Through a Gender Lens: The Economic Security of Women and Girls in Forsyth County

The first research of its kind to focus specifically on the circumstances and needs of women in Forsyth County, this report draws attention to the individual, social and systemic issues and barriers to economic security by examining poverty rates, wages, educational attainment and occupations as well as the cost of necessary expenses such as housing, utilities, food, transportation, childcare and healthcare

Box C/D snoRNP catalysed methylation is aided by additional pre-rRNA base-pairing

Box C/D small nucleolar RNPs catalyse 2′-O-methylation of eukaryotic ribosomal RNA. A large-scale analysis of yeast box C/D snoRNAs reveals conserved ‘extra base-pairing' between snoRNAs and regions adjacent to their rRNA methylation site and points to a role for the non-catalytic protein subunits Nop56 and Nop58 in rRNA binding

Utility of broad-spectrum antibiotics for diagnosing pulmonary tuberculosis in adults : a systematic review and meta-analysis

Funding: Helse Nord RHF, Wellcome Trust, and the UK Commonwealth Scholarship Commission.Suboptimal diagnostics for pulmonary tuberculosis drive the use of the so-called trial of antibiotics, a course of broad-spectrum antibiotics without activity against Mycobacterium tuberculosis that is given to patients who are mycobacteriology negative but symptomatic, with the aim of distinguishing pulmonary tuberculosis from bacterial lower respiratory tract infection. The underlying assumption—that patients with lower respiratory tract infection will improve, whereas those with pulmonary tuberculosis will not—has an unclear evidence base for such a widely used intervention (at least 26·5 million courses are prescribed per year). We aimed to collate available evidence on the diagnostic performance of the trial of antibiotics.Publisher PDFPeer reviewe

Sensitivity and specificity of using trial-of-antibiotics versus sputum mycobacteriology for diagnosis of tuberculosis : protocol for a systematic literature review

TD is funded by the Commonwealth Scholarship Commission and the Helse Nord RHF. This review is part of his PhD work at London School of Hygiene & Tropical Medicine.Background:  Suboptimal diagnostics for pulmonary tuberculosis (PTB) drives use of ‘trial-of-antibiotics (non-tuberculosis)’ in an attempt to distinguish PTB patients from those with bacterial lower respiratory tract infection (LRTI). The underlying assumption—that patients with LRTI will report ‘response’ to broad-spectrum antibiotics, while those with PTB will not—has minimal evidence base for such a widely used intervention. Numerous potential causes of misclassification include bacterial super-infection of active PTB, placebo effect, and antimicrobial resistance (AMR). The main aim of this systematic review is to collate available evidence on the performance of trial-of-antibiotics as a diagnostic test and to explore the timing, interpretation, and decision-making process. Methods:  We will search MEDLINE, Embase, and Global Health using the Ovid platform for published studies that recruited adults being investigated for PTB, performed trial-of-antibiotics accompanied by mycobacteriological investigations, and reported both diagnostic test outcomes at the individual level. Following article selection, two authors will independently review titles and abstracts against eligibility criteria then perform full-text screening and extraction into a spreadsheet. We will conduct a risk of bias assessment at the level of the study using QUADAS-2 (University of Bristol) tool that assesses diagnostic evaluation work in four domains: (1) patient selection, (2) the index test, (3) the reference standard, and (4) patient flow and timing of tests. We will perform a narrative synthesis and, where possible, meta-analyses addressing our primary outcome. Our protocol adheres to the standards recommended by the PRISMA-P. Discussion:  Pooling all available evidence on the accuracy, approach, and interpretation of results of trial-of-antibiotics in the context of PTB diagnosis will meet an urgent need, considering the widespread utilisation and potential for antimicrobial resistance. We therefore believe that our findings will have impact on policy and that they will inform the design of future detailed investigations into this important diagnostic approach.Publisher PDFPeer reviewe

Accuracy and consequences of using trial-of-antibiotics for TB diagnosis (ACT-TB study) : protocol for a randomised controlled clinical trial

