Smallest Dirac Eigenvalue Distribution from Random Matrix Theory

We derive the hole probability and the distribution of the smallest eigenvalue of chiral hermitian random matrices corresponding to Dirac operators coupled to massive quarks in QCD. They are expressed in terms of the QCD partition function in the mesoscopic regime. Their universality is explicitly related to that of the microscopic massive Bessel kernel.Comment: 4 pages, 1 figure, REVTeX. Minor typos in subscripts corrected. Version to appear in Phys. Rev.

Fake symmetry transitions in lattice Dirac spectra

In a recent lattice investigation of Ginsparg-Wilson-type Dirac operators in the Schwinger model, it was found that the symmetry class of the random matrix theory describing the small Dirac eigenvalues appeared to change from the unitary to the symplectic case as a function of lattice size and coupling constant. We present a natural explanation for this observation in the framework of a random matrix model, showing that the apparent change is caused by the onset of chiral symmetry restoration in a finite volume. A transition from unitary to symplectic symmetry does not occur.Comment: 6 pages, 3 figures, REVTe

The Large-NN Limit of the Two-Hermitian-matrix model by the hidden BRST method

This paper discusses the large N limit of the two-Hermitian-matrix model in zero dimensions, using the hidden BRST method. A system of integral equations previously found is solved, showing that it contained the exact solution of the model in leading order of large $N$.Comment: 19 pages, Latex,CERN--TH-6531/9

A new Chiral Two-Matrix Theory for Dirac Spectra with Imaginary Chemical Potential

We solve a new chiral Random Two-Matrix Theory by means of biorthogonal polynomials for any matrix size $N$. By deriving the relevant kernels we find explicit formulas for all $(n,k)$-point spectral (mixed or unmixed) correlation functions. In the microscopic limit we find the corresponding scaling functions, and thus derive all spectral correlators in this limit as well. We extend these results to the ordinary (non-chiral) ensembles, and also there provide explicit solutions for any finite size $N$, and in the microscopic scaling limit. Our results give the general analytical expressions for the microscopic correlation functions of the Dirac operator eigenvalues in theories with imaginary baryon and isospin chemical potential, and can be used to extract the tree-level pion decay constant from lattice gauge theory configurations. We find exact agreement with previous computations based on the low-energy effective field theory in the two special cases where comparisons are possible.Comment: 31 pages 2 figures, v2 missing term in partially quenched results inserted, fig 2 update

A new chiral two-matrix theory for dirac spectra with imaginary chemical potential

We solve a new chiral Random Two-Matrix Theory by means of biorthogonal polynomials for any matrix size $N$. By deriving the relevant kernels we find explicit formulas for all $(n,k)$-point spectral (mixed or unmixed) correlation functions. In the microscopic limit we find the corresponding scaling functions, and thus derive all spectral correlators in this limit as well. We extend these results to the ordinary (non-chiral) ensembles, and also there provide explicit solutions for any finite size $N$, and in the microscopic scaling limit. Our results give the general analytical expressions for the microscopic correlation functions of the Dirac operator eigenvalues in theories with imaginary baryon and isospin chemical potential, and can be used to extract the tree-level pion decay constant from lattice gauge theory configurations. We find exact agreement with previous computations based on the low-energy effective field theory in the two special cases where comparisons are possible

Predictions of bedaquiline and pretomanid target attainment in lung lesions of tuberculosis patients using translational minimal physiologically based pharmacokinetic modeling

BACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nSite-of-action concentrations for bedaquiline and pretomanid from tuberculosis patients are unavailable. The objective of this work was to predict bedaquiline and pretomanid site-of-action exposures using a translational minimal physiologically based pharmacokinetic (mPBPK) approach to understand the probability of target attainment (PTA).\nA general translational mPBPK framework for the prediction of lung and lung lesion exposure was developed and validated using pyrazinamide site-of-action data from mice and humans. We then implemented the framework for bedaquiline and pretomanid. Simulations were conducted to predict site-of-action exposures following standard bedaquiline and pretomanid, and bedaquiline once-daily dosing. Probabilities of average concentrations within lesions and lungs greater than the minimum bactericidal concentration for non-replicating (MBCNR) and replicating (MBCR) bacteria were calculated. Effects of patient-specific differences on target attainment were evaluated.\nThe translational modeling approach was successful in predicting pyrazinamide lung concentrations from mice to patients. We predicted that 94% and 53% of patients would attain bedaquiline average daily PK exposure within lesions (Cavg-lesion) > MBCNR during the extensive phase of bedaquiline standard (2 weeks) and once-daily (8 weeks) dosing, respectively. Less than 5% of patients were predicted to achieve Cavg-lesion > MBCNR during the continuation phase of bedaquiline or pretomanid treatment, and more than 80% of patients were predicted to achieve Cavg-lung >MBCR for all simulated dosing regimens of bedaquiline and pretomanid.\nThe translational mPBPK model predicted that the standard bedaquiline continuation phase and standard pretomanid dosing may not achieve optimal exposures to eradicate non-replicating bacteria in most patients.Pharmacolog

