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Background: Hereditary pyruvate kinase (PK) deficiency results in chronic hemolysis that may lead to reduced bone mineral density (BMD). Mitapivat (AG-348) is an investigational, first-in-class, allosteric activator of PKR that has been shown to improve hemoglobin and other hemolysis markers in non-regularly transfused patients (pts) and reduce transfusion burden in regularly transfused pts. Mitapivat has mild aromatase inhibition effects; however, a recent study of 30 non-regularly transfused pts with PK deficiency showed that mitapivat did not appear to promote progression of BMD abnormalities for up to 56 months (mos). The large-pooled analysis presented here assessed BMD over time in a broader PK deficiency population including both non-regularly transfused and regularly transfused pts receiving long-term treatment with mitapivat. Methods: This study included pts enrolled in DRIVE-PK (NCT02476916), ACTIVATE (NCT03548220), ACTIVATE-T (NCT03559699), and the long-term extension (LTE) study (NCT03853798). All trials included pts ≥ 18 years (yrs) with a confirmed diagnosis of PK deficiency treated with mitapivat. DRIVE-PK (N = 52) was a Phase (Ph.) 2, global, randomized open-label study. ACTIVATE (N = 80) was a Ph. 3, randomized, double-blind, placebo-controlled study. ACTIVATE-T (N = 27) was a Ph. 3, open-label, single-arm study. Pts in DRIVE-PK and ACTIVATE were not regularly transfused, defined as ≤ 3 and ≤ 4 units of red blood cells in the prior 12 mos, and no transfusions in the prior 4 and 3 mos, respectively. Pts in ACTIVATE-T were regularly transfused, defined as ≥ 6 transfusion episodes in the prior 12 mos. Data from 90 pts who received mitapivat for > 12 mos were pooled from these 3 trials along with the LTE study of pts from ACTIVATE and ACTIVATE-T who elected to continue or crossover (if on placebo) to mitapivat. BMD changes over time were measured using dual-energy X-ray absorptiometry (DXA) scans at 3 locations (total femur [combined femoral neck and total hip], femoral neck, and spine). Based on DXA T-scores, pts were classified according to standard definitions as having normal BMD (≥ -1.0 at all locations), osteopenia (> -2.5 to < -1.0 at ≥ 1 locations), or osteoporosis (≤ -2.5 at ≥ 1 locations). DXA scans were obtained locally for all 3 studies and interpreted locally for DRIVE-PK and centrally for ACTIVATE, ACTIVATE-T, and LTE. Scans were collected at baseline (BL), between week (wk) 24 and 28, every 6 mos through mo 30, and then annually for DRIVE-PK; at BL and wk 24 for ACTIVATE; at BL, wk 16, and wk 40 for ACTIVATE-T; and at BL, every 24 wks until wk 96, and then every 48 wks for the LTE study. Results: Of 90 pts assessed (median age 34.5 yrs [range 18-71]; 50.0% female), median exposure to mitapivat was 20 mos (range 12.2-64.9). Eight pts (8.9%) had concomitant use of bisphosphonate medications, 8 pts (8.9%) had a prior medical history of fracture, and 6 pts (6.7%) reported fractures or joint injuries during the study period. BL BMD T-scores were collected for 88 pts. At BL, 24 pts (26.7%) had a T-score ≥ -1.0 (normal BMD), 48 pts (53.3%) had a worst T-score > -2.5 to < -1.0 (osteopenia), 16 pts (17.8%) had a worst T-score ≤ -2.5 (osteoporosis), and 2 pts (2.2%) were missing T-score data. At last BMD assessment (data cut-off 03Mar2021), 76 of 88 pts (86.4%) remained stable, 7 pts (7.5%) improved, and 5 pts (5.7%) worsened (Figure 1a). As of the last assessment, 27 (30.0%), 46 (51.1%), and 17 (18.9%) of 90 pts had a T-score indicating normal BMD, osteopenia, and osteoporosis, respectively (Table 1b). Among 24 pts with BL T-scores ≥ -1.0, 21 pts remained stable, and 3 pts showed worsening BMD. Of 48 pts with a BL T-score > -2.5 to < -1.0, 6 pts improved to a T-score indicating normal BMD, 40 pts remained stable, and 2 pts worsened. Of 16 pts with a BL T-score of ≤ -2.5, 1 pt improved to a T-score of > -2.5 to < -1.0. Conclusions: This large-pooled analysis showed that BMD remained largely stable over time in adult pts with PK deficiency receiving long-term treatment with mitapivat for up to 65 mos. As these pts had a substantial degree of reduced BMD at BL which did not progress, it is hypothesized that mitapivat may halt bone loss in PK deficiency patients via its mechanism of action by decreasing hemolysis and ineffective erythropoiesis and stabilizing iron homeostasis. BMD data will continue to be monitored as part of the ongoing LTE study to further understand this process. Figure 1 Figure 1. Disclosures Al-Samkari: Novartis: Consultancy; Dova/Sobi: Consultancy, Research Funding; Argenx: Consultancy; Rigel: Consultancy; Amgen: Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. Grace: Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Glenthoej: Novo Nordisk: Honoraria; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Barcellini: Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding. Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Kuo: Bluebird Bio: Consultancy; Apellis: Consultancy; Novartis: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Alexion: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding. Layton: Cerus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morado: Sanofi Genzyme: Honoraria. Viprakasit: La Jolla Pharmaceuticals: Consultancy, Research Funding; Ionis Pharmaceuticals,: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Vifor Pharma: Consultancy, Research Funding. Dong: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Infinity Pharmaceuticals: Current equity holder in publicly-traded company; Jazz Pharmaceuticals: Current equity holder in publicly-traded company. Tai: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Grekas: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Khoja: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Gheuens: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. McGee: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Porter: Protagonism: Honoraria; Agios: Consultancy, Honoraria; La Jolla Pharmaceuticals: Honoraria; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Van Beers: RR Mechatronics: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

