Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia

Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab substantially reduce low‐density lipoprotein cholesterol (LDL‐C) when added to statin therapy in patients who need additional LDL‐C reduction. Methods and Results: We conducted a systematic review and network meta‐analysis of randomized trials of lipid‐lowering therapies from database inception through August 2016 (45 058 records retrieved). We found 69 trials of lipid‐lowering therapies that enrolled patients requiring further LDL‐C reduction while on maximally tolerated medium‐ or high‐intensity statin, of which 15 could be relevant for inclusion in LDL‐C reduction networks with evolocumab, alirocumab, ezetimibe, and placebo as treatment arms. PCSK9 inhibitors significantly reduced LDL‐C by 54% to 74% versus placebo and 26% to 46% versus ezetimibe. There were significant treatment differences for evolocumab 140 mg every 2 weeks at the mean of weeks 10 and 12 versus placebo (−74.1%; 95% credible interval −79.81% to −68.58%), alirocumab 75 mg (−20.03%; 95% credible interval −27.32% to −12.96%), and alirocumab 150 mg (−13.63%; 95% credible interval −22.43% to −5.33%) at ≥12 weeks. Treatment differences were similar in direction and magnitude for PCSK9 inhibitor monthly dosing. Adverse events were similar between PCSK9 inhibitors and control. Rates of adverse events were similar between PCSK9 inhibitors versus placebo or ezetimibe. Conclusions: PCSK9 inhibitors added to medium‐ to high‐intensity statin therapy significantly reduce LDL‐C in patients requiring further LDL‐C reduction. The network meta‐analysis showed a significant treatment difference in LDL‐C reduction for evolocumab versus alirocumab

Oral treatment with Eubacterium hallii improves insulin sensitivity in db/db mice

F.B. is supported by Swedish Research Council, Swedish Diabetes Foundation, Swedish Heart Lung Foundation, Swedish Foundation for Strategic Research, Knut and Alice Wallenberg foundation, Göran Gustafsson Foundation, Ingbritt and Arne Lundberg’s foundation, Swedish Heart Lung Foundation, Torsten Söderberg’s Foundation, Ragnar Söderberg’s Foundation, NovoNordisk Foundation, AFA insurances, and LUA-ALF grants from Västra Götalandsregionen and Stockholm County Council. F.B. is a recipient of ERC Consolidator Grant (European Research Council, Consolidator grant 615362—METABASE). W.M.d.V. is supported by the Finland Academy of Sciences (grants 137389, 141140 and 1272870 ), the Netherlands Organization for Scientific Research (Spinoza Award and SIAM Gravity Grant 024.002.002) and the European Research Council (ERC Advanced Grant 250172 MicrobesInside). M.N. is supported by a ZONMW-VIDI grant 2013 (016.146.327).Peer reviewe

Організаційно-економічні передумови та особливості формування сфери фінансових послуг в економічній системі

Glucocorticoids (GCs) are widely used anti-inflammatory drugs well known to cause many adverse effects. Still, there is a dearth of data on the long-term cardiovascular effects of GCs in patients with established cardiovascular disease and the effect on atherosclerotic plaque composition. A total of 1894 patients who underwent carotid endarterectomy (CEA), of whom 40 patients received systemic GCs, were included in the Athero-Express Biobank. Atherosclerotic plaque samples and peripheral blood samples were obtained during CEA. Cardiovascular events during 3 years of follow-up were investigated using Cox regression modeling to adjust for possible confounding. Atherosclerotic plaque composition was examined using immunohistochemical staining. Use of GCs at inclusion was associated with markedly increased incidences of ischemic stroke (15.2% vs. 5.9%), composite events (48.5% vs. 26.9%), and cardiovascular death (21.2% vs. 5.7%), as well as an increased risk of cardiovascular death (hazards ratio 2.7, 95% confidence interval, 1.1-6.7) and all-cause death (hazards ratio 2.3, 95% confidence interval, 1.1-4.8) after 2.6 years of follow-up. None of the histological features of atherosclerotic plaques were significantly different in patients using GCs. After CEA, the use of systemic GCs is independently associated with an increased incidence of cardiovascular events and an increased risk of cardiovascular and all-cause death, but not atherosclerotic plaque compositio