The clinical trial is funded by the Commonwealth Scholarship Commission and the Helse Nord RHF grant awarded to THD. This work is part of THD’s PhD work at London School of Hygiene & Tropical Medicine (LSHTM). LSHTM is the sponsor of this clinical trial (sponsor address: Keppel Street, Bloomsbury, London WC1E 7HT). ELC is funded by a Wellcome Trust Senior Research Fellowship in Clinical Science: WT200901.Introduction Over 40% of global tuberculosis case notifications are diagnosed clinically without mycobacteriological confirmation. Standard diagnostic algorithms include ‘trial-of-antibiotics’—empirical antibiotic treatment given to mycobacteriology-negative individuals to treat infectious causes of symptoms other than tuberculosis, as a ‘rule-out’ diagnostic test for tuberculosis. Potentially 26.5 million such antibiotic courses/year are prescribed globally for the 5.3 million/year mycobacteriology-negative patients, making trial-of-antibiotics the most common tuberculosis diagnostic, and a global-scale risk for antimicrobial resistance (AMR). Our systematic review found no randomised controlled trial (RCT) to support use of trial-of-antibiotic. The RCT aims to determine the diagnostic and clinical value and AMR consequences of trial-of-antibiotics. Methods and analysis A three-arm, open-label, RCT randomising (1:1:1) Malawian adults (≥18 years) seeking primary care for cough into: (a) azithromycin 500 mg one time per day for 3 days or (b) amoxicillin 1 g three times per day for 5 days or (c) standard-of-care (no immediate antibiotic). We will perform mycobacteriology tests (microscopy, Xpert MTB/RIF (Mycobacterium tuberculosis/rifampicin) and Mycobacterium tuberculosis culture) at baseline. We will use audiocomputer-assisted self-interview to assess clinical improvement at day 8. First primary outcome will be proportion of patients reporting day 8 improvement out of those with negative mycobacteriology (specificity). Second primary outcome will be day 29 incidence of a composite endpoint of either death or hospitalisation or missed tuberculosis diagnosis. To determine AMR impact we compare proportion of resistant nasopharyngeal Streptococcus pneumoniae isolates on day 29. 400 mycobacteriology-negative participants/arm will be required to detect a ≥10% absolute difference in diagnostic specificity with 80% power. We will estimate measures of effect by comparing outcomes in antibiotic arms (combined and individually) to standard-of-care. Ethics and dissemination The study has been reviewed and approved by Malawi College of Medicine Research and Ethics Committee, London School of Hygiene & Tropical Medicine (LSHTM) Research Ethics Committee and Regional Committee for Health and Research Ethics – Norway, and Malawi Pharmacy, Medicines and Poisons Board. We will present abstracts at relevant conferences, and prepare a manuscript for publication in a peer-reviewed journal.Publisher PDFPeer reviewe

Effect of the duration of antimicrobial exposure on the development of antimicrobial resistance (AMR) for macrolide antibiotics: protocol for a systematic review with a network meta-analysis

THD is funded by the Commonwealth Scholarship Commission and the Helse Nord RHF. This review is part of his PhD work at LSHTM. ELC is funded by a Wellcome Trust Senior Research Fellowship in Clinical Science: WT200901. HRS is supported by the Medical Research Council [MR/R008345/1].Background: Antimicrobial resistance generates a huge health and economic burden and has the potential to become the leading cause of death globally, but its underlying drivers are yet to be fully described. The association between a microbe’s exposure to antimicrobials and subsequent development of, or selection for, resistance is well documented, as are the exacerbating microbial and human factors. However, the nature and extent of this risk, and how it varies by antimicrobial class and duration of treatment, is poorly defined. The goal of our systematic review and network meta-analysis is to determine the relationship between the duration of antimicrobial exposure and selection for resistance. We will use macrolides as the antimicrobial class of interest and Streptococcus pneumoniae carriage as an indicator organism. Our secondary outcomes include duration of symptoms, risk of treatment failure and recurrence, and descriptions of resistance mechanisms. Methods:  We will conduct a systematic review, selecting studies if they are published randomised controlled trials (RCTs) which report the relationship between taking a macrolide for any indication and incidence of resistant Streptococcus pneumoniae in patients of any age group. We will use a predefined search strategy to identify studies meeting these eligibility criteria in MEDLINE, Embase, Global Health and the Cochrane Central Register of RCTs. Two authors will independently screen titles and abstracts, review the full texts and undertake data extraction. We will use the Cochrane Collaboration’s tool to assess the quality of included RCTs. If feasible, we will perform pair-wise meta-analysis modelling to determine the relationship between the duration of macrolide treatment and development of macrolide resistant Streptococcus pneumoniae. If the identified studies meet the assumptions for a network meta-analysis (NMA), we will additionally model this relationship using indirect comparisons. Our protocol utilises reporting guidance by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the extensions for protocols (PRISMA-P) and network meta-analyses (PRISMA for NMA). Our review will also report to these standards. Discussion:  Establishing the relationship between the duration of antimicrobial exposure and development of, or selection for, resistance will inform the design of antimicrobial prescriptions, treatment guidelines and the behaviour of both physicians and patients. This work will therefore be a strong contribution towards the full realisation of current antimicrobial resistance stewardship strategies.Publisher PDFPeer reviewe

