Toxicity associated with tuberculosis chemotherapy in the REMoxTB study

Abstract Background The incidence and severity of tuberculosis chemotherapy toxicity is poorly characterised. We used data available from patients in the REMoxTB trial to provide an assessment of the risks associated with the standard regimen and two experimental regimens containing moxifloxacin. Methods All grade 3 & 4 adverse events (AEs) and their relationship to treatment for patients who had taken at least one dose of therapy in the REMoxTB clinical trial were recorded. Univariable logistic regression was used to test the relationship of baseline characteristics to the incidence of grade 3 & 4 AEs and significant characteristics (p < 0.10) were incorporated into a multivariable model. The timing of AEs during therapy was analysed in standard therapy and the experimental arms. Logistic regression was used to investigate the relationship between AEs (total and related-only) and microbiological cure on treatment. Results In the standard therapy arm 57 (8.9%) of 639 patients experienced ≥1 related AEs with 80 of the total 113 related events (70.8%) occurring in the intensive phase of treatment. Both four-month experimental arms (“isoniazid arm” with moxifloxacin substituted for ethambutol & “ethambutol arm” with moxifloxacin substituted for isoniazid) had a lower total of related grade 3 & 4 AEs than standard therapy (63 & 65 vs 113 AEs). Female gender (adjOR 1.97, 95% CI 0.91–1.83) and HIV-positive status (adjOR 3.33, 95% CI 1.55–7.14) were significantly associated with experiencing ≥1 related AE (p < 0.05) on standard therapy. The most common adverse events on standard therapy related to hepatobiliary, musculoskeletal and metabolic disorders. Patients who experienced ≥1 related AE were more likely to fail treatment or relapse (adjOR 3.11, 95% CI 1.59–6.10, p < 0.001). Conclusions Most AEs considered related to standard therapy occurred in the intensive phase of treatment with female patients and HIV-positive patients demonstrating a significantly higher risk of AEs during treatment. Almost a tenth of standard therapy patients had a significant side effect, whereas both experimental arms recorded a lower incidence of toxicity. That patients with one or more AE are more likely to fail treatment suggests that treatment outcomes could be improved by identifying such patients through targeted monitoring

Randomized controlled trial of urokinase versus placebo for nondraining malignant pleural effusion

Rationale: Patients with malignant pleural effusion experience breathlessness, which is treated by drainage and pleurodesis. Incomplete drainage results in residual dyspnea and pleurodesis failure. Intrapleural fibrinolytics lyse septations within pleural fluid, improving drainage. Objectives: To assess the effects of intrapleural urokinase on dyspnea and pleurodesis success in patients with nondraining malignant effusion. Methods: We conducted a prospective, double-blind, randomized trial. Patients with nondraining effusion were randomly allocated in a 1:1 ratio to intrapleural urokinase (100,000 IU, three doses, 12-hourly) or matched placebo. Measurements and Main Results: Co–primary outcome measures were dyspnea (average daily 100-mm visual analog scale scores over 28 d) and time to pleurodesis failure to 12 months. Secondary outcomes were survival, hospital length of stay, and radiographic change. A total of 71 subjects were randomized (36 received urokinase, 35 placebo) from 12 U.K. centers. The baseline characteristics were similar between the groups. There was no difference in mean dyspnea between groups (mean difference, 3.8 mm; 95% confidence interval [CI], −12 to 4.4 mm; P = 0.36). Pleurodesis failure rates were similar (urokinase, 13 of 35 [37%]; placebo, 11 of 34 [32%]; adjusted hazard ratio, 1.2; P = 0.65). Urokinase was associated with decreased effusion size visualized by chest radiography (adjusted relative improvement, −19%; 95% CI, −28 to −11%; P < 0.001), reduced hospital stay (1.6 d; 95% CI, 1.0 to 2.6; P = 0.049), and improved survival (69 vs. 48 d; P = 0.026). Conclusions: Use of intrapleural urokinase does not reduce dyspnea or improve pleurodesis success compared with placebo and cannot be recommended as an adjunct to pleurodesis. Other palliative treatments should be used. Improvements in hospital stay, radiographic appearance, and survival associated with urokinase require further evaluation. Clinical trial registered with ISRCTN (12852177) and EudraCT (2008-000586-26)

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study.

BackgroundDrug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment.MethodsPatients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements.ResultsA total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin &gt; 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14-56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged &gt;55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p &lt; 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p &lt; 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008).ConclusionsOur results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing

Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.

BACKGROUND Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. METHODS We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment. RESULTS From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups). CONCLUSIONS Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.)

