Multi-Trait Genomic Risk Stratification for Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is continuously rising with more disease cases every year. T2DM is a chronic disease with many severe comorbidities and therefore remains a burden for the patient and the society. Disease prevention, early diagnosis, and stratified treatment are important elements in slowing down the increase in diabetes prevalence. T2DM has a substantial genetic component with an estimated heritability of 40–70%, and more than 500 genetic loci have been associated with T2DM. Because of the intrinsic genetic basis of T2DM, one tool for risk assessment is genome-wide genetic risk scores (GRS). Current GRS only account for a small proportion of the T2DM risk; thus, better methods are warranted for more accurate risk assessment. T2DM is correlated with several other diseases and complex traits, and incorporating this information by adjusting effect size of the included markers could improve risk prediction. The aim of this study was to develop multi-trait (MT)-GRS leveraging correlated information. We used phenotype and genotype information from the UK Biobank, and summary statistics from two independent T2DM studies. Marker effects for T2DM and seven correlated traits, namely, height, body mass index, pulse rate, diastolic and systolic blood pressure, smoking status, and information on current medication use, were estimated (i.e., by logistic and linear regression) within the UK Biobank. These summary statistics, together with the two independent training summary statistics, were incorporated into the MT-GRS prediction in different combinations. The prediction accuracy of the MT-GRS was improved by 12.5% compared to the single-trait GRS. Testing the MT-GRS strategy in two independent T2DM studies resulted in an elevated accuracy by 50–94%. Finally, combining the seven information traits with the two independent T2DM studies further increased the prediction accuracy by 34%. Across comparisons, body mass index and current medication use were the two traits that displayed the largest weights in construction of the MT-GRS. These results explicitly demonstrate the added benefit of leveraging correlated information when constructing genetic scores. In conclusion, constructing GRS not only based on the disease itself but incorporating genomic information from other correlated traits as well is strongly advisable for obtaining improved individual risk stratification

Exploring the capability of wireless near infrared spectroscopy as a portable seizure detection device for epilepsy patients

AbstractPurposeNear infrared spectroscopy (NIRS) has proved useful in measuring significant hemodynamic changes in the brain during epileptic seizures. The advance of NIRS-technology into wireless and portable devices raises the possibility of using the NIRS-technology for portable seizure detection.MethodsThis study used NIRS to measure changes in oxygenated (HbO), deoxygenated (HbR), and total hemoglobin (HbT) at left and right side of the frontal lobe in 33 patients with epilepsy undergoing long-term video-EEG monitoring. Fifteen patients had 34 focal seizures (20 temporal-, 11 frontal-, 2 parietal-lobe, one unspecific) recorded and analyzed with NIRS. Twelve parameters consisting of maximum increase and decrease changes of HbO, HbR and HbT during seizures (1min before- to 3min after seizure-onset) for left and right side, were compared with the patients’ own non-seizure periods (a 2-h period and a 30-min exercise-period). In both non-seizure periods a 4min moving windows with maximum overlapping were applied to find non-seizure maxima of the 12 parameters. Detection was defined as positive when seizure maximum change exceeded non-seizure maximum change.ResultsWhen analyzing the 12 parameters separately the positive seizure detection was in the range of 6–24%. The increase in hemodynamics was in general better at detecting seizures (15–24%) than the decrease in hemodynamics (6–18%) (P=0.02).ConclusionNIRS did not seem to be a suitable technology for generic seizure detection given the device, settings, and methods used in this study. There are still several challenges to overcome before the NIRS-technology can be used as a home-monitoring seizure detection device

Evaluation of the Performance of Vortex Generators on the DU 91-W2-250 Profile using Stereoscopic PIV

Stereoscopic PIV measurements investigating the effect of Vortex Generators on the lift force near stall and on glide ratio at best aerodynamic performance have been carried out in the LM Glasfiber wind tunnel on a DU 91-W2-250 profile. Measurements at two Reynolds numbers were analyzed; Re=0.9·10 6 and 2.4·10 6 . The results show that one can resolve the longitudinal vortex structures generated by the devices and that mixing is created close to the wall, transferring high momentum fluid into the near wall region. It is also seen that the vortex generators successfully can obstruct separation near stall

