High‐Saturated‐Fat Diet Increases Circulating Angiotensin‐Converting Enzyme, Which Is Enhanced by the rs4343 Polymorphism Defining Persons at Risk of Nutrient‐Dependent Increases of Blood Pressure

Background Angiotensin‐converting enzyme (ACE) plays a major role in blood pressure regulation and cardiovascular homeostasis. Contrary to the assumption that ACE levels are stable, circulating ACE has been shown to be altered in obesity and weight loss. We sought to examine effects of a high‐saturated‐fat (HF) diet on ACE within the NUtriGenomic Analysis in Twins (NUGAT) study. Methods and Results Forty‐six healthy and nonobese twin pairs initially consumed a carbohydrate‐rich, low‐fat diet over a period of 6 weeks to standardize for nutritional behavior prior to the study, followed by 6 weeks of HF diet under isocaloric conditions. After 6 weeks of HF diet, circulating ACE concentrations increased by 15% (P=1.6×10−30), accompanied by an increased ACE gene expression in adipose tissue (P=3.8×10−6). Stratification by ACE rs4343, a proxy for the ACE insertion/deletion polymorphism (I/D), revealed that homozygous carriers (GG) of the variant had higher baseline ACE concentrations (P=7.5×10−8) and additionally showed a 2‐fold increase in ACE concentrations in response to the HF diet as compared to non‐ or heterozygous carriers (AA/AG, P=2×10−6). GG carriers also responded with higher systolic blood pressure as compared to AA/AG carriers (P=0.008). The strong gene‐diet interaction was confirmed in a second independent, cross‐sectional cohort, the Metabolic Syndrome Berlin Potsdam (MeSyBePo) study. Conclusions The HF‐diet‐induced increase of ACE serum concentrations reveals ACE to be a potential molecular link between dietary fat intake and hypertension and cardiovascular disease (CVD). The GG genotype of the ACE rs4343 polymorphism represents a robust nutrigenetic marker for an unfavorable response to high‐saturated‐fat diets. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01631123

Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques

We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6±1.0 years, BMI 31.5±0.4 kg/m2; 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6–62H2] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39–56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r2 = 27–32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P<0.001). However, when validated against the alternative dataset all indices performed comparably with the standard homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.54, P<0.001). Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations

Effects of weight loss and long-term weight maintenance with diets varying in protein and glycemic index on cardiovascular risk factors: the diet, obesity, and genes (DiOGenes) study: a randomized, controlled trial

BACKGROUND: We sought to separately examine the effects of either weight loss or diets varying in protein content and glycemic index without further changes in body weight on cardiovascular risk factors within the Diet, Obesity, and Genes study (DiOGenes). METHODS AND RESULTS: DiOGenes is a pan-European controlled dietary intervention study in 932 overweight adults who first lost body weight on an 8-week low-calorie diet and were then randomized to 1 of 5 ad libitum diets for 26 weeks. The diets were either high or low protein or high or low glycemic index in 4 combinations or control. Weight loss (-11.23 kg; 95% confidence interval, -11.54 to -10.92; P<0.001) reduced high-sensitivity C-reactive protein (-1.15 mg/L; 95% confidence interval, -1.30 to -0.41; P<0.001), low- and high-density lipoprotein cholesterol, triglycerides, and blood pressure. During the 26-week weight maintenance period in the intention-to-treat analysis, the further decrease of high-sensitivity C-reactive protein blood levels was -0.46 mg/L greater (95% confidence interval, -0.79 to -0.13) in the groups assigned to low-glycemic-index diets than in those on high-glycemic-index diets (P<0.001). Groups on low-protein diets achieved a -0.25 mg/L greater reduction in high-sensitivity C-reactive protein (95% confidence interval, -0.59 to -0.17) than those on high-protein diets (P<0.001), whereas lipid profiles and blood pressure were not differently affected. CONCLUSIONS: This large-scale intervention study clearly separates weight loss from dietary composition-related effects. Low-glycemic-index carbohydrates and, to a lesser extent, low-protein intake may specifically reduce low-grade inflammation and associated comorbidities in overweight/obese adults

Treatment and Outcome of Osteoporotic Thoracolumbar Vertebral Fractures With Anterior or Posterior Tension Band Failure (OF 5): Short-Term Results From the Prospective EOFTT Multicenter Study.

