Moduli Spaces for Principal Bundles in Arbitrary Characteristic

In this article, we solve the problem of constructing moduli spaces of semistable principal bundles (and singular versions of them) over smooth projective varieties over algebraically closed ground fields of positive characteristic.Comment: V4: Final version, to appear in Advances in Mathematics, 69p

Stratifying quotient stacks and moduli stacks

Recent results in geometric invariant theory (GIT) for non-reductive linear algebraic group actions allow us to stratify quotient stacks of the form [X/H], where X is a projective scheme and H is a linear algebraic group with internally graded unipotent radical acting linearly on X, in such a way that each stratum [S/H] has a geometric quotient S/H. This leads to stratifications of moduli stacks (for example, sheaves over a projective scheme) such that each stratum has a coarse moduli space.Comment: 25 pages, submitted to the Proceedings of the Abel Symposium 201

Iron deficiency after kidney transplantation

Iron deficiency (ID) is highly prevalent in kidney transplant recipients (KTRs) and has been independently associated with an excess mortality risk in this population. Several causes lead to ID in KTRs, including inflammation, medication and an increased iron need after transplantation. Although many studies in other populations indicate a pivotal role for iron as a regulator of the immune system, little is known about the impact of ID on the immune system in KTRs. Moreover, clinical trials in patients with chronic kidney disease or heart failure have shown that correction of ID, with or without anaemia, improves exercise capacity and quality of life, and may improve survival. ID could therefore be a modifiable risk factor to improve graft and patient outcomes in KTRs; prospective studies are warranted to substantiate this hypothesis.</p

Body composition is associated with tacrolimus pharmacokinetics in kidney transplant recipients

PURPOSE: A population pharmacokinetic (popPK) model may be used to improve tacrolimus dosing and minimize under- and overexposure in kidney transplant recipients. It is unknown how body composition parameters relate to tacrolimus pharmacokinetics and which parameter correlates best with tacrolimus exposure. The aims of this study were to investigate which body composition parameter has the best association with the pharmacokinetics of tacrolimus and to describe this relationship in a popPK model. METHODS: Body composition was assessed using bio-impedance spectroscopy (BIS). Pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM). Lean tissue mass, adipose tissue mass, over-hydration, and phase angle were measured with BIS and then evaluated as covariates. The final popPK model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis. RESULTS: In 46 kidney transplant recipients, 284 tacrolimus concentrations were measured. The base model without body composition parameters included age, plasma albumin, plasma creatinine, CYP3A4 and CYP3A5 genotypes, and hematocrit as covariates. After full forward inclusion and backward elimination, only the effect of the phase angle on clearance (dOFV =  − 13.406; p < 0.01) was included in the final model. Phase angle was positively correlated with tacrolimus clearance. The inter-individual variability decreased from 41.7% in the base model to 34.2% in the final model. The model was successfully validated. CONCLUSION: The phase angle is the bio-impedance spectroscopic parameter that correlates best with tacrolimus pharmacokinetics. Incorporation of the phase angle in a popPK model can improve the prediction of an individual’s tacrolimus dose requirement after transplantation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00228-022-03323-0

Individualized dosing algorithms for tacrolimus in kidney transplant recipients:current status and unmet needs

Introduction: Tacrolimus is a potent immunosuppressive drug with many side effects including nephrotoxicity and post-transplant diabetes mellitus. To limit its toxicity, therapeutic drug monitoring (TDM) is performed. However, tacrolimus’ pharmacokinetics are highly variable within and between individuals, which complicates their clinical management. Despite TDM, many kidney transplant recipients will experience under- or overexposure to tacrolimus. Therefore, dosing algorithms have been developed to limit the time a patient is exposed to off-target concentrations. Areas Covered: Tacrolimus starting dose algorithms and models for follow-up doses developed and/or tested since 2015, encompassing both adult and pediatric populations. Literature was searched in different databases, i.e. Embase, PubMed, Web of Science, Cochrane Register, and Google Scholar, from inception to February 2023 Expert Opinion: Many algorithms have been developed, but few have been prospectively evaluated. These performed better than bodyweight-based starting doses, regarding the time a patient is exposed to off-target tacrolimus concentrations. No benefit in reduced tacrolimus toxicity has yet been observed. Most algorithms were developed from small datasets, contained only a few tacrolimus concentrations per person, and were not externally validated. Moreover, other matrices should be considered which might better correlate with tacrolimus toxicity than the whole-blood concentration, e.g. unbound plasma or intra-lymphocytic tacrolimus concentrations.</p

Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review

BACKGROUND: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosu

Cardiac magnetic resonance findings predicting mortality in patients with pulmonary arterial hypertension: a systematic review and meta-analysis

Objectives: To provide a comprehensive overview of all reported cardiac magnetic resonance (CMR) findings that predict clinical deterioration in pulmonary arterial hypertension (PAH). Methods: MEDLINE and EMBASE electronic databases were systematically searched for longitudinal studies published by April 2015 that reported associations between CMR findings and adverse clinical outcome in PAH. Studies were appraised using previously developed criteria for prognostic studies. Meta-analysis using random effect models was performed for CMR findings investigated by three or more studies. Results: Eight papers (539 patients) investigating 21 different CMR findings were included. Meta-analysis showed that right ventricular (RV) ejection fraction was the strongest predictor of mortality in PAH (pooled HR 1.23 [95 % CI 1.07–1.41], p = 0.003) per 5 % decrease. In addition, RV end-diastolic volume index (po

Towards an eficient atomic frequency comb quantum memory

We present an efficient photon-echo experiment based on atomic frequency combs [Phys. Rev. A 79, 052329 (2009)]. Echoes containing an energy of up to 35% of that of the input pulse are observed in a Pr3+-doped Y2SiO5 crystal. This material allows for the precise spectral holeburning needed to make a sharp and highly absorbing comb structure. We compare our results with a simple theoretical model with satisfactory agreement. Our results show that atomic frequency combs has the potential for high-efficiency storage of single photons as required in future long-distance communication based on quantum repeaters.Comment: 10 pages, 5 figure