An Effective Metaheuristic for Multiple Traveling Repairman Problem with Distance Constraints

Multiple Traveling Repairman Problem with Distance Constraints (MTRPD) is an extension of the NP-hard Multiple Traveling Repairman Problem. In MTRPD, a fleet of identical vehicles is dispatched to serve a set of customers with the following constraints. First, each vehicle's travel distance is limited by a threshold. Second, each customer must be visited exactly once. Our goal is to find the visiting order that minimizes the sum of waiting times. To solve MTRPD we propose to combine the Insertion Heuristic (IH), Variable Neighborhood Search (VNS), and Tabu Search (TS) algorithms into an effective two-phase metaheuristic that includes a construction phase and an improvement phase. In the former phase, IH is used to create an initial solution. In the latter phase, we use VNS to generate various neighborhoods, while TS is employed to mainly prohibit from getting trapped into cycles. By doing so, our algorithm can support the search to escape local optima. In addition, we introduce a novel neighborhoods’ structure and a constant time operation which are efficient for calculating the cost of each neighboring solution. To show the efficiency of our proposed metaheuristic algorithm, we extensively experiment on benchmark instances. The results show that our algorithm can find the optimal solutions for all instances with up to 50 vertices in a fraction of seconds. Moreover, for instances from 60 to 80 vertices, almost all found solutions fall into the range of 0.9 %-1.1 % of the optimal solutions' lower bounds in a reasonable duration. For instances with a larger number of vertices, the algorithm reaches good-quality solutions fast. Moreover, in a comparison to the state-of-the-art metaheuristics, our proposed algorithm can find better solutions

Catalytic Dye Oxidation over CeO2 Nanoparticles Supported on Regenerated Cellulose Membrane

A novel regenerated cellulose (RC) membrane containing cerium oxide (CeO2) nanoparticles is described in detail. In this work, CeO2 nanoparticles with high surface area and mesoporosity were prepared by a modified template-assisted precipitation method. Successful synthesis was achieved using cerium nitrate as a precursor, adjusting the final pH solution to around 11 by ammonium hydroxide and ethylene diamine, and annealing at 550 °C for 3 hours under a protective gas flow. This resulted in a surface area of 55.55 m².g–1 for the nanoparticles. The regenerated cellulose membrane containing CeO2 particles was synthesized by the novel and environmentally friendly method. The catalyst CeO2 and cellulose/CeO2 membrane were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Electron paramagnetic resonance (EPR), and Brunauer-Emmett-Teller (BET) measurements. The g-value of 2.276 has confirmed the presence of the surface superoxide species of CeO2 nanoparticles in EPR. The photocatalytic activity of the catalyst and the membrane containing the catalyst was evaluated through the degradation of methylene blue under visible light irradiation by UV-VIS measurements. The cellulose/CeO2 membrane degraded 80% of the methylene blue solution in 120 minutes, showing a better photocatalytic activity than the CeO2 catalyst, which degraded approximately 62% in the same period. It has been proven that the RC membrane is not only a good transparent supporting material but also a good adsorption for high-performance of CeO2 catalyst. Copyright © 2022 by Authors, Published by BCREC Group. This is an open access article under the CC BY-SA License (https://creativecommons.org/licenses/by-sa/4.0).

Dexamethasone and long-term outcome of tuberculous meningitis in Vietnamese adults and adolescents.

