Pre-treatment cerebrospinal fluid bacterial load correlates with inflammatory response and predicts neurological events during tuberculous meningitis treatment.

Background Mycobacterium tuberculosis (Mtb) bacillary load in the brain of those with tuberculous meningitis (TBM) may reflect the host ability to control the pathogen and determine disease severity and treatment outcomes. Methods We measured pre-treatment cerebrospinal fluid (CSF) Mtb bacterial load by GeneXpert in 692 adults with TBM. We sought to understand the relationship between CSF bacterial load and inflammation, and their respective impact on disease severity and treatment outcomes. Results Ten-fold higher Mtb load was associated with increased disease severity (Odds Ratio=1.59, p=0.001 for grade 1 versus grade 3), and increased CSF neutrophils (r=0.364, p<0.0001) and cytokine concentrations (r=0.438, p<0.0001). High Mtb load predicted new neurological events after starting treatment (Multinomial logistic regression, p=0.005), but not death. Death was previously associated with attenuated inflammatory response at the start of treatment, with reduced cytokine concentrations compared to survivors. In contrast, patients with high pre-treatment CSF bacterial loads, cytokines, and neutrophils were more likely to subsequently suffer neurological events. Conclusions Pre-treatment GeneXpert-derived Mtb load may be a useful predictor of neurological complications occurring during TBM treatment. Therapeutic strategies aimed at reducing neurological complications and deaths from TBM may need reassessment, given the evidence for their divergent pathogenesis

Spin-dependent effective interactions for halo nuclei

We discuss the spin-dependence of the effective two-body interactions appropriate for three-body computations. The only reasonable choice seems to be the fine and hyperfine interactions known for atomic electrons interacting with the nucleus. One exception is the nucleon-nucleon interaction imposing a different type of symmetry. We use the two-neutron halo nucleus 11Li as illustration. We demonstrate that models with the wrong spin-dependence are basically without predictive power. The Pauli forbidden core and valence states must be consistently treated.Comment: TeX file, 6 pages, 3 postscript figure

Two-neutron overlap functions for 6He from a microscopic structure model

A fully antisymmetrized microscopic model is developed for light two-neutron halo nuclei using a hyper-spherical basis to describe halo regions. The many-body wavefunction is optimized variationally. The model is applied to 6He bound by semi realistic Minnesota nucleon-nucleon forces. The two-neutron separation energy and the radius of the halo are reproduced in agreement with experiment. Antisymmetrization effects between 4He and halo neutrons are found to be crucial for binding of 6He. We also properly extract two-neutron overlap functions and find that there is a significant increase of 30%-70% in their normalization due to microscopic effects as compared to the results of three-body models.Comment: To be published in Nucl. Phys.

Clinical Outcomes of Patients With Drug-Resistant Tuberculous Meningitis Treated With an Intensified Antituberculosis Regimen.

Drug-resistant tuberculous meningitis (TBM) is difficult to diagnose and treat. Mortality is high and optimal treatment is unknown. We compared clinical outcomes of drug-resistant and -susceptible TBM treated with either standard or intensified antituberculosis treatment. We analyzed the influence of Mycobacterium tuberculosis drug resistance on the outcomes of patients with TBM enrolled into a randomized controlled trial comparing a standard, 9-month antituberculosis regimen (containing rifampicin 10 mg/kg/day) with an intensified regimen with higher-dose rifampicin (15 mg/kg/day) and levofloxacin (20 mg/kg/day) for the first 8 weeks. The primary endpoint of the trial was 9-month survival. In this subgroup analysis, resistance categories were predefined as multidrug resistant (MDR), isoniazid resistant, rifampicin susceptible (INH-R), and susceptible to rifampicin and isoniazid (INH-S + RIF-S). Outcome by resistance categories and response to intensified treatment were compared and estimated by Cox regression. Of 817 randomized patients, 322 had a known drug resistance profile. INH-R was found in 86 (26.7%) patients, MDR in 15 (4.7%) patients, rifampicin monoresistance in 1 patient (0.3%), and INH-S + RIF-S in 220 (68.3%) patients. Multivariable regression showed that MDR (hazard ratio [HR], 5.91 [95% confidence interval {CI}, 3.00-11.6]), P < .001), was an independent predictor of death. INH-R had a significant association with the combined outcome of new neurological events or death (HR, 1.58 [95% CI, 1.11-2.23]). Adjusted Cox regression, corrected for treatment adjustments, showed that intensified treatment was significantly associated with improved survival (HR, 0.34 [95% CI, .15-.76], P = .01) in INH-R TBM. Early intensified treatment improved survival in patients with INH-R TBM. Targeted regimens for drug-resistant TBM should be further explored

