the questionnaires was rated per measurement property, based on the number and quality of the included studies and the reported results. RESULTS: Of 6286 unique hits, 21 studies met our criteria evaluating nine different questionnaires in multiple settings and languages. The methodological quality of the included studies was variable for the different measurement properties: 9/15 studies scored 'good' or 'excellent' on internal consistency, 2/5 on reliability, 0/1 on content validity, 10/10 on structural validity, 8/11 on hypothesis testing, 1/5 on cross-cultural validity, and 4/9 on criterion validity. For the CES-D, there was strong evidence for good internal consistency, structural validity, and construct validity; moderate evidence for good criterion validity; and limited evidence for good cross-cultural validity. The PHQ-9 and WHO-5 also performed well on several measurement properties. However, the evidence for structural validity of the PHQ-9 was inconclusive. The WHO-5 was less extensively researched and originally not developed to measure depression. CONCLUSION: Currently, the CES-D is best supported for measuring depressive symptoms in diabetes patients.

Effectiveness of a stepped-care intervention to prevent major depression in patients with type 2 diabetes mellitus and/or coronary heart disease and subthreshold depression: A pragmatic cluster randomized controlled trial.

PURPOSE: Given the public health significance of poorly treatable co-morbid major depressive disorders (MDD) among patients with type 2 diabetes mellitus (DM2) and coronary heart disease (CHD), we need to investigate whether strategies to prevent the development of major depression could reduce its burden of disease. We therefore evaluated the effectiveness of a stepped-care program for subthreshold depression in comparison with usual care in patients with DM2 and/or CHD. METHODS: A cluster randomized controlled trial, with 27 primary care centers serving as clusters. A total of 236 DM2 and/or CHD patients with subthreshold depression (nine item Patient Health Questionnaire (PHQ-9) score ≥ 6, no current MDD according to DSM-IV criteria) were allocated to the intervention group (N = 96) or usual care group (n = 140). The stepped-care program was delivered by trained practice nurses during one year and consisted of four sequential treatment steps: watchful waiting, guided self-help, problem solving treatment and referral to the general practitioner. The primary outcome was the 12-month cumulative incidence of MDD as measured with the Mini International Neuropsychiatric Interview (MINI). Secondary outcomes included severity of depression (measured by PHQ-9) at 3, 6, 9 and 12 months. RESULTS: Of 236 patients (mean age, 67,5 (SD 10) years; 54.7% men), 210 (89%) completed the MINI at 12 months. The cumulative incidence of MDD was 9 of 89 (10.1%) participants in the intervention group and 12 of 121 (9.9%) participants in the usual care group. We found no statistically significant overall effect of the intervention (OR = 1.21; 95% confidence interval (0.12 to 12.41)) and there were no statistically significant differences in the course or severity of depressive symptoms between the two groups. CONCLUSIONS: This study suggest that Step-Dep was not more effective in preventing MDD than usual care in a primary care population with DM2 and/or CHD and subthreshold depression.

Process evaluation of a stepped-care program to prevent depression in primary care: patients' and practice nurses' experiences.

BACKGROUND: Depression is common in patients with diabetes type 2 (DM2) and/or coronary heart disease (CHD), with high personal and societal burden and may even be preventable. Recently, a cluster randomized trial of stepped care to prevent depression among patients with DM2 and/or CHD and subthreshold depression in Dutch primary care (Step-Dep) versus usual care showed no effectiveness. This paper presents its process evaluation, exploring in-depth experiences from a patient and practice nurse perspective to further understand the results. METHODS: A qualitative study was conducted. Using a purposive sampling strategy, data were collected through semi-structured interviews with 24 participants (15 patients and nine practice nurses). All interviews were audiotaped and transcribed verbatim. Atlas.ti 5.7.1 software was used for coding and structuring of themes. A thematic analysis of the data was performed. RESULTS: The process evaluation showed, even through a negative trial, that Step-Dep was perceived as valuable by both patients and practice nurses; perceived effectiveness on improving depressive symptoms varied greatly, but most felt that it had been beneficial for patients' well-being. Facilitators were: increased awareness of mental health problems in chronic disease management and improved accessibility and decreased experienced stigma of receiving mental health care. The Patient Health Questionnaire 9 (PHQ-9), used to determine depression severity, functioned as a useful starting point for the conversation on mental health and patients gained more insight into their mental health by regularly filling out the PHQ-9. However, patients and practice nurses did not widely support its use for monitoring depressive symptoms or making treatment decisions. Monitoring mental health was deemed important in chronically ill patients by both patients and practice nurses and was suggested to start at the time of diagnosis of a chronic disease. Appointed barriers were that patients were primarily motivated to participate in scientific research rather than their intrinsic need to improve depressive symptoms. Additionally, various practice nurses preferred offering individually based therapy over pre-determined interventions in a protocolled sequence and somatic practice nurses expressed a lack of competence to recognise and treat mental health problems. CONCLUSION: This study demonstrates both the benefits and unique demands of programs such as Step-Dep. The appointed facilitators and barriers could guide the development of future studies aiming to prevent depression in similar patient groups.

