Glycaemic Control in Diabetes.

Reduction of glucose is the hallmark of diabetes therapy proven to reduce micro- and macro-vascular risk in patients with type 1 diabetes. However glucose-lowering efficacy trials in type 2 diabetes didn't show major cardiovascular benefit. Then, a paradigm change in the treatment of patients with type 2 diabetes has emerged due to the introduction of new blood glucose-lowering agents. Cardiovascular endpoint studies have proven HbA1c-independent cardioprotective effects for GLP-1 receptor agonists and SGLT-2 inhibitors. Furthermore, SGLT-2 inhibitors reduce the risk for heart failure and chronic kidney disease. Mechanisms for these blood glucose independent drug target-related effects are still an enigma. Recent research has shown that GLP-1 receptor agonists might have anti-inflammatory and plaque stabilising effects whereas SGLT-2 inhibitors primarily reduce pre- and after-load of the heart and increase work load efficiency of the heart. In addition, reduction of intraglomerular pressure, improved energy supply chains and water regulation appear to be major mechanisms for renoprotection by SGLT-2 inhibitors. These studies and observations have led to recent changes in clinical recommendations and treatment guidelines for type 2 diabetes. In patients with high or very high cardio-renal risk, SGLT-2 inhibitors or GLP-1 receptor agonists have a preferred recommendation independent of baseline HbA1c levels due to cardioprotection. In patients with chronic heart failure, chronic kidney disease or at respective risks SGLT-2 inhibitors are the preferred choice. Therefore, the treatment paradigm of glucose control in diabetes has changed towards using diabetes drugs with evidence-based organ protection improving clinical prognosis.

In situ kinetics studies of Zn-Al LDH intercalation with corrosion related species.

Kinetic parameters for three anion exchange reactions - Zn-LDH-NO3→ Zn-LDH-Cl, Zn-LDH-NO3→ Zn-LDH-SO4 and Zn-LDH-NO3→ Zn-LDH-VOx- were obtained by in situ synchrotron study. The first and the second ones are two-stage reactions; the first stage is characterized by the two-dimensional diffusion-controlled reaction following deceleratory nucleation and the second stage is a one-dimensional diffusion-controlled reaction also with a decelerator nucleation effect. In the case of exchange NO3-→ Cl- host anions are completely released, while in the case of NO3-→ SO42- the reaction ends without complete release of nitrate anions. The exchange of Zn-LDH-NO3→ Zn-LDH-VOx is a one-stage reaction and goes much slower than the previous two cases. The latter is characterized by a one stage two-dimensional reaction with an instantaneous nucleation. As a result, at the end of this process there are two crystalline phases with different polyvanadate species, presumably V4O124- and V2O74-, nitrate anions were not completely released. The rate of replacing NO3- anions by guest ones can be represented as Cl- > SO42- > VOxy-.

Influence of the Molecular Weight and the Presence of Calcium Ions on the Molecular Interaction of Hyaluronan and DPPC.

Hyaluronan is an essential physiological bio macromolecule with different functions. One prominent area is the synovial fluid which exhibits remarkable lubrication properties. However, the synovial fluid is a multi-component system where different macromolecules interact in a synergetic fashion. Within this study we focus on the interaction of hyaluronan and phospholipids, which are thought to play a key role for lubrication. We investigate how the interactions and the association structures formed by hyaluronan (HA) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) are influenced by the molecular weight of the bio polymer and the ionic composition of the solution. We combine techniques allowing us to investigate the phase behavior of lipids (differential scanning calorimetry, zeta potential and electrophoretic mobility) with structural investigation (dynamic light scattering, small angle scattering) and theoretical simulations (molecular dynamics). The interaction of hyaluronan and phospholipids depends on the molecular weight, where hyaluronan with lower molecular weight has the strongest interaction. Furthermore, the interaction is increased by the presence of calcium ions. Our simulations show that calcium ions are located close to the carboxylate groups of HA and, by this, reduce the number of formed hydrogen bonds between HA and DPPC. The observed change in the DPPC phase behavior can be attributed to a local charge inversion by calcium ions binding to the carboxylate groups as the binding distribution of hyaluronan and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine is not changed.