We consider a model of energy minimization arising in the study of the mechanical behavior caused by cell contraction within a fibrous biological medium. The macroscopic model is based on the theory of non rank-one convex nonlinear elasticity for phase transitions. We study appropriate numerical approximations based on the discontinuous Galerkin treatment of higher gradients and used succesfully in numerical simulations of experiments. We show that the discrete minimizers converge in the limit to minimizers of the continuous problem. This is achieved by employing the theory of $\Gamma$-convergence of the approximate energy functionals to the continuous model when the discretization parameter tends to zero. The analysis is involved due to the structure of numerical approximations which are defined in spaces with lower regularity than the space where the minimizers of the continuous variational problem are sought. This fact leads to the development of a new approach to $\Gamma$-convergence, appropriate for discontinuous finite element discretizations, which can be applied to quite general energy minimization problems. Furthermore, the adoption of exponential terms penalising the interpenetration of matter requires a new framework based on Orlicz spaces for discontinuous Galerkin methods which is developed in this paper as well.

Through mechanical forces, biological cells remodel the surrounding collagen network, generating striking deformation patterns. Tethers—tracts of high densification and fibre alignment—form between cells, thinner bands emanate from cell clusters. While tethers facilitate cell migration and communication, how they form is unclear. Combining modelling, simulation and experiment, we show that tether formation is a densification phase transition of the extracellular matrix, caused by buckling instability of network fibres under cell-induced compression, featuring unexpected similarities with martensitic microstructures. Multiscale averaging yields a two-phase, bistable continuum energy landscape for fibrous collagen, with a densified/aligned second phase. Simulations predict strain discontinuities between the undensified and densified phase, which localizes within tethers as experimentally observed. In our experiments, active particles induce similar localized patterns as cells. This shows how cells exploit an instability to mechanically remodel the extracellular matrix simply by contracting, thereby facilitating mechanosensing, invasion and metastasis.