AusTraits: a curated plant trait database for the Australian flora

INTRODUCTION AusTraits is a transformative database, containing measurements on the traits of Australia’s plant taxa, standardised from hundreds of disconnected primary sources. So far, data have been assembled from &gt; 250 distinct sources, describing &gt; 400 plant traits and &gt; 26,000 taxa. To handle the harmonising of diverse data sources, we use a reproducible workflow to implement the various changes required for each source to reformat it suitable for incorporation in AusTraits. Such changes include restructuring datasets, renaming variables, changing variable units, changing taxon names. While this repository contains the harmonised data, the raw data and code used to build the resource are also available on the project’s GitHub repository, http://traitecoevo.github.io/austraits.build/. Further information on the project is available in the associated publication and at the project website austraits.org. Falster, Gallagher et al (2021) AusTraits, a curated plant trait database for the Australian flora. Scientific Data 8: 254, https://doi.org/10.1038/s41597-021-01006-6 CONTRIBUTORS The project is jointly led by Dr Daniel Falster (UNSW Sydney), Dr Rachael Gallagher (Western Sydney University), Dr Elizabeth Wenk (UNSW Sydney), and Dr Hervé Sauquet (Royal Botanic Gardens and Domain Trust Sydney), with input from &gt; 300 contributors from over &gt; 100 institutions (see full list above). The project was initiated by Dr Rachael Gallagher and Prof Ian Wright while at Macquarie University. We are grateful to the following institutions for contributing data Australian National Botanic Garden, Brisbane Rainforest Action and Information Network, Kew Botanic Gardens, National Herbarium of NSW, Northern Territory Herbarium, Queensland Herbarium, Western Australian Herbarium, South Australian Herbarium, State Herbarium of South Australia, Tasmanian Herbarium, Department of Environment, Land, Water and Planning, Victoria. AusTraits has been supported by investment from the Australian Research Data Commons (ARDC), via their “Transformative data collections” (https://doi.org/10.47486/TD044) and “Data Partnerships” (https://doi.org/10.47486/DP720) programs; fellowship grants from Australian Research Council to Falster (FT160100113), Gallagher (DE170100208) and Wright (FT100100910), a grant from Macquarie University to Gallagher. The ARDC is enabled by National Collaborative Research Investment Strategy (NCRIS). ACCESSING AND USE OF DATA The compiled AusTraits database is released under an open source licence (CC-BY), enabling re-use by the community. A requirement of use is that users cite the AusTraits resource paper, which includes all contributors as co-authors: Falster, Gallagher et al (2021) AusTraits, a curated plant trait database for the Australian flora. Scientific Data 8: 254, https://doi.org/10.1038/s41597-021-01006-6 In addition, we encourage users you to cite the original data sources, wherever possible. Note that under the license data may be redistributed, provided the attribution is maintained. The downloads below provide the data in two formats: austraits-3.0.2.zip: data in plain text format (.csv, .bib, .yml files). Suitable for anyone, including those using Python. austraits-3.0.2.rds: data as compressed R object. Suitable for users of R (see below). Both objects contain all the data and relevant meta-data. AUSTRAITS R PACKAGE For R users, access and manipulation of data is assisted with the austraits R package. The package can both download data and provides examples and functions for running queries. STRUCTURE OF AUSTRAITS The compiled AusTraits database has the following main components: austraits ├── traits ├── sites ├── contexts ├── methods ├── excluded_data ├── taxanomic_updates ├── taxa ├── definitions ├── contributors ├── sources └── build_info These elements include all the data and contextual information submitted with each contributed datasets. A schema and definitions for the database are given in the file/component definitions, available within the download. The file dictionary.html provides the same information in textual format. Full details on each of these components and columns are contained within the definition. Similar information is available at http://traitecoevo.github.io/austraits.build/articles/Trait_definitions.html and http://traitecoevo.github.io/austraits.build/articles/austraits_database_structure.html. CONTRIBUTING We envision AusTraits as an on-going collaborative community resource that: Increases our collective understanding the Australian flora; and Facilitates accumulation and sharing of trait data; Builds a sense of community among contributors and users; and Aspires to fully transparent and reproducible research of the highest standard. As a community resource, we are very keen for people to contribute. Assembly of the database is managed on GitHub at traitecoevo/austraits.build. Here are some of the ways you can contribute: Reporting Errors: If you notice a possible error in AusTraits, please post an issue on GitHub. Refining documentation: We welcome additions and edits that make using the existing data or adding new data easier for the community. Contributing new data: We gladly accept new data contributions to AusTraits. See full instructions on how to contribute at http://traitecoevo.github.io/austraits.build/articles/contributing_data.html

AusTraits, a curated plant trait database for the Australian flora

International audienceWe introduce the austraits database-a compilation of values of plant traits for taxa in the Australian flora (hereafter AusTraits). AusTraits synthesises data on 448 traits across 28,640 taxa from field campaigns, published literature, taxonomic monographs, and individual taxon descriptions. Traits vary in scope from physiological measures of performance (e.g. photosynthetic gas exchange, water-use efficiency) to morphological attributes (e.g. leaf area, seed mass, plant height) which link to aspects of ecological variation. AusTraits contains curated and harmonised individual-and species-level measurements coupled to, where available, contextual information on site properties and experimental conditions. This article provides information on version 3.0.2 of AusTraits which contains data for 997,808 trait-by-taxon combinations. We envision AusTraits as an ongoing collaborative initiative for easily archiving and sharing trait data, which also provides a template for other national or regional initiatives globally to fill persistent gaps in trait knowledge