Thermoresponsive Pentablock Copolymer on Silica: Temperature Effects on Adsorption, Surface Forces, and Friction.

The adsorption of hydrophilic or amphiphilic multiblock copolymers provides a powerful means to produce well-defined "smart" surfaces, especially if one or several blocks are sensitive to external stimuli. We focus here on an A-B-A-B-A copolymer, where A is a cationic poly((3-acrylamido-propyl)-trimethylammonium chloride) (PAMPTMA) block containing 15 (end blocks) or 30 (middle block) repeat units and B is a neutral thermosensitive water-soluble poly(2-isopropyl-2-oxazoline) (PIPOZ) block with 50 repeat units. X-ray reflectivity and quartz crystal microbalance with dissipation monitoring were employed to study the adsorption of PAMPTMA15-PIPOZ50-PAMPTMA30-PIPOZ50-PAMPTMA15 on silica surfaces. The latter technique was employed at different temperatures up to 50 °C. Surface forces and friction between the two silica surfaces across aqueous pentablock copolymer solutions at different temperatures were determined with the atomic force microscopy colloidal probe force and friction measurements. The cationic pentablock copolymer was found to have a high affinity to the negatively charged silica surface, leading to a thin (2 nm) and rigid adsorbed layer. A steric force was encountered at a separation of around 3 nm from hard wall contact. A capillary condensation of a polymer-rich phase was observed at the cloud point of the solution. The friction forces were evaluated using Amontons' rule modified with an adhesion term.

Influence of high hydrostatic pressure on solid supported DPPC bilayers with hyaluronan in the presence of Ca2+ ions.

The molecular mechanisms responsible for outstanding lubrication of natural systems, like articular joints, have been the focus of scientific research for several decades. One essential aspect is the lubrication under pressure, where it is important to understand how the lubricating entities adapt under dynamic working conditions in order to fulfill their function. We made a structural investigation of a model system consisting of two of the molecules present at the cartilage interface, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and hyaluronan, at high hydrostatic pressure. Phospholipid layers are found at the cartilage surfaces and are able to considerably reduce friction. Their behavior under load and varied solution conditions is important as pressures of 180 bar are encountered during daily life activities. We focus on how divalent ions, like Ca2+, affect the interaction between DPPC and hyaluronan, as other investigations have indicated that calcium ions influence their interaction. It could be shown that already low amounts of Ca2+ strongly influence the interaction of hyaluronan with DPPC. Our results suggest that the calcium ions increase the amount of adsorbed hyaluronan indicating an increased electrostatic interaction. Most importantly, we observe a modification of the DPPC phase diagram as hyaluronan absorbs to the bilayer which results in an Lα-like structure at low temperatures and a decoupling of the leaflets forming an asymmetric bilayer structure.

Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials.

AIM: To assess the lipid-lowering efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in people with hypercholesterolaemia and prediabetes at baseline vs people with normoglycaemia at baseline in a pooled analysis of 10 ODYSSEY phase III trials. METHODS: People classified as having prediabetes had baseline HbA1c ≥39 mmol/mol (5.7%) and <48 mmol/mol (6.5%), or two baseline fasting plasma glucose values ≥5.6 mmol/l (100 mg/dl) but no more than one fasting plasma glucose value ≥7.0 mmol/l (126 mg/dl), or had specific terms reported in their medical history; people diagnosed with diabetes at baseline were excluded, and the remainder were classified as having normoglycaemia. Participants received alirocumab or control (placebo/ezetimibe) for 24-104 weeks, with maximally tolerated statin in most cases. The primary efficacy endpoint was LDL cholesterol reductions from baseline to week 24 in the intention-to-treat population using the mixed-effect model with a repeated measures approach. RESULTS: Reductions in LDL cholesterol from baseline to week 24 with alirocumab were 44.0-61.8% (prediabetes group) and 45.8-59.5% (normoglycaemia group). In both subgroups, LDL cholesterol reductions were generally similar in those with and without baseline triglycerides ≥1.7 mmol/l (150 mg/dl). Alirocumab was not associated with changes in HbA1c or fasting plasma glucose over time in either subgroup (up to 24 months' follow-up). Adverse event rates were generally similar in those with and without prediabetes. CONCLUSIONS: Over a mean follow-up of 24-104 weeks, alirocumab treatment resulted in significant LDL cholesterol reductions from baseline that were similar in participants with prediabetes and those with normoglycaemia at baseline, with no effect on glycaemia and a safety profile similar to that of the control.