Effect of prenatal DHA supplementation on the infant epigenome: results from a randomized controlled trial.

BACKGROUND: Evidence is accumulating that nutritional exposures in utero can influence health outcomes in later life. Animal studies and human epidemiological studies have implicated epigenetic modifications as playing a key role in this process, but there are limited data from large well-controlled human intervention trials. This study utilized a large double-blind randomized placebo-controlled trial to test whether a defined nutritional exposure in utero, in this case docosahexaenoic acid (DHA), could alter the infant epigenome. Pregnant mothers consumed DHA-rich fish oil (800 mg DHA/day) or placebo supplements from 20 weeks' gestation to delivery. Blood spots were collected from the children at birth (n = 991) and blood leukocytes at 5 years (n = 667). Global DNA methylation was measured in all samples, and Illumina HumanMethylation450K BeadChip arrays were used for genome-wide methylation profiling in a subset of 369 children at birth and 65 children at 5 years. RESULTS: There were no differences in global DNA methylation levels between the DHA and control group either at birth or at 5 years, but we identified 21 differentially methylated regions (DMRs) at birth, showing small DNA methylation differences (<5%) between the treatment groups, some of which seemed to persist until 5 years. The number of DMRs at birth was greater in males (127 DMRs) and in females (72 DMRs) separately, indicating a gender-specific effect. CONCLUSION: Maternal DHA supplementation during the second half of pregnancy had small effects on DNA methylation of infants. While the potential functional significance of these changes remains to be determined, these findings further support the role of epigenetic modifications in developmental programming in humans and point the way for future studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12605000569606 and ACTRN12611001127998.

Diagnostic accuracy of the Patient Health Questionnaire-9 for assessment of depression in type II diabetes mellitus and/or coronary heart disease in primary care.

BACKGROUND: Depression is common among type 2 diabetes mellitus (DM2)/coronary heart disease (CHD) patients and is associated with adverse health effects. A promising strategy to reduce burden of disease is to identify patients at risk for depression in order to offer indicated prevention. This study aims to assess the diagnostic accuracy of the Patient Health Questionnaire-9 (PHQ-9) to be used as a tool to identify high risk patients. METHODS: In this cross-sectional study, 586 consecutive DM2/CHD patients aged >18 were recruited through 23 general practices. PHQ-9 outcomes were compared to the Mini International Neuropsychiatric Interview (MINI), which was considered the reference standard. Diagnostic accuracy was evaluated for minor and major depression, comparing both sum- and algorithm based PHQ-9 scores. RESULTS: For minor depression, the optimal cut-off score was 8 (sensitivity 71%, specificity 71% and an AUC of 0.74). For major depression, the optimal cut-off score was 10 resulting in a sensitivity of 84%, a specificity of 82%, and an AUC of 0.88. The positive predictive value of the PHQ-9 algorithm for diagnosing minor and major depression was 25% and 33%, respectively. LIMITATIONS: Two main limitations apply. MINI Interviewers were not blinded for PHQ-9 scores and less than 10% of all invited patients could be included in the analyses. This could have resulted in biased outcomes. CONCLUSIONS: The PHQ-9 sum score performs well in identifying patients at high risk of minor and major depression. However, the PHQ-9 showed suboptimal results for diagnostic purposes. Therefore, it is recommended to combine the use of the PHQ-9 with further diagnostics to identify depression.

Simultaneous and selective decarboxylation of L-serine and deamination of L-phenylalanine in an amino acid mixture--a means of separating amino acids for synthesizing biobased chemicals.

