Alternative dosing guidelines to improve outcomes in childhood tuberculosis : a mathematical modelling study

Background Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden. Methods We used an integrated model that linked country-specific demographic data at the individual level from the 20 countries with the highest disease burden to pharmacokinetic, outcome, and epidemiological models. We estimated tuberculosis treatment outcomes in children younger than 5 years following WHO guidelines (children are dosed by weight bands corresponding to the number of fixed-dose combination tablets [75 mg rifampicin, 50 mg isoniazid, 150 mg pyrazinamide]) and two alternative dosing strategies: one based on a proposed algorithm that uses age, weight, and available formulations, in which underweight children would receive the same drug doses as would normal weight children of the same age; and another based on an individualised algorithm without dose limitations, in which derived doses results in target exposure attainment for the typical child. Findings We estimated that 57 234 (43%) of 133 302 children younger than 5 years who were treated for tuberculosis in 2017 were underdosed with WHO dosing and only 47% of children would reach the rifampicin exposure target. Underdosing and subtherapeutic exposures were more common among malnourished children than among age-matched healthy children. The proposed dosing approach improved estimated rifampicin target exposure attainment to 62% and equalised outcomes by nutritional status. An estimated third of unfavourable treatment outcomes might be resolved with this dosing strategy, saving the lives of a minimum of 2423 children in these countries annually. With individualised dosing approaches, almost all children could achieve adequate exposure for cure. Interpretation This work shows that a simple change in dosing procedure to include age and nutritional status, requiring no additional measurements or new drug formulations, is one approach to improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality

The role of aerodynamic forces in a mathematical model for suspension bridges

In a fish-bone model for suspension bridges studied by us in a previous paper we introduce linear aerodynamic forces. We numerically analyze the role of these forces and we theoretically show that they do not influence the onset of torsional oscillations. This suggests a new explanation for the origin of instability in suspension bridges: it is a combined interaction between structural nonlinearity and aerodynamics and it follows a precise pattern. This gives an answer to a long-standing question about the origin of torsional instability in suspension bridges

Supercritical biharmonic equations with power-type nonlinearity

The biharmonic supercritical equation $\Delta^2u=|u|^{p-1}u$, where $n>4$ and $p>(n+4)/(n-4)$, is studied in the whole space $\mathbb{R}^n$ as well as in a modified form with $\lambda(1+u)^p$ as right-hand-side with an additional eigenvalue parameter $\lambda>0$ in the unit ball, in the latter case together with Dirichlet boundary conditions. As for entire regular radial solutions we prove oscillatory behaviour around the explicitly known radial {\it singular} solution, provided $p\in((n+4)/(n-4),p_c)$, where $p_c\in ((n+4)/(n-4),\infty]$ is a further critical exponent, which was introduced in a recent work by Gazzola and the second author. The third author proved already that these oscillations do not occur in the complementing case, where $p\ge p_c$. Concerning the Dirichlet problem we prove existence of at least one singular solution with corresponding eigenvalue parameter. Moreover, for the extremal solution in the bifurcation diagram for this nonlinear biharmonic eigenvalue problem, we prove smoothness as long as $p\in((n+4)/(n-4),p_c)$

Strongly nonlinear perturbations of nonnegative boundary value problems with kernel

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22609/1/0000159.pd

A Computer-Assisted Uniqueness Proof for a Semilinear Elliptic Boundary Value Problem

A wide variety of articles, starting with the famous paper (Gidas, Ni and Nirenberg in Commun. Math. Phys. 68, 209-243 (1979)) is devoted to the uniqueness question for the semilinear elliptic boundary value problem -{\Delta}u={\lambda}u+u^p in {\Omega}, u>0 in {\Omega}, u=0 on the boundary of {\Omega}, where {\lambda} ranges between 0 and the first Dirichlet Laplacian eigenvalue. So far, this question was settled in the case of {\Omega} being a ball and, for more general domains, in the case {\lambda}=0. In (McKenna et al. in J. Differ. Equ. 247, 2140-2162 (2009)), we proposed a computer-assisted approach to this uniqueness question, which indeed provided a proof in the case {\Omega}=(0,1)x(0,1), and p=2. Due to the high numerical complexity, we were not able in (McKenna et al. in J. Differ. Equ. 247, 2140-2162 (2009)) to treat higher values of p. Here, by a significant reduction of the complexity, we will prove uniqueness for the case p=3