Breakup Reactions of 11Li within a Three-Body Model

We use a three-body model to investigate breakup reactions of 11Li (n+n+9Li) on a light target. The interaction parameters are constrained by known properties of the two-body subsystems, the 11Li binding energy and fragmentation data. The remaining degrees of freedom are discussed. The projectile-target interactions are described by phenomenological optical potentials. The model predicts dependence on beam energy and target, differences between longitudinal and transverse momentum distributions and provides absolute values for all computed differential cross sections. We give an almost complete series of observables and compare with corresponding measurements. Remarkably good agreement is obtained. The relative neutron-9Li p-wave content is about 40%. A p-resonance, consistent with measurements at about 0.5 MeV of width about 0.4 MeV, seems to be necessary. The widths of the momentum distributions are insensitive to target and beam energy with a tendency to increase towards lower energies. The transverse momentum distributions are broader than the longitudinal due to the diffraction process. The absolute values of the cross sections follow the neutron-target cross sections and increase strongly for beam energies decreasing below 100 MeV/u.Comment: 19 pages, 14 figures, RevTeX, psfig.st

Commutative association schemes

Association schemes were originally introduced by Bose and his co-workers in the design of statistical experiments. Since that point of inception, the concept has proved useful in the study of group actions, in algebraic graph theory, in algebraic coding theory, and in areas as far afield as knot theory and numerical integration. This branch of the theory, viewed in this collection of surveys as the "commutative case," has seen significant activity in the last few decades. The goal of the present survey is to discuss the most important new developments in several directions, including Gelfand pairs, cometric association schemes, Delsarte Theory, spin models and the semidefinite programming technique. The narrative follows a thread through this list of topics, this being the contrast between combinatorial symmetry and group-theoretic symmetry, culminating in Schrijver's SDP bound for binary codes (based on group actions) and its connection to the Terwilliger algebra (based on combinatorial symmetry). We propose this new role of the Terwilliger algebra in Delsarte Theory as a central topic for future work.Comment: 36 page

Enhanced Private Sector Engagement for Tuberculosis Diagnosis and Reporting through an Intermediary Agency in Ho Chi Minh City, Viet Nam

Under-detection and -reporting in the private sector constitute a major barrier in Viet Nam’s fight to end tuberculosis (TB). Effective private-sector engagement requires innovative approaches. We established an intermediary agency that incentivized private providers in two districts of Ho Chi Minh City to refer persons with presumptive TB and share data of unreported TB treatment from July 2017 to March 2019. We subsidized chest x-ray screening and Xpert MTB/RIF testing, and supported test logistics, recording, and reporting. Among 393 participating private providers, 32.1% (126/393) referred at least one symptomatic person, and 3.6% (14/393) reported TB patients treated in their practice. In total, the study identified 1203 people with TB through private provider engagement. Of these, 7.6% (91/1203) were referred for treatment in government facilities. The referrals led to a post-intervention increase of +8.5% in All Forms TB notifications in the intervention districts. The remaining 92.4% (1112/1203) of identified people with TB elected private-sector treatment and were not notified to the NTP. Had this private TB treatment been included in official notifications, the increase in All Forms TB notifications would have been +68.3%. Our evaluation showed that an intermediary agency model can potentially engage private providers in Viet Nam to notify many people with TB who are not being captured by the current system. This could have a substantial impact on transparency into disease burden and contribute significantly to the progress towards ending TB

Dynamic Prediction of Death in Patients With Tuberculous Meningitis Using Time-updated Glasgow Coma Scale and Plasma Sodium Measurements.

