Old dog begging for new tricks: current practices and future directions in the diagnosis of delayed antimicrobial hypersensitivity

Purpose of review: Antimicrobials are a leading cause of severe T cell-mediated adverse drug reactions (ADRs). The purpose of this review is to address the current understanding of antimicrobial cross-reactivity and the ready availability of and evidence for in-vitro, in-vivo, and ex-vivo diagnostics for T cell-mediated ADRs. Recent findings: Recent literature has evaluated the efficacy of traditional antibiotic allergy management, including patch testing, skin prick testing, intradermal testing, and oral challenge. Although patch and intradermal testing are specific for the diagnosis of immune-mediated ADRs, they suffer from drug-specific limitations in sensitivity. The use of ex-vivo diagnostics, especially enzyme-linked immunospot, has been highlighted as a promising new approach to assigning causality. Knowledge of true rates of antimicrobial cross-reactivity aids empirical antibiotic choice in the setting of previous immune-mediated ADRs. Summary: In an era of increasing antimicrobial resistance and use of broad-spectrum antimicrobial therapy, ensuring patients are assigned the correct ‘allergy label’ is essential. Re-exposure to implicated antimicrobials, especially in the setting of severe adverse cutaneous reaction, is associated with significant morbidity and mortality. The process through which an antibiotic label gets assigned, acted on and maintained is still imprecise. Predicting T cell-mediated ADRs via personalized approaches, including human leukocyte antigen-typing, may pave future pathways to safer antimicrobial prescribing guidelines

HLAs: Key regulators of T-cell-mediated drug hypersensitivity

Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose-dependent. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug's interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast, off-target ADRs, including immune-mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B-cell-mediated (Gell-Coombs type I-III reactions) and T-cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life-threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms and drug-induced liver disease. T-cell-mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which are in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding

Gaps in appropriate use of treatment strategies in osteoarthritis

Optimal management of osteoarthritis (OA) requires a combination of therapies, with behavioral (e.g., exercise and weight management) and rehabilitative components at the core, accompanied by pharmacological treatments and, in later stages, consideration of joint replacement surgery. Although multiple sets of OA treatment guidelines have been developed, there are gaps in the implementation of these recommendations. Key areas of concern include the underuse of exercise, weight management, and other behavioral and rehabilitation strategies as well as the overuse of opioid analgesics. In this review, we describe the major categories of treatment strategies for OA, including self-management, physical activity, weight management, physical therapy and other rehabilitative therapies, pharmacotherapies, and joint replacement surgery. For each category, we discuss the current evidence base to report on appropriate use, data regarding adherence to treatment recommendations, and potential approaches to optimize use. © 201

Ab initio Quantum and ab initio Molecular Dynamics of the Dissociative Adsorption of Hydrogen on Pd(100)

The dissociative adsorption of hydrogen on Pd(100) has been studied by ab initio quantum dynamics and ab initio molecular dynamics calculations. Treating all hydrogen degrees of freedom as dynamical coordinates implies a high dimensionality and requires statistical averages over thousands of trajectories. An efficient and accurate treatment of such extensive statistics is achieved in two steps: In a first step we evaluate the ab initio potential energy surface (PES) and determine an analytical representation. Then, in an independent second step dynamical calculations are performed on the analytical representation of the PES. Thus the dissociation dynamics is investigated without any crucial assumption except for the Born-Oppenheimer approximation which is anyhow employed when density-functional theory calculations are performed. The ab initio molecular dynamics is compared to detailed quantum dynamical calculations on exactly the same ab initio PES. The occurence of quantum oscillations in the sticking probability as a function of kinetic energy is addressed. They turn out to be very sensitive to the symmetry of the initial conditions. At low kinetic energies sticking is dominated by the steering effect which is illustrated using classical trajectories. The steering effects depends on the kinetic energy, but not on the mass of the molecules. Zero-point effects lead to strong differences between quantum and classical calculations of the sticking probability. The dependence of the sticking probability on the angle of incidence is analysed; it is found to be in good agreement with experimental data. The results show that the determination of the potential energy surface combined with high-dimensional dynamical calculations, in which all relevant degrees of freedon are taken into account, leads to a detailed understanding of the dissociation dynamics of hydrogen at a transition metal surface.Comment: 15 pages, 9 figures, subm. to Phys. Rev.

HOPX functions as a tumour suppressor in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is generalized term that encompasses a diverse group of cancers that includes tumours of the oral cavity (OSCC), oropharynx (OPSCC) and nasopharynx (NPC). Genetic alterations that are common to all HNSCC types are likely to be important for squamous carcinogenesis. In this study, we have investigated the role of the homeodomain-only homeobox gene, HOPX, in the pathogenesis of HNSCC. We show that HOPX mRNA levels are reduced in OSCC and NPC cell lines and tissues and there is a general reduction of HOPX protein expression in these tumours and OPSCCs. HOPX promoter methylation was observed in a subset of HNSCCs and was associated with a worse overall survival in HPV negative tumours. RNAseq analysis of OSCC cells transfected with HOPX revealed a widespread deregulation of the transcription of genes related to epithelial homeostasis and ectopic over-expression of HOPX in OSCC and NPC cells inhibited cell proliferation, plating efficiency and migration, and enhanced sensitivity to UVA-induced apoptosis. Our results demonstrate that HOPX functions as a tumour suppressor in HNSCC and suggest a central role for HOPX in suppressing epithelial carcinogenesis