Measurement of the partial widths of the Z into up- and down-type quarks

Using the entire OPAL LEP1 on-peak Z hadronic decay sample, Z -> qbarq gamma decays were selected by tagging hadronic final states with isolated photon candidates in the electromagnetic calorimeter. Combining the measured rates of Z -> qbarq gamma decays with the total rate of hadronic Z decays permits the simultaneous determination of the widths of the Z into up- and down-type quarks. The values obtained, with total errors, were Gamma u = 300 ^{+19}_{-18} MeV and Gamma d = 381 ^{+12}_{-12} MeV. The results are in good agreement with the Standard Model expectation.Comment: 22 pages, 5 figures, Submitted to Phys. Letts.

Search for R-Parity Violating Decays of Scalar Fermions at LEP

A search for pair-produced scalar fermions under the assumption that R-parity is not conserved has been performed using data collected with the OPAL detector at LEP. The data samples analysed correspond to an integrated luminosity of about 610 pb-1 collected at centre-of-mass energies of sqrt(s) 189-209 GeV. An important consequence of R-parity violation is that the lightest supersymmetric particle is expected to be unstable. Searches of R-parity violating decays of charged sleptons, sneutrinos and squarks have been performed under the assumptions that the lightest supersymmetric particle decays promptly and that only one of the R-parity violating couplings is dominant for each of the decay modes considered. Such processes would yield final states consisting of leptons, jets, or both with or without missing energy. No significant single-like excess of events has been observed with respect to the Standard Model expectations. Limits on the production cross- section of scalar fermions in R-parity violating scenarios are obtained. Constraints on the supersymmetric particle masses are also presented in an R-parity violating framework analogous to the Constrained Minimal Supersymmetric Standard Model.Comment: 51 pages, 24 figures, Submitted to Eur. Phys. J.

Measurement of the Strong Coupling alpha s from Four-Jet Observables in e+e- Annihilation

Data from e+e- annihilation into hadrons at centre-of-mass energies between 91 GeV and 209 GeV collected with the OPAL detector at LEP, are used to study the four-jet rate as a function of the Durham algorithm resolution parameter ycut. The four-jet rate is compared to next-to-leading order calculations that include the resummation of large logarithms. The strong coupling measured from the four-jet rate is alphas(Mz0)= 0.1182+-0.0003(stat.)+-0.0015(exp.)+-0.0011(had.)+-0.0012(scale)+-0.0013(mass) in agreement with the world average. Next-to-leading order fits to the D-parameter and thrust minor event-shape observables are also performed for the first time. We find consistent results, but with significantly larger theoretical uncertainties.Comment: 25 pages, 15 figures, Submitted to Euro. Phys. J.

Measurement of the Hadronic Photon Structure Function F_2^gamma at LEP2

The hadronic structure function of the photon F_2^gamma is measured as a function of Bjorken x and of the factorisation scale Q^2 using data taken by the OPAL detector at LEP. Previous OPAL measurements of the x dependence of F_2^gamma are extended to an average Q^2 of 767 GeV^2. The Q^2 evolution of F_2^gamma is studied for average Q^2 between 11.9 and 1051 GeV^2. As predicted by QCD, the data show positive scaling violations in F_2^gamma. Several parameterisations of F_2^gamma are in agreement with the measurements whereas the quark-parton model prediction fails to describe the data.Comment: 4 pages, 2 figures, to appear in the proceedings of Photon 2001, Ascona, Switzerlan