Background The purpose of this work was to investigate the links between oxidative stress, inflammation and coagulation and their effect on Mediterranean diet–diabetes relationship. Methods In 2001–2002, a random sample of 1514 men (18–87 years old) and 1528 women (18–89 years old) was selected to participate in the ATTICA study, where Athens is the major metropolis. A validated questionnaire was used to assess lifestyle and dietary factors. Adherence to Mediterranean diet was recorded using MedDietScore. Among others, oxidative stress and inflammatory biomarkers were recorded. During 2011–2012, the 10-year follow-up was performed. Diabetes incidence was defined according to the American Diabetes Association criteria. Results A total of 191 incident cases of diabetes were documented, yielding an incidence of 12.9% (13.4% in men and 12.4% in women). Medium and high adherence was found to decrease diabetes risk by 49% (95% CI: 0.30, 0.88) and 62% (95% CI: 0.16, 0.88), respectively, compared with low adherence. A logarithmic trend between Mediterranean diet and diabetes incidence was also revealed (p for trend = 0.042). Individuals with abnormal waist circumference (>94 for men, >80 for women) were benefited the most. Wholegrain cereals, fruits and legumes had the greatest predictive ability. The anti-diabetic effect of Mediterranean diet correlated with measurements of tumour necrosis factor-α, homocysteine and total antioxidant capacity. Conclusions The reported results support the role of Mediterranean diet as a promising dietary tool for the primary prevention of diabetes, by attenuating inflammation and fostering total antioxidant capacity. This dietary pattern may have therapeutic potential for many cardiometabolic disorders associated with inflammation and/or oxidative stress. Copyright © 2015 John Wiley & Sons, Ltd.

AIM: To identify dietary patterns among apparently healthy individuals and to determine their long-term effect on diabetes incidence. METHODS: During 2001-2002, a random sample of 3,042 men and women (18-89 years old), living in greater Athens, was randomly selected to participate in the study. During 2011-2012, the 10-year follow-up was performed in 2,583 participants (15% drop-out rate). After excluding participants with diabetes at baseline and those for whom no information on diabetes status was available at follow- up, the working sample consisted of 1,485 participants. Dietary habits were assessed by means of a validated semiquantitative, food frequency questionnaire. Factor analysis was performed to extract dietary patterns from 18 food groups. RESULTS: Diabetes diagnosis at follow-up was made in 191 participants, yielding an incidence rate of 12.9%. Six factors (i.e. dietary patterns) were identified that explained 54% of the variation in consumption. After adjusting for major confounders, and stratification by age-group, logistic regression revealed that the most healthful pattern consisted of the consumption of fruits, vegetables, legumes, bread, rusk, and pasta which reduced the 10-year diabetes risk by 40%, among participants aged 45-55 years. The association reached marginal statistical significance (95% CI: 0.34, 1.07), while no significant association was observed for the other age-groups. When the analysis was additionally adjusted for carbohydrate percentage, statistical significance was lost completely, suggesting a possibly mediating effect of this macronutrient. CONCLUSIONS: The results confirm the potentially protective effect of a plant-based dietary pattern in the primary prevention of diabetes, in particular among middle-aged people. Carbohydrate content may be a specific factor in this relationship; other micronutrients found in plant-based food groups may also play a role. © by Lab & Life Press/SBDR.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

Objectives The aim of this study was to compare lung deposition and assess the bioequivalence of two formulations containing budesonide and formoterol and being delivered via Elpenhaler and Turbuhaler, respectively. A pharmacokinetic (PK) study was conducted. Methods An open, randomized, two-sequence, two-period, crossover, single-dose study in 100 asthmatic patients under fasting conditions was performed. Wash out period was 6 days. Equivalence in lung deposition was assessed after a single inhalation of each treatment with concomitant oral administration of activated charcoal (40 g) to prevent gastrointestinal absorption of the drugs. Several PK parameters were estimated, the area under the drug concentration in plasma versus time curve (AUC0−t) and the maximum drug concentration in plasma (Cmax) being the primary response variables. Equivalent lung deposition was concluded if the 90% confidence interval (CI) for the Elpenhaler/Turbuhaler geometric mean ratio of AUC0−t and Cmax, for both drug substances fell within the regulatory limits (0.80–1.25). Key findings Acceptance criteria were met. Equivalent lung deposition can be concluded. No statistically significant differences between treatments in the incidence of adverse events were found. Conclusions The formulations are bioequivalent regarding both rate and extent of absorption. The treatments were also well tolerated by the participating subjects.