A six question screen to facilitate primary cardiovascular disease prevention

Background: European guidelines on primary prevention of cardiovascular disease (CVD) recommend the SCORE risk charts for determining CVD risk, which include blood pressure and serum cholesterol as risk parameters. To facilitate cost-effective large-scale screening, we aimed to construct a risk score with 'non-invasive' parameters as a first screening step to identify persons at increased CVD risk requiring further risk assessment. Methods: We used data of Dutch employees from 25 organisations participating in a health risk assessment between August 2007 and January 2013. Backward multivariate logistic regression analysis was employed to select non-invasive, independent predictors of high CVD risk, defined as the 10-year risk of fatal CVD of ≥5 % based on the SCORE formula. The total CVD risk score was calculated as the summed coefficients of the retained variables. Results: Data of 6189 male participants was used for the development and validation of the risk score. Age, tobacco use, history of hypertension, alcohol consumption, BMI, and waist circumference were independent predictors of high CVD risk. Ten-fold cross-validation resulted in an area under the curve of 0.95 (SE 0.01, 95 % confidence interval 0.94-0.96). A cut-off score ≥45 on the CVD risk score yielded a sensitivity of 0.93, and a specificity of 0.85. Conclusions: We developed a simple, non-invasive risk score that accurately identifies persons at increased CVD risk according to the SCORE formula in a population of working men. The risk score enables a stepwise approach in large screening programmes, strongly reducing the number of persons that require full risk estimation including blood pressure and cholesterol measures

Precision oncology in esophagogastric cancer:From biomarker to personalized treatment

Despite the benefits achieved through multimodality treatment, the prognosis of esophageal and gastric remains dismal. Hence, improvement of current therapeutic strategies is imperative. In this thesis, we focus on intensification of non-targeted treatment, as well as precision oncology in esophagogastric cancer with the use of targeted therapies. The results in this thesis show a lack of feasibility of administrating adjuvant chemotherapy in patients with resectable esophageal adenocarcinoma in an unselected cohort, suggesting a role for treatment intensification in the neoadjuvant setting. Moreover, our findings enable optimization of HER2 directed therapy in patients with resectable esophageal adenocarcinoma by broadening our understanding of HER2 targeting through potential interactions with the tumor immune microenvironment, unraveling resistance mechanisms, and identifying predictive biomarkers which could be used for patient stratification. Furthermore, we investigated targeting of angiogenesis through the multikinase inhibitor regorafenib in advanced gastroesophageal cancer, providing biomarkers for patient selection and suggestions for novel treatment combinations. Taken together, these findings can guide the development of novel therapeutic strategies in patients with esophagogastric cancer, ultimately aiming to improve the overall outcome of patients with esophageal and gastric cancer

Characterization of Tryptophanase from Vibrio cholerae O1

AbstractTryptophanase (Trpase) encoded by the tnaA gene catalyzes the conversion of tryptophan to indole, which is an extracellular signaling molecule detected in various bacteria including Vibrio cholerae. Indole has been demonstrated to regulate biofilm formation, drug resistance, plasmid maintenance and spore formation of bacteria. In the present study, the tnaA gene from V. cholerae O1 (VcTrpase) was cloned and expressed in E. coli BL21(DE3) tn5:tnaA (a Trpase-deficient competent). VcTrpase was purified by Ni2+-NTA chromatography. The obtained VcTrpase had a molecular mass of approximately 49 kDa, a specific activity of 3 U/mg protein, and absorption peaks at 330 and 435nm. Using a site-directed mutagenesis technique, replacement of Arg419 by Val resulted in a VcTrpase completely devoid of activity. Thus, this site can be a target for drug design for controlling V. cholerae