Macromolecular pHPMA-Based Nanoparticles with Cholesterol for Solid Tumor Targeting: Behavior in HSA Protein Environment.

Nanoparticles (NPs) that form by self-assembly of amphiphilic poly(N-(2-hydroxypropyl)-methacrylamide) (pHPMA) copolymers bearing cholesterol side groups are potential drug carriers for solid tumor treatment. Here, we investigate their behavior in solutions of human serum albumin (HSA) in phosphate buffered saline. Mixed solutions of NPs, from polymer conjugates with or without the anticancer drug doxorubicin (Dox) bound to them, and HSA at concentrations up to the physiological value are characterized by synchrotron small-angle X-ray scattering and isothermal titration calorimetry. When Dox is absent, a small amount of HSA molecules bind to the cholesterol groups that form the core of the NPs by diffusing through the loose pHPMA shell or get caught in meshes formed by the pHPMA chains. These interactions are strongly hindered by the presence of Dox, which is distributed in the pHPMA shell, meaning that the delivery of Dox by the NPs in the human body is not affected by the presence of HSA.

Solution structure and excitation energy transfer in phycobiliproteins of Acaryochloris marina investigated by small angle scattering.

The structure of phycobiliproteins of the cyanobacterium Acaryochloris marina was investigated in buffer solution at physiological temperatures, i.e. under the same conditions applied in spectroscopic experiments, using small angle neutron scattering. The scattering data of intact phycobiliproteins in buffer solution containing phosphate can be well described using a cylindrical shape with a length of about 225Å and a diameter of approximately 100Å. This finding is qualitatively consistent with earlier electron microscopy studies reporting a rod-like shape of the phycobiliproteins with a length of about 250 (M. Chen et al., FEBS Letters 583, 2009, 2535) or 300Å (J. Marquart et al., FEBS Letters 410, 1997, 428). In contrast, phycobiliproteins dissolved in buffer lacking phosphate revealed a splitting of the rods into cylindrical subunits with a height of 28Å only, but also a pronounced sample aggregation. Complementary small angle neutron and X-ray scattering experiments on phycocyanin suggest that the cylindrical subunits may represent either trimeric phycocyanin or trimeric allophycocyanin. Our findings are in agreement with the assumption that a phycobiliprotein rod with a total height of about 225Å can accommodate seven trimeric phycocyanin subunits and one trimeric allophycocyanin subunit, each of which having a height of about 28Å. The structural information obtained by small angle neutron and X-ray scattering can be used to interpret variations in the low-energy region of the 4.5K absorption spectra of phycobiliproteins dissolved in buffer solutions containing and lacking phosphate, respectively.

Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

Complex solutions under shear and pressure: a rheometer setup for X-ray scattering experiments.

A newly developed high-pressure rheometer for in situ X-ray scattering experiments is described. A commercial rheometer was modified in such a way that X-ray scattering experiments can be performed under different pressures and shear. First experiments were carried out on hyaluronan, a ubiquitous biopolymer that is important for different functions in the body such as articular joint lubrication. The data hint at a decreased electrostatic interaction at higher pressure, presumably due to the increase of the dielectric constant of water by 3% and the decrease of the free volume at 300 bar.

Solution structure of monomeric and trimeric photosystem I of Thermosynechococcus elongatus investigated by small-angle X-ray scattering.