Model‐based dose optimization framework for bedaquiline, pretomanid, and linezolid for the treatment of drug‐resistant tuberculosis

AIM\nMETHODS\nRESULTS\nCONCLUSION\nBedaquiline, pretomanid, and linezolid combination (BPaL) treatment against Mycobacterium tuberculosis is promising yet safety and adherence concerns exist that motivates exploration of alternative dosing regimens. We developed a mechanistic modeling framework to compare the efficacy of the current and alternative BPaL treatment strategies.\nPharmacodynamic models for each drug in the BPaL combination treatment were developed using in vitro time-kill data. These models were combined with pharmacokinetic models, incorporating bodyweight, lesion volume, site-of-action distribution, bacterial susceptibility, and pharmacodynamic interactions to assemble the framework. The model was qualified by comparing the simulations against the observed clinical data. Simulations were performed evaluating bedaquiline and linezolid approved (bedaquiline 400mg once daily (QD) 14-days followed by 200mg three times a week, linezolid 1200mg QD) and alternative dosing regimens (bedaquiline 200mg QD, linezolid 600mg QD).\nThe framework adequately described the observed anti-bacterial activity data in patients following monotherapy for each drug and approved BPaL dosing. The simulations suggested a minor difference in median time to colony forming units (CFU)-clearance state with the bedaquiline alternative compared to the approved dosing and the linezolid alternative compared to the approved dosing. Median time to non-replicating-clearance state was predicted to be 15-days from the CFU-clearance state.\nThe model-based simulations suggested that comparable efficacy can be achieved using alternative bedaquiline and linezolid dosing, which may improve safety and adherence in drug-resistant tuberculosis patients. The framework can be utilized to evaluate treatment optimization approaches, including dosing regimen and duration of treatment predictions to eradicate both replicating- and non-replicating bacteria from lung and lesions.Pharmacolog

Host-directed therapies for tuberculosis: quantitative systems pharmacology approaches

Host-directed therapies (HDTs) that modulate host-pathogen interactions offer an innovative strategy to combat Mycobacterium tuberculosis (Mtb) infections. When combined with tuberculosis (TB) antibiotics, HDTs could contribute to improving treatment outcomes, reducing treatment duration, and preventing resistance development. Translation of the interplay of host-pathogen interactions leveraged by HDTs towards therapeutic outcomes in patients is challenging. Quantitative understanding of the multifaceted nature of the host-pathogen interactions is vital to rationally design HDT strategies. Here, we (i) provide an overview of key Mtb host-pathogen interactions as basis for HDT strategies; and (ii) discuss the components and utility of quantitative systems pharmacology (QSP) models to inform HDT strategies. QSP models can be used to identify and optimize treatment targets, to facilitate preclinical to human translation, and to design combination treatment strategies.Animal science

Two-Dimensional Unoriented Strings And Matrix Models

We investigate unoriented strings and superstrings in two dimensions and their dual matrix quantum mechanics. Most of the models we study have a tachyon tadpole coming from the RP^2 worldsheet which needs to be cancelled by a renormalization of the worldsheet theory. We find evidence that the dual matrix models describe the renormalized theory. The singlet sector of the matrix models is integrable and can be formulated in terms of fermions moving in an external potential and interacting via the Calogero-Moser potential. We show that in the double-scaling limit the latter system exhibits particle-hole duality and interpret it in terms of the dual string theory. We also show that oriented string theories in two dimensions can be continuously deformed into unoriented ones by turning on non-local interactions on the worldsheet. We find two unoriented superstring models for which only oriented worldsheets contribute to the S-matrix. A simple explanation for this is found in the dual matrix model.Comment: 36 pages, harvmac, 2 eps figure