Objective/methodsDNA methylation plays an important role in obesity and related metabolic complications. We examined genome-wide DNA promoter methylation along with mRNA profiles in paired samples of human subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from non-obese vs. obese individuals.ResultsWe identified negatively correlated methylation and expression of several obesity-associated genes in our discovery dataset and in silico replicated ETV6 in two independent cohorts. Further, we identified six adipose tissue depot-specific genes (HAND2, HOXC6, PPARG, SORBS2, CD36, and CLDN1). The effects were further supported in additional independent cohorts. Our top hits might play a role in adipogenesis and differentiation, obesity, lipid metabolism, and adipose tissue expandability. Finally, we show that in vitro methylation of SORBS2 directly represses gene expression.ConclusionsTaken together, our data show distinct tissue specific epigenetic alterations which associate with obesity.

Objective: Apelin is an adipokine which plays a role in the regulation of glucose homeostasis and may contribute to the link between increased adipose tissue mass and obesity related metabolic diseases. Here we investigate the role of omental and subcutaneous (SC) adipose tissue apelin and its receptor APJ mRNA expression in human obesity and test the hypothesis that changes in circulating apelin are associated with reduced fat mass in three weight loss intervention studies. Methods: Apelin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which omental and SC apelin mRNA expression has been analyzed and in three interventions: 12 weeks exercise (n = 60), 6 months calorie-restricted diet (n = 19), 12 months after bariatric surgery (n = 32). Results: Apelin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes and correlates with circulating apelin, BMI, body fat, C-reactive protein, and insulin sensitivity. Obesity surgery-induced weight loss causes a significant reduction in omental and SC apelin expression. All interventions led to significantly reduced apelin serum concentrations which significantly correlate with improved insulin sensitivity, independently of changes in BMI. Conclusions: Reduced apelin expression and serum concentration may contribute to improved insulin sensitivity beyond significant weight loss.

Weight loss has been shown to significantly improve Adipose tissue (AT) function, however changes in AT gene expression profiles particularly in visceral AT (VAT) have not been systematically studied. Here, we tested the hypothesis that extensive weight loss in response to bariatric surgery (BS) causes AT gene expression changes, which may affect energy and lipid metabolism, inflammation and secretory function of AT. We assessed gene expression changes by whole genome expression chips in AT samples obtained from six morbidly obese individuals, who underwent a two step BS strategy with sleeve gastrectomy as initial and a Roux-en-Y gastric bypass as second step surgery after 12 ± 2 months. Global gene expression differences in VAT and subcutaneous (S)AT were analyzed through the use of genome-scale metabolic model (GEM) for adipocytes. Significantly altered gene expressions were PCR-validated in 16 individuals, which also underwent a two-step surgery intervention. We found increased expression of cell death-inducing DFFA-like effector a (CIDEA), involved in formation of lipid droplets in both fat depots in response to significant weight loss. We observed that expression of the genes associated with metabolic reactions involved in NAD+, glutathione and branched chain amino acid metabolism are significantly increased in AT depots after surgery-induced weight loss.

Hospital information systems are increasingly used as part of decision support tools for planning at strategic, tactical and operational decision levels. Clinical pathways are an effective and efficient approach in standardising the progression of treatment, to support patient care and facilitate clinical decision making. This literature review proposes a taxonomy of problems related to clinical pathways and explores the intersection between Information Systems (IS), Operational Research (OR) and industrial engineering. A structured search identified 175 papers included in the taxonomy and analysed in this review. The findings suggest that future work should consider industrial engineering integrated with OR techniques, with an aim to improving the handling of multiple scopes within one model, while encouraging interaction between the disjoint care levels and with a more direct focus on patient outcomes. Achieving this would continue to bridge the gap between OR, IS and industrial engineering, for clinical pathways to aid decision support.

In this paper, we address the problem of planning the patient flow in hospitals subject to scarce medical resources with the objective of maximizing the contribution margin. We assume that we can classify a large enough percentage of elective patients according to their diagnosis-related group (DRG) and clinical pathway. The clinical pathway defines the procedures (such as different types of diagnostic activities and surgery) as well as the sequence in which they have to be applied to the patient. The decision is then on which day each procedure of each patient's clinical pathway should be done, taking into account the sequence of procedures as well as scarce clinical resources, such that the contribution margin of all patients is maximized. We develop two mixed-integer programs (MIP) for this problem which are embedded in a static and a rolling horizon planning approach. Computational results on real-world data show that employing the MIPs leads to a significant improvement of the contribution margin compared to the contribution margin obtained by employing the planning approach currently practiced. Furthermore, we show that the time between admission and surgery is significantly reduced by applying our models.

Background/Aims: Altered expression and circulating levels of glutathione peroxidase 3 (GPX3) have been observed in obesity and type 2 diabetes (T2D) across species. Here, we investigate whether GPX3 serum concentrations and adipose tissue (AT) GPX3 mRNA expression are related to obesity and weight loss. Methods: GPX3 serum concentration was measured in 630 individuals, including a subgroup (n = 293) for which omental and subcutaneous (SC) GPX3 mRNA expression has been analyzed. GPX3 analyses include three interventions: 6 months after bariatric surgery (n = 80) or combined exercise/hypocaloric diet (n = 20) or two-step bariatric surgery (n = 24) studies. Results: Bariatric surgery-induced weight loss (–25.8 ± 8.4%), but not a moderate weight reduction of –8.8 ± 6.5% was associated with significantly reduced GPX3 serum concentrations. GPX3 mRNA is significantly higher expressed in AT from individuals with normal glucose metabolism compared to T2D patients. SC AT GPX3 expression is significantly higher in lean compared to obese as well as in insulin-sensitive compared insulin-resistant individuals with obesity. Weight loss after bariatric surgery causes a significant increase in SC AT GPX3 expression. AT GPX3 expression significantly correlates with age, BMI, fat distribution, insulin sensitivity (only SC AT), but not with circulating GPX3. Conclusion: Our data support the notion that SC AT GPX3 expression is associated with obesity, fat distribution and related to whole body insulin resistance.

In this paper, we address the problem of planning the patient flow in hospitals subject to scarce medical resources with the objective of maximizing the contribution margin. We assume that we can classify a large enough percentage of elective patients according to their diagnosis-related group (DRG) and clinical pathway. The clinical pathway defines the procedures (such as different types of diagnostic activities and surgery) as well as the sequence in which they have to be applied to the patient. The decision is then on which day each procedure of each patient's clinical pathway should be done, taking into account the sequence of procedures as well as scarce clinical resources, such that the contribution margin of all patients is maximized. We develop two mixed-integer programs (MIP) for this problem which are embedded in a static and a rolling horizon planning approach. Computational results on real-world data show that employing the MIPs leads to a significant improvement of the contribution margin compared to the contribution margin obtained by employing the planning approach currently practiced. Furthermore, we show that the time between admission and surgery is significantly reduced by applying our models.

The combination of SIRT with state-of-the-art liver surgery opens up new therapeutic options in patients with liver metastases.