Søren P. Madsen

Long‐term Cardiac Outcomes in Renal Transplant Recipients Receiving Fluvastatin: The ALERT Extension Study

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.

Risk factors for reaching renal endpoints in the assessment of Lescol in renal transplantation (ALERT) trial

Background. 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. Methods. 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. Results. 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-&mgr;M 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. Conclusions. 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.

Increased prevalence of gastrointestinal symptoms associated with impaired quality of life in renal transplant recipients.

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, Norway, 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% CI: 1.1–1.6), and sirolimus with indigestion (OR: 2.9; 95% CI: 1.0–8.1) and abdominal pain (OR: 2.2; 95% CI: 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.

Up-conversion enhancement in Er3+ doped TiO2 through plasmonic coupling: Experiments and finite-element modeling

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.

THz Generation Using Fluxon Dynamics in High Temperature Superconductors

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.

Plasmonically enhanced upconversion of 1500 nm light via trivalent Er in a TiO2 matrix

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...

Particle-particle interactions in large, sparse arrays of randomly distributed plasmonic metal nanoparticles: a two-particle model

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.

Topology optimized gold nanostrips for enhanced near-infrared photon upconversion

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 ...

High-Q cavity-induced fluxon bunching in inductively coupled Josephson junctions

We consider fluxon dynamics in a stack of inductively coupled long Josephson junctions connected capacitively to a common resonant cavity at one of the boundaries. We study, through theoretical and numerical analyses, the possibility for the cavity to induce a transition from the energetically favored state of spatially separated shuttling fluxons in the different junctions to a high-velocity high-energy state of identical fluxon modes.

No Detrimental Effect On Renal Function During Long-term Use Of Fluvastatin

BACKGROUND Concerns have recently been raised regarding a potential harmful effect of statins on renal function. This study investigated the effect of fluvastatin treatment on renal function in renal transplant recipients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) trial. METHODS ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40-80 mg daily (n = 1050) or placebo (n = 1052) on cardiac and renal outcomes in renal transplant recipients over a follow-up period of five to six years. The incidence of graft loss, changes in serum creatinine, calculated creatinine clearance and proteinuria, and the incidence of renal adverse events (AEs) were assessed in both treatment groups. RESULTS Fluvastatin treatment in ALERT had no significant effect compared with placebo on renal function, assessed by serum creatinine (overall adjusted mean +/- SEM: fluvastatin, 175.4 +/- 2.20 micromol/L; placebo, 172.7 +/- 2.20 micromol/L; p = 0.39), creatinine clearance (fluvastatin, 55.3 +/- 0.30 mL/min; placebo, 55.8 +/- 0.30 mL/min; p = 0.26) or proteinuria (fluvastatin, 0.58 +/- 0.03 g/24 h; placebo, 0.53 +/- 0.03 g/24 h; p = 0.31). There were no significant differences between treatment groups when the 283 patients suffering graft loss were excluded from the analysis. Fluvastatin also had no detrimental effect on creatinine clearance or proteinuria in the subgroup of 340 diabetic patients without graft loss in ALERT. No notable differences in the rate of renal or musculoskeletal AEs were observed between fluvastatin and placebo groups. CONCLUSIONS Fluvastatin had no detrimental effect on renal function, or the risk of renal AEs, in renal transplant recipients with or without diabetes enrolled in ALERT. Fluvastatin treatment for the prevention of cardiac events may therefore be used without fear of jeopardizing renal function.