BACKGROUND: Dexamethasone has been shown to reduce mortality in patients with tuberculous meningitis but the long-term outcome of the disease is unknown. METHODS: Vietnamese adults and adolescents with tuberculous meningitis recruited to a randomised, double-blind, placebo-controlled trial of adjunctive dexamethasone were followed-up at five years, to determine the effect of dexamethasone on long-term survival and neurological disability. RESULTS: 545 patients were randomised to receive either dexamethasone (274 patients) or placebo (271 patients). 50 patients (9.2%) were lost to follow-up at five years. In all patients two-year survival, probabilities tended to be higher in the dexamethasone arm (0.63 versus 0.55; p = 0.07) but five-year survival rates were similar (0.54 versus 0.51, p = 0.51) in both groups. In patients with grade 1 TBM, but not with grade 2 or grade 3 TBM, the benefit of dexamethasone treatment tended to persist over time (five-year survival probabilities 0.69 versus 0.55, p = 0.07) but there was no conclusive evidence of treatment effect heterogeneity by TBM grade (p = 0.36). The dexamethasone group had a similar proportion of severely disabled patients among survivors at five years as the placebo group (17/128, 13.2% vs. 17/116, 14.7%) and there was no significant association between dexamethasone treatment and disability status at five years (p = 0.32). CONCLUSIONS: Adjunctive dexamethasone appears to improve the probability of survival in patients with TBM, until at least two years of follow-up. We could not demonstrate a five-year survival benefit of dexamethasone treatment which may be confined to patients with grade 1 TBM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01317654

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

Clinical presentations, diagnosis, mortality and prognostic markers of tuberculous meningitis in Vietnamese children: a prospective descriptive study

Background Tuberculous meningitis in adults is well characterized in Vietnam, but there are no data on the disease in children. We present a prospective descriptive study of Vietnamese children with TBM to define the presentation, course and characteristics associated with poor outcome. Methods A prospective descriptive study of 100 consecutively admitted children with TBM at Pham Ngoc Thach Hospital, Ho Chi Minh City. Cox and logistic regression were used to identify factors associated with risk of death and a combined endpoint of death or disability at treatment completion. Results The study enrolled from October 2009 to March 2011. Median age was 32.5 months; sex distribution was equal. Median duration of symptoms was 18.5 days and time from admission to treatment initiation was 11 days. Fifteen of 100 children died, 4 were lost to follow-up, and 27/81 (33 %) of survivors had intermediate or severe disability upon treatment completion. Microbiological confirmation of disease was made in 6 %. Baseline characteristics associated with death included convulsions (HR 3.46, 95CI 1.19–10.13, p = 0.02), decreased consciousness (HR 22.9, 95CI 3.01–174.3, p 5 years) and hydrocephalus were also associated with the combined endpoint of death or disability. Conclusions Tuberculous meningitis in Vietnamese children has significant mortality and morbidity. There is significant delay in diagnosis; interventions that increase the speed of diagnosis and treatment initiation are likely to improve outcomes

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

Dexamethasone and Long-Term Outcome of Tuberculous Meningitis in Vietnamese Adults and Adolescents

BACKGROUND: Dexamethasone has been shown to reduce mortality in patients with tuberculous meningitis but the long-term outcome of the disease is unknown. METHODS: Vietnamese adults and adolescents with tuberculous meningitis recruited to a randomised, double-blind, placebo-controlled trial of adjunctive dexamethasone were followed-up at five years, to determine the effect of dexamethasone on long-term survival and neurological disability. RESULTS: 545 patients were randomised to receive either dexamethasone (274 patients) or placebo (271 patients). 50 patients (9.2%) were lost to follow-up at five years. In all patients two-year survival, probabilities tended to be higher in the dexamethasone arm (0.63 versus 0.55; p = 0.07) but five-year survival rates were similar (0.54 versus 0.51, p = 0.51) in both groups. In patients with grade 1 TBM, but not with grade 2 or grade 3 TBM, the benefit of dexamethasone treatment tended to persist over time (five-year survival probabilities 0.69 versus 0.55, p = 0.07) but there was no conclusive evidence of treatment effect heterogeneity by TBM grade (p = 0.36). The dexamethasone group had a similar proportion of severely disabled patients among survivors at five years as the placebo group (17/128, 13.2% vs. 17/116, 14.7%) and there was no significant association between dexamethasone treatment and disability status at five years (p = 0.32). CONCLUSIONS: Adjunctive dexamethasone appears to improve the probability of survival in patients with TBM, until at least two years of follow-up. We could not demonstrate a five-year survival benefit of dexamethasone treatment which may be confined to patients with grade 1 TBM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01317654

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