Amino acids (AAs) obtained from the hydrolysis of biomass-derived proteins are interesting feedstocks for the chemical industry. They can be prepared from the byproduct of biofuel production and agricultural wastes. They are rich in functionalities needed in petrochemicals, providing the opportunity to save energy, reagents, and process steps. However, their separation is required before they can be applied for further applications. Electrodialysis (ED) is a promising separation method, but its efficiency needs to be improved when separating AAs with similar isoelectric points. Thus, specific conversions are required to form product with different charges. Here we studied the enzymatic conversions which can be used as a means to aid the ED separation of neutral AAs. A model mixture containing L-serine, L-phenylalanine and L-methionine was used. The reactions of L-serine decarboxylase and L-phenylalanine ammonia-lyase were employed to specifically convert serine and phenylalanine into ethanolamine and trans-cinnamic acid. At the isoelectric point of methionine (pH 5.74), the charge of ethanolamine and trans-cinnamic acid are +1 and -1, therefore facilitating potential separation into three different streams by electrodialysis. Here the enzyme kinetics, specificity, inhibition and the operational stabilities were studied, showing that both enzymes can be applied simultaneously to aid the ED separation of neutral AAs.

High fat challenges with different fatty acids affect distinct atherogenic gene expression pathways in immune cells from lean and obese subjects.

SCOPE: Early perturbations in vascular health can be detected by imposing subjects to a high fat (HF) challenge and measure response capacity. Subtle responses can be determined by assessment of whole-genome transcriptional changes. We aimed to magnify differences in health by comparing gene-expression changes in peripheral blood mononuclear cells toward a high MUFA or saturated fatty acids (SFA) challenge between subjects with different cardiovascular disease risk profiles and to identify fatty acid specific gene-expression pathways. METHODS AND RESULTS: In a cross-over study, 17 lean and 15 obese men (50-70 years) received two 95 g fat shakes, high in SFAs or MUFAs. Peripheral blood mononuclear cell gene-expression profiles were assessed fasted and 4-h postprandially. Comparisons were made between groups and shakes. During fasting, 294 genes were significantly differently expressed between lean and obese. The challenge increased differences to 607 genes after SFA and 2516 genes after MUFA. In both groups, SFA decreased expression of cholesterol biosynthesis and uptake genes and increased cholesterol efflux genes. MUFA increased inflammatory genes and PPAR-α targets involved in ß-oxidation. CONCLUSION: Based upon gene-expression changes, we conclude that an HF challenge magnifies differences in health, especially after MUFA. Our findings also demonstrate how SFAs and MUFAs exert distinct effects on lipid handling pathways in immune cells.

Recent developments on the role of epigenetics in obesity and metabolic disease.

The increased prevalence of obesity and related comorbidities is a major public health problem. While genetic factors undoubtedly play a role in determining individual susceptibility to weight gain and obesity, the identified genetic variants only explain part of the variation. This has led to growing interest in understanding the potential role of epigenetics as a mediator of gene-environment interactions underlying the development of obesity and its associated comorbidities. Initial evidence in support of a role of epigenetics in obesity and type 2 diabetes mellitus (T2DM) was mainly provided by animal studies, which reported epigenetic changes in key metabolically important tissues following high-fat feeding and epigenetic differences between lean and obese animals and by human studies which showed epigenetic changes in obesity and T2DM candidate genes in obese/diabetic individuals. More recently, advances in epigenetic methodologies and the reduced cost of epigenome-wide association studies (EWAS) have led to a rapid expansion of studies in human populations. These studies have also reported epigenetic differences between obese/T2DM adults and healthy controls and epigenetic changes in association with nutritional, weight loss, and exercise interventions. There is also increasing evidence from both human and animal studies that the relationship between perinatal nutritional exposures and later risk of obesity and T2DM may be mediated by epigenetic changes in the offspring. The aim of this review is to summarize the most recent developments in this rapidly moving field, with a particular focus on human EWAS and studies investigating the impact of nutritional and lifestyle factors (both pre- and postnatal) on the epigenome and their relationship to metabolic health outcomes. The difficulties in distinguishing consequence from causality in these studies and the critical role of animal models for testing causal relationships and providing insight into underlying mechanisms are also addressed. In summary, the area of epigenetics and metabolic health has seen rapid developments in a short space of time. While the outcomes to date are promising, studies are ongoing, and the next decade promises to be a time of productive research into the complex interactions between the genome, epigenome, and environment as they relate to metabolic disease.

Synthesis of bio-based methacrylic acid by decarboxylation of itaconic acid and citric acid catalyzed by solid transition-metal catalysts.

