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In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).

Background and Objective: This study aimed to develop and evaluate a population pharmacokinetic model and limited sampling strategy for isoniazid to be used in model-based therapeutic drug monitoring. Methods: A population pharmacokinetic model was developed based on isoniazid and acetyl-isoniazid pharmacokinetic data from seven studies with in total 466 patients from three continents. Three limited sampling strategies were tested based on the available sampling times in the dataset and practical considerations. The tested limited sampling strategies sampled at 2, 4, and 6 h, 2 and 4 h, and 2 h after dosing. The model-predicted area under the concentration–time curve from 0 to 24 h (AUC24) and the peak concentration from the limited sampling strategies were compared to predictions using the full pharmacokinetic curve. Bias and precision were assessed using the mean error (ME) and the root mean square error (RMSE), both expressed as a percentage of the mean model-predicted AUC24 or peak concentration on the full pharmacokinetic curve. Results: Performance of the developed model was acceptable and the uncertainty in parameter estimations was generally low (the highest relative standard error was 39% coefficient of variation). The limited sampling strategy with sampling at 2 and 4 h was determined as most suitable with an ME of 1.1% and RMSE of 23.4% for AUC24 prediction, and ME of 2.7% and RMSE of 23.8% for peak concentration prediction. For the performance of this strategy, it is important that data on both isoniazid and acetyl-isoniazid are used. If only data on isoniazid are available, a limited sampling strategy using 2, 4, and 6 h can be employed with an ME of 1.7% and RMSE of 20.9% for AUC24 prediction, and ME of 1.2% and RMSE of 23.8% for peak concentration prediction. Conclusions: A model-based therapeutic drug monitoring strategy for personalized dosing of isoniazid using sampling at 2 and 4 h after dosing was successfully developed. Prospective evaluation of this strategy will show how it performs in a clinical therapeutic drug monitoring setting. [ABSTRACT FROM AUTHOR]

The objective of this case report is to determine the accurate localization of a malignant ventricular tachycardia (VT)focus by combining multichannel magnetocardiographic (MCG) information with morphologic data. The localization was obtained by calculating the three-dimensional current density distribution (3D-CDD) on the left ventricular surface. To estimate the accuracy of this localization technique, examinations of a healthy volunteer were additionally performed. The MCG-signals wererecorded in a magneticallyshielded roombya 49-channel magnetogradiometer. The corresponding morphologic information was recorded by magnetic resonance tomography(MRT). Thecoordinatesystems werematched with thehelp of markers. The3D-CDDwas calculated bythePhilips CURRY software package. The origin of a malignant VT determined by X-ray images of the ablation catheter position during the electrophysiological examination (EPE), was used as the gold standard. This was then compared with the localization results obtained by the 3D-CDD. It was found that the localization coordinates showed a difference of less than 10 mm. [ABSTRACT FROM AUTHOR]

A correction to this paper has been published: https://doi.org/10.1007/s40262-021-01018-w [ABSTRACT FROM AUTHOR]

Background: CD4 measurement is pivotal in the management of advanced human immunodeficiency virus (HIV) disease. VISITECT CD4 Advanced Disease (VISITECT; AccuBio, Ltd) is an instrument-free, point-of-care, semiquantitative test allowing visual identification of CD4 ≤ 200 cells/µL or >200 cells/ µL from finger-prick or venous blood., Methods: As part of a diagnostic accuracy study of FUJIFILM SILVAMP TB LAM, people with HIV ≥18 years old were prospectively recruited in 7 countries from outpatient departments if a tuberculosis symptom was present, and from inpatient departments. Participants provided venous blood for CD4 measurement using flow cytometry (reference standard) and finger-prick blood for VISITECT (index text), performed at point-of-care. Sensitivity, specificity, and positive and negative predictive values of VISITECT to determine CD4 ≤ 200 cells/ µL were evaluated., Results: Among 1604 participants, the median flow cytometry CD4 was 367 cells/µL (interquartile range, 128-626 