All non-adherence is equal, but is some more equal than others? TB in the digital era

Karina Kielmann - ORCID 0000-0001-5519-1658 https://orcid.org/0000-0001-5519-1658Aaron S. Karat - ORCID 0000-0001-9643-664X https://orcid.org/0000-0001-9643-664XReplaced AM with VoR 2020-11-06Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization’s recommendation of the direct observation of treatment in the 1990s. Recent advances in digital adherence technologies (DATs) have renewed discussion on how to best address non-adherence, as well as offering important information on dose-by-dose adherence patterns and their variability between countries and settings. Previous studies have largely focussed on percentage thresholds to delineate sufficient adherence, but this is misleading and limited, given the complex and dynamic nature of adherence over the treatment course. Instead, we apply a standardised taxonomy- as adopted by the international adherence community- to dose-by-dose medication-taking data, which divides missed doses into a) late/non-initiation (starting treatment later than expected/not starting), b) discontinuation (ending treatment early), and c) suboptimal implementation (intermittent missed doses). Using this taxonomy, we can consider the implications of different forms of non-adherence for intervention and regimen design. For example, can treatment regimens be adapted to increase the ‘forgiveness’ of common patterns of suboptimal implementation to protect against treatment failure and the development of drug resistance? Is it reasonable to treat all missed doses of treatment as equally problematic and equally common when deploying DATs? Can DAT data be used to indicate the patients that need enhanced levels of support during their treatment course? Critically, we pinpoint key areas where knowledge regarding treatment adherence is sparse and impeding scientific progress.https://doi.org/10.1183/23120541.00315-20206pubpub

Understand, Desing, Act: Climate-proof your supply chain

Presentations of Understand, Desing, Act: Climate-proof your supply chain Module 1: Understand climate change Module 2: How is climate change affecting my supply chain Module 3: How can I manage the effects climate change in having on my supply chain? Module 4: How can I scale up climate smart agriculture? Module 5: How do I know my investment in climate smart agriculture is working? Module 6: How can I convince my company and others to work on CSA

Trial-of-antibiotics to assist tuberculosis diagnosis in symptomatic adults in Malawi (ACT-TB study): a randomised controlled trial.

BACKGROUND: Clinical practice and diagnostic algorithms often assume that tuberculosis can be ruled out in mycobacteriology-negative individuals whose symptoms improve with a trial-of-antibiotics. We aimed to investigate diagnostic performance, clinical benefit, and antimicrobial resistance using a randomised controlled trial. METHODS: In this three-arm, individually randomised, open-label, controlled trial, we enrolled Malawian adults (aged ≥18 years) attending primary care who reported being unwell for at least 14 days (including cough) with no immediate indication for hospitalisation at Limbe and Ndirande Health Centres in Blantyre. Participants were randomly allocated (1:1:1) to azithromycin (500 mg taken once per day for 3 days), amoxicillin (1 g taken three times per day for 5 days), or standard of care with no immediate antibiotics, stratified by study site. Sputum at enrolment and day 8 was tested for tuberculosis (microscopy, Xpert MTB/RIF, and culture). The primary efficacy outcome was day 8 specificity (percentage with symptom improvement among mycobacteriology-negative participants), and day 29 clinical outcome (death, hospitalisation, or missed tuberculosis diagnosis) among all randomised participants. This study is registered with ClinicalTrials.gov, NCT03545373. FINDINGS: Between Feb 25, 2019, and March 14, 2020, 5825 adults were screened and 1583 (mean age 36 years; 236 [14·9%] HIV positive) were randomly assigned to standard of care (530 participants), azithromycin (527 participants), or amoxicillin (526 participants) groups. Overall, 6·3% (100 of 1583 participants) had positive baseline sputum mycobacteriology. 310 (79·1%) of 392 patients receiving standard of care reported symptom improvement at day 8, compared with 340 (88·7%) of 383 patients receiving azithromycin (adjusted difference 8·6%, 95% CI 3·9-13·3%; p<0·0004) and 346 (89·4%) of 387 receiving amoxicillin (adjusted difference 8·8%, 4·0-13·6%; p=0·0003). The proportion of participants with day 29 composite clinical outcomes was similar between groups (standard of care 1% [7 of 530 participants], azithromycin 1% [6 of 527 participants], amoxicillin 2% [12 of 526 participants]). INTERPRETATION: Routine outpatient trial-of-antibiotics during tuberculosis investigations modestly improved diagnostic specificity for mycobacteriologically confirmed tuberculosis but had no appreciable effect on death, hospitalisation, and missed tuberculosis diagnosis. These results confirm the limited benefit of trial-of-antibiotics, presenting an opportunity for discontinuation of trial-of-antibiotics and improved antimicrobial stewardship during tuberculosis screening, without affecting clinical outcomes. FUNDING: Northern Norway Regional Health Authority (Helse Nord RHF), Commonwealth Scholarship Commission in the UK, Wellcome Trust, UK Medical Research Council, and the UK Department for International Development