Methacrylic acid, an important monomer for the plastics industry, was obtained in high selectivity (up to 84%) by the decarboxylation of itaconic acid using heterogeneous catalysts based on Pd, Pt and Ru. The reaction takes place in water at 200-250 °C without any external added pressure, conditions significantly milder than those described previously for the same conversion with better yield and selectivity. A comprehensive study of the reaction parameters has been performed, and the isolation of methacrylic acid was achieved in 50% yield. The decarboxylation procedure is also applicable to citric acid, a more widely available bio-based feedstock, and leads to the production of methacrylic acid in one pot in 41% selectivity. Aconitic acid, the intermediate compound in the pathway from citric acid to itaconic acid was also used successfully as a substrate.

Postprandial fatty acid specific changes in circulating oxylipins in lean and obese men after high-fat challenge tests.

SCOPE: Circulating oxylipins may affect peripheral tissues and are assumed to play an important role in endothelial function. They are esterified in triglyceride-rich lipoproteins that are increased after a high-fat (HF) meal, depending on BMI and fatty acid (FA) type. Yet, it is unclear which oxylipins appear in circulation after HF meals differing in FA composition. METHODS AND RESULTS: In a double-blind randomized crossover challenge study, we characterized the postprandial oxylipin response after different HF challenges in lean and obese men receiving HF milkshakes, either high in saturated FAs (SFA), monounsaturated FAs (MUFA), or omega 3 (n-3) polyunsaturated FAs (PUFA). Plasma oxylipin profiles were significantly altered at 2 and 4 h after shake consumption when compared to baseline. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived oxylipins increased after n-3 PUFA shake consumption. MUFA shake consumption increased levels of cytochrome P450 mediated oxylipins. SFA shake consumption led to strong increases in linoleic acid (LA) derived HODEs. No differences were observed between lean and obese individuals at baseline and after any shake consumption. CONCLUSION: We are the first demonstrating acute effects on circulating oxylipins after HF meal challenges. These changes were strongly influenced by different dietary FAs and may affect endothelial function.

Cost-effectiveness of a stepped-care intervention to prevent major depression in patients with type 2 diabetes mellitus and/or coronary heart disease and subthreshold depression: design of a cluster-randomized controlled trial.

BACKGROUND: Co-morbid major depression is a significant problem among patients with type 2 diabetes mellitus and/or coronary heart disease and this negatively impacts quality of life. Subthreshold depression is the most important risk factor for the development of major depression. Given the highly significant association between depression and adverse health outcomes and the limited capacity for depression treatment in primary care, there is an urgent need for interventions that successfully prevent the transition from subthreshold depression into a major depressive disorder. Nurse led stepped-care is a promising way to accomplish this. The aim of this study is to evaluate the cost-effectiveness of a nurse-led indicated stepped-care program to prevent major depression among patients with type 2 diabetes mellitus and/or coronary heart disease in primary care who also have subthreshold depressive symptoms. METHODS/DESIGN: An economic evaluation will be conducted alongside a cluster-randomized controlled trial in approximately thirty general practices in the Netherlands. Randomization takes place at the level of participating practice nurses. We aim to include 236 participants who will either receive a nurse-led indicated stepped-care program for depressive symptoms or care as usual. The stepped-care program consists of four sequential but flexible treatment steps: 1) watchful waiting, 2) guided self-help treatment, 3) problem solving treatment and 4) referral to the general practitioner. The primary clinical outcome measure is the cumulative incidence of major depressive disorder as measured with the Mini International Neuropsychiatric Interview. Secondary outcomes include severity of depressive symptoms, quality of life, anxiety and physical outcomes. Costs will be measured from a societal perspective and include health care utilization, medication and lost productivity costs. Measurements will be performed at baseline and 3, 6, 9 and 12 months. DISCUSSION: The intervention being investigated is expected to prevent new cases of depression among people with type 2 diabetes mellitus and/or coronary heart disease and subthreshold depression, with subsequent beneficial effects on quality of life, clinical outcomes and health care costs. When proven cost-effective, the program provides a viable treatment option in the Dutch primary care system. TRIAL REGISTRATION: Dutch Trial Register NTR3715.

A high-fat SFA, MUFA, or n3 PUFA challenge affects the vascular response and initiates an activated state of cellular adherence in lean and obese middle-aged men.