Background/Aims: In experimental models of polycystic kidney disease impaired bioavailability of nitric oxide (NO) and elevated mRNA expression of oxidative stress markers at the kidney level was noted. However, clinical studies investigating the potential role of endothelial dysfunction and oxidative stress in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) are limited. We evaluated asymmetric dimethylarginine (ADMA) as marker of NO synthase inhibitor as well as 15-F2t-Isoprostane and oxidized-low density lipoprotein (oxidized-LDL) as measures of oxidative stress in patients with early stages ADPKD. Methods: We recruited 26 ADPKD patients (Group A) with modestly impaired renal function (eGFR 45-70 ml/min/1.73m2), 26 age- and sex-matched ADPKD patients (Group B) with relatively preserved renal function (eGFR)>70 ml/min/1.73m2), and 26 age- and sex-matched controls (Group C). Determination of circulating levels of ADMA, 15-F2t-Isoprostane, oxidized-LDL and routine biochemistry was performed. Results: Group A and B had significantly higher ADMA levels as compared to controls (1.68±0.7 vs 0.51±0.2 μmol/l, P2t-IsoP and oxidized-LDL levels were also significantly higher in Group B relative to controls (788.8±185.0 vs 383.1±86.0 pgr/ml, P2t-Isoprostane (r=0.811, PConclusion: This study shows elevation in circulating levels of ADMA along with aggravation of oxidative stress from the early stages of ADPKD.

Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid found in tissues and cells that circulates in plasma and is excreted in urine. It inhibits nitric oxide synthases (NOs) and produces considerable cardiovascular biological effects. Several studies have suggested that plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. In animal and in population studies ADMA has been associated with progression of CKD. Several mechanisms may be involved in this association, such as compromise of the integrity of the glomerular filtration barrier and development of renal fibrosis. This review summarizes the existing literature on the biology and physiology of ADMA focusing on its role in the progression of renal disease.

Matrix metalloproteinases (MMPs) are zinc-dependent proteases that degrade components of the extracellular matrix (ECM). In glomerular disease, MMPs are major regulators of ECM degradation as well as structural and functional integrity in the glomerulus. In altered matrix composition diseases, glomerular damage is due to increased degradation of kidney and vessel basement membranes (BMs) by MMPs. MMP -2 and -9 are both considered as the main enzymes that degrade collagen type-IV (coll-IV), which represents the key collagenous component of ECM and constitutes the architectural structure of vessels and glomerular BM. Τhere is growing evidence implicating MMPs in atherosclerosis as well as in cardiovascular disease (CVD) and chronic kidney disease (CKD). Specific endogenous tissue inhibitors of MMPs (TIMPs) are also implicated in CKD, CVD and diabetic nephropathy (DN). The present review discusses the role of MMPs -2 and -9 in DN, as a leading cause of end-stage renal disease and as a model of the link between progressive glomerulosclerosis and MMP expression.