Quark exchange model for charmonium dissociation in hot hadronic matter

A diagrammatic approach to quark exchange processes in meson-meson scattering is applied to the case of inelastic reactions of the type (Q\barQ)+(q\barq)\rightarrow (Q\barq) + (q\barQ), where $Q$ and $q$ refer to heavy and light quarks, respectively. This string-flip process is discussed as a microscopic mechanism for charmonium dissociation (absorption) in hadronic matter. The cross section for the reaction $J/\psi + \pi \to D+ \bar D$ is calculated using a potential model, which is fitted to the meson mass spectrum. The temperature dependence of the relaxation time for the \J/Psi distribution in a homogeneous thermal pion gas is obtained. The use of charmonium for the diagnostics of the state of hot hadronic matter produced in ultrarelativistic nucleus-nucleus collisions is discussed.Comment: 24 pages, 3 tables, 7 figure

HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms

Background Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS) which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy which impacts future treatment choices. Variations in human leukocyte antigen (HLA) class I in particular have been associated with serious T-cell mediated adverse drug reactions which has led to preventive screening strategies for some drugs. Objective To determine if variation in the HLA region is associated with vancomycin-induced DRESS. Methods Probable vancomycin DRESS cases were matched 1:2 with tolerant controls based on sex, race, and age using BioVU, Vanderbilt’s deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by conditional logistic regression. An extended sample set from BioVU was utilized to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele. Results Twenty-three individuals met inclusion criteria for vancomycin-associated DRESS. 19/23 (82.6%) cases carried HLA-A*32:01 compared to 0/46 (0%) of the matched vancomycin tolerant controls (p=1x10-8) and 6.3% of the BioVU population (n=54,249) (p=2x10-16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01 positive group indicated that 19.2% developed DRESS and did so within four weeks. Conclusions HLA-A*32:01 is strongly associated with vancomycin DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug and preserve future treatment options with co-administered antibiotics

The Synthesis of [{n-Bu2Sn(S2N2)}2] and its use in the preparation of Organometallic Iridium Sulfur Nitrogen Complexes

The addition of [n-Bu2SnCl2] to a solution of [S4N3][Cl] in liquid ammonia gave after extraction of the dry reaction mixture the new tin disulfur dinitrido compound [{n-Bu2Sn(S2N2)}(2)] (1). Reaction of [{n-Bu2Sn(S2N2)}(2)] (1) with the pentamethylcyclopentadienyl (Cp*) iridium derivatives [{IrCl(mu-Cl)(eta(5)-C5Me5)}(2)] or [(eta(5)-C5Me5)IrCl2(PPh3)] gave different products, which were dependent on the reactant ratios. A 1:1 reaction between 1 and [{IrCl(mu-Cl)(eta(5)-C5Me5)}(2)] gave only [(eta(5)-C5Me5)Ir(S2N2)] (2) in moderate yield; the same product in higher yield was obtained from a 2:1 reaction between 1 and [(eta(5)-C5Me5)IrCl2(PPh3)]. Reaction of 1 and [(eta(5)-C5Me5)(2)IrCl2(PPh3)] (1:1 molar ratio) in the presence of NH4[PF6] gave the unusual bimetallic species [(eta(5)-C5Me5)IrCl(PPh3)(S2N2)Ir(eta(5)-C5Me5)][PF6] (3). The X-ray crystal structures of 1, 2, and 3 are reported.PostprintPeer reviewe

Social Network Analysis: Recent Achievements and Current Controversies

Network analysis has grown rapidly over the past two decades, but criticisms of the approach have increased as well This article focuses on several accomplishments and unresolved problems of the network approach In the first section. I illustrate the value of the network model in several substantive areas. focusing on studies of centrahty and power, network subgroups, and interorganizational relations I then discuss three issues over which the approach has provoked controversy the relation between network analysis and rational choice theory; the role of norms and culture, and the question of human agency I conclude with some examples of how network theorists are addressing these problemsPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68023/2/10.1177_000169939403700403.pd

Measurement of the Charged Multiplicities in b, c and Light Quark Events from Z0 Decays

Average charged multiplicities have been measured separately in $b$, $c$ and light quark ($u,d,s$) events from $Z^0$ decays measured in the SLD experiment. Impact parameters of charged tracks were used to select enriched samples of $b$ and light quark events, and reconstructed charmed mesons were used to select $c$ quark events. We measured the charged multiplicities: $\bar{n}_{uds} = 20.21 \pm 0.10 (\rm{stat.})\pm 0.22(\rm{syst.})$, $\bar{n}_{c} = 21.28 \pm 0.46(\rm{stat.}) ^{+0.41}_{-0.36}(\rm{syst.})$ $\bar{n}_{b} = 23.14 \pm 0.10(\rm{stat.}) ^{+0.38}_{-0.37}(\rm{syst.})$, from which we derived the differences between the total average charged multiplicities of $c$ or $b$ quark events and light quark events: $\Delta \bar{n}_c = 1.07 \pm 0.47(\rm{stat.})^{+0.36}_{-0.30}(\rm{syst.})$ and $\Delta \bar{n}_b = 2.93 \pm 0.14(\rm{stat.})^{+0.30}_{-0.29}(\rm{syst.})$. We compared these measurements with those at lower center-of-mass energies and with perturbative QCD predictions. These combined results are in agreement with the QCD expectations and disfavor the hypothesis of flavor-independent fragmentation.Comment: 19 pages LaTex, 4 EPS figures, to appear in Physics Letters