TOPFARM wind farm optimization tool

A wind farm optimization framework is presented in detail and demonstrated on two test cases: 1) Middelgrunden and 2) Stags Holt/Coldham. A detailed flow model describing the instationary flow within a wind farm is used together with an aeroelastic model to determine production and fatigue loading of wind farm wind turbines. Based on generic load cases, the wind farm production and fatigue evaluations are subsequently condensed in a large pre-calculated database for rapid calculation of lifetime equivalent loads and energy production in the optimization loop.. The objective function defining the optimization problem includes elements as energy production, turbine degradation, operation and maintenance costs, electrical grid costs and foundation costs. The objective function is optimized using a dedicated multi fidelity approach with the locations of individual turbines in the wind farm spanning the design space. . The results are over all satisfying and are giving some interesting insights on the pros and cons of the design choices. They show in particular that the inclusion of the fatigue loads costs give rise to some additional details in comparison with pure power based optimization. The Middelgrunden test case resulted in an improvement of the financial balance of 2.1 M€ originating from a very large increase in the energy production value of 9.3 M€ mainly counterbalanced by increased electrical grid costs. The Stags Holt/Coldham test case resulted in an improvement of the financial balance of 3.1 M€

The Effects of 12-Weeks Whey Protein Supplements on Markers of Bone Turnover in Adults With Abdominal Obesity – A <i style="">Post Hoc</i> Analysis

BACKGROUND: While osteoporosis is characterized by skeletal fragility due to increased bone turnover and low bone mineral density (BMD), subjects with abdominal obesity and type-2 diabetes have increased risk of bone fractures despite low bone turnover and increased BMD. Diets with increased protein content are reported to increase bone turnover in healthy adults and may be a point of interest in preserving bone strength in subjects with abdominal obesity and/or type-2 diabetes. METHODS: We examined the effect of 12-weeks dietary intervention on bone turnover in 64 adults with abdominal obesity using data from the MERITS trial. The trial was a randomized, controlled, double blinded study in which participants were allocated to receive either 60 g/d of whey protein hydrolysate or maltodextrin in combination with either high (30 g/d) or low dietary fiber intake (10 g/d). Primarily, we assessed changes in plasma markers of bone turnover Procollagen type 1 N-terminal propeptide (p1NP), C-terminal telopeptide type-1 collagen (CTX), and parathyroid hormone (PTH) within the four intervention groups. In addition, we measured u-calcium and u-carbamide excretion, 25(OH)D, and BMD by whole body DXA scans. Finally, we compared changes in insulin resistance (Homeostasis-model assessment of insulin resistance, HOMA-IR) with changes in bone turnover markers. The trial was registered at www.clinicaltrials.gov as NCT02931630. RESULTS: Sixty-four subjects were included in the study. We did not find any effect of twelve weeks of high protein or high fiber intake on plasma levels of P1NP or CTX. There was a nonsignificant positive association between protein intake and PTH levels (p=0.06). U-calcium and u-carbamide increased in both protein groups. There was a positive association between change in HOMA-IR and PTH (p=0.042), while changes in P1NP and CTX did not associate to changes in HOMA-IR. CONCLUSION: Twelve weeks of increased whey protein intake in subjects with abdominal obesity did not affect markers of bone turnover significantly, although tended to increase PTH levels. Dietary fiber intake did not affect bone turnover. We report a positive association between change in HOMA-IR and PTH supporting a hypothesis of insulin resistance as a potential key factor in the expanding field of bone fragility in T2D subjects

The risk of major osteoporotic fractures with GLP-1 receptor agonists when compared to DPP-4 inhibitors:A Danish nationwide cohort study

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with an increased fracture risk. There is little evidence for the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA) on fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) for treatment with GLP-1RA compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) as add-on therapies to metformin. METHODS: We conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either GLP-1RA or DPP-4i were enrolled from 2007 to 2018. Subjects were propensity-score matched 1:1 based on age, sex, and index date. MOF were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. In addition, Aalen’s Additive Hazards model was applied to examine additive rather than relative hazard effects while allowing time-varying effects. RESULTS: In total, 42,816 individuals treated with either combination were identified and included. After matching, 32,266 individuals were included in the main analysis (16,133 in each group). Median follow-up times were 642 days and 529 days in the GLP-1RA and DPP-4i group, respectively. We found a crude HR of 0.89 [0.76–1.05] for MOF with GLP-1RA compared to DPP-4i. In the fully adjusted model, we obtained an unaltered HR of 0.86 [0.73–1.03]. For the case of hip fracture, we found a crude HR of 0.68 [0.49–0.96] and a similar adjusted HR. Fracture risk was lower in the GLP-1RA group when examining higher daily doses of the medications, when allowing follow-up to continue after medication change, and when examining hip fractures, specifically. Additional subgroup- and sensitivity analyses yielded results similar to the main analysis. CONCLUSION: In our primary analysis, we did not observe a significantly different risk of MOF between treatment with GLP-1RA and DPP-4i. We conclude that GLP-1RA are safe in terms of fracture