Background: The purpose of this work was to investigate the links between oxidative stress, inflammation and coagulation and their effect on Mediterranean diet-diabetes relationship. Methods: In 2001-2002, a random sample of 1514 men (18-87 years old) and 1528 women (18-89 years old) was selected to participate in the ATTICA study, where Athens is the major metropolis. A validated questionnaire was used to assess lifestyle and dietary factors. Adherence to Mediterranean diet was recorded using MedDietScore. Among others, oxidative stress and inflammatory biomarkers were recorded. During 2011-2012, the 10-year follow-up was performed. Diabetes incidence was defined according to the American Diabetes Association criteria. Results: A total of 191 incident cases of diabetes were documented, yielding an incidence of 12.9% (13.4% in men and 12.4% in women). Medium and high adherence was found to decrease diabetes risk by 49% (95% CI: 0.30, 0.88) and 62% (95% CI: 0.16, 0.88), respectively, compared with low adherence. A logarithmic trend between Mediterranean diet and diabetes incidence was also revealed (p for trend=0.042). Individuals with abnormal waist circumference (>94 for men, >80 for women) were benefited the most. Wholegrain cereals, fruits and legumes had the greatest predictive ability. The anti-diabetic effect of Mediterranean diet correlated with measurements of tumour necrosis factor-α, homocysteine and total antioxidant capacity. Conclusions: The reported results support the role of Mediterranean diet as a promising dietary tool for the primary prevention of diabetes, by attenuating inflammation and fostering total antioxidant capacity. This dietary pattern may have therapeutic potential for many cardiometabolic disorders associated with inflammation and/or oxidative stress. © 2016 John Wiley & Sons, Ltd.

BACKGROUND: Prediabetes has been related to an increased risk of developing diabetes and cardiovascular disease (CVD). AIM: The aim of the present study was to examine the effect of the Mediterranean diet on diabetes and CVD risk in subjects with impaired fasting glucose (IFG, i.e. fasting plasma glucose 100-125 mg/dl). METHODS: During 2001-2002, 3042 men and women (>18y) were enrolled for the study. The participants showed no clinical evidence of CVD or any other chronic disease, and were living in the greater Athens (Greece) area. In 2011 and 2012, the 10-year follow-up examinations were performed, including a working sample of n = 1875 participants without diabetes at baseline. Adherence to the Mediterranean diet at baseline evaluation was assessed using the MedDietScore (range 0-55). RESULTS: The prediabetic subjects (n = 343) had a significantly higher incidence of diabetes (25% vs. 10%, p < 0.001) and CVD (17.8% vs. 12.3%, p = 0.007) compared with subjects with normal glucose values. A significant trend towards lower diabetes and CVD incidence was observed with medium and high adherence to the Mediterranean diet compared with low adherence (p < 0.001). High adherence to the Mediterranean diet (>35/55 score) was associated with lower 10-year incidence of diabetes and CVD. In multiple logistic regression models, participants with high levels of adherence to the Mediterranean diet were significantly less affected by diabetes and CVD than those with low adherence levels. CONCLUSION: High adherence to the Mediterranean diet is associated with a low risk of developing diabetes and CVD in prediabetic subjects. © by Lab & Life Press/SBDR.

Aims: To evaluate the influence of metabolic syndrome (MetS) as well as inflammatory and renal markers on cardiovascular disease (CVD) incidence. Methods and results: During 2001-2002, 1514 men and 1528 women (>18y) without any clinical evidence of CVD or any other chronic disease, at baseline, living in greater Athens area, Greece, were enrolled. In 2011-2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Incidence of fatal or non-fatal CVD was defined according to WHO-ICD-10 criteria. MetS was defined using three definitions, provided by the National Cholesterol Education Program Adult Treatment panel III (revised NCEP ATP III), the International Diabetes Federation (IDF) or the Harmonized definition. Furthermore, the contributory predictive role of C-reactive protein (CRP), inteleukin-6, uric acid and estimated glomerular filtration rate in the aforementioned models was evaluated. History of MetS-NCEP was positively associated with CVD, adjusting for potential confounding factors (OR:1.83, 95%CI:1.24-2.72). Not statistically significant associations with CVD incidence were observed when using the IDF or the Harmonized definition. Additionally, none of the added inflammatory and renal function markers mediated the influence of MetS on CVD incidence (all p's from Sobel test >0.40). C-statistic values for the MetS definitions used exceeded 0.789 (CI:0.751-0.827), indicating fair-to-good predictive probability of the models. Conclusion: Results of the present work revealed the negative impact of MetS-NCEP, but not of the other MetS definitions, on CVD incidence, a key-point that may help in better understanding the role of IDF and Harmonized MetS definitions on CVD. © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.