STUDY DESIGN Subgroup analysis of a multicenter prospective cohort study. OBJECTIVE To analyse surgical strategies applied to osteoporotic thoracolumbar osteoporotic fracture (OF) 5 injuries with anterior or posterior tension band failure and to assess related complications and clinical outcome. METHODS A multicenter prospective cohort study (EOFTT) was conducted at 17 spine centers including 518 consecutive patients who were treated for an osteoporotic vertebral fracture (OVF). For the present study, only patients with OF 5 fractures were analysed. Outcome parameters were complications, Visual Analogue Scale (VAS), Oswestry Disability Questionnaire (ODI), Timed Up & Go test (TUG), EQ-5D 5L, and Barthel Index. RESULTS In total, 19 patients (78 ± 7 years, 13 female) were analysed. Operative treatment consisted of long-segment posterior instrumentation in 9 cases and short-segment posterior instrumentation in 10 cases. Pedicle screws were augmented in 68 %, augmentation of the fractured vertebra was performed in 42%, and additional anterior reconstruction was done in 21 %. Two patients (11 %) received short-segment posterior instrumentation without either anterior reconstruction or cement-augmentation of the fractured vertebra. No surgical or major complications occurred, but general postoperative complications were observed in 45%. At a follow-up of mean 20 ± 10 weeks (range, 12 to 48 weeks), patients showed significant improvements in all functional outcome parameters. CONCLUSIONS In this analysis of patients with type OF 5 fractures, surgical stabilization was the treatment of choice and lead to significant short-term improvement in terms of functional outcome and quality of life despite a high general complication rate

Treatment and Outcome of Osteoporotic Thoracolumbar Vertebral Body Fractures With Deformation of Both Endplates With or Without Posterior Wall Involvement (OF 4): Short-Term Results from the Prospective EOFTT Multicenter Study.

STUDY DESIGN: Multicenter prospective cohort study. OBJECTIVE: To analyse therapeutical strategies applied to osteoporotic thoracolumbar OF 4 injuries, to assess related complications and clinical outcome. METHODS: A multicenter prospective cohort study (EOFTT) including 518 consecutive patients who were treated for an Osteoporotic vertebral compression fracture (OVCF). For the present study, only patients with OF 4 fractures were analysed. Outcome parameters were complications, Visual Analogue Scale, Oswestry Disability Questionnaire, Timed Up & Go test, EQ-5D 5L, and Barthel Index after a minimum follow-up of 6 weeks. RESULTS: A total of 152 (29%) patients presented with OF 4 fractures with a mean age of 76 years (range 41-97). The most common treatment was short-segment posterior stabilization (51%; hybrid stabilization in 36%). Mean follow up was 208 days (±131 days), mean ODI was 30 ± 21. Dorsoventral stabilized patients were younger compared to the other groups (P .602, Barthel: P > .252, EQ-5D 5L index value: P > .610, VAS-EQ-5D 5L: P = 1.000). The inpatient complication rate was 8% after conservative and 16% after surgical treatment. During follow-up period 14% of conservatively treated patients and 3% of surgical treated patients experienced neurological deficits. CONCLUSIONS: Conservative therapy of OF 4 injuries seems to be viable option in patients with only moderate symptoms. Hybrid stabilization was the dominant treatment strategy leading to promising clinical short-term results. Stand-alone cement augmentation seems to be a valid alternative in selected cases

Georg Schmorl prize of the German spine society (DWG) 2022: current treatment for inpatients with osteoporotic thoracolumbar fractures-results of the EOFTT study

AIM Osteoporotic thoracolumbar fractures are of increasing importance. To identify the optimal treatment strategy this multicentre prospective cohort study was performed. PURPOSE Patients suffering from osteoporotic thoracolumbar fractures were included. Excluded were tumour diseases, infections and limb fractures. Age, sex, trauma mechanism, OF classification, OF-score, treatment strategy, pain condition and mobilization were analysed. METHODS A total of 518 patients' aged 75 ± 10 (41-97) years were included in 17 centre. A total of 174 patients were treated conservatively, and 344 were treated surgically, of whom 310 (90%) received minimally invasive treatment. An increase in the OF classification was associated with an increase in both the likelihood of surgery and the surgical invasiveness. RESULTS Five (3%) complications occurred during conservative treatment, and 46 (13%) occurred in the surgically treated patients. 4 surgical site infections and 2 mechanical failures requested revision surgery. At discharge pain improved significantly from a visual analogue scale score of 7.7 (surgical) and 6.0 (conservative) to a score of 4 in both groups (p < 0.001). Over the course of treatment, mobility improved significantly (p = 0.001), with a significantly stronger (p = 0.007) improvement in the surgically treated patients. CONCLUSION Fracture severity according to the OF classification is significantly correlated with higher surgery rates and higher invasiveness of surgery. The most commonly used surgical strategy was minimally invasive short-segmental hybrid stabilization followed by kyphoplasty/vertebroplasty. Despite the worse clinical conditions of the surgically treated patients both conservative and surgical treatment led to an improved pain situation and mobility during the inpatient stay to nearly the same level for both treatments

