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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.

Background: Glycated hemoglobin A1c (HbA1c) among diabetic hemodialysis patients continues to be the standard of care, although its limitations are well recognized. This study evaluated glycated albumin (GA) and glycated serum protein (GSP) as alternatives to HbA1c in detecting glycemic control among diabetic hemodialysis patients using continuous-glucose-monitoring (CGM)-derived glucose as reference standard. Methods: A CGM system (iPRO) was applied for 7 days in 37 diabetic hemodialysis patients to determine glycemic control. The accuracy of GA and GSP versus HbA1c in detecting a 7-day average glucose ≥184 mg/dL was evaluated via receiver-operating-characteristic (ROC) analysis. Results: CGM-derived glucose exhibited strong correlation (r = 0.970, p < 0.001) and acceptable agreement with corresponding capillary glucose measurements obtained by the patients themselves in 1,169 time-points over the 7-day-long CGM. The area under ROC curve (AUC) for GA, GSP, and HbA1c to detect poor glycemic control was 0.976 (0.862–1.000), 0.682 (0.502–0.862), and 0.776 (0.629–0.923) respectively. GA levels >20.3% had 90.9% sensitivity and 96.1% specificity in detecting a 7-day average glucose ≥184 mg/dL. The AUC for GA was significantly higher than the AUC for GSP (difference between areas: 0.294, p < 0.001) and the AUC for HbA1c (difference between areas: 0.199, p < 0.01). Conclusion: Among diabetic hemodialysis patients, GA is a stronger indicator of poor glycemic control assessed with 7-day-long CGM when compared to GSP and HbA1c.

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.

Background and aims: Dairy products are a very diverse food group with multiple effects on the cardiac health of men and women. The aim of this work was to evaluate the sex-specific association between dairy products (total and subtypes) and 10-year first fatal/nonfatal cardiovascular disease (CVD) incidence. Methods and results: In 2001–2002, n = 1514 men and n = 1528 women (>18 years old) from greater Athens area, Greece, were enrolled. Dietary assessment was based on a validated semi-quantitative food frequency questionnaire. Dairy product consumption was examined in relation to 10-year CVD incidence. Follow-up (2011–2012) was achieved in n = 2020 participants (n = 317 CVD cases). Ranking from lowest (2 servings/day) total dairy intake, CVD incidence in men was 17.8%, 15.0%, and 10.9% (p = 0.41), while in women it was 14%, 6.0%, and 5.7% (p = 0.02). Multiadjusted analysis revealed that total dairy intake protected against CVD only in women [Hazard Ratio (HR) = 0.48 and 95% Confidence Interval (95% CI) (0.23, 0.90)], irrespective of the fat content. Further analysis revealed that only fermented products (yogurt and cheese), protected against CVD. For per 200 g/day yogurt consumption, CVD risk was 20%–30% lower with this claim being more evident in women, while for per 30 g/day cheese intake, about 5% lower risk was observed particularly in men. As for butter, nonsignificant associations were highlighted. These associations were mainly retained in the case of hepatic steatosis, insulin resistance, and systemic inflammation. Conclusions: This work provides incentives for researchers to elucidate the diversity of ingredients and mechanisms through which dairy products exert their effect on cardiac health separately for men and women. © 2020 The Italian Diabetes Society, 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

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.

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.