Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by ...integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth. CD11b activation promotes pro-inflammatory macrophage polarization by stimulating expression of microRNA Let7a. In contrast, inhibition of CD11b prevents Let7a expression and induces cMyc expression, leading to immune suppressive macrophage polarization, vascular maturation, and accelerated tumor growth. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy.
Suspected perioperative allergic reactions are rare but can be life-threatening. The diagnosis is difficult to make in the perioperative setting, but prompt recognition and correct treatment is ...necessary to ensure a good outcome. A group of 26 international experts in perioperative allergy (anaesthesiologists, allergists, and immunologists) contributed to a modified Delphi consensus process, which covered areas such as differential diagnosis, management during and after anaphylaxis, allergy investigations, and plans for a subsequent anaesthetic. They were asked to rank the appropriateness of statements related to the immediate management of suspected perioperative allergic reactions. Statements were selected to represent areas where there is a lack of consensus in existing guidelines, such as dosing of epinephrine and fluids, the management of impending cardiac arrest, and reactions refractory to standard treatment. The results of the modified Delphi consensus process have been included in the recommendations on the management of suspected perioperative allergic reactions. This paper provides anaesthetists with an overview of relevant knowledge on the immediate and postoperative management of suspected perioperative allergic reactions based on current literature and expert opinion. In addition, it provides practical advice and recommendations in areas where consensus has been lacking in existing guidelines.
Objectives The objective of this study was to compare the physiological determinants of ejection fraction (EF)—ventricular size, contractile function, and ventricular-arterial (VA) interaction—and ...their associations with clinical outcomes in chronic heart failure (HF). Background EF is a potent predictor of HF outcomes, but represents a complex summary measure that integrates several components including left ventricular size, contractile function, and VA coupling. The relative importance of each of these parameters in determining prognosis is unknown. Methods In 466 participants with chronic systolic HF, we derived quantitative echocardiographic measures of EF: cardiac size (end-diastolic volume EDV); contractile function (the end-systolic pressure volume relationship slope Eessb and intercept V0 ); and VA coupling (arterial elastance Ea/Eessb ). We determined the association between these parameters and the following adverse outcomes: 1) the combined endpoint of death, cardiac transplantation, or ventricular assist device (VAD) placement; and 2) cardiac hospitalization. Results Over a median follow-up of 3.4 years, there were 76 deaths, 52 transplantations, 14 VAD placements, and 684 cardiac hospitalizations. EF was independently associated with death, transplantation, and VAD placement (adjusted hazard ratio HR: 3.0; 95% confidence interval CI: 1.8 to 5.0 comparing third and first tertiles), as were EDV (HR: 2.6; 95% CI: 1.5 to 4.2); V0 (HR: 3.6; 95% CI: 2.1 to 6.1); and Ea/Eessb (HR: 2.1; 95% CI: 1.3 to 3.3). EDV, V0 , and Ea/Eessb were also associated with risk of cardiac hospitalization. Eessb was not significantly associated with any adverse outcomes in adjusted analyses. Conclusions Left ventricular size, V0 , and VA coupling are associated with prognosis in systolic HF, but end-systolic elastance (Eessb ) is not. Assessment of VA coupling via Ea/Eessb is an additional noninvasively derived metric that can be used to gauge prognosis in human HF.
Antibiotic allergies, especially penicillin, are the most frequent drug allergy listed in the medical record. Proactive evaluations of antibiotic allergies, particularly penicillin allergies, have ...been recommended by various specialty societies.
To review the history of the discovery of penicillin, implications of the penicillin allergy label, various delabeling strategies as well as a brief overview of the approach to cephalosporin, fluoroquinolone, and macrolide allergy.
Recent studies on penicillin allergy delabeling and on cephalosporin and fluoroquinolone allergies were reviewed.