cells/µL) and 521 (32.5%) had CD4 ≤ 200 cells/µL. VISITECT sensitivity was 92.7% (483/521; 95% confidence interval [CI], 90.1%-94.7%) and specificity was 61.4% (665/1083; 95% CI, 58.4%-64.3%). For participants with CD4 0-100, 101-200, 201-300, 301-500, and >500 cells/µL, VISITECT misclassified 4.5% (95% CI, 2.5%-7.2%), 12.5 (95% CI, 8.0%-18.2%), 74.1% (95% CI, 67.0%-80.5%), 48.0% (95% CI, 42.5%-53.6%), and 22.6% (95% CI, 19.3%-26.3%), respectively., Conclusions: VISITECT's sensitivity, but not specificity, met the World Health Organization's minimal sensitivity and specificity threshold of 80% for point-of-care CD4 tests. VISITECT's quality needs to be assessed and its accuracy optimized. VISITECT's utility as CD4 triage test should be investigated. Clinical Trials Registration. NCT04089423., Competing Interests: Potential conflicts of interest. R. S., A. M., C. M. D., and M. R. are or were employed by FIND, the global alliance for diagnostics at the time of the study. FIND is a not-for-profit foundation that supports the evaluation of publicly prioritized tuberculosis assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics for tuberculosis and other diseases. These agreements strictly define FIND's independence and neutrality with regards to these private sector companies. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Diagnostic delays for tuberculosis are common, with high resultant mortality. Urine-Xpert Ultra (Cepheid) could improve time to diagnosis of tuberculosis disease and rifampicin resistance. We previously reported on lot-to-lot variation of the Fujifilm SILVAMP TB LAM. In this prespecified secondary analysis of the same cohort, we aimed to determine the diagnostic yield and accuracy of Urine-Xpert Ultra for tuberculosis in people with HIV, compared with an extended microbiological reference standard (eMRS) and composite reference standard (CRS) and also compared with Determine TB LAM Ag (AlereLAM, Abbott)., Methods: In this prospective, multicentre, diagnostic accuracy study, we recruited consecutive inpatients and outpatients (aged ≥18 years) with HIV from 13 hospitals and clinics in seven countries (Malawi, South Africa, Tanzania, Thailand, Uganda, Viet Nam, and Zambia). Patients with no isoniazid preventive therapy in the past 6 months and fewer than three doses of tuberculosis treatment in the past 60 days were included. Reference and index testing was performed in real time. The primary outcome of this secondary analysis was the diagnostic yield and accuracy of Urine-Xpert Ultra compared with the eMRS and CRS. Diagnostic accuracy was compared with AlereLAM and diagnostic yield was compared with both AlereLAM and Sputum-Xpert Ultra. This study was registered with ClinicalTrials.gov, NCT04089423, and is complete., Findings: Between Dec 13, 2019, and Aug 5, 2021, 3528 potentially eligible individuals were screened and 1731 were enrolled, of whom 1602 (92·5%) were classifiable by the eMRS (median age 40 years [IQR 33-48], 838 [52·3%] of 1602 were female, 764 [47·7%] were male, 937 [58·5%] were outpatients, 665 [41·5%] were inpatients, median CD4 count was 374 cells per μL [IQR 138-630], and 254 [15·9%] had microbiologically confirmed tuberculosis). Against eMRS as reference, sensitivities of Urine-Xpert Ultra and AlereLAM were 32·7% (95% CI 27·2-38·7) and 30·7% (25·4-36·6) and specificities were 98·0% (97·1-98·6) and 90·4% (88·7-91·8), respectively. Against CRS as reference, sensitivities of Urine-Xpert Ultra and AlereLAM were 21·1% (95% CI 17·6-25·1), and 30·5% (26·4-34·9), and specificities were 99·1% (98·3-99·6) and 95·1% (93·5-96·3), respectively. The combination of Sputum-Xpert Ultra with AlereLAM or Urine-Xpert Ultra diagnosed 202 (77·1%) and 204 (77·9%) of 262 eMRS-positive participants, respectively, in incompletely overlapping groups; combining all three tests diagnosed 214 (81·7%) of 262 eMRS-positive participants INTERPRETATION: Urine-Xpert Ultra could offer promising clinical utility in addition to AlereLAM and Sputum-Xpert Ultra. In inpatient settings where both AlereLAM and Urine-Xpert Ultra are possible, both should be offered to support rapid diagnosis and treatment., Funding: Global Health Innovative Technology Fund, KfW Development Bank, Commonwealth of Australia represented by the Department of Foreign Affairs and Trade, and the Netherlands Enterprise Agency., Competing Interests: Declaration of interests RS, BE, CMD, and MR are or were employed by FIND, the