Improved Appropriateness of Advanced Diagnostic Imaging After Implementation of Clinical Decision Support Mechanism.

The Protecting Access to Medicare Act (PAMA) mandates clinical decision support mechanism (CDSM) consultation for all advanced imaging. There are a growing number of studies examining the association of CDSM use with imaging appropriateness, but a paucity of multicenter data. This observational study evaluates the association between changes in advanced imaging appropriateness scores with increasing provider exposure to CDSM. Each provider's first 200 consecutive anonymized requisitions for advanced imaging (CT, MRI, ultrasound, nuclear medicine) using a single CDSM (CareSelect, Change Healthcare) between January 1, 2017 and December 31, 2019 were collected from 288 US institutions. Changes in imaging requisition proportions among four appropriateness categories ("usually appropriate" [green], "may be appropriate" [yellow], "usually not appropriate" [red], and unmapped [gray]) were evaluated in relation to the chronological order of the requisition for each provider and total provider exposure to CDSM using logistic regression fits and Wald tests. The number of providers and requisitions included was 244,158 and 7,345,437, respectively. For 10,123 providers with ≥ 200 requisitions (2,024,600 total requisitions), the fraction of green, yellow, and red requisitions among the last 10 requisitions changed by +3.0% (95% confidence interval +2.6% to +3.4%), -0.8% (95% CI -0.5% to -1.1%), and -3.0% (95% CI 3.3% to -2.7%) in comparison with the first 10, respectively. Providers with > 190 requisitions had 8.5% (95% CI 6.3% to 10.7%) more green requisitions, 2.3% (0.7% to 3.9%) fewer yellow requisitions, and 0.5% (95% CI -1.0% to 2.0%) fewer red (not statistically significant) requisitions relative to providers with ≤ 10 requisitions. Increasing provider exposure to CDSM is associated with improved appropriateness scores for advanced imaging requisitions.

Expression of Siglec-11 by human and chimpanzee ovarian stromal cells, with uniquely human ligands: implications for human ovarian physiology and pathology.

Siglecs (Sialic acid-binding Immunoglobulin Superfamily Lectins) are cell surface signaling receptors of the I-type lectin group that recognize sialic acid-bearing glycans. CD33-related-Siglecs are a subset with expression primarily in cells of hematopoietic origin and functional relevance to immune reactions. Earlier we reported a human-specific gene conversion event that markedly changed the coding region for the extracellular domain of Siglec-11, associated with human-specific expression in microglia (Hayakawa T, Angata T, Lewis AL, Mikkelsen TS, Varki NM, Varki A. 2005. A human-specific gene in microglia. Science. 309:1693). Analyzing human gene microarrays to define new patterns of expression, we observed high levels of SIGLEC11 transcript in the ovary and adrenal cortex. Thus, we examined human and chimpanzee tissues using a well-characterized anti-Siglec-11 mouse monoclonal antibody. Although adrenal expression was variable and confined to infiltrating macrophages in capillaries, ovarian expression of Siglec-11 in both humans and chimpanzees was on fibroblasts, the first example of Siglec expression on mesenchyme-derived stromal cells. Cytokines from such ovarian stromal fibroblasts play important roles in follicle development and ovulation. Stable transfection of SIGLEC11 into a primary human ovarian stromal fibroblast cell line altered the secretion of growth-regulated oncogene α, interleukin (IL)-10, IL-7, transforming growth factor ß1 and tumor necrosis factor-α, cytokines involved in ovarian physiology. Probing for Siglec-11 ligands revealed distinct and strong mast cell expression in human ovaries, contrasting to diffuse stromal ligands in chimpanzee ovaries. Interestingly, there was a trend of increased Siglec-11 expression in post-menopausal ovaries compared with pre-menopausal ones. Siglec-11 expression was also found on human ovarian stromal tumors and in polycystic ovarian syndrome, a human-specific disease. These results indicate potential roles for Siglec-11 in ovarian physiology and human evolution.

Calcineurin inhibitor-free CD28 blockade-based protocol protects allogeneic islets in nonhuman primates.

Recent success using a steroid-free immunosuppressive regimen has renewed enthusiasm for the use of islet transplantation to treat diabetes. Toxicities associated with the continued use of a calcineurin inhibitor may limit the wide-spread application of this therapy. Biological agents that block key T-cell costimulatory signals, in particular the CD28 pathway, have demonstrated extraordinary promise in animal models. LEA29Y (BMS-224818), a mutant CTLA4-Ig molecule with increased binding activity, was evaluated for its potential to replace tacrolimus and protect allogeneic islets in a preclinical primate model. Animals received either the base immunosuppression regimen (rapamycin and anti-IL-2R monoclonal antibody [mAb]) or the base immunosuppression and LEA29Y. Animals receiving the LEA29Y/rapamycin/anti-IL-2R regimen (n = 5) had significantly prolonged islet allograft survival (204, 190, 216, 56, and >220 days). In contrast, those animals receiving the base regimen alone (n = 2) quickly rejected the transplanted islets at 1 week (both at 7 days). The LEA29Y-based regimen prevented the priming of anti-donor T- and B-cell responses, as detected by interferon-gamma enzyme-linked immunospot and allo-antibody production, respectively. The results of this study suggest that LEA29Y is a potent immunosuppressant that can effectively prevent rejection in a steroid-free immunosuppressive protocol and produce marked prolongation of islet allograft survival in a preclinical model.

