High performance implementation of the hierarchical likelihood for generalized linear mixed models: an application to estimate the potassium reference range in massive electronic health records datasets.

Background: Converting electronic health record (EHR) entries to useful clinical inferences requires one to address the poor scalability of existing implementations of Generalized Linear Mixed Models (GLMM) for repeated measures. The major computational bottleneck concerns the numerical evaluation of multivariable integrals, which even for the simplest EHR analyses may involve millions of dimensions (one for each patient). The hierarchical likelihood (h-lik) approach to GLMMs is a methodologically rigorous framework for the estimation of GLMMs that is based on the Laplace Approximation (LA), which replaces integration with numerical optimization, and thus scales very well with dimensionality.

Richter's transformation as leptomeningeal infiltration in a chronic lymphocytic leukemia patient receiving venetoclax. Could blood-brain barrier be a disease "sanctuary" during venetoclax treatment?

Our unique case of Richter's Transformation presenting as leptomeningial infiltration in a CLL patient receiving venetoclax raises questions on whether the drug penetrates the blood-brain barrier and at what extend, especially in reduced doses given for drug-drug interactions.

Erdheim-Chester Disease and Acute Myeloid Leukemia with Mutated in a Patient with Clonal Hematopoiesis: A Case Report.

Background: Erdheim-Chester Disease (ECD) is a clonal non-Langerhans histiocytosis, classified as a macrophage-dendritic cell neoplasm in the 2016 WHO classification. The exact cell of origin of ECD is unknown, although some limited evidence suggests that it arises from myeloid progenitors.

Case Presentation: A 43-year-old patient, diagnosed with mutated ECD, developed acute myeloid leukemia (AML) with wild-type , 15 months after the initial ECD diagnosis.

Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL.

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets.

B-cell oligoclonal expansions in renal tissue of patients with immune-mediated glomerular disease.

B-cell clonal expansion has been sporadically described in the blood and/or renal tissue of patients with glomerulonephritides, albeit with unclear pathogenetic role. Herein, using spectratyping analysis, we observed oligoclonal intrarenal B-cell populations in 59% of glomerulonephritis patients with podocyte injury (6/7 with focal segmental glomerulosclerosis, 1/3 minimal change disease, 1/3 idiopathic membranous nephropathy, 3/4 IgA nephropathy, 2/5 membranous lupus nephritis), 20% of glomerulonephritis patients without podocyte involvement (4/13 with mesangial or proliferative lupus nephritis, 0/3 idiopathic membranoproliferative glomerulonephritis, 0/4 pauci-immune vasculitis) and 17% of control patients with renal cancer. In multivariate analysis, oligoclonal B-cells were associated with podocyte injury and the grade of glomerulosclerosis (both p = .

Bone marrow PARP1 mRNA levels predict response to treatment with 5-azacytidine in patients with myelodysplastic syndrome.

Poly (ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that participates in the DNA repair of malignant cells, with various consequences on their survival. We have recently shown that PARP1 mRNA levels in the bone marrow of patients with myelodysplastic syndrome (MDS) are correlated to prognosis. To evaluate PARP1 as a biomarker of response to 5-azacytidine in patients with MDS, we measured PARP1 mRNA levels by a quantitative real-time PCR in diagnostic bone marrow samples of 77 patients with MDS treated with 5-azacytidine.

Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations.

The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e.

Detection of L265P MYD-88 mutation in a series of clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ).

Clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ) is a recently described entity characterized by the presence of clonal B cells in the blood and/or bone marrow (BM) with morphologic and immunophenotypic features consistent with marginal zone derivation in otherwise healthy individuals. CBL-MZ is commonly associated with paraproteinemia, usually immunoglobulin M (IgM), raising diagnostic difficulties from Waldenstrom macroglobulinemia (WM). The aim of the present study was to determine the presence of MYD-88 L265P mutation in a well-characterized series of CBL-MZ to identify cases that may in fact represent WM.

Revisiting the Middle Molecule Hypothesis of Uremic Toxicity: A Systematic Review of Beta 2 Microglobulin Population Kinetics and Large Scale Modeling of Hemodialysis Trials In Silico.

Background: Beta-2 Microglobulin (β2M) is a prototypical "middle molecule" uremic toxin that has been associated with a higher risk of death in hemodialysis patients. A quantitative description of the relative importance of factors determining β2M concentrations among patients with impaired kidney function is currently lacking.

Methods: Herein we undertook a systematic review of existing studies reporting patient level data concerning generation, elimination and distribution of β2M in order to develop a population model of β2M kinetics.

Expression, prognostic significance and mutational analysis of protein tyrosine phosphatase SHP-1 in chronic myeloid leukemia.

The protein tyrosine phosphatase SHP-1 dephosphorylates BCR-ABL1, thereby serving as a potential control mechanism of BCR-ABL1 kinase activity. Pathways regulating SHP-1 expression, which could be exploited in the therapeutics of TKI-resistant chronic myeloid leukemia (CML), remain unknown. Moreover, the questions of whether there is any kind of SHP-1 deregulation in CML, contributing to disease initiation or evolution, as well as the question of prognostic significance of SHP-1, have not been definitively answered.

Clonotypic analysis of immunoglobulin heavy chain sequences in patients with Waldenström's macroglobulinemia: correlation with MYD88 L265P somatic mutation status, clinical features, and outcome.

We performed IGH clonotypic sequence analysis in WM in order to determine whether a preferential IGH gene rearrangement was observed and to assess IGHV mutational status in blood and/or bone marrow samples from 36 WM patients. In addition we investigated the presence of MYD88 L265P somatic mutation. After IGH VDJ locus amplification, monoclonal VDJ rearranged fragments were sequenced and analyzed.

Relative validity of a semiquantitative food frequency questionnaire designed for schoolchildren in western Greece.

Background: The use of food frequency questionnaires (FFQs) has become increasingly important in epidemiologic studies. During the past few decades, a wide variety of nutritional studies have used the semiquantitative FFQ as a tool for assessing and evaluating dietary intake. One of the main concerns in a dietary analysis is the validity of the collected dietary data.