Adsorption Behaviour of Delta-Manganese Dioxide in Relation to its Use as a Resin in Trace Metal Speciation Studies

The accuracy of the δ-MnO₂ method in determining Conditional Stability Constants (CSC's) for trace metal - organic complexes depends on the precise modeling of trace metal uptake by δ-MnO₂. Accordingly, characteristics of δ-MnO₂ and its adsorption behaviour for Cu were studied. Laboratory preparation of δ-MnO₂ is influenced by pH. A neutral redox process and an acid reduction of Mn⁺⁷ yield δ-MnO₂, but an alkaline oxidation of Mn²⁺ does not produce δ-MnO₂. Positive identification of MnOᵪ as δ-MnO₂ includes confirmation of characteristics such as x > 1.9, an adsorption capacity (ɼmax) ≥ 0.25 mol Cu/mol MnO₂, an amorphous XRD pattern, a specific TEM morphology and 1 Natural and simulated aging of δ-MnO₂ depends on temperature, pH and K content of the solid, and causes reduction of surface area and adsorption capacity by a factor 1.5 (natural) to 7 (simulated). Adsorption of trace metals onto δ-MnO₂ is described almost exclusively by a linearized Single Langmuir isotherm in the literature. This study found that Cu adsorption on δ-MnO₂ deviates from Langmuir linearity at low surface coverages. Explanations include the existence of two adsorption sites (Double Langmuir model) and non-constant activity of surface groups. The Implicit Langmuir expression is derived from surface complexation theory to model the latter, and has the form: [equation removed] where ɼads (= mol Cu adsorbed/mol MnO₂) and the free Cu²⁺ concentration in solution are measured. r ,B and n are the adsorption parameters. This model predicts the observed deviation from linearity. The bindings energy depends on the pH, the H⁺/Cu²⁺ exchange ratio (n), the surface coverage (ɼads/ɼmax) and a constant B. Adsorption isotherms were obtained over a pH range of 6 to 8.5, and a Cutotal range of 1 - 40 μM with glycine added to prevent precipitation of Cu. Adsorption results were fitted to Single, Double and Implicit Langmuir models, and compared. The Implicit Langmuir model describes Cu uptake by δ-MnO₂ most accurately, and CSC's for Cu-NTA and Cu-glycine complexes were readily determined using this model. ¹⁴C studies indicated that NTA, glycine and aspartic acid do not adsorb on δ-MnO₂.Doctor of Philosophy (PhD

Random variables with completely independent subcollections

AbstractWe investigate the algebra and geometry of the independence conditions on discrete random variables in which we consider a collection of random variables and study the condition of independence of some subcollections. We interpret independence conditions as an ideal of algebraic relations. After a change of variables, this ideal is generated by generalized 2×2 minors of multi-way tables and linear forms. In particular, let Δ be a simplicial complex on some random variables and A be the table corresponding to the product of those random variables. If A is Δ-independent table then A can be written as the entrywise sum AI+A0 where AI is a completely independent table and A0 is identically 0 in its Δ-margins.We compute the isolated components of the original ideal, showing that there is only one component that could correspond to probability distributions, and relate the algebra and geometry of the main component to that of the Segre embedding. If Δ has fewer than three facets, we are able to compute generators for the main component, show that it is Cohen–Macaulay, and give a full primary decomposition of the original ideal

Efficacy and tolerability of evolocumab vs. ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial

Importance: Muscle-related statin intolerance is reported by 5% to 20% of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Main Outcome and Measures: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, −16.7% (95% CI, −20.8% to −12.5%); absolute change, −31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, −52.8% (95% CI, −55.8% to −49.8%); absolute change, −102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was −37.8%; absolute difference, −75.8 mg/dL. For week 24, between-group difference in LDL-C was −36.1%; absolute difference, –71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety