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Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. “Diversity Outbred in Australia (DOz)” is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle’s contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators of endocytosis and muscle proteostasis. To enrich for causality, we refined this network by focussing on negatively associated, genetically regulated proteins, resulting in a 76-protein fingerprint of insulin resistance. We sought to perturb this network and restore insulin action with small molecules by integrating the Broad Institute Connectivity Map platform andin vitroassays of insulin action using the Prestwick chemical library. These complimentary approaches identified the antibiotic thiostrepton as an insulin resistance reversal agent. Subsequent validation inex vivoinsulin resistant mouse muscle, and palmitate induced insulin resistant myotubes demonstrated potent insulin action restoration, potentially via up-regulation of glycolysis. This work demonstrates the value of a drug-centric framework to validate systems level analysis by identifying potential therapeutics for insulin resistance.

The failure of metabolic tissues to appropriately respond to insulin (“insulin resistance”) is an early marker in the pathogenesis of type 2 diabetes. Protein phosphorylation is central to the adipocyte insulin response, but how adipocyte signaling networks are dysregulated upon insulin resistance is unknown. Here we employed phosphoproteomics to delineate insulin signal transduction in adipocyte cells and adipose tissue. Across a range of insults triggering insulin resistance, we observed marked rewiring of the insulin signaling network. This included both attenuated insulin-responsive phosphorylation, and the emergence of phosphorylation uniquely insulin-regulated in insulin resistance. Identifying signaling changes common to multiple insults revealed subnetworks likely containing causal drivers of insulin resistance. Focusing on defective GSK3 signaling initially observed in a relatively small subset of well-characterized substrates, we employed a pipeline for identifying context-specific kinase substrates. This facilitated robust identification of widespread dysregulated GSK3 signaling. Pharmacological inhibition of GSK3 partially reversed insulin resistance in cells and tissue explants. These data highlight that insulin resistance is a multi-nodal signaling defect that encompasses dysregulated GSK3 activity.

Skeletal muscle and adipose tissue insulin resistance are major drivers of metabolic disease. To uncover pathways involved in insulin resistance, specifically in these tissues, we leveraged the metabolic diversity of different dietary exposures and discrete inbred mouse strains. This revealed that muscle insulin resistance was driven by gene-by-environment interactions and was strongly correlated with hyperinsulinemia and decreased levels of ten key glycolytic enzymes. Remarkably, there was no relationship between muscle and adipose tissue insulin action. Adipocyte size profoundly varied across strains and diets, and this was strongly correlated with adipose tissue insulin resistance. The A/J strain, in particular, exhibited marked adipocyte insulin resistance and hypertrophy despite robust muscle insulin responsiveness, challenging the role of adipocyte hypertrophy per se in systemic insulin resistance. These data demonstrate that muscle and adipose tissue insulin resistance can occur independently and underscore the need for tissue-specific interrogation to understand metabolic disease.

The pattern of weight loss and regain, termed "weight cycling," is common in overweight individuals. It is unclear whether the well-established benefits of weight loss persist following weight regain or whether weight cycling is harmful. Human studies of weight cycling have conflicting results reflecting limitations of the observational designs of these studies. By controlling the macronutrient content of diets in animal studies, weight cycling can be studied in a highly controlled manner, thereby overcoming the limitations of human studies. We conducted a systematic review and meta-analysis of animal studies which assessed the health consequences of weight cycling. Studies were classified into those which compared weight cycling to lifelong obesity and those which compared weight cycling to later onset obesity. There were no differences in health outcomes between weight cycled animals and those with lifelong obesity, highlighting that weight regain reverses health benefits achieved by weight loss. In comparison with animals with later onset obesity, weight cycled animals had higher fasting glucose levels and more impaired glucose tolerance following weight regain. Our review of animal studies suggests that health benefits of diet-induced weight loss do not persist after weight regain and weight cycling results in adverse metabolic outcomes.

White adipose tissue is deposited mainly as subcutaneous adipose tissue (SAT), often associated with metabolic protection, and abdominal/visceral adipose tissue (VAT), which contributes to metabolic disease. To investigate the molecular underpinnings of these differences, we conducted comprehensive proteomics profiling of whole tissue and isolated adipocytes from these two depots across two diets from C57Bl/6J mice. The adipocyte proteomes from lean mice were highly conserved between depots, with the major depot-specific differences encoded by just 3% of the proteome. Adipocytes from SAT (SAdi) were enriched in pathways related to mitochondrial complex I and beiging, whereas visceral adipocytes (VAdi) were enriched in structural proteins and positive regulators of mTOR presumably to promote nutrient storage and cellular expansion. This indicates that SAdi are geared toward higher catabolic activity, while VAdi are more suited for lipid storage.By comparing adipocytes from mice fed chow or Western diet (WD), we define a core adaptive proteomics signature consisting of increased extracellular matrix proteins and decreased fatty acid metabolism and mitochondrial Coenzyme Q biosynthesis. Relative to SAdi, VAdi displayed greater changes with WD including a pronounced decrease in mitochondrial proteins concomitant with upregulation of apoptotic signaling and decreased mitophagy, indicating pervasive mitochondrial stress. Furthermore, WD caused reduction in lipid handling and glucose uptake pathways particularly in VAdi, consistent with adipocyte de-differentiation. By overlaying the proteomics changes with diet in whole adipose tissue and isolated adipocytes, we uncovered concordance between adipocytes and tissue only in the VAT, indicating a unique tissue-specific adaptation to sustained WD in SAT.Finally, an in-depth comparison of isolated adipocytes and 3T3-L1 proteomes revealed a high degree of overlap, supporting the utility of the 3T3-L1 adipocyte model. These deep proteomes provide an invaluable resource highlighting differences between white adipose depots that may fine-tune their unique functions and adaptation to an obesogenic environment.

This paper investigates the applicability of numerical and semi-empirical heat flow models for calculating average fluid temperatures in groups of quadratic, precast pile heat exchangers. A 3D finite element model (FEM), verified with experimental data, is extended to account for multiple pile heat exchangers. Semi-empirical dimensionless temperature g-functions for multiple piles are developed by utilising single pile 3D FEM heat transport simulations with temporal and spatial superposition techniques to account for the thermal interaction between piles. The multiple pile g-functions, yet less accurate for short times, yield fluid temperatures similar to those obtained with full 3D modelling (with 7% of largest deviation), at minimal computational cost.

Topology optimization is applied in an idealized structural fire safety model, where the minimum compliance problem is constrained by temperature-controlled structural degradation. The constraint ensures a certain structural stiffness after a prescribed time. As this time period is extended, resulting optimized topologies tend to become thicker or introduce redundant members that can take over when structural parts near the origin of the fire lose their load carrying capability. Hence, the structural degradation model acts as an erosion operator on the topology and indirectly enforces a minimum length scale on the final designs.

Upconversion of sub-band-gap photons constitutes a promising way for improving the efficiency of silicon-based solar cells beyond the Shockley-Queisser limit. 1500 to 980 nm upconversion by trivalent erbium ions is well-suited for this purpose, but the small absorption cross section hinders real-world applications. We employ tailored gold nanostructures to vastly improve the upconversion efficiency in erbium-doped TiO$_2$ thin films. The nanostructures are found using topology optimization and parameter optimization and fabricated by electron beam lithography. In qualitative agreement with a theoretical model, the samples show substantial electric-field enhancements inside the upconverting films for excitation at 1500 nm for both s- and p-polarization under a wide range of incidence angles and excitation intensities. An unprecedented upconversion enhancement of 913(51) is observed at an excitation intensity of 1.7 Wcm$^{-2}$. We derive a semi-empirical expression for the photonically enhanced upconversion efficiency, valid for all excitation intensities. This allows us to determine the upconversion properties needed to achieve significant improvements in real-world solar-cell devices through photonic-enhanced upconversion., Comment: 9 pages (main text), 4 figures, 1 supporting information of 15 pages

We propose a simplified rate-equation model for the 1500 nm to 980 nm upconversion in Er$^{3+}$. The simplifications, based on typical experimental conditions as well as on conclusions based on previously published more advanced models, enable an analytical solution of the rate equations, which reproduces known properties of upconversion. We have compared the model predictions with intensity-dependent measurements on four samples with different optical properties, such as upconversion-luminescence yield and the characteristic lifetime of the $^4I_{13/2}$ state. The saturation of the upconversion is in all cases well-described by the model over several orders of magnitude in excitation intensities. Finally, the model provides a new measure for the quality of upconverter systems based on Er$^{3+}$ -- the saturation intensity. This parameter provides valuable information on upconversion parameters such as the rates of energy-transfer upconversion and cross-relaxation. In the present investigation, we used the saturation intensity to conclude that the differences in upconversion performance of the investigated samples are mainly due to differences in the non-radiative relaxation rates., Comment: 8 pages, 6 figures, to be submitted to PRB

Nicotinamide adenine dinucleotide (NAD

A two-particle model is proposed which enables the assessment of particle-particle interactions in large, sparse arrays of randomly distributed plasmonic metal nanoparticles of arbitrary geometry in inhomogeneous environments. The two-particle model predicts experimentally observed peak splittings in the extinction cross section spectrum for randomly distributed gold nanocones on a TiO2:Er3+ thin film with average center-to-center spacings of 3-5 diameters. The main physical mechanism responsible is found to be interference between the incident field and the far-field component of the single-particle scattered field which is guided along the film.

The large energy-density enhancements, associated with the near-field of plasmonic metal nanoparticles (MNPs), can potentially be utilized to increase the efficiency of nonlinear processes such as upconversion (UC). A drawback of employing metallic structures for UC applications is luminescence quenching, i.e. the transfer of energy from the upconverter material to the metal, where it is dissipated as heat. In this study, a rate-equation model is applied to study the interplay between near-field enhancement and luminescence quenching for a range of different geometries. It is found that while shapes that incorporate pointy features and/or narrow gaps support stronger near-field enhancements, they also suffer more severely from luminescence quenching. Due to the strong correlation between the two effects, the predicted enhancement in UC luminescence is similar across all considered geometries ranging from 1 to 3. Our results indicate that the near-field of plasmonic MNPs might not be suitable for increasing UC efficiency.

Two-phase flow and heat transfer, such as boiling and condensing flows, are complicated physical phenomena that generally prohibit an exact solution and even pose severe challenges for numerical approaches. If numerical solution time is also an issue the challenge increases even further. We present here a numerical implementation and novel study of a fully distributed dynamic one-dimensional model of two-phase flow in a tube, including pressure drop, heat transfer, and variations in tube cross-section. The model is based on a homogeneous formulation of the governing equations, discretized by a high resolution finite difference scheme due to Kurganov and Tadmore.The homogeneous formulation requires a set of thermodynamic relations to cover the entire range from liquid to gas state. This leads a number of numerical challenges since these relations introduce discontinuities in the derivative of the variables and are usually very slow to evaluate. To overcome these challenges, we use an interpolation scheme with local refinement.The simulations show that the method handles crossing of the saturation lines for both liquid to two-phase and two-phase to gas regions. Furthermore, a novel result obtained in this work, the method is stable towards dynamic transitions of the inlet/outlet boundaries across the saturation lines. Results for these cases are presented along with a numerical demonstration of conservation of mass under dynamically varying boundary conditions. Finally we present results for the stability of the code in a case of a tube with a narrow section.

A detailed comparison of continuum and valence force field strain calculations in quantum-dot structures is presented with particular emphasis to boundary conditions, their implementation in the finite-element method, and associated implications for electronic states. The first part of this work provides the equation framework for the elastic continuum model including piezoelectric effects in crystal structures as well as detailing the Keating model equations used in the atomistic valence force field calculations. Given the variety of possible structure shapes, a choice of pyramidal, spherical and cubic-dot shapes is made having in mind their pronounced shape differences and practical relevance. In this part boundary conditions are also considered; in particular the relevance of imposing different types of boundary conditions is highlighted and discussed.

The topic of fluxons in Josephson junctions appears often and in many contexts within superconductivity. The potential applications and the appearance of high-T c superconductivity are some of the reasons for this recently increased interest. Several comprehensive reviews of fluxons (solitons) in long Josephson junctions [8], [2], [10], [9] exist, of which particularly the most recent [9] gives an excellent overview of the state of the art for low- T c niobium-type long Josephson junctions. In recent years the properties of long Josephson junctions stacked on top of each other has been studied quite intensively. This is because such systems model existing low-T c superconducting multilayers. In addition these models have revealed surprising dynamical properties. The appearance of high-T c ceramic superconductors has also had quite an impact on the topic of fluxons in superconductors, in particular stacked long Josephson junctions. Here the fluxons play a very important role, for example, in the BSCCO type of material with a layered structure and big anisotropy. Dynamic properties of fluxons are also relevant for the material properties such as the bulk current density and the behaviour near the transition temperature. Some of these high-T c phenomena we will try to include in our description below.

We compare continuum and atomistic models for the electromechanical fields in wurtzite GaN/AlN quantum dots and their relative impact on the electronic band structure. Qualitative agreement between atomistic strain calculations and continuum elastic models for a wurtzite hexagonal quantum-dot structure is demonstrated; however, significant quantitative discrepancies of up to 100 meV are observed. A smaller difference of approximately 15 meV is found between fully coupled and semi-coupled continuum models.

We consider THz emission due to fluxon dynamics in a stack of inductively coupled long Josephson junctions connected electrically to a resonant cavity. By comparing to experiments on Josephson junction parametric amplifiers we consider the role of a negative resistance in connection with THz emission experiments. We suggest that indeed the negative resistance has a big influence on the experimental results.

The performance of three different functions (penalty, Lagrange–Newton, and projection) used in combination with three different Newton-based optimization algorithms for solving large-scale constrained optimizations is investigated. The test cases correspond to locating minima on seams between two force field energy functions, which can be used to model transitions structures in chemical reactions. The Lagrange–Newton function used in combination with a standard Newton–Raphson optimization is found to be the most efficient for systems up to ∼500 atoms, while an iterative algorithm becomes preferable for larger systems.

The BSCCO type intrinsic Josephson junction has been modeled as a stack of inductively coupled long Josephson junctions, which were described by a system of coupled sine-Gordon equations. In a system of 10 long Josephson junctions coupled to a linear cavity, we numerically investigate how the cavity perturbs fluxon motion in the junctions. Fluxons in neighboring junctions are repulsive leading to anti-phase motion. The cavity provides a force which perturbs this anti-phase motion, and may even force the fluxons to build a square lattice, i.e. to perform in-phase motion. For different values of the inductive coupling strength, we investigate the cavity current, fluxon phase difference, and current–voltage characteristic. The stack-cavity system with in-phase fluxon motion may be utilized as a THz oscillator.

A stack of inductively coupled long Josephson junctions are modeled as a system of coupled sine-Gordon equations. One boundary of the stack is coupled electrically to a resonant cavity. With one fluxon in each Josephson junction, the inter-junction fluxon forces are repulsive. We look at a possible transition, induced by the cavity, to a bunched state.

Background. Immunosuppressive therapies have been associated with gastrointestinal (GI) side effects, which may impair health-related quality of life (HRQoL). Methods. In this survey, 4,232 renal transplant recipients from Denmark, Finland, Nor-way, and Sweden completed the Short-Form 36 (SF-36) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). SF-36 scores were compared with country norm values. Multiple logistic regression analysis was used to identify immunosuppressants associated with GI symptoms. Results. The prevalence of troublesome GI symptoms (GSRS > 1) was 83% for indigestion, 69% for abdominal pain, 58% for constipation, 53% for diarrhea, 47% for reflux, and 92% for any GI symptom. Compared with the general population, HRQoL was most commonly meaningfully impaired in the general health dimension (53% of patients). The presence and severity of GI symptoms were associated with worse HRQoL. Tacrolimus showed a significant association with diarrhea (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.4-2.0) and constipation (OR: 1.3; 95% Cl: 1.1-1.6), and sirolimus with indigestion (OR: 2.9; 95% Cl: 1.0-8.1) and abdominal pain (OR: 2.2; 95% Cl: 1.1-4.4). Conclusions. GI symptoms are associated with impaired HRQoL in the renal transplant population. Managing GI symptoms by careful choice of immunosuppressants should be a focus for improving HRQoL in renal transplant recipients (Less)

The Josephson fluxon behaviour in layered BSCCO-type single crystals is modelled by coupled long Josephson junctions described by coupled sine?Gordon equations. Among all the possible solutions, particularly interesting are the so-called in-phase fluxon solutions with coherent motion of all the fluxons. Recently, generation of electromagnetic waves at almost terahertz (THz) frequencies in BSCCO single crystals was reported. In order to maximize the power of such generation, these in-phase fluxon solutions are essential. Two different avenues to obtain in-phase fluxon motion have been suggested, i.e.?either using the interaction with a cavity to phase lock the fluxon motion or applying a large magnetic field to create in-phase flux flow solutions. We have numerically considered both mechanisms. The results provide an understanding of the system and a guidance to experimentalists looking for THz generation in BSCCO.

Josephson vortex flux flow states in stacked Josephson junctions are investigated numerically. The aim of the work is to understand the mechanisms behind the formation of triangular (anti-phase) and square (in-phase) vortex lattices, and is motivated by recent experiments on layered BSCCO type high- T c superconductors in a magnetic field. In order to keep the problem as simple as possible we consider in detail only the case with two junctions in the stack.

Renal transplantation is associated with an increased risk for premature cardiovascular disease. We analyzed the data in the placebo arm of Assessment of Lescol in Renal Transplantation (ALERT) to improve our understanding of the relationship between cardiovascular risk factors and outcomes in this unique population.We performed Cox survival analysis for myocardial infarction, cardiac death, and noncardiac death in 1,052 patients recruited to the placebo arm of ALERT. These subjects were aged 30 to 75 years, had stable graft function at least 6 months after transplantation, had a serum total cholesterol level between 155 and 348 mg/dL (4 and 9 mmol/L), and were receiving cyclosporine-based immunosuppression.The results confirm previous studies. In multivariate analysis, preexisting coronary heart disease (hazard ratio [HR], 3.69; P0.001), total cholesterol level (HR, 1.55 per 50 mg/dL; P = 0.0045), and prior acute rejection (HR, 2.36; P = 0.0023) were independent risk factors. Conversely, independent risk factors for cardiac death were age (HR, 1.58 per decade; P = 0.0033), diabetes (HR, 3.35; P = 0.0002), ST-T changes on the ECG (HR, 3.17; P = 0.0004), and serum creatinine level (HR, 2.65 per milligram per deciliter; P0.0001).This analysis confirms that renal transplant recipients share risk factors for myocardial infarction and cardiac death with the general population. However, the pattern of risk factors and their relationship with outcomes is atypical, highlighting the unique nature of cardiovascular risk in transplant recipients.

We look for domain wall and textured vortex solutions in a two-component Ginzburg–Landau model inspired by two-band superconductivity. The two-dimensional two-component model, with equal coherence lengths and no magnetic field, shows some interesting properties. In the absence of a Josephson type coupling between the two order parameters a “textured vortex” is found by analytical and numerical solution of the Ginzburg–Landau equations. With a Josephson type coupling between the two order parameters we find the system to split up in two domains separated by a domain wall, where the order parameter is depressed to zero.

Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial.BackgroundHyperlipidemia is a risk factor for long-term renal transplant dysfunction, but no prospective clinical trials have investigated the effects of statin treatment on graft function in renal transplant recipients. The aim of the present study was to evaluate the effect of fluvastatin on long-term renal transplant function and development of chronic allograft nephropathy in the ALERT (Assessment of Lescol in Renal Transplantation) study.MethodsALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 mg and 80 mg daily, in renal transplant recipients. Patients were randomized to receive either fluvastatin (N = 1050) or placebo (N = 1052) and followed for five to six years. Renal end points included graft loss or doubling of serum creatinine or death; glomerular filtration rate (GFR) was also measured during follow-up in a subset of patients (N = 439).ResultsThere were 283 patients (13.5%) with graft loss, mainly due to chronic rejection (82%), yielding an annual rate of 2.4%. Fluvastatin treatment significantly lowered mean low-density lipoprotein (LDL)-cholesterol levels by 32% (95% CI -33 to -30) compared with placebo, but had no significant effect on the incidence of renal graft loss or doubling of serum creatinine, or decline in GFR throughout follow-up in the whole study population. Neither was any treatment effect by fluvastatin found in any of the subgroups analyzed.ConclusionFluvastatin treatment significantly improves lipid values in renal transplant recipients but has no effect on graft loss or doubling of serum creatinine.

The electrical behavior of anisotropic BSCCO single crystals is modeled by mutually coupled long Josephson junctions. We show that although the fluxons in the different layers do not a priori prefer the in-phase motion desired for many potential applications it is possible to induce such behavior by coupling the system to a high-Q resonator with a resonance frequency corresponding to fluxon in-phase motion. The resulting model is a set of coupled non-linear partial differential equations. By direct numerical simulations we have demonstrated that the qualitative behavior of the combined stacked long Josephson junctions and cavity system can be understood on the basis of the general concepts of nonlinear oscillators interacting with a resonator. For some region of the parameter space it is possible to reach the desired synchronous state, making the system potentially suitable for applications. We also look at the different dynamical states defined by different fluxon dynamical states in combination with different cavity properties.

We show how to construct fluxon modes from plasma modes in the inductively coupled stacked Josephson junctions, and consider some special cases of these fluxon modes analytically. In some cases we can find exact analytical solutions when we choose the bias current in a special way. We also consider numerically what happens to these modes when the bias current is chosen to be equal in all junctions, which is the natural way of having the bias current in an experimental setup.

We consider a system of stacked Josephson junctions and investigate the different fluxon modes. Some of these modes can be used to construct an oscillator with a frequency in the range 200 GHz–1 THz. We discuss the output that can be expected from the different fluxon modes, and we calculate the theoretical maximum output numerically.

This letter presents a topology optimization study of metal nanostructures optimized for electric-field enhancement in the infrared spectrum. Coupling of such nanostructures with suitable ions allows for an increased photon-upconversion yield, with one application being an increased solar-cell efficiency by exploiting the long-wavelength part of the solar spectrum. In this work, topology optimization is used to design a periodic array of two-dimensional gold nanostrips for electric-field enhancements in a thin film doped with upconverting erbium ions. The infrared absorption band of erbium is utilized by simultaneously optimizing for two polarizations, up to three wavelengths, and three incident angles. Geometric robustness towards manufacturing variations is implemented considering three different design realizations simultaneously in the optimization. The polarization-averaged field enhancement for each design is evaluated over an 80 nm wavelength range and a ±15-degree incident angle span. The highest polarization-averaged field enhancement is 42.2 varying by maximally 2% under ±5 nm near-uniform design perturbations at three different wavelengths (1480 nm, 1520 nm, and 1560 nm). The proposed method is generally applicable to many optical systems and is therefore not limited to enhancing photon upconversion.

Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ('statins') reduces morbidity and mortality from coronary heart disease in diverse patient populations.The aim of the present ALERT (Assessment of Lescol in Renal Transplantation) study is to determine whether renal transplant recipients would also benefit from statin therapy. ALERT is a multicentre, randomized, double-blind, placebo-controlled trial to assess the effect of fluvastatin in renal transplant recipients with mild-to-moderate hypercholesterolaemia. The primary objective is to investigate the effects of fluvastatin on major adverse cardiac events (MACE). In addition, the effects on cardiovascular and all-cause mortality, as well as renal function, will be addressed.The study population contains patients with functioning renal allografts of more than 6 months' duration, recruited from 75 centres in Northern Europe and Canada. Patients of both sexes, aged 30-75 years, with a total cholesterol level of 4.0-9.0 mmol/l (155-348 mg/dl) were included, except for those with a history of myocardial infarction, where the upper limit for inclusion was 7.0 mmol/l (270 mg/dl).A total of 2100 patients were recruited by the end of October 1997 and will be followed for up to 6 years. This report presents the design features of the study (recruitment, follow-up, sample size, data analysis and study organization), along with baseline results. ALERT is the first large-scale prospective, randomized, double-blind study to address the prevention of cardiovascular mortality in renal transplant patients receiving an HMGCoA reductase inhibitor.

The case history of a hypoparathyroid female with short bowel syndrome and long-standing therapy-resistant symptomatic hypocalcemia is reported. During treatment with massive doses of the potent vitamin D analog, 1 alpha-hydroxyvitamin D3(1 alpha(OH)D3), normocalcemia was re-established and clinical symptoms of hypocalcemia were relieved. Furthermore, significant improvement of t of intestinal calcium absorption and bone mineral content was observed after three months of treatment with 1 alpha(OH)D3. The data suggest that 1 alpha(OH)D3 may be of therapeutical value in patients with hypoparathyroidism and intestinal malabsorption.

We discuss non-spectroscopic (astrometric) ways to determine radial velocities and their potentials in future astrometric missions. Radial-velocity accuracies are presented, based on Hipparcos parallax and proper motion data for several open clusters.

The apparent radial velocity of a star, as deduced from wavelength shifts, comprises not merely its true velocity, but also components arising from dynamics in the star’s atmosphere, gravitational redshift, and other effects. For the Sun, such phenomena can be segregated since the relative Sun-Earth motion is known from planetary system dynamics. This is now becoming possible also for other stars, whose true radial motions are determined through space astrometry. A study of the differences between accurate astrometric velocities (from Hipparcos), and precise spectroscopic values (from ELODIE) is in progress. Data for cool stars in the Hyades indicate a tendency of relative blueshifts among earlier main-sequence F-type stars, and in giants. This is theoretically expected: an increased convective blueshift due to the more vigorous convection in F-stars, and a decreased gravitational redshift in giants.

Accuracy levels of metres per second require the concept of ‘radial velocity’ to be examined, in particular with respect to relativistic velocity effects and spectroscopic measurements made inside gravitational fields. Already in a classical (non-relativistic) framework the line-of-sight velocity component is an ambiguous concept. In the relativistic context, the observed wavelength shifts depend e.g. on the transverse velocity of the star and the gravitational potential at the source. We argue that the observational quantity resulting from high-precision radial-velocity measurements is not a physical velocity but a spectroscopic radial-velocity measure, which only for historic and practical reasons is expressed in velocity units. This radial-velocity measure may be defined as cz, where c is the speed of light and z is the observed relative wavelength shift reduced to the solar system barycentre. To first order, cz equals the line-of-sight velocity, but its precise interpretation is model dependent.

Using large suction caissons for offshore wind turbines is an upcoming technology also referred to as bucket foundations. During installation the bucket is loaded by uniform external pressure and vertical forces. Typically, the bucket foundation is a large cylindrical monopod foundation made of steel. In this paper, an alternative design/shape of the suction caisson, having a smaller risk of buckling under high pressure is presented. The risk of structural buckling is addressed using numerical methods to determine the buckling pressures of the re-designed bucket foundation during installation. Further, the effect of the lateral restraint offered by the surrounding soil on the buckling pressures is analysed. It is found that the new design enables a significantly larger buckling load compared to the traditional design.

In this letter, we present a comparative experimental–simulation study of Au-nanodisc-enhanced upconversion of 1500 nm light in an Er3+ doped TiO2 thin film. The geometry of the Au nanodiscs was guided by finite-element simulations based on a single nanodisc in a finite computational domain and controlled experimentally using electron-beam lithography. The surface-plasmon resonances (SPRs) exhibited a well-known spectral red shift with increasing diameter, well explained by the model. However, an experimentally observed double-peak SPR, which resulted from inter-particle interactions, was expectedly not captured by the single-particle model. At resonance, the model predicted a local-field enhancement of the upconversion yield, and experimentally, the luminescence measurements showed such enhancement up to nearly 7 fold from a nanodisc with 315 nm diameter and 50 nm height. The upconversion enhancement agreed qualitatively with the theoretical predictions, however with 3–5 times higher enhancement, which w...

A discussion of computational methods for calculating strain and piezoelectric fields in nanostructures is presented. Emphasis is on a comparison of continuum and valence force field atomistic models and the validity of the former in predicting, accurately, strain fields for nanostructures with dimensions down to a few nm. This is done on the experimentally relevant InAs/InGaAs quantum-dot wetting layer structures and on spherical quantum dot structures. We next address the influence of boundary conditions imposed at the computational domain for strain fields near and inside the quantum dot; a point largely missing in literature. Boundary conditions discussed include fixed, free, fixed-free, and periodic, and it is shown that the particular choice of boundary conditions is unimportant for the strain results; a conclusion that allows to choose the computationally most effective one being the fixed-free boundary conditions as it requires the smallest computational domain for obtaining convergent results. While this result is fortunate, it is not obvious from a mathematical point of view. A further important, and a priori not obvious conclusion, is that a continuum model captures well atomistic strain results; a fact that allows us to use a continuum formulation even in cases where structure dimensions are down to only a few lattice constants. In realistically grown structures, inhomogeneous concentration profiling exists. We present investigations for strain and piezoelectric results in the case where a spherical quantum dot region is gradually profiled from GaAs to InAs assuming the concentration is a function of the distance to the quantum dot sphere center. It is shown that quantum dot concentration profiling affects strain fields and biaxial strains in particular, electronic states and hence optical properties. We finally present some effective quasi-analytical studies of electronic states and strain fields in curved quantum dots based on applications of differential geometry and perturbation theory.

Using large suction caissons for offshore wind turbines is an upcoming technology also referred to as bucket foundations. The bucket foundation does not require heavy installation equipment, but since it is constructed as a thin steel shell structure, instability, in form of buckling, becomes a crucial issue during installation. This paper addresses the hydrostatic buckling pressure of the bucket foundation using threedimensional, non-linear finite element analysis. The main finding of this paper is that introducing an imperfect geometry based on the first linear pre-buckling mode shape, can increase the buckling load significantly.

Gastrointestinal (GI) symptoms are common in renal transplant recipients and are associated with impaired health-related quality of life (HRQoL). We investigated clinician attitudes to GI symptoms and HRQoL in these patients by surveying 145 nephrologists from Sweden, Denmark, Finland, and Norway. In total, 79 clinicians responded. They estimated that 20% of their patients experienced GI discomfort and that 36% had impaired HRQoL. We previously conducted a survey of the renal transplant recipients treated by these clinicians, in which 92% reported troublesome GI symptoms and 53% had impaired HRQoL compared with the general population. Nephrologists were more likely to manage GI symptoms by reducing immunosuppressant dose (87%) than by switching medication to one with fewer GI side effects (66%). We conclude that clinicians appear to underestimate the prevalence of GI symptoms and impaired HRQoL. Improving patient-clinician communication could lead to more informed management, resulting in better HRQoL and increased graft survival.

Silver nanoparticles, placed on top of an Er3+ doped TiO2 thin film, were investigated as a means of achieving enhanced up-conversion. Finite-element modeling was used to determine the nanoparticle dimensions (height and diameter) yielding the largest plasmonic enhancement for an incident light wavelength of 808 nm. In order to mimic the experimentally observed up-conversion enhancement, the electric-field enhancement from the Ag nanoparticles was integrated over the entire thickness of the thin film. Based on these calculations, four samples were prepared and tested. The trends predicted by the models were found to correlate well with the trends of the experimentally obtained plasmonic enhanced up-conversion yields. The largest plasmonic enhancement for 808 nm excitation was observed for Ag nanoparticles of diameter 91 ± 5 nm and height 14 ± 1 nm, yielding 163- and 51-fold enhancements for the green (525 nm and 550 nm) and red (660 nm) emissions peaks, respectively.

Renal transplant recipients (RTR) have an increased risk of premature cardiovascular disease. The ALERT study is the first trial to evaluate the effect of statin therapy on cardiac outcomes following renal transplantation. Patients initially randomized to fluvastatin or placebo in the 5-6 year ALERT study were offered open-label fluvastatin XL 80 mg/day in a 2-year extension to the original study. The primary endpoint was time to first major adverse cardiac event (MACE). Of 1787 patients who completed ALERT, 1652 (92%) were followed in the extension. Mean total follow-up was 6.7 years. Mean LDL-cholesterol was 98 mg/dL (2.5 mmol/L) at last follow-up compared to a pre-study level of 159 mg/dL (4.1 mmol/L). Patients randomized to fluvastatin had a reduced risk of MACE (hazards ratio [HR] 0.79, 95% CI 0.63-0.99, p = 0.036), and a 29% reduction in cardiac death or definite non-fatal MI (HR 0.71, 95% CI 0.55-0.93, p = 0.014). Total mortality and graft loss did not differ significantly between groups. Fluvastatin produces a safe and effective reduction in LDL-cholesterol associated with reduced risk of MACE in RTR. The lipid-lowering and cardiovascular benefits of fluvastatin are comparable to those of statins in other patient groups, and support use of fluvastatin in RTR.

We numerically investigate Josephson vortex flux flow states in stacked Josephson junctions, motivated by recent experiments trying to observe the vortices in a square vortex lattice when a magnetic field is applied to layered high-${T}_{c}$ superconductors of the ${\mathrm{Bi}}_{2}{\mathrm{Sr}}_{2}\mathrm{Ca}{\mathrm{Cu}}_{2}{\mathrm{O}}_{x}$ type. By extensive numerical simulations, we are able to clearly distinguish between triangular and square vortex lattices and to identify the parameters leading to an in-phase vortex configuration.

Background. Renal transplant recipients have a significantly reduced life expectancy, largely due to premature cardiovascular disease. The aim of the current analysis was to investigate the importance of time of initiation of therapy after transplantation, on the benefits of statin therapy. Methods. 2102 renal transplant recipients with total cholesterol levels of 4.0-9.0 mmol/l were randomly assigned to treatment with fluvastatin (n = 1050) or placebo (n = 1052) and followed for a mean time of 5.1 years. The end-points were major cardiac events. The average median time from transplantation to randomization was 4.5 years (range: 0.5-29 years). Results. In patients starting treatment with fluvastatin 6 years, respectively. The risk reduction for patients initiating therapy with fluvastatin at years 0-2 (compared with >6 years) following transplantation was 59% (RR: 0.41; 95% CI: 0.18-0.92; P = 0.0328). This is also reflected in total time on renal replacement therapy: in patients in the first quartile (120 months) (P = 0.033). Conclusions. Our data support an early introduction of fluvastatin therapy in a population of transplant recipients at high risk of premature coronary heart disease

The aim of the study was to identity risk factors for long-term renal transplant function and development of chronic allograft nephropathy (CAN) in renal transplant recipients included in the Assessment of Lescol in Renal Transplantation (ALERT) trial.The ALERT trial was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 and 80 mg/day, in renal transplant recipients who were randomized to receive fluvastatin (Lescol) (n = 1,050) or placebo (n = 1,052) over 5 to 6 years of follow-up. Renal endpoints including graft loss or doubling of serum creatinine or death were analyzed by univariate and multivariate regression analysis in the placebo group.There were 137 graft losses (13.5%) in the placebo group, mainly caused by CAN (82%). Univariate risk factors for graft loss or doubling of serum creatinine were as follows: serum creatinine, proteinuria, hypertension, pulse pressure, time since transplantation, donor age, human leukocyte antigen-DR mismatches, treatment for rejection, low high-density lipoprotein cholesterol, and smoking. Multivariate analysis revealed independent risk factors for graft loss as follows: serum creatinine (relative risk [RR], 3.12 per 100-microM increase), proteinuria (RR, 1.64 per 1-g/24 hr increase), and pulse pressure (RR, 1.12 per 10 mm Hg), whereas age was a protective factor. With patient death in the composite endpoint, diabetes mellitus, smoking, age, and number of transplantations were also risk factors.Independent risk factors for graft loss or doubling of serum creatinine or patient death are mainly related to renal transplant function, proteinuria, and blood pressure, which emphasizes the importance of renoprotective treatment regimens in this population.