Statistical effects in the multistream model for quantum plasmas.

A statistical multistream description of quantum plasmas is formulated, using the Wigner-Poisson system as dynamical equations. A linear stability analysis of this system is carried out, and it is shown that a Landau-like damping of plane wave perturbations occurs due to the broadening of the background Wigner function that arises as a consequence of statistical variations of the wave function phase. The Landau-like damping is shown to suppress instabilities of the one- and two-stream type.

Nonlocal effects in high-energy charged-particle beams.

Within the framework of the thermal wave model, an investigation is made of the longitudinal dynamics of high-energy charged-particle beams. The model includes the nonlinear self-consistent interaction between the beam and its surroundings in terms of a coupling impedance, and when resistive as well as reactive parts are included, the evolution equation becomes a generalized nonlinear Schrödinger equation including a nonlocal nonlinear term. The consequences of the resistive part on the propagation of particle bunches are examined using analytical as well as numerical methods.

Case study: two fatal case reports of acute yohimbine intoxication.

Yohimbine is an alkaloid that has been encountered on the streets as an aphrodisiac, hallucinogen, dietary supplement and erectile dysfunction drug. Yohimbine hydrochloride is an alpha 2-adrenoreceptor antagonist, blocking the pre- and postsynaptic alpha-2 adrenoreceptors and causing an increased release of noradrenaline and dopamine. An average oral dose of 5-15 mg produces a therapeutic whole blood level range of 40-400 ng/mL. Overdoses leading to neurotoxic effects have been seen with blood concentrations up to 5,000 ng/mL. The laboratories from the Maricopa County Medical Examiner and the Los Angeles County Department of Coroner each encountered a case in which yohimbine was identified in whole blood by means of a liquid-liquid basic drug extraction with detection on a GC-MS. Because validated quantitative methods for yohimbine did not exist at either facility, both agencies referred the blood specimens to NMS Labs, Inc. The reference laboratory analyzed the blood specimens with an LC-MS-MS and determined the quantitative values of yohimbine to be 7,400 and 5,400 ng/mL. Given the absence of other significant positive findings and the substantial yohimbine blood concentrations cited, the respective Medical Examiners determined the cause of death to be acute yohimbine intoxication with the mode being an accident. Yohimbine is a rarely encountered drug in medical examiner casework, and interpretation of the results is difficult to assess toward the cause and manner of death without such case studies being described.

Asenapine (Saphris®): GC-MS method validation and the postmortem distribution of a new atypical antipsychotic medication.

Asenapine (Saphris®) is an atypical antipsychotic approved in the USA in 2009 for the treatment of schizophrenia and bipolar disorder. The Los Angeles County Department of Coroner Toxicology Laboratory developed an analytical method for the detection and quantitation of asenapine by gas chromatography-mass spectroscopy in multiple specimens of postmortem casework. Asenapine was isolated from specimens through a basic, liquid-liquid extraction procedure and quantitated utilizing D5-fentanyl as an internal standard. Method validation for asenapine was conducted utilizing the Scientific Working Group Toxicology (SWGTOX) method validation draft proposal and the tissue distribution of four case studies was determined. The authors believe that these are the first cases to be reported in the literature and are intended to assist other forensic toxicologists with interpreting their casework.

Retinal safety of near-infrared lasers in cataract surgery.

Femtosecond lasers have added unprecedented precision and reproducibility to cataract surgery. However, retinal safety limits for the near-infrared lasers employed in surgery are not well quantified. We determined retinal injury thresholds for scanning patterns while considering the effects of reduced blood perfusion from rising intraocular pressure and retinal protection from light scattering on bubbles and tissue fragments produced by laser cutting. We measured retinal damage thresholds of a stationary, 1030-nm, continuous-wave laser with 2.6-mm retinal spot size for 10- and 100-s exposures in rabbits to be 1.35 W (1.26 to 1.42) and 0.78 W (0.73 to 0.83), respectively, and 1.08 W (0.96 to 1.11) and 0.36 W (0.33 to 0.41) when retinal perfusion is blocked. These thresholds were input into a computational model of ocular heating to calculate damage threshold temperatures. By requiring the tissue temperature to remain below the damage threshold temperatures determined in stationary beam experiments, one can calculate conservative damage thresholds for cataract surgery patterns. Light scattering on microbubbles and tissue fragments decreased the transmitted power by 88% within a 12 deg angle, adding a significant margin for retinal safety. These results can be used for assessment of the maximum permissible exposure during laser cataract surgery under various assumptions of blood perfusion, treatment duration, and scanning patterns.