The structure of monomeric and trimeric photosystem I (PS I) of Thermosynechococcus elongatus BP1 (T. elongatus) was investigated by small-angle X-ray scattering (SAXS). The scattering data reveal that the protein-detergent complexes possess radii of gyration of 58 and 78 Å in the cases of monomeric and trimeric PS I, respectively. The results also show that the samples are monodisperse, virtually free of aggregation, and contain empty detergent micelles. The shape of the protein-detergent complexes can be well approximated by elliptical cylinders with a height of 78 Å. Monomeric PS I in buffer solution exhibits minor and major radii of the elliptical cylinder of about 50 and 85 Å, respectively. In the case of trimeric PS I, both radii are equal to about 110 Å. The latter model can be shown to accommodate three elliptical cylinders equal to those describing monomeric PS I. A structure reconstitution also reveals that the protein-detergent complexes are larger than their respective crystal structures. The reconstituted structures are larger by about 20 Å mainly in the region of the hydrophobic surfaces of the monomeric and trimeric PS I complexes. This seeming contradiction can be resolved by the addition of a detergent belt constituted by a monolayer of dodecyl-ß-D-maltoside molecules. Assuming a closest possible packing, a number of roughly 1024 and 1472 detergent molecules can be determined for monomeric and trimeric PS I, respectively. Taking the monolayer of detergent molecules into account, the solution structure can be almost perfectly modeled by the crystal structures of monomeric and trimeric PS I.

[Diabetology as an interdisciplinary challenge]. / Diabetologie als fächerübergreifende interdisziplinäre Herausforderung.

Type 2 diabetes mellitus is a growing chronic disease with a complex pathophysiology and multiple therapeutic options. Clinical prognosis is determined by multimorbidity and cardiovascular complications. For example, the prognosis of patients with diabetes hospitalized for heart failure is very poor with up to 50% mortality rate over the 3 years thereafter. Therefore, three levels have to be addressed in our approach to interdisciplinary diabetes care: screening and prevention, efficient patient-centered drug therapy, and a strategy for care including social environment of the patient suffering from complex diseases. Thus, we need diabetes specialists in out- and in-patient settings. Transsectoral interdisciplinary approaches to clinical care, as exemplary shown for the treatment of the diabetes foot syndrome, should be developed for other comorbidities, like renal and heart failure, respectively. The basis in the therapy of the cardiometabolic high-risk patient is prevention and multimodal treatment of cardiovascular risk factors. In this context, it is interesting to note that new cardiovascular outcome trials with a so-called safety design have shown that the GLP-1 receptor agonist liraglutide and the SGLT-2 inhibitor empagliflozin can reduce cardiovascular event rates. In addition, empagliflozin has significantly reduced the rate of hospitalization for heart failure. The latter has been included in the recent guidelines on heart failure by the European Society of Cardiology.

Studying solutions at high shear rates: a dedicated microfluidics setup.

The development of a dedicated small-angle X-ray scattering setup for the investigation of complex fluids at different controlled shear conditions is reported. The setup utilizes a microfluidics chip with a narrowing channel. As a consequence, a shear gradient is generated within the channel and the effect of shear rate on structure and interactions is mapped spatially. In a first experiment small-angle X-ray scattering is utilized to investigate highly concentrated protein solutions up to a shear rate of 300000 s(-1). These data demonstrate that equilibrium clusters of lysozyme are destabilized at high shear rates.

Structure of DPPC-hyaluronan interfacial layers - effects of molecular weight and ion composition.

