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Resolution of tuberculosis blood RNA signatures fails to discriminate persistent sputum culture positivity after 8 weeks of anti-tuberculous treatment.
Get PDFBACKGROUND: Concerted efforts aim to reduce the burden of 6 months of anti-tuberculous treatment for tuberculosis (TB). Treatment cessation at 8 weeks is effective for most but incurs increased risk of disease relapse. We tested the hypothesis that blood RNA signatures or C-reactive protein (CRP) measurements discriminate 8-week sputum culture status, as a prerequisite for a biomarker to stratify risk of relapse following treatment cessation at this time-point.
METHODS: We identified blood RNA signatures of TB disease or cure by systematic review. We evaluated these signatures and CRP measurements in a pulmonary TB cohort, pre-treatment, at 2 and 8 weeks of treatment, and sustained cure after treatment completion. We tested biomarker discrimination of 8-week sputum culture status using area under the receiver operating characteristic curve (AUROC) analysis and, secondarily, assessed correlation of biomarker scores with time to culture positivity at 8 weeks of treatment.
RESULTS: 12 blood RNA signatures were reproduced in the dataset from 44 individuals with sputum culture-positive pulmonary TB. These normalised over time from TB treatment initiation. 11 out of 44 cases with blood RNA, CRP and sputum culture results were sputum culture-positive at 8 weeks of treatment. None of the contemporary blood RNA signatures discriminated sputum culture status at this time-point or correlated with bacterial load. CRP achieved modest discrimination with AUROC 0.69 (95% CI 0.52-0.87).
CONCLUSIONS: Selected TB blood RNA signatures and CRP do not provide biomarkers of microbiological clearance to support TB treatment cessation at 8 weeks. Resolution of blood transcriptional host responses in sputum culture-positive individuals suggests Mycobacterium tuberculosis may colonise the respiratory tract without triggering a detectable immune response
Opportunities and challenges to the development and deployment of vaccines for pregnant women in Germany.
Get PDFMaternal immunisation is a powerful tool to protect both pregnant women and their children. A new maternal RSV vaccine holds promise to protect newborns from RSV-associated illness in the first few months of life, but no official recommendation has been made in Germany. Since RSV causes a significant burden of paediatric hospital admissions, we consider it a pertinent opportunity to review barriers to maternal vaccination in Germany, which might also apply to other settings. Access to vaccination for pregnant women in Germany is shaped by an interplay of legal, regulatory, institutional, and sociocultural factors, with a less permissive clinical research environment, delays in recommendation and roll-out, and lower acceptance by healthcare professionals and the population. Actionable recommendations to improve availability and uptake include coordination with other national regulatory bodies to reduce delays, awareness and literacy campaigns for health professionals and the general public, and capacity building for vaccine clinical research
Mid-Upper Arm Circumference Is a Strong Predictor of Mortality Among Ugandan Adults With HIV-Associated Cryptococcal Meningitis: A Prospective Cohort Study.
Get PDFBACKGROUND: Mortality among adults diagnosed with HIV-associated cryptococcal meningitis remains high (24%-40%). We hypothesized that nutritional state, as measured by mid-upper arm circumference (MUAC), is a potentially modifiable risk factor for mortality.
METHODS: Ugandan adults hospitalized with HIV-associated cryptococcal meningitis had MUAC measurements performed at baseline. We compared MUAC measurements with baseline clinical and demographic variables and investigated associations with survival using Cox regression.
RESULTS: Of 433 participants enrolled, 41% were female, the median CD4 T-cell count (interquartile range [IQR]) was 15 (6-41) cells/μL, and 37% were antiretroviral therapy naïve. The median MUAC (IQR) was 24 (22-26) cm, the median weight (IQR) was 53 (50-60) kg, and MUAC correlated with weight (Pearson r = 0.6; P 22 cm (unadjusted hazard ratio, 1.82; 95% CI, 1.36-2.42; P < .001). Following adjustment for antiretroviral therapy status, CD4 count, hemoglobin, amphotericin dose, and tuberculosis status, the adjusted hazard ratio was 1.84 (95% CI, 1.27-2.65; P < .001). As a continuous variable, 18-week mortality was reduced by 10% for every 1-cm increase in MUAC. CSF Th17 immune responses were positively associated with MUAC quartile.