The 2011 nuclear medicine technology job analysis project of the American Registry of Radiologic Technologists.

The American Registry of Radiologic Technologists (ARRT) conducts periodic job analysis projects to update the content and eligibility requirements for all certification examinations. In 2009, the ARRT conducted a comprehensive job analysis project to update the content specifications and clinical competency requirements for the nuclear medicine technology examination. ARRT staff and a committee of volunteer nuclear medicine technologists designed a job analysis survey that was sent to a random sample of 1,000 entry-level staff nuclear medicine technologists. Through analysis of the survey data and judgments of the committee, the project resulted in changes to the nuclear medicine technology examination task list, content specifications, and clinical competency requirements. The primary changes inspired by the project were the introduction of CT content to the examination and the expansion of the content covering cardiac procedures.

Heart disease is common in humans and chimpanzees, but is caused by different pathological processes.

Heart disease is common in both humans and chimpanzees, manifesting typically as sudden cardiac arrest or progressive heart failure. Surprisingly, although chimpanzees are our closest evolutionary relatives, the major cause of heart disease is different in the two species. Histopathology data of affected chimpanzee hearts from two primate centers, and analysis of literature indicate that sudden death in chimpanzees (and in gorillas and orangutans) is commonly associated with diffuse interstitial myocardial fibrosis of unknown cause. In contrast, most human heart disease results from coronary artery atherosclerosis, which occludes myocardial blood supply, causing ischemic damage. The typical myocardial infarction of humans due to coronary artery thrombosis is rare in these apes, despite their human-like coronary-risk-prone blood lipid profiles. Instead, chimpanzee 'heart attacks' are likely due to arrythmias triggered by myocardial fibrosis. Why do humans not often suffer from the fibrotic heart disease so common in our closest evolutionary cousins? Conversely, why do chimpanzees not have the kind of heart disease so common in humans? The answers could be of value to medical care, as well as to understanding human evolution. A preliminary attempt is made to explore possibilities at the histological level, with a focus on glycosylation changes.

Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.

Current success in organ transplantation is dependent upon the use of calcineurin-inhibitor-based immunosuppressive regimens. Unfortunately, current immunotherapy targets molecules with ubiquitous expression resulting in devastating non-immune side effects. T-cell costimulation has been identified as a new potential immunosuppressive target. The best characterized pathway includes CD28, its homologue CTLA4 and their ligands CD80 and CD86. While an immunoglobulin fusion protein construct of CTLA4 suppressed rejection in rodents, it lacked efficacy in primate transplant models. In an attempt to increase the biologic potency of the parent molecule a novel, modified version of CTLA4-Ig, LEA29Y (belatacept), was constructed. Two amino acid substitutions (L104E and A29Y) gave rise to slower dissociation rates for both CD86 and CD80. The increased avidity resulted in a 10-fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre-clinical primate model. The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants.

Human-specific regulation of alpha 2-6-linked sialic acids.

Many microbial pathogens and toxins recognize animal cells via cell surface sialic acids (Sias) that are alpha 2-3- or alpha 2-8-linked to the underlying glycan chain. Human influenza A/B viruses are unusual in preferring alpha 2-6-linked Sias, undergoing a switch from alpha 2-3 linkage preference during adaptation from animals to humans. This correlates with the expression of alpha 2-6-linked Sias on ciliated human airway epithelial target cells and of alpha 2-3-linked Sias on secreted soluble airway mucins, which are unable to inhibit virus binding. Given several known differences in Sia biology between humans and apes, we asked whether this pattern of airway epithelial Sia linkages is also human-specific. Indeed, we show that since the last common ancestor with apes, humans underwent a concerted bidirectional switch in alpha 2-6-linked Sia expression between airway epithelial cell surfaces and secreted mucins. This can explain why the chimpanzee appears relatively resistant to experimental infection with human Influenza viruses. Other tissues showed additional examples of human-specific increases or decreases in alpha 2-6-linked Sia expression and only one example of a change specific to certain great apes. Furthermore, while human and great ape leukocytes both express alpha 2-6-linked Sias, only human erythrocytes have markedly up-regulated expression. These cell type-specific changes in alpha 2-6-Sia expression during human evolution represent another example of a human-specific change in Sia biology. Because the data set involves multiple great apes, we can also conclude that Sia linkage expression patterns can be conserved during millions of years of evolution within some vertebrate taxa while undergoing sudden major changes in other closely related ones.