BACKGROUND: Pretreatment predictors of death from tuberculous meningitis (TBM) are well established, but whether outcome can be predicted more accurately after the start of treatment by updated clinical variables is unknown. Hence, we developed and validated models that dynamically predict mortality using time-updated Glasgow Coma Scale (GCS) and plasma sodium measurements, together with patient baseline characteristics. METHODS: We included 1048 adults from 4 TBM studies conducted in southern Vietnam from 2004 to 2016. We used a landmarking approach to predict death within 120 days after treatment initiation using time-updated data during the first 30 days of treatment. Separate models were built for patients with and without human immunodeficiency virus (HIV) infection. We used the area under the receiver operating characteristic curve (AUC) to evaluate performance of the models at days 10, 20, and 30 of treatment to predict mortality by 60, 90, and 120 days. Our internal validation was corrected for overoptimism using bootstrap. We provide a web-based application that computes mortality risk within 120 days. RESULTS: Higher GCS indicated better prognosis in all patients. In HIV-infected patients, higher plasma sodium was uniformly associated with good prognosis, whereas in HIV-uninfected patients the association was heterogeneous over time. The bias-corrected AUC of the models ranged from 0.82 to 0.92 and 0.81 to 0.85 in HIV-uninfected and HIV-infected individuals, respectively. The models outperformed the previously published baseline models. CONCLUSIONS: Time-updated GCS and plasma sodium measurements improved predictions based solely on information obtained at diagnosis. Our models may be used in practice to define those with poor prognosis during treatment.This work was supported by the Wellcome Trust (grant number 106680/B/14/Z) and the Wellcome Trust Intermediate Fellowship (grant number WT097147MA to J. D.). M. E. T. is a Clinician Scientist Fellow supported by the Academy of Medical Sciences, the Health Foundation, the MRC Newton Fund, and the National Institute for Health Research Cambridge Biomedical Research Centre

Prognostic models for 9 month mortality in tuberculous meningitis

Background: Tuberculous meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis. We developed and validated prognostic models for 9-month mortality in HIV-uninfected and HIV-infected adults with TBM. Methods: We included 1699 subjects from four randomized clinical trials and one prospective observational study conducted at two major referral hospitals in Southern Vietnam from 2001-2015. Modelling was based on multivariable Cox proportional hazards regression. The final prognostic models were validated internally and temporally, and displayed using nomograms and a web-based app (https://thaole.shinyapps.io/tbmapp/). Results: A total of 951 HIV-uninfected and 748 HIV-infected subjects with TBM were included, of whom 219/951 (23.0%) and 384/748 (51.3%) died during 9-month follow-up. Common predictors for increased mortality in both populations were higher Medical Research Council (MRC) disease severity grade and lower cerebrospinal fluid lymphocyte cells count. In HIV-uninfected subjects, older age, previous tuberculosis, not receiving adjunctive dexamethasone, and focal neurological signs were additional risk factors; in HIV-infected subjects, lower weight, lower peripheral blood CD4 cell count, and abnormal plasma sodium were additional risk factors. The areas under the receiver operating characteristic curves (AUCs) for the final prognostic models were 0.77 (HIV-uninfected population) and 0.78 (HIV-infected population), demonstrating markedly better discrimination than the MRC grade (AUC 0.66 and 0.70) or the Glasgow Coma Score (AUC 0.68 and 0.71) alone. Conclusions: The developed models showed good performance and could be used in clinical practice to assist doctors in identifying TBM patients at high risk of death and at increased need of supportive care.This work was supported by the Academy of Medical Sciences and the Health Foundation (Clinician Scientist Fellowship to M. E. T.), the National Institute of Health Research Cambridge Biomedical Research Centre (M. E. T), and a Wellcome Trust Intermediate Fellowship (grant number WT097147MA) to J.D

Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial [version 1; referees: 2 approved]

Background: Tuberculosis kills more people than any other bacterial infection worldwide. In tuberculous meningitis (TBM), a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), predicts pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected individuals. The primary aim of this study is to determine whether LTA4H genotype determines benefit or harm from adjunctive dexamethasone in HIV-uninfected Vietnamese adults with TBM. The secondary aim is to investigate alternative management strategies in individuals who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy.  Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled,  multi-centre Phase III non-inferiority trial, comparing dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype. The primary endpoint will be death or new neurological event. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. 640 participants with CC or CT- LTA4H genotype will be randomised to either dexamethasone or placebo, and the remaining TT- genotype participants will be treated with standard-of-care dexamethasone. We will also perform a randomised comparison of three management strategies for anti-tuberculosis DILI. An identical ancillary study will also be perfomed in the linked randomised controlled trial of dexamethasone in HIV-infected adults with TBM (ACT HIV).  Discussion: Previous data have shown that LTA4H genotype may be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response in TBM. We will stratify dexamethasone therapy according to LTA4H genotype in HIV-uninfected adults, which may indicate a role for targeted anti-inflammatory therapy according to variation in LTA4H C/T transition. A comparison of DILI management strategies may allow the safe continuation of rifampicin and isoniazid