Trial-of-antibiotics to assist tuberculosis diagnosis in symptomatic adults in Malawi (ACT-TB study): a randomised controlled trial.

Background: Clinical practice and diagnostic algorithms often assume that tuberculosis can be ruled out in mycobacteriology-negative individuals whose symptoms improve with a trial-of-antibiotics. We aimed to investigate diagnostic performance, clinical benefit, and antimicrobial resistance using a randomised controlled trial. Methods: In this three-arm, individually randomised, open-label, controlled trial, we enrolled Malawian adults (aged ≥18 years) attending primary care who reported being unwell for at least 14 days (including cough) with no immediate indication for hospitalisation at Limbe and Ndirande Health Centres in Blantyre. Participants were randomly allocated (1:1:1) to azithromycin (500 mg taken once per day for 3 days), amoxicillin (1 g taken three times per day for 5 days), or standard of care with no immediate antibiotics, stratified by study site. Sputum at enrolment and day 8 was tested for tuberculosis (microscopy, Xpert MTB/RIF, and culture). The primary efficacy outcome was day 8 specificity (percentage with symptom improvement among mycobacteriology-negative participants), and day 29 clinical outcome (death, hospitalisation, or missed tuberculosis diagnosis) among all randomised participants. This study is registered with ClinicalTrials.gov, NCT03545373. Findings: Between Feb 25, 2019, and March 14, 2020, 5825 adults were screened and 1583 (mean age 36 years; 236 [14·9%] HIV positive) were randomly assigned to standard of care (530 participants), azithromycin (527 participants), or amoxicillin (526 participants) groups. Overall, 6·3% (100 of 1583 participants) had positive baseline sputum mycobacteriology. 310 (79·1%) of 392 patients receiving standard of care reported symptom improvement at day 8, compared with 340 (88·7%) of 383 patients receiving azithromycin (adjusted difference 8·6%, 95% CI 3·9-13·3%; p<0·0004) and 346 (89·4%) of 387 receiving amoxicillin (adjusted difference 8·8%, 4·0-13·6%; p=0·0003). The proportion of participants with day 29 composite clinical outcomes was similar between groups (standard of care 1% [7 of 530 participants], azithromycin 1% [6 of 527 participants], amoxicillin 2% [12 of 526 participants]). Interpretation: Routine outpatient trial-of-antibiotics during tuberculosis investigations modestly improved diagnostic specificity for mycobacteriologically confirmed tuberculosis but had no appreciable effect on death, hospitalisation, and missed tuberculosis diagnosis. These results confirm the limited benefit of trial-of-antibiotics, presenting an opportunity for discontinuation of trial-of-antibiotics and improved antimicrobial stewardship during tuberculosis screening, without affecting clinical outcomes. Funding: Northern Norway Regional Health Authority (Helse Nord RHF), Commonwealth Scholarship Commission in the UK, Wellcome Trust, UK Medical Research Council, and the UK Department for International Development