Hyaluronan and phospholipids play an important role in lubrication in articular joints and provide in combination with glycoproteins exceptionally low friction coefficients. We have investigated the structural organization of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) Langmuir layers at the solution-air interface at different length scales with respect to the adsorption of hyaluronan (HA). This allows us to assemble a comprehensive picture of the adsorption and the resulting structures, and how they are affected by the molecular weight of HA and the presence of calcium ions. Brewster angle microscopy and grazing incident diffraction were used to determine the lateral structure at the micro- and macro scale. The data reveals an influence of HA on both the macro and micro structure of the DPPC Langmuir layer, and that the strength of this effect increases with decreasing molecular weight of HA and in presence of calcium ions. Furthermore, from X-ray reflectivity measurements we conclude that HA adsorbs to the hydrophilic part of DPPC, but data also suggest that two types of interfacial structures are formed at the interface. We argue that hydrophobic forces and electrostatic interactions play important rules for the association between DPPC and HA. Surface pressure area isotherms were used to determine the influence of HA on the phase behavior of DPPC while electrophoretic mobility measurements were used to gain insight into the binding of calcium ions to DPPC vesicles and hyaluronan.

[PCSK9 inhibitors : New treatment option in clinical practice]. / PCSK9-Inhibitoren : Neue Therapieoption im klinischen Alltag.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors leading to their degradation in the liver. Inhibition of PCSK9 leads to an increase in LDL receptors and as a result to a reduction of LDL cholesterol in blood. Currently, two antibodies against PCSK9 are available for clinical treatment in Germany, evolocumab (Repatha®) and alirocumab (Praluent®). Clinical studies have shown that treatment with these antibodies, which must be subcutaneously injected by patients every 2 or 4 weeks, in addition to an already existing lipid therapy can lower the LDL cholesterol level in blood by an average of 50-60 %. Data from previous study programs show that this treatment is safe although long-term data are still lacking. The results of currently running cardiovascular endpoint studies are not yet available, whereby a beneficial effect is to be expected after the preliminary analyses. These novel effective therapy approaches open up new perspectives for the treatment of patients whose LDL cholesterol values are still in excess of the corresponding target values despite previous maximum lipid-reducing therapy and suffer from a preexisting cardiovascular disease, statin intolerance, genetic forms of familiar hypercholesterolemia and patients on LDL apheresis.

A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma.

BACKGROUND: Aldoxorubicin, a prodrug of doxorubicin, covalently binds to serum albumin, allowing for the administration of much higher doses of doxorubicin in a previous clinical study. The current phase 1B/2 study evaluated the safety of aldoxorubicin, including preliminary efficacy and safety of its maximum tolerated dose (MTD). METHODS: Patients aged 18 to 70 years with recurrent/refractory malignant solid tumors received aldoxorubicin at a dose of 230 mg/m(2) , 350 mg/m(2) , or 450 mg/m(2) (170 mg/m(2) , 260 mg/m(2) , or 335 mg/m(2) doxorubicin equivalents, respectively) by intravenous infusion once every 21 days for up to 8 consecutive cycles. RESULTS: A total of 25 patients were enrolled, including 17 patients (68%) with advanced soft tissue sarcoma (STS). The MTD of aldoxorubicin was 350 mg/m(2) ; dose-limiting toxicities included grade 4 neutropenia and grade 3 febrile neutropenia (NCI CTCAE v4.0). Drug-related adverse events included myelosuppression, nausea, fatigue, alopecia, stomatitis, vomiting, and oropharyngeal pain. No clinically significant cardiac toxicities were reported. Seven patients (28%) had elevated serum troponin levels while taking part in the study, but these elevations were not clinically significant or associated with cardiac findings. A partial response was achieved in 20% of patients, and stable disease was reported in 40% of patients. The median progression-free survival was 4.80 months, and the median overall survival was 11.25 months. Among patients with STS who were treated at the MTD (13 patients), a partial response was achieved in 38% and stable disease in 46%; the median progression-free survival was 11.25 months and the median overall survival was 21.71 months. CONCLUSIONS: Aldoxorubicin at a dose of 350 mg/m(2) administered once every 21 days for up to 8 cycles was found to be acceptably safe and demonstrated preliminary efficacy in patients with advanced solid tumors, including STS. Further investigation of aldoxorubicin is ongoing.

Mixed Layers of Nonionic Dendritic Amphiphiles and DPPC at the Water Surface.

