Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Thermal Instability and Current-Voltage Scaling in Superconducting Fault Current Limiters

We have developed a computer model for the simulation of resistive superconducting fault current limiters in three dimensions. The program calculates the electromagnetic and thermal response of a superconductor to a time-dependent overload voltage, with different possible cooling conditions for the surfaces, and locally variable superconducting and thermal properties. We find that the cryogen boil-off parameters critically influence the stability of a limiter. The recovery time after a fault increases strongly with thickness. Above a critical thickness, the temperature is unstable even for a small applied AC voltage. The maximum voltage and maximum current during a short fault are correlated by a simple exponential law.Comment: submitted to Superconductor Science and Technology (Dec 2003

Asthma Severity and Prevalence: An Ongoing Interaction between Exposure, Hygiene, and Lifestyle

Why are the prevalence and severity of asthma increasing? Platts-Mills looks at the key studies that can help to anwer this important questio

Test of CPT Symmetry and Quantum Mechanics with Experimental data from CPLEAR

We use fits to recent published CPLEAR data on neutral kaon decays to $\pi^+\pi^-$ and $\pi e\nu$ to constrain the CPT--violation parameters appearing in a formulation of the neutral kaon system as an open quantum-mechanical system. The obtained upper limits of the CPT--violation parameters are approaching the range suggested by certain ideas concerning quantum gravity.Comment: 9 pages of uuencoded postscript (includes 3 figures

T Cell Epitope Immunotherapy Induces a CD4(+) T Cell Population with Regulatory Activity

BACKGROUND: Synthetic peptides, representing CD4(+) T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils. METHODS AND FINDINGS: In this study we address the mechanism of action of peptide immunotherapy (PIT) in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs) after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4(+) cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4(neg) PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4(+) and CD8(+) PBMCs. CONCLUSION: This study provides evidence for the induction of a population of CD4(+) T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen

Dispersion relation analysis of the neutral kaon regeneration amplitude in carbon

We apply a forward dispersion relation to the regeneration amplitude for kaon scattering on \PCtw using all available data. The CPLEAR data at low energies allow the determination of the net contribution from the subthreshold region which turns out to be much smaller than earlier evaluations, solving a long standing puzzle

Determination of the T- and CPT-violation parameters in the neutral-kaon system using the Bell-Steinberger relation and data from CPLEAR

Data from the CPLEAR experiment, together with the most recent world averages for some of the neutral-kaon parameters, were constrained with the Bell--Steinberger (or unitarity) relation, allowing the T-violation parameter \ree and the CPT-violation parameter \imd of the neutral-kaon mixing matrix to be determined with an increased accuracy: \ree = (164.9 \pm 2.5)\times 10^{-5}, \imd = ( 2.4 \pm 5.0)\times 10^{-5}. Moreover, the constraint allows the CPT-violation parameter for the neutral-kaon semileptonic decays, \rey, to be determined for the first time. The $\Delta S \neq \Delta Q$ parameters \rexm and \imxp are given with an increased accuracy. The quantity $\mathrm{Re}(y~+~x_-)$, which enters the T-violation CPLEAR asymmetry previously published, is determined to be $(0.2 \pm 0.3)\times 10^{-3}$. The value obtained for \red is in agreement with the one resulting from a previous unconstrained fit and has a slightly smaller error

Measurement of the KL−KSK_{L}-K_{S} mass difference using semileptonic decays of tagged neutral kaons

We report on a new measurement of the \kl--\ks\ mass difference \dm\ using the CPLEAR full data sample of neutral-kaon decays to \semi. The result is \dm = (0.5295 \pm 0.0020_{\stat} \pm 0.0003_{\syst}) \times 10^{10}\ \hbs. It includes earlier data reported in Ref. \cite{deltam1}. A measurement of the \dsdq\ violating parameter \rex\ is also obtained

MultiRTA: A simple yet reliable method for predicting peptide binding affinities for multiple class II MHC allotypes

abstract: Background The binding of peptide fragments of antigens to class II MHC is a crucial step in initiating a helper T cell immune response. The identification of such peptide epitopes has potential applications in vaccine design and in better understanding autoimmune diseases and allergies. However, comprehensive experimental determination of peptide-MHC binding affinities is infeasible due to MHC diversity and the large number of possible peptide sequences. Computational methods trained on the limited experimental binding data can address this challenge. We present the MultiRTA method, an extension of our previous single-type RTA prediction method, which allows the prediction of peptide binding affinities for multiple MHC allotypes not used to train the model. Thus predictions can be made for many MHC allotypes for which experimental binding data is unavailable. Results We fit MultiRTA models for both HLA-DR and HLA-DP using large experimental binding data sets. The performance in predicting binding affinities for novel MHC allotypes, not in the training set, was tested in two different ways. First, we performed leave-one-allele-out cross-validation, in which predictions are made for one allotype using a model fit to binding data for the remaining MHC allotypes. Comparison of the HLA-DR results with those of two other prediction methods applied to the same data sets showed that MultiRTA achieved performance comparable to NetMHCIIpan and better than the earlier TEPITOPE method. We also directly tested model transferability by making leave-one-allele-out predictions for additional experimentally characterized sets of overlapping peptide epitopes binding to multiple MHC allotypes. In addition, we determined the applicability of prediction methods like MultiRTA to other MHC allotypes by examining the degree of MHC variation accounted for in the training set. An examination of predictions for the promiscuous binding CLIP peptide revealed variations in binding affinity among alleles as well as potentially distinct binding registers for HLA-DR and HLA-DP. Finally, we analyzed the optimal MultiRTA parameters to discover the most important peptide residues for promiscuous and allele-specific binding to HLA-DR and HLA-DP allotypes. Conclusions The MultiRTA method yields competitive performance but with a significantly simpler and physically interpretable model compared with previous prediction methods. A MultiRTA prediction webserver is available at http://bordnerlab.org/MultiRTA.The electronic version of this article is the complete one and can be found online at: http://bmcbioinformatics.biomedcentral.com/articles/10.1186/1471-2105-11-48

Measurement of the neutral kaon regeneration amplitude in carbon at momenta below 1 GeV/c

The neutral kaon regeneration amplitude in carbon at momenta between 250 and 750~MeV/$c$ was determined by measuring the interference of inherent and coherently regenerated \PKS\ amplitudes. This interference appears in the rates of initially pure (tagged) \PKz\ and \PaKz\ decaying to \Pgpp\Pgpm\ after crossing a carbon absorber