Clinical Evaluation of the Osteoporotic Fracture Treatment Score (OF-Score): Results of the Evaluation of the Osteoporotic Fracture Classification, Treatment Score and Therapy Recommendations (EOFTT) Study.

STUDY DESIGN Multicenter prospective cohort study. OBJECTIVE The study aims to validate the recently developed OF score for treatment decisions in patients with osteoporotic vertebral compression fractures (OVCF). METHODS This is a prospective multicenter cohort study (EOFTT) in 17 spine centers. All consecutive patients with OVCF were included. The decision for conservative or surgical therapy was made by the treating physician independent of the OF score recommendation. Final decisions were compared to the recommendations given by the OF score. Outcome parameters were complications, Visual Analogue Scale, Oswestry Disability Questionnaire, Timed Up & Go test, EQ-5D 5 L, and Barthel Index. RESULTS In total, 518 patients (75.3% female, age 75 ± 10) years were included. 344 (66%) patients received surgical treatment. 71% of patients were treated following the score recommendations. For an OF score cut-off value of 6.5, the sensitivity and specificity to predict actual treatment were 60% and 68% (AUC .684, P < .001). During hospitalization overall 76 (14.7%) complications occurred. The mean follow-up rate and time were 92% and 5 ± 3.5 months, respectively. While all patients in the study cohort improved in clinical outcome parameters, the effect size was significantly less in the patients not treated in line with the OF score's recommendation. Eight (3%) patients needed revision surgery. CONCLUSIONS Patients treated according to the OF score's recommendations showed favorable short-term clinical results. Noncompliance with the score resulted in more pain and impaired functional outcome and quality of life. The OF score is a reliable and save tool to aid treatment decision in OVCF

Effects of insoluble cereal fibre on body fat distribution in the optimal fibre trial

Scope: The Optimal Fibre Trial (OptiFiT) investigates metabolic effects of insoluble cereal fibre in subjects with impaired glucose tolerance (IGT), showing moderate glycemic and anti-inflammatory benefits, especially in subjects with an obesity-related phenotype. An OptiFiT sub-group is analysed for effects on body fat distribution. Methods and results: 180 participants with IGT receive a blinded, randomized supplementation with insoluble cereal fibre or placebo for 2 years. Once a year, all subjects undergo fasting blood sampling, oral glucose tolerance test, and anthropometric measurements. A subgroup (n=47) also received magnetic resonance imaging and spectroscopy for quantification of adipose tissue distribution and liver fat content. We compared MR, metabolic and inflammatory outcomes between fibre and placebo group metabolism and inflammation. Visceral and non-visceral fat, fasting glucose, HbA1c, fasting insulin, insulin resistance, and uric acid decrease only in the fibre group, mirroring effects of the entire cohort. However, after adjustment for weight loss, there are no significant between-group differences. There is a statistical trend for fibre-driven liver fat reduction in subjects with confirmed non-alcoholic fatty liver disease (NAFLD; n = 19). Conclusions: Data and evidence on beneficial effects of insoluble cereal fibre on visceral and hepatic fatstorage is limited, but warrants further research. Targeted trials are required

Path to AWAKE : evolution of the concept

This paper describes the conceptual steps in reaching the design of the AWAKE experiment currently under construction at CERN. We start with an introduction to plasma wakefield acceleration and the motivation for using proton drivers. We then describe the self-modulation instability - a key to an early realization of the concept. This is then followed by the historical development of the experimental design, where the critical issues that arose and their solutions are described. We conclude with the design of the experiment as it is being realized at CERN and some words on the future outlook. A summary of the AWAKE design and construction status as presented in this conference is given in Gschwendtner et al. [1]