Factors influencing transfusion-associated HLA sensitization in patients bridged to heart transplantation using ventricular assist device.

BackgroundBridging heart failure patients with mechanical ventricular assist devices (VAD) enables access to transplantation. However, VAD is associated with increased risk for anti-HLA antibodies associated with rejection of subsequent allografts. Factors determining alloantibody formation in these patients remain undefined.MethodsWe performed a single-center retrospective cohort study of 164 patients undergoing heart transplantation from 2014 to 2017. Medical records including use of VAD, transfused blood products, anti-HLA antibody testing, crossmatch, and time to transplant were evaluated.ResultsPatients received an average of 13.8 red blood cell and 1.9 single-donor platelet units associated with VAD. There was a 28.7% increase in the incidence of anti-HLA antibodies after VAD. Development of anti-HLA antibodies did not correlate with volume or type of blood products, but with pre-VAD HLA sensitization status; relative risk of new alloantibodies in patients with pre-VAD antibodies was 3.5-fold higher than those without prior antibodies (P = .008). Development of new anti-HLA antibodies was associated with an increased time to transplant (169 vs 330 days, P = .013).ConclusionsOur findings indicate that the presence of anti-HLA antibodies pre-VAD was the most significant risk factor for developing additional antibodies post-VAD, suggesting that a subset of patients may be predisposed to alloantibody formation

CD4+ lymphocyte adenosine triphosphate determination in sepsis: a cohort study

INTRODUCTION: Patients suffering from sepsis are currently classified on a clinical basis (i.e., sepsis, severe sepsis, septic shock); however, this clinical classification may not accurately reflect the overall immune status of an individual patient. Our objective was to describe a cohort of patients with sepsis in terms of their measured immune status. METHODS: Fifty-two patients with sepsis (n = 13), severe sepsis (n = 21), or septic shock (n = 18) were studied. The immune status was determined by measuring the CD4+ lymphocyte adenosine triphosphate (ATP) content after mitogen stimulation in whole blood. RESULTS: The measured CD4+ lymphocyte ATP content at the time of ICU admission did not differ among the various groups defined by the sepsis classification system (sepsis = 454 ± 79 ng/ml; severe sepsis = 359 ± 54 ng/ml; septic shock = 371 ± 53 ng/ml; P = 0.44). Furthermore, survivors of sepsis had a significantly higher CD4+ lymphocyte ATP content at the time of ICU admission than did nonsurvivors of sepsis (431 ± 41 ng/mL vs. 266 ± 53 ng/mL, respectively; P = 0.04). CONCLUSIONS: The sepsis classification system that is currently used is not representative of the individual immune status as determined by measuring the CD4+ lymphocyte ATP content. Moreover, a lower CD4+ ATP content at the time of ICU admission is associated with a worse clinical outcome in those suffering from sepsis

New evidence for a massive black hole at the centre of the quiescent galaxy M32

Massive black holes are thought to reside at the centres of many galaxies, where they power quasars and active galactic nuclei. But most galaxies are quiescent, indicating that any central massive black hole present will be starved of fuel and therefore detectable only through its gravitational influence on the motions of the surrounding stars. M32 is a nearby, quiescent elliptical galaxy in which the presence of a black hole has been suspected; however, the limited resolution of the observational data and the restricted classes of models used to interpret this data have made it difficult to rule out alternative explanations, such as models with an anisotropic stellar velocity distribution and no dark mass or models with a central concentration of dark objects (for example, stellar remnants or brown dwarfs). Here we present high-resolution optical HST spectra of M32, which show that the stellar velocities near the centre of this galaxy exceed those inferred from previous ground-based observations. We use a range of general dynamical models to determine a central dark mass concentration of (3.4 +/- 1.6) x 10^6 solar masses, contained within a region only 0.3 pc across. This leaves a massive black hole as the most plausible explanation of the data, thereby strengthening the view that such black holes exist even in quiescent galaxies.Comment: 8 pages, LaTeX, 3 figures; mpeg animation of the stellar motions in M32 available at http://oposite.stsci.edu/pubinfo/Anim.htm

The insulin A-chain epitope recognized by human T cells is posttranslationally modified

The autoimmune process that destroys the insulin-producing pancreatic β cells in type 1 diabetes (T1D) is targeted at insulin and its precursor, proinsulin. T cells that recognize the proximal A-chain of human insulin were identified recently in the pancreatic lymph nodes of subjects who had T1D. To investigate the specificity of proinsulin-specific T cells in T1D, we isolated human CD4+ T cell clones to proinsulin from the blood of a donor who had T1D. The clones recognized a naturally processed, HLA DR4–restricted epitope within the first 13 amino acids of the A-chain (A1–13) of human insulin. T cell recognition was dependent on the formation of a vicinal disulfide bond between adjacent cysteine residues at A6 and A7, which did not alter binding of the peptide to HLA DR4. CD4+ T cell clones that recognized this epitope were isolated from an HLA DR4+ child with autoantibodies to insulin, and therefore, at risk for T1D, but not from two healthy HLA DR4+ donors. We define for the first time a novel posttranslational modification that is required for T cell recognition of the insulin A-chain in T1D