Background and aims: To better understand the metabolic syndrome (MS) spectrum through principal components analysis and further evaluate the role of the Mediterranean diet on MS presence. Methods: During 2001-2002, 1514 men and 1528 women (>18y) without any clinical evidence of CVD or any other chronic disease, at baseline, living in greater Athens area, Greece, were enrolled. In 2011-2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Incidence of fatal or non-fatal CVD was defined according to WHO-ICD-10 criteria. MS was defined by the National Cholesterol Education Program Adult Treatment panel III (revised NCEP ATP III) definition. Adherence to the Mediterranean diet was assessed using the MedDietScore (range 0-55). Results: Five principal components were derived, explaining 73.8% of the total variation, characterized by the: a) body weight and lipid profile, b) blood pressure, c) lipid profile, d) glucose profile, e) inflammatory factors. All components were associated with higher likelihood of CVD incidence. After adjusting for various potential confounding factors, adherence to the Mediterranean dietary pattern for each 10% increase in the MedDietScore, was associated with 15% lower odds of CVD incidence (95%CI: 0.71-1.06). For the participants with low adherence to the Mediterranean diet all five components were significantly associated with increased likelihood of CVD incidence. However, for the ones following closely the Mediterranean pattern positive, yet not significant associations were observed. Conclusion: Results of the present work propose a wider MS definition, while highlighting the beneficial role of the Mediterranean dietary pattern. © 2015 Elsevier Ireland Ltd.

Noninvasive screening studies may identify hemodialysis (HD) patients at increased risk of sudden cardiac death. Interventions that improve the findings of such screening studies may reduce sudden cardiac death.Randomized and controlled clinical trial.59 HD patients were randomly assigned to an exercise training group (group A; 30 patients) or control group (group B; 29 patients).Group A participated in a 10-month supervised exercise training program during the HD sessions (3 times weekly).Each risk factor separately and the composite risk score. Patients were considered high risk according to the criteria (aerobic capacity: peak oxygen consumption [Vo(2)peak]or = 14 mL/kg/min, left ventricular ejection fractionor = 30%, SD of normal RR intervals [SDNN]or = 70 milliseconds, positive T-wave alternans, or positive late potentials). Statistical analysis included a 2-group comparison of change scores and analysis of covariance adjusting for baseline.At entry and end of the study, Vo(2)peak and left ventricular ejection fraction were estimated, heart rate variability was calculated (measurement of SDNN, mean RR intervals), and the ratio between low- (LF) to high-frequency (HF) components (LF/HF) and late potentials and T-wave alternans were detected.Baseline measurements were similar between the 2 groups. At follow-up, 9 patients from group A and 20 from group B (P = 0.003) were considered high risk. The change in number of risk markers over time was significantly different between groups (-0.5 +/- 0.7 in group A versus 0.07 +/- 0.3 in group B; P0.001). Additionally, the change in Vo(2)peak over time was 3.5 +/- 3.2 in group A and -0.2 +/- 3.5 mL/kg/min in group B (P0.001), left ventricular ejection fractions were 3.4% +/- 3.9% and 0.2% +/- 7.7% (P0.05), SDNNs were 12.6 +/- 16.3 and -1.1 +/- 10.2 milliseconds (P0.001), and LF/HF ratios were 0.3 +/- 0.4 and -0.1 +/- 0.3 (P0.001), respectively. Change in numerical score of the signal-averaged electrocardiogram also was found to be statistically different (P0.05) between groups.Clinical outcomes, including survival, were not assessed.Exercise training improves aerobic capacity and ameliorates some indicators of risk of sudden cardiac death in HD patients.