Nonionic dendritic amphiphiles that self-assemble into defined supramolecular aggregates are useful for the efficient solubilization of active agents, for example, in drug delivery. We investigated a new class of dendritic amphiphiles based on a hydrophilic polyol dendron head connected to a two-chain hydrophobic block. In analogy to phospholipids, these molecules form well-organized layers in bulk (vesicles) or at the water surface (Langmuir monolayer). The actual study focuses on the phase behavior and microscopic structure of mixed Langmuir layers of theses dendritic amphiphiles with the well-known phospholipid DPPC. The combination of surface pressure area isotherms with X-ray grazing incident diffraction and Brewster angle microscopy gives us information on the phase behavior of the mixed monolayers and the orientation of the amphiphiles inside the condensed domains with molecular resolution. We could prove that the dendritic generation and, by this, the headgroup size of the amphiphilic molecules have a significant influence on their interaction with DPPC at the air-water interface. Thus, our findings are important for the understanding of mixed lipid membranes in general as well as for the preparation of artificial membranes and vesicles with adjustable properties, e.g., their drug delivery potential.

[Lipid therapy for patients with coronary heart disease and diabetes. Current state and perspectives]. / Lipidtherapie bei koronarer Herzkrankheit und Diabetes. Gegenwärtiger Stand und Perspektiven.

For patients with diabetes mellitus and coronary heart disease high-dose statin therapy is recommended independent of basal low density lipoprotein (LDL) cholesterol levels and with a target value <70 mg/dl (1.8 mmol/l). Drug combinations which lower LDL, e.g. cholesterol absorption inhibitors, are an option. Fibrates have not been proven to have a cardiovascular advantage but these drugs could be of value in diabetic microangiopathy. A low level of high density lipoprotein (HDL) cholesterol is the most common phenomenon in diabetes. Clinical endpoint studies for the combination with nicotinic acid were negative but therapeutic alternatives are lacking. Therefore, statin therapy is the primary lipid lowering therapy also for diabetic dyslipidemia.

[New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk : Statement of the D•A•CH Society for Prevention of Cardiovascular Diseases, the Austrian Atherosclerosis Society and the Working Group on Lipids and Atherosclerosis (AGLA) of the Swiss Society for Cardiology]. / Neue AHA- und ACC-Leitlinie zur Risikoreduktion von Herz-Kreislauf-Erkrankungen durch Cholesterinsenkung : Stellungnahme der D•A•CH-Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen e. V., der Österreichischen Atherosklerose Gesellschaft und der Arbeitsgruppe Lipide und Atherosklerose (AGLA) der Schweizer Gesellschaft für Kardiologie.

Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines.

Data analysis of the influence of microstructure, composition, and loading conditions on stress corrosion cracking behavior of Mg alloys.

Stress corrosion cracking (SCC) can be a crucial problem in applying rare earth (RE) Magnesium alloys in environments where mechanical loads and electrochemical driven degradation processes interact. It has been proven already that the SCC behavior is associated with microstructural features, compositions, loading conditions, and corrosive media, especially in-vivo. However, it is still unclear when and how mechanisms acting on multiple scales and respective system descriptors predictable contribute to SCC for the wide set of existing Mg alloys. In the present work, suitable literature data along SCC of Mg alloys has been analyzed to enable the development of a reliable SCC model for MgGd binary alloys. Pearson correlation coefficient and linear fitting are utilized to describe the contribution of selected parameters to corrosion and mechanical properties. Based on our data analysis, a parameter ranking is obtained, providing information on the SCC impact with regard to ultimate tensile strength (UTS) and fracture elongation of respective materials. According to the analyzed data, SCC susceptibility can be grouped and mapped onto Ashby type diagrams for UTS and elongation of respective base materials tested in air and in corrosive media. The analysis reveals the effect of secondary phase content as a crucial materials descriptor for our analyzed materials and enables better understanding towards SCC model development for Mg-5Gd alloy based implant.