Although Alexander Fleming is often solely credited with the discovery of penicillin, other scientists were critical to the development of penicillin as a life-saving antibiotic. The vast majority of patients with a penicillin allergy label are not allergic; however, this label results in increased morbidities and mortality. A variety of penicillin delabeling strategies can be used in both the outpatient and the inpatient settings. The role of direct penicillin challenge in patients at low risk is emerging and is the method of choice for children. Patients with an unconfirmed penicillin allergy have a low risk of reacting to cephalosporins. The R1 side chain largely dictates cephalosporin allergy and cross-reactivity. Drug challenge is the preferred method for evaluation of both fluoroquinolone and macrolide allergy.
Multiple effective methods are available to delabel patients of common antibiotic allergies. Delabeling patients in a proactive manner can reduce patient morbidity.
Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic ...nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone.
Penicillin allergy testing is underutilized in inpatients despite its potential to immediately impact antibiotic treatment. Although most tested patients are able to tolerate penicillin, limited ...availability and awareness of this tool leads to the use of costly and harmful substitutes.
We established an inpatient service at a large academic hospital to identify and test patients with a history of penicillin allergy with the goals of removing inaccurate diagnoses, reducing the use of beta-lactam alternatives, and educating patients and clinicians about the procedure.
Eligible inpatients were flagged daily through the electronic medical record and prioritized via a specialized algorithm. A trained clinical pharmacist performed penicillin skin tests and challenges preemptively or by provider request. Clinical characteristics and antibiotic use were analyzed in tested patients.
A total of 1203 applicable charts were detected by our system leading to 252 direct evaluations over 18 months. Overall, 228 subjects (90.5%) had their penicillin allergy removed. Of these, 223 were cleared via testing and 5 by discovery of prior penicillin tolerance. Among patients testing negative, 85 (38%) subsequently received beta-lactams, preventing 504 inpatient days and 648 outpatient days on alternative agents.
Penicillin allergy testing using a physician-pharmacist team model effectively removes reported allergies in hospitalized patients. The electronic medical record is a valuable asset for locating and stratifying individuals who benefit most from intervention. Proactive testing substantially reduces unnecessary inpatient and outpatient use of beta-lactam alternatives that may otherwise go unaddressed.
The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single ...individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Chief Editors Linda Cox, MD Department of Medicine Nova Southeastern University College of Osteopathic Medicine Davie, Florida Richard Lockey, MD Division of Allergy and Immunology Department of Internal Medicine University of South Florida College of Medicine and James A. Haley Veterans' Hospital Tampa, Florida Harold Nelson, MD Department of Medicine National Jewish Health Denver, Colorado Work Group Members Christopher Calabria, MD Glen Burnie, Maryland Thomas Chacko, MD Roswell, Georgia Ira Finegold, MD New York, New York Michael Nelson, MD, PhD Washington, DC Richard Weber, MD Denver, Colorado Joint Task Force Reviewers David Bernstein, MD Department of Medicine and Environmental Health University of Cincinnati College of Medicine Cincinnati, Ohio David A. Khan, MD Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas Joann Blessing-Moore, MD Departments of Medicine and Pediatrics Stanford University Medical Center Department of Immunology Palo Alto, California David M. Lang, MD Allergy/Immunology Section Division of Medicine Allergy and Immunology Fellowship Training Program Cleveland Clinic Foundation Cleveland, Ohio Richard A. Nicklas, MD Department of Medicine George Washington Medical Center Washington, DC John Oppenheimer, MD Department of Internal Medicine New Jersey Medical School Pulmonary and Allergy Associates Morristown, New Jersey Jay M. Portnoy, MD Section of Allergy, Asthma & Immunology The Children's Mercy Hospital Department of Pediatrics University of Missouri-Kansas City School of Medicine Kansas City, Missouri Christopher Randolph, MD Yale University New Haven, Connecticut Diane E. Schuller, MD Department of Pediatrics Pennsylvania State University Milton S. Hershey Medical College Hershey, Pennsylvania Sheldon L. Spector, MD Department of Medicine UCLA School of Medicine Los Angeles, California Stephen A. Tilles, MD Department of Medicine University of Washington School of Medicine Redmond, Washington Dana V. Wallace, MD Department of Medicine Nova Southeastern University Davie, Florida Invited Reviewers Don Aaronson, MD, JD, MPH Chicago, Illinois Desiree Larenas-Linnemann, MD Mexico city, Mexico Bryan Leatherman, MD Gulfport, Mississippi Sandra Y. Lin, MD Johns Hopkins Department of Otolaryngology-Head & Neck Surgery Baltimore, Maryland Oral and sublingual immunotherapy for food hypersensitivity Wesley Burkes, MD Duke University Raleigh, North Carolina Venom hypersensitivity David Golden, MD Baltimore, Maryland Theodore M. Freeman, MD Helotes, Texas Allergen extract section Derek Constable, PhD Spokane, Washington Robert Esch, PhD Lenoir, North Carolina Larry Garner, CPT, BA Spokane, Washington Richard Lankow, PhD Round Rock, Texas Greg Plunkett, PhD Round Rock, Texas Ronald Rabin, MD Rockville, Maryland Assigned Reviewers Paul Greenberger, MD Northwestern University Feinberg School of Medicine Chicago, Illinois Bryan Martin, DO Ohio State University Columbus, Ohio Preface This document was developed by the Joint Task Force on Practice Parameters, which represents the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology (JCAAI).