global alliance for diagnostics, at the time of the study; FIND is a not-for-profit foundation that supports the evaluation of publicly prioritised tuberculosis assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants; FIND has product evaluation agreements with several private sector companies that design diagnostics for tuberculosis and other diseases; these agreements strictly define FIND's independence and neutrality with regard to these private sector companies. CMD reports funding from the US National Institutes of Health for the R2D2 project (1U01AI152087-01). All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: To improve tuberculosis case-finding, rapid, non-sputum triage tests need to be developed according to the World Health Organization target product profile (TPP) (>90% sensitivity, >70% specificity). We prospectively evaluated and compared artificial intelligence-based, computer-aided detection software, CAD4TBv7, and C-reactive protein assay (CRP) as triage tests at health facilities in Lesotho and South Africa., Methods: Adults (≥18 years) presenting with ≥1 of the 4 cardinal tuberculosis symptoms were consecutively recruited between February 2021 and April 2022. After informed consent, each participant underwent a digital chest X-ray for CAD4TBv7 and a CRP test. Participants provided 1 sputum sample for Xpert MTB/RIF Ultra and Xpert MTB/RIF and 1 for liquid culture. Additionally, an expert radiologist read the chest X-rays via teleradiology. For primary analysis, a composite microbiological reference standard (ie, positive culture or Xpert Ultra) was used., Results: We enrolled 1392 participants, 48% were people with HIV and 24% had previously tuberculosis. The receiver operating characteristic curve for CAD4TBv7 and CRP showed an area under the curve of .87 (95% CI: .84-.91) and .80 (95% CI: .76-.84), respectively. At thresholds corresponding to 90% sensitivity, specificity was 68.2% (95% CI: 65.4-71.0%) and 38.2% (95% CI: 35.3-41.1%) for CAD4TBv7 and CRP, respectively. CAD4TBv7 detected tuberculosis as well as an expert radiologist. CAD4TBv7 almost met the TPP criteria for tuberculosis triage., Conclusions: CAD4TBv7 is accurate as a triage test for patients with tuberculosis symptoms from areas with a high tuberculosis and HIV burden. The role of CRP in tuberculosis triage requires further research., Clinical Trials Registration: Clinicaltrials.gov identifier: NCT04666311., Competing Interests: Potential conflicts of interest. B. v. G. reports that his group received royalties from Delft Imaging Systems and that he holds shares in Thirona. K. R., B. v. G., A. v. H., A. S., K. M., L. L., T. Z., B. K. M. J., S. B., T. M., and M. K. report support related to this work from the European and Developing Countries Clinical Trials Partnership 2 (EDCTP2). K. R. reports grants unrelated to this work from EDCTP2 and Horizon 2020, as well as unpaid participation on a data safety monitoring board or scientific advisory board for evaluation of new TB diagnostics. S. B. reports a grant unrelated to this work from the National Institutes of Health (NIH) and travel support from MSD. T. M. reports travel support from MSD. N. D. L. reports support for travel from ViiV Healthcare and Gilead Sciences Sarl as well as for attending a board meeting from ViiV Healthcare and Pharming. S. B. and T. M. report travel support from MSD. The other authors report no potential conflict of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Computer-aided detection (CAD) software packages quantify tuberculosis (TB)-compatible chest X-ray (CXR) abnormality as continuous scores. In practice, a threshold value is selected for binary CXR classification. We assessed the diagnostic accuracy of an alternative approach to applying CAD for TB triage: incorporating CAD scores in multivariable modeling., Methods: We pooled individual patient data from four studies. Separately, for two commercial CAD, we used logistic regression to model microbiologically confirmed TB. Models included CAD score, study site, age, sex, human immunodeficiency virus status, and prior TB. We compared specificity at target sensitivities ≥90% between the multivariable model and the current threshold-based approach for CAD use., Results: We included 4,733/5,640 (84%) participants with complete covariate data (median age 36 years; 45% female; 22% with prior TB; 22% people living with human immunodeficiency virus). A total of 805 (17%) had