No Impact of the Analytical Method used for Determing Cystatin C on Estimating lomerular Filtration Rate in Children

Background: Measurement of inulin clearance is considered to be the gold standard for determining kidney function in children, but this method is time consuming and expensive. The glomerular filtration rate (GFR) is on the other hand easier to calculate by using various creatinine- and/or cystatin C (Cys C)-based formulas. However, for the determination of serum creatinine (Scr) and Cys C, different and non-interchangeable analytical methods exist. Given the fact that different analytical methods for the determination of creatinine and Cys C were used in order to validate existing GFR formulas, clinicians should be aware of the type used in their local laboratory. In this study, we compared GFR results calculated on the basis of different GFR formulas and either used Scr and Cys C values as determined by the analytical method originally employed for validation or values obtained by an alternative analytical method to evaluate any possible effects on the performance. Methods: Cys C values determined by means of an immunoturbidimetric assay were used for calculating the GFR using equations in which this analytical method had originally been used for validation. Additionally, these same values were then used in other GFR formulas that had originally been validated using a nephelometric immunoassay for determining Cys C. The effect of using either the compatible or the possibly incompatible analytical method for determining Cys C in the calculation of GFR was assessed in comparison with the GFR measured by creatinine clearance (CrCl). Results: Unexpectedly, using GFR equations that employed Cys C values derived from a possibly incompatible analytical method did not result in a significant difference concerning the classification of patients as having normal or reduced GFR compared to the classification obtained on the basis of CrCl. Sensitivity and specificity were adequate. On the other hand, formulas using Cys C values derived from a compatible analytical method partly showed insufficient performance when compared to CrCl. Conclusion: Although clinicians should be aware of applying a GFR formula that is compatible with the locally used analytical method for determining Cys C and creatinine, other factors might be more crucial for the calculation of correct GFR values

THEORY OF PHASE-LOCKING IN SMALL JOSEPHSON JUNCTION CELLS

Within the RSJ model, we performed a theoretical analysis of phase-locking in elementary strongly coupled Josephson junction cells. For this purpose, we developed a systematic method allowing the investigation of phase-locking in cells with small but non-vanishing loop inductance.The voltages across the junctions are found to be locked with very small phase difference for almost all values of external flux. However, the general behavior of phase-locking is found to be just contrary to that according to weak coupling. In case of strong coupling there is nearly no influence of external magnetic flux on the phases, but the locking-frequency becomes flux-dependent. The influence of parameter splitting is considered as well as the effect of small capacitive shunting of the junctions. Strongly coupled cells show synchronization even for large parameter splitting. Finally, a study of the behavior under external microwave radiation shows that the frequency locking-range becomes strongly flux-dependent, whereas the locking frequency itself turns out to be flux-independent.Comment: 26 pages, REVTEX, 9 PS figures appended in uuencoded form at the end, submitted to Phys. Rev. B

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers

How Job Changes Affect People's Lives Evidence from Subjective Well-Being Data

For representative German panel data, we document that voluntary job switching is associated with higher levels of life satisfaction, though only for some time, whereas forced job changes do not affect life satisfaction clearly. Using plant closures as an exogenous trigger of switching to a new employer, we find that job mobility turns out to be harmful for satisfaction with family life. By investigating people's lives beyond their workplaces, our study complements research on the well-being impact of labour mobility, suggesting some positive welfare effects of flexible labour markets, but also a previously undocumented potential for negative implications

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Generation and Validation of a Limited Sampling Strategy to Monitor Mycophenolic Acid Exposure in Children With Nephrotic Syndrome

Background: Mycophenolate mofetil (MMF) plays an increasingly important role in the treatment of children with nephrotic syndrome, especially in steroid sparing protocols. Recent publications show the relationship of exposure to its active moiety mycophenolic acid (MPA) and clinical efficacy. Performance of full-time pharmacokinetic (PK) profiles, however, is inconvenient and laborious. Established limited sampling strategies (LSS) to estimate the area under the concentration (AUC) versus time curve of MPA (MPA-AUC) in pediatric renal transplant recipients cannot be easily transferred to children suffering from nephrotic syndrome, mainly because of the lack of concomitant immunosuppressive therapy. We therefore aimed for the generation and validation of a LSS to estimate MPA exposure to facilitate therapeutic drug monitoring in children with nephrotic syndrome. Methods: We performed 27 complete PK profiles in 23 children in remission [mean age (+/- SD):12.3 +/- 4.26 years] to generate and validate an LSS. Sampling time points were before administration (C-0) and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours after the administration of MMF. MPA was measured by enzyme multiplied immunoassay technique. There was no concomitant treatment with calcineurin inhibitors. Results: Mean daily dose of MMF was 927 +/- 209 mg/m(2) of body surface area resulting in a mean MPA-AUC(0-12) value of 59.2 +/- 29.3 mg x h/L and a predose level of 3.03 +/- 2.24 mg/L. Between-patient variability of dose-normalized MPA-AUC(0-12) was high (coefficient of variation: 45.5%). Correlation of predose levels with the corresponding MPA-AUC(0-12) was moderate (r(2) = 0.59) in a subgroup of 18 patients (20 PK profiles, generation group). An algorithm based on 3 PK sampling time points during the first 2 hours after MMF dosing (estimated AUC(0-12) = 8.7 + 4.63 x C-0 + 1.90 x C-1 + 1.52 x C-2) was able to predict MPA-AUC with a low percentage prediction error (3.88%) and a good correlation of determination (r(2) = 0.90). Validation of this algorithm in a randomized separate group of 6 patients (7 PK profiles, validation group) resulted in comparably good correlation (r(2) = 0.95) and low percentage prediction error (5.57%). Conclusions: An abbreviated profile within the first 2 hours after MMF dosing gives a good estimate of MPA exposure in children with nephrotic syndrome and hence has the potential to optimize MMF therapy