Influence of the magnetic sublattices in the double perovskite LaCaNiReO6

The magnetism of double perovskites is a complex phenomenon, determined from intra- or interatomic magnetic moment interactions, and strongly influenced by geometry. We take advantage of the complementary length and timescales of the muon spin rotation, relaxation, and resonance (μ+SR) microscopic technique and bulk ac/dc magnetic susceptibility measurements to study the magnetic phases of the LaCaNiReO6 double perovskite. As a result, we are able to discern and report ferrimagnetic ordering below TC=102K and the formation of different magnetic domains above TC. Between TC<T<270K, the following two magnetic environments appear, a dense spin region and a static-dilute spin region. The paramagnetic state is obtained only above T>270K. An evolution of the interaction between Ni and Re magnetic sublattices, in this geometrically frustrated fcc perovskite structure, is revealed as a function of temperature through the critical behavior and thermal evolution of microscopic and macroscopic physical quantities

Standardized Urine-Based Tuberculosis (TB) Screening With TB-Lipoarabinomannan and Xpert MTB/RIF Ultra in Ugandan Adults With Advanced Human Immunodeficiency Virus Disease and Suspected Meningitis.

BACKGROUND: Diagnosis of extrapulmonary tuberculosis (TB) remains challenging. We sought to determine the prevalence of disseminated TB by testing urine with TB-lipoarabinomannan (TB-LAM) lateral flow assay and Xpert MTB/RIF Ultra (Ultra) in hospitalized adults. METHODS: We prospectively enrolled human immunodeficiency virus (HIV)-positive adults with suspected meningitis in Uganda during 2018-2020. Participants underwent standardized urine-based TB screening. Urine (60 mcL) was tested with TB-LAM (Alere), and remaining urine was centrifuged with the cell pellet resuspended in 2 mL of urine for Xpert Ultra testing. RESULTS: We enrolled 348 HIV-positive inpatients with median CD4 of 37 cells/mcL (interquartile range, 13-102 cells/mcL). Overall, 26% (90 of 348; 95% confidence interval [CI], 21%-30%) had evidence of disseminated TB by either urine assay. Of 243 participants with both urine TB-LAM and Ultra results, 20% (48 of 243) were TB-LAM-positive, 12% (29 of 243) were Ultra-positive, and 6% (14 of 243) were positive by both assays. In definite and probable TB meningitis, 37% (14 of 38) were TB-LAM-positive and 41% (15 of 37) were Ultra-positive. In cryptococcal meningitis, 22% (40 of 183) were TB-LAM-positive and 4.4% (6 of 135) were Ultra-positive. Mortality trended higher in those with evidence of disseminated TB by either assay (odds ratio = 1.44; 95% CI, 0.83-2.49; P = .19) and was 6-fold higher in those with definite TB meningitis who were urine Ultra-positive (odds ratio = 5.67; 95% CI, 1.13-28.5; P = .04). CONCLUSIONS: In hospitalized Ugandans with advanced HIV disease and suspected meningitis, systematic screening with urine TB-LAM and Ultra found a high prevalence of urine TB test positivity (26%). In those with TB meningitis, urine tests were positive in over one third. There was little concordance between Ultra and TB-LAM, which warrants further investigation

A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways; (ii) the concentrations in the tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, it is deduced that measured end-tidal breath concentrations of acetone determined during resting conditions and free breathing will be rather poor indicators for endogenous levels. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases.Comment: 38 page

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

PERT: A Method for Expression Deconvolution of Human Blood Samples from Varied Microenvironmental and Developmental Conditions

The cellular composition of heterogeneous samples can be predicted using an expression deconvolution algorithm to decompose their gene expression profiles based on pre-defined, reference gene expression profiles of the constituent populations in these samples. However, the expression profiles of the actual constituent populations are often perturbed from those of the reference profiles due to gene expression changes in cells associated with microenvironmental or developmental effects. Existing deconvolution algorithms do not account for these changes and give incorrect results when benchmarked against those measured by well-established flow cytometry, even after batch correction was applied. We introduce PERT, a new probabilistic expression deconvolution method that detects and accounts for a shared, multiplicative perturbation in the reference profiles when performing expression deconvolution. We applied PERT and three other state-of-the-art expression deconvolution methods to predict cell frequencies within heterogeneous human blood samples that were collected under several conditions (uncultured mono-nucleated and lineage-depleted cells, and culture-derived lineage-depleted cells). Only PERT's predicted proportions of the constituent populations matched those assigned by flow cytometry. Genes associated with cell cycle processes were highly enriched among those with the largest predicted expression changes between the cultured and uncultured conditions. We anticipate that PERT will be widely applicable to expression deconvolution strategies that use profiles from reference populations that vary from the corresponding constituent populations in cellular state but not cellular phenotypic identity