TB. Multivariable models demonstrated excellent performance (areas under the receiver operating characteristic curve [95% confidence interval]: software A, 0.91 [0.90-0.93]; software B, 0.92 [0.91-0.93]). Compared with threshold scores, multivariable models increased specificity (e.g., at 90% sensitivity, threshold vs model specificity [95% confidence interval]: software A, 71% [68-74%] vs 75% [74-77%]; software B, 69% [63-75%] vs 75% [74-77%])., Conclusion: Using CAD scores in multivariable models outperformed the current practice of CAD-threshold-based CXR classification for TB diagnosis., Competing Interests: Declarations of competing interest FAK currently holds a grant from CIHR to study CAD in Canada. FAK also reports salary support from the Fonds de Recherche du Quebec Santé. FAK reports that the following developers of computer-aided detection software provided his research group with either free or reduced pricing access to their software for evaluative research, governed by contracts with the Research Institute of the McGill University Health Centre that ensure that the groups did not have any role in the study design, analysis, result interpretation, or decision to publish previous research and the submitted work: Delft (Netherlands, makers of CAD4TB), qure.ai (India, makers of qXR), and Lunit (South Korea, makers of LUNIT INSIGHT). MB reports grants from European and Development Countries Clinical Trials Partnership during the conduct of the study., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) impose a substantial economic burden globally. This systematic review summarised the evidence on the costs of COPD, including post-TB diseases in low- and middle-income countries., Methods: A systematic review was conducted and studies published between 1 January 2013 and 28 March 2022 (the date of the search) were identified using various electronic databases without language restrictions. Titles, abstracts and full texts were screened in duplicate and data were extracted and verified by reviewers. Eligible studies were categorised as cost analysis and/or economic burden studies, and costs were converted to 2021 United State dollar. Meta-analysis was conducted on the costs of hospitalisations, medication and outpatient visits., Results: 128 cost studies and 65 economic burden studies were included in this review. The data collected are presented in the Cost Database of COPD and Post-TB (CD-CPTB). The majority of studies were from Asia, Eastern Europe and Latin America, with a few from other middle-income countries. There were extremely limited data on the costs of post-TB sequelae and only a few studies were from Africa (n=6) and low-income (n=5) countries. The direct medical costs of COPD ranged from $26 per hospitalisation in India to $2694 per year per patient with severe disease in Mexico, while the costs of acute exacerbation of COPD ranged from $137 to $4207 per exacerbation with both the minimum and maximum costs occurring in Turkey. The costs were lower in lower middle-income countries compared with upper middle-income countries. Finally, considerable economic burden was attributable to smoking and air pollution., Conclusion: The review and the CD-CPTB database give a thorough snapshot of the current evidence of the costs and economic burden of COPD and post-TB diseases. Future research is needed to investigate the economic impact after TB treatment and should be prioritised in Africa and low-income countries where there has been a lack of data collection., Protocol Registration Number: CRD42022326609., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

A positive urine TB-LAM result should lead to TB treatment initiation. TB treatment uptake was low after a positive TB-LAM but negative Xpert test. A lack of trust in TB-LAM results by clinicians and false-positive results may contribute to these results. https://bit.ly/3VGHekC., Competing Interests: Conflict of interest: The authors report no conflicts of interest., (Copyright ©The authors 2024.)

We assessed the diagnostic yield of urine GeneXpert MTB/RIF Ultra and factors associated with a positive test among adult patients suspected to have extrapulmonary tuberculosis. Urine Ultra was positive in 14% of participants with definite or probable tuberculosis. Hospitalization, disseminated tuberculosis, and human immunodeficiency virus infection were associated with a positive result., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)