These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & ...Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing “Stinging insect hypersensitivity: a practice parameter update II.” Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or the ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. These parameters are not designed for use by pharmaceutical companies in drug promotion. The Joint Task Force understands that the cost of diagnostic tests and therapeutic agents is an important concern that may appropriately influence the work-up and treatment chosen for a given patient. The Joint Task Force recognizes that the emphasis of our primary recommendations regarding a medication may vary, for example, depending on third party payer issues and product patent expiration dates. However, since a given test or agent's cost is so widely variable, and there is a paucity of pharmacoeconomic data, the Joint Task Force generally does not consider cost when formulating Practice Parameter recommendations. In extraordinary circumstances, when the cost benefit of an intervention is prohibitive as supported by pharmacoeconomic data, commentary may be provided.
Typical differential single-nucleus gene expression (snRNA-seq) analyses in Alzheimer's disease (AD) provide fixed snapshots of cellular alterations, making the accurate detection of temporal cell ...changes challenging. To characterize the dynamic cellular and transcriptomic differences in AD neuropathology, we apply the novel concept of RNA velocity to the study of single-nucleus RNA from the cortex of 60 subjects with varied levels of AD pathology. RNA velocity captures the rate of change of gene expression by comparing intronic and exonic sequence counts. We performed differential analyses to find the significant genes driving both cell type-specific RNA velocity and expression differences in AD, extensively compared these two transcriptomic metrics, and clarified their associations with multiple neuropathologic traits. The results were cross-validated in an independent dataset. Comparison of AD pathology-associated RNA velocity with parallel gene expression differences reveals sets of genes and molecular pathways that underlie the dynamic and static regimes of cell type-specific dysregulations underlying the disease. Differential RNA velocity and its linked progressive neuropathology point to significant dysregulations in synaptic organization and cell development across cell types. Notably, most of the genes underlying this synaptic dysregulation showed increased RNA velocity in AD subjects compared to controls. Accelerated cell changes were also observed in the AD subjects, suggesting that the precocious depletion of precursor cell pools might be associated with neurodegeneration. Overall, this study uncovers active molecular drivers of the spatiotemporal alterations in AD and offers novel insights towards gene- and cell-centric therapeutic strategies accounting for dynamic cell perturbations and synaptic disruptions.
Deep learning has achieved remarkable success in diverse applications; however, its use in solving partial differential equations (PDEs) has emerged only recently. Here, we present a feasibility ...study of applying physics-informed deep learning methods for solving PDEs related to the physical laws of electromagnetics. The methodology uses automatic differentiation, and the loss function is formulated based on the underlying PDE and boundary conditions. The feasibility of the method is shown using three electromagnetic problems of varying complexity and the results show close agreement with the ground truth from a finite-element analysis solver. The application of transfer learning is also explored and results in faster training. Furthermore, a hybrid approach involving physics-based governing equations and labeled data is also introduced to improve the accuracy of the results.
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