Resolution of null fiber and conormal bundles on the Lagrangian Grassmannian

We study the null fiber of a moment map related to dual pairs. We construct an equivariant resolution of singularities of the null fiber, and get conormal bundles of closed $K_C$-orbits in the Lagrangian Grassmannian as the categorical quotient. The conormal bundles thus obtained turn out to be a resolution of singularities of the closure of nilpotent $K_C$-orbits, which is a "quotient" of the resolution of the null fiber.Comment: 17 pages; completely revised and add reference

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

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

Clinical validation of Anyplex? II HPV HR Detection according to the guidelines for HPV test requirements for cervical cancer screening.

BACKGROUND: Anyplex? II HPV HR Detection (Seegene, Seoul, Korea) is a multiplex real-time PCR using tagging oligonucleotide cleavage and extension (TOCE) technology for simultaneous detection and genotyping of 14 high-risk (HR) HPV types, including HPV16 and HPV18. OBJECTIVES: To evaluate whether the clinical performance and reproducibility of Anyplex? II HPV HR Detection meet the international consensus guidelines for HPV test requirements for cervical cancer screening [1]. STUDY DESIGN: The clinical performance of Anyplex? II HPV HR Detection for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was determined relative to that of the reference assay, i.e., HR HPV GP5+/6+-PCR-EIA, by analysis of a total of 879 cervical liquid based cytology (LBC) specimens from a screening population, of which 60 were from women with CIN2+. The intra-laboratory reproducibility and inter-laboratory agreement were determined on 509 LBC samples, of which 172 were positive by the reference assay. RESULTS: Anyplex? II HPV HR Detection showed a clinical sensitivity for CIN2+ of 98.3% (59/60; 95% CI: 89.1-99.8) and a clinical specificity for CIN2+ of 93.6% (764/816; 95% CI: 89.8-96.1). The clinical sensitivity and specificity were non-inferior to those of HR HPV GP5+/6+-PCR-EIA (non-inferiority score test: P=0.005 and P=0.023, respectively). Both intra-laboratory reproducibility (96.8%; 95% CI: 95.3-98.1; kappa value of 0.93) and inter-laboratory agreement (96.0%; 95% CI: 94.3-97.4; kappa value of 0.91) were high. CONCLUSIONS: Anyplex? II HPV HR Detection performs clinically non-inferior to HR HPV GP5+/6+-PCR-EIA. Anyplex? II HPV HR Detection complies with international consensus validation metrics for HPV DNA tests for cervical cancer screening [1]

Aberrant phenotype of circulating antigen presenting cells in giant cell arteritis and polymyalgia rheumatica

BACKGROUND: Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR) are overlapping inflammatory diseases. Antigen-presenting cells (APCs), including monocytes and dendritic cells (DCs), are main contributors to the immunopathology of GCA and PMR. However, little is known about APC phenotypes in the peripheral blood at the time of GCA/PMR diagnosis.METHODS: APCs among peripheral blood mononuclear cells (PBMCs) of treatment-naive GCA and PMR patients were compared to those in age- and sex-matched healthy controls (HCs) using flow cytometry (n=15 in each group). We identified three monocyte subsets, and three DC subsets: plasmacytoid DCs (pDCs), CD141+ conventional DCs (cDC1) and CD1c+ conventional DCs (cDC2). Each of these subsets was analyzed for expression of pattern recognition receptors (TLR2, TLR4), immune checkpoints (CD86, PDL1, CD40) and activation markers (HLA-DR, CD11c).RESULTS: t-SNE plots revealed a differential clustering of APCs between GCA/PMR and HCs. Further analyses showed shifts in monocyte subsets and a lower proportion of the small population of cDC1 cells in GCA/PMR, whereas cDC2 proportions correlated negatively with CRP (r=-0.52). Classical monocytes of GCA/PMR patients show reduced expression of TLR2, HLA-DR, CD11c, which was in contrast to non-classical monocytes that showed higher marker expression. Additionally, single cell RNA sequencing in GCA patients identified a number of differentially expressed genes related to inflammation and metabolism in APCs.CONCLUSION: Circulating non-classical monocytes display an activated phenotype in GCA/PMR patients at diagnosis, whereas classical monocytes show reduced expression of activation markers. Whether these findings reflect APC migration patterns or the effects of long-term inflammation remains to be investigated.</p

Crystal Graphs and qq-Analogues of Weight Multiplicities for the Root System AnA_n

We give an expression of the $q$-analogues of the multiplicities of weights in irreducible \sl_{n+1}-modules in terms of the geometry of the crystal graph attached to the corresponding U_q(\sl_{n+1})-modules. As an application, we describe multivariate polynomial analogues of the multiplicities of the zero weight, refining Kostant's generalized exponents.Comment: LaTeX file with epic, eepic pictures, 17 pages, November 1994, to appear in Lett. Math. Phy