Probability state modeling of memory CD8+ T-cell differentiation

AbstractFlow cytometric analysis enables the simultaneous single-cell interrogation of multiple biomarkers for phenotypic and functional identification of heterogeneous populations. Analysis of polychromatic data has become increasingly complex with more measured parameters. Furthermore, manual gating of multiple populations using standard analysis techniques can lead to errors in data interpretation and difficulties in the standardization of analyses. To characterize high-dimensional cytometric data, we demonstrate the use of probability state modeling (PSM) to visualize the differentiation of effector/memory CD8+ T cells. With this model, four major CD8+ T-cell subsets can be easily identified using the combination of three markers, CD45RA, CCR7 (CD197), and CD28, with the selection markers CD3, CD4, CD8, and side scatter (SSC). PSM enables the translation of complex multicolor flow cytometric data to pathway-specific cell subtypes, the capability of developing averaged models of healthy donor populations, and the analysis of phenotypic heterogeneity. In this report, we also illustrate the heterogeneity in memory T-cell subpopulations as branched differentiation markers that include CD127, CD62L, CD27, and CD57

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

HyperLog TM Transform HyperLog TM -A Flexible Log-like Transform for Negative, Zero, and Positive Valued Data

Abstract: The remarkable success of cytometry over the last thirty years is largely due to its uncanny ability to display populations that vastly differ in numbers and fluorescence intensity on one scale. The log (L) transform, either implemented in hardware as a log amplifier, or in software, normalizes signals or channels such that these populations appear as clearly discernable peaks. With the advent of multiple fluorescence cytometry, spectral-crossover compensation of these signals has been necessary to properly interpret the data. Unfortunately, since compensation is a subtractive process, it can produce negative and zero valued data. The log transform is undefined for these values and as a result, forces computer algorithms to truncate these values, creating a few problems for Cytometrists. Data truncation biases displays making properly compensated data appear undercompensated; thus, enticing many operators to over-compensate their data. Also, events truncated into the first histogram channel are not normally visible with typical two dimensional graphic displays, hiding a large number of events and obscuring the true proportionality of negative distributions. In addition, the L transform creates unequal binning which can dramatically distort negative population distributions. The HyperLog TM (HL) transform is a log-like transform that admits negative, zero, and positive values. The transform is a hybrid type of transform specifically designed for compensated data. One of its parameters allows it to smoothly transition from a logarithmic to linear type of transform which is ideal for compensated data. The HL transform is easily implemented in computer systems and results in display systems that present compensated data in an unbiased manner. HyperLog TM Transform

Fast-Track Authority and International Trade Negotiations

We develop a simple model of trade relations in which legislators with different stakes in import-competing and export industries decide whether to grant fast-track authority (FTA) to the president, giving up the power to amend international trade agreements. We show that strategic delegation motives are key to understanding FTA votes, which involve a decision between alternative country representatives: the executive or the majority in Congress. We then examine the determinants of all votes by US congressmen on FTA since the introduction of this institutional procedure in 1974. Our empirical analysis provides strong support for the predictions of the model.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Dynamic Models of Religious Conformity and Conversion: Theory and Calibrations

This paper develops behavioral and deterministic overlapping generations models to explain and simulate changes in the proportion of secular and religious people. Under the behavioral approach, the role of the church is to generate an externality associated with the investment in enhancing the conformity rate among young believers. Under the deterministic approach, changes in the number of nonbelievers are explained by different birth rates among secular and religious parents as well as the relative proportion of nonconformists among the young in each group. This model is then used to calibrate for (non)conformity rates among secular and religious people.Diese Arbeit entwickelt deterministische und Verhaltensmodelle mit überlappenden Generationen, welche die Veränderungen des Zahlenverhältnisses von nicht religiösen zu religiösen Menschen erklären und simulieren. Im Verhaltensansatz wird aufgezeigt, dass der Kirche die Aufgabe zukommt, einen externen Effekt zu erzeugen, der dafür sorgt, dass junge Gläubige mit der Glaubenseinstellung ihrer Eltern konform gehen. Der deterministische Ansatz erklärt die Veränderungen in der Anzahl Nichtgläubiger einerseits mit den unterschiedlichen Geburtenraten unter nichtgläubigen Eltern im Vergleich zu religiösen Eltern und andererseits durch den relativen Anteil von Nichtkonformen unter der jungen Generation in jeder Gruppe. Dieses Modell wird verwandt, um (Nicht-)Konformitätsraten – nach denen junge Menschen ihren Eltern im Glauben folgen oder nicht - innerhalb der Gruppen weltlicher sowie religiöser Menschen zu berechnen