BMI and fatty acid type affect postprandial metabolic TG responses, but whether these factors also affect vascular, inflammatory, and leukocyte adherence responses remains unclear. We therefore compared those postprandial responses between lean and obese men after 3 high-fat challenges differing in fatty acid composition. In a crossover double-blind study, 18 lean (BMI: 18-25 kg/m(2)) and 18 obese (BMI >29 kg/m(2)) middle-aged men received 3 isocaloric high-fat milkshakes containing 95 g fat (88% of energy), either high in SFAs (54% of energy/total fat), MUFAs (83% of energy/total fat), or n3 (omega-3) PUFAs (40% of energy/total fat). Hemodynamics, augmentation index (AIX), leukocyte cell surface adhesion markers, and plasma cytokines involved in vascular adherence, coagulation, and inflammation were measured before and after consumption of the milkshakes. In both groups and after all shakes were consumed, AIX decreased; plasma soluble intercellular adhesion molecule (sICAM) 1, sICAM3, soluble vascular cell adhesion molecule (sVCAM) 1, and interleukin-8 increased; monocyte CD11a, CD11b, and CD621 expression increased; neutrophil CD11a, CD11b, and CD621 expression increased; and lymphocyte CD62l expression increased (P < 0.05). Lymphocyte CD11a and CD11b expression decreased in lean participants after consumption of all shakes but did not change in obese participants (P < 0.05). Obese participants had a less pronounced decrease in heart rate after the consumption of all shakes (P < 0.05). MUFA consumption induced a more pronounced decrease in blood pressure and AIX compared with the other milkshakes in both lean and obese participants (P < 0.05). High-fat consumption initiates an activated state of cellular adherence and an atherogenic milieu. This response was independent of fatty acid type consumed or of being lean or obese, despite the clear differences in postprandial TG responses between the groups and different milkshakes. These findings suggest that in addition to increased TGs, other mechanisms are involved in the high-fat consumption-induced activated state of cellular adherence.

Responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes: a randomized trial.

BACKGROUND: The ability of subjects to respond to nutritional challenges can reflect the flexibility of their biological system. Nutritional challenge tests could be used as an indicator of health status but more knowledge on metabolic and immune responses of different subjects to nutritional challenges is needed. The aim of this study was to compare the responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-over design 42 men (age 50-70 y) consumed three high-fat shakes containing saturated fat (SFA), monounsaturated fat (MUFA) or n-3 polyunsaturated (PUFA). Men were selected on BMI and health status (lean, obese or obese diabetic) and phenotyped with MRI for adipose tissue distribution. Before and 2 and 4 h after shake consumption blood was drawn for measurement of expression of metabolic and inflammation-related genes in peripheral blood mononuclear cells (PBMCs), plasma triglycerides (TAG), glucose, insulin, cytokines and ex vivo PBMC immune response capacity. The MUFA and n-3 PUFA challenge, compared to the SFA challenge, induced higher changes in expression of inflammation genes MCP1 and IL1ß in PBMCs. Obese and obese diabetic subjects had different PBMC gene expression and metabolic responses to high-fat challenges compared to lean subjects. The MUFA challenge induced the most pronounced TAG response, mainly in obese and obese diabetic subjects. CONCLUSION/SIGNIFICANCE: The PBMC gene expression response and metabolic response to high-fat challenges were affected by fat type and metabolic risk phenotype. Based on our results we suggest using a MUFA challenge to reveal differences in response capacity of subjects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00977262.

Consumption of a high monounsaturated fat diet reduces oxidative phosphorylation gene expression in peripheral blood mononuclear cells of abdominally overweight men and women.

The Mediterranean (MED) diet is often considered health-promoting due to its high content of MUFA and polyphenols. These bioactive compounds can affect gene expression and accordingly may regulate pathways and proteins related to cardiovascular disease prevention. This study aimed to identify the effects of a MED-type diet, and the replacement of SFA with MUFA in a Western-type diet, on peripheral blood mononuclear cell (PBMC) gene expression and plasma proteins. Abdominally overweight men and women (waist: women ≥80 cm, men ≥94 cm) were allocated to an 8-wk, completely controlled SFA diet (19% daily energy as SFA), a MUFA diet (20% daily energy MUFA), or a MED diet (21% daily energy MUFA). Concentrations of 124 plasma proteins and PBMC whole-genome transcriptional profiles were assessed. Consumption of the MUFA and MED diets, compared with the SFA diet, decreased the expression of oxidative phosphorylation (OXPHOS) genes, plasma connective tissue growth factor, and apoB concentrations. Compared with the MED and SFA diets, the MUFA diet changed the expression of genes involved in B-cell receptor signaling and endocytosis signaling. Participants who consumed the MED diet had lower concentrations of proinflammatory proteins at 8 wk compared with baseline. We hypothesize that replacement of SFA with MUFA may improve health, thereby reducing metabolic stress and OXPHOS activity in PBMC. The MED diet may have additional antiatherogenic effects by lowering proinflammatory plasma proteins.