Additional figures may be found at http://www.stat.berkeley.edu/~bolstad/normalize/index.html

SUMMARY Background

Hyperphosphatemia is common among patients with CKD stage 5D and is associated with morbidity and mortality. Current guidelines recommend lowering serum phosphate concentrations toward normal. Tenapanor is a minimally absorbed small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 that functions in the gut to reduce sodium and phosphate absorption. This randomized, double-blind, placebocontrolled trial assessed the effects of tenapanor on serum phosphate concentration in patients with hyperphosphatemia receiving hemodialysis. After a 1-to 3-week washout of phosphate binders, we randomly assigned 162 eligible patients (serum phosphate =6.0 to ,10.0 mg/dl and a 1.5-mg/dl increase from before washout) to one of six tenapanor regimens (3 or 30 mg once daily or 1, 3, 10, or 30 mg twice daily) or placebo for 4 weeks. The primary efficacy end point was change in serum phosphate concentration from baseline (randomization) to end of treatment. In total, 115 patients (71%) completed the study. Mean serum phosphate concentrations at baseline (after washout) were 7.32-7.92 mg/dl for tenapanor groups and 7.87 mg/dl for the placebo group. Tenapanor provided dose-dependent reductions in serum phosphate level from baseline (least squares mean change: tenapanor =0.47-1.98 mg/dl; placebo =0.54 mg/dl; P=0.01). Diarrhea was the most common adverse event (tenapanor =18%-68%; placebo =12%) and frequent at the highest tenapanor doses. In conclusion, tenapanor treatment resulted in statistically significant, dose-dependent reductions in serum phosphate concentrations in patients with hyperphosphatemia receiving hemodialysis. Additional studies are required to clarify the optimal dosing of tenapanor in patients with CKD-related hyperphosphatemia. 28: 193328: -194228: , 201728: . doi: https://doi.org/10.1681 Disorders of mineral metabolism are common among persons with CKD. 1 Impaired kidney function reduces urinary phosphate excretion, the principal mechanism by which normal phosphate balance is maintained. 2 Modulation of tubular reabsorption of phosphate, mediated in large part by parathyroid hormone (PTH) and the phosphatonin fibroblast growth factor 23 (FGF23), allows for maintenance of serum phosphate concentrations within a physiologic range, despite wide variation in phosphate intake on a day to day basis. However, in advanced CKD, dietary phosphate intake generally exceeds excretory capacity; for patients on dialysis, even with dietary phosphate restriction, hyperphosphatemia is almost inevitable without specific treatment. 3 Among patients receiving dialysis, evidence from observational studies, 1,4 retrospective database analyses, 5,6 and to a lesser extent, prospective controlled trials 7,8 has shown that hyperphosphatemia is associated with mortality, 1,4-6 fractures, 5 and cardiovascular disease, including vascular calcification 8 and left ventricular hypertrophy. 7 J Am Soc Nephrol

Affymetrix high-density oligonucleotide array is a tool that has the capacity to simultaneously measure the abundance of thousands of mRNA sequences in biological samples. In order to allow direct array-to-array comparisons, normalization is a necessity. When deciding on an appropriate normalization procedure there are a couple questions that need to be addressed, e.g., on which level should the normalization be performed: On the level of feature intensities or on the level of expression indexes? Should all features/expression indexes be used or can we choose a subset of features likely to be unregulated? Another question is how to actually perform the normalization: normalize using the overall mean intensity or use a smooth normalization curve? Most of the currently used normalization methods are linear; e.g., the normalization method implemented in the Affymetrix software GeneChip is based on the overall mean intensity. However, along with alternative methods of summarizing feature intensities into an expression index, nonlinear methods have recently started to appear. For many of these alternative methods, the natural choice is to normalize on the level of feature intensities, either using all feature intensities or only perfect match intensities. In this report, a nonlinear normalization procedure aimed for normalizing feature intensities is proposed.

SUMMARY BackgroundSelective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans.

AimsTo characterize ticagrelor exposure‐response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using nonlinear mixed effects modelling and simulation.MethodsPlatelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR‐C1249010XX in a population pharmacokinetic (PK) and pharmacodynamic (PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS‐TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily.ResultsPlatelet inhibition by ticagrelor was described by a sigmoidal Emax model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol l–1. Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak‐to‐trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations.ConclusionsIn patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modelled doses <60 mg, the response is reduced overall, more variable between patients, and patients will display greater peak‐to‐trough variability.

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