CONCLUSIONS: MUAC measurement is a simple bedside tool that can identify adults with HIV-associated cryptococcal meningitis at high risk for mortality for whom an enhanced bundle of care, including nutritional supplementation, should be further investigated
Trial to compare mixed-use (multi-use and single-use) intermittent catheter management with single-use management over 12 months (The MultICath Trial): protocol for a non-inferiority randomised controlled trial.
Get PDFINTRODUCTION: Evaluating the safety and acceptability of reusing catheters for intermittent catheterisation (IC) is one of the top 10 continence research priorities identified by the UK James Lind Alliance Priority Setting Partnership in 2008. There are an estimated 50 000 IC users in England and this number is rising. Globally, both single-use catheters (thrown away after use) and multi-use/reusable ones (cleaned between uses) are used. Using multi-use catheters as well as single-use ones (mixed-use) could bring benefits (eg, reducing plastic waste and patients never running out of catheters) and offer more choice to users. Evidence is needed that mixed-use is at least as safe and acceptable as using only single-use catheters.
METHODS: The MultICath Trial is a non-inferiority randomised controlled trial involving 578 participants. The aim is to compare mixed-use catheter management with single-use catheter management over 12 months. Participants are randomised on a 1:1 basis to either mixed-use catheter management, which includes an evidence-based cleaning method for the multi-use catheters (intervention) or single-use catheter management (control). Following randomisation, participants are followed up for 12 months. The primary outcome is at least one episode of microbiologically confirmed symptomatic urinary tract infection with help-seeking or self-help behaviour over the 12-month follow-up period. Laboratory analysis of patient-initiated urine samples is blind. Secondary outcomes include antibiotic use, microhaematuria, visible blood on catheter/in urine, quality of life and health economics. A qualitative sub-study to examine participant experiences using mixed-use is included.
ETHICS AND DISSEMINATION: Ethical review was undertaken by South Central-Hampshire A Research Ethics Committee and favourable opinion was granted on 12 July 2019 (reference: 19/SC/0334). Written, informed consent to participate was obtained from all participants. Results will be disseminated in peer-reviewed publications, in the National Institute for Health and Care Research journal library and to participants and the public via a lay summary published on the trial website.
TRIAL REGISTRATION NUMBER: ISRCTN42028483
The performance of digital technologies for measuring tuberculosis medication adherence: a systematic review.
Get PDFINTRODUCTION: Digital adherence technologies (DATs), such as phone-based technologies and digital pillboxes, can provide more person-centric approaches to support tuberculosis (TB) treatment. However, there are varying estimates of their performance for measuring medication adherence.
METHODS: We conducted a systematic review (PROSPERO-CRD42022313526), which identified relevant published literature and preprints from January 2000 to April 2023 in five databases. Studies reporting quantitative data on the performance of DATs for measuring TB medication adherence against a reference standard, with at least 20 participants, were included. Study characteristics and performance outcomes (eg, sensitivity, specificity and predictive values) were extracted. Sensitivity was the proportion correctly classified as adherent by the DAT, among persons deemed adherent by a reference standard. Specificity was the proportion correctly classified as non-adherent by the DAT, among those deemed non-adherent by a reference standard.
RESULTS: Of 5692 studies identified by our systematic search, 13 met inclusion criteria. These studies investigated medication sleeves with phone calls (branded as '99DOTS'; N=4), digital pillboxes N=5), ingestible sensors (N=2), artificial intelligence-based video-observed therapy (N=1) and multifunctional mobile applications (N=1). All but one involved persons with TB disease. For medication sleeves with phone calls, compared with urine testing, reported sensitivity and specificity were 70%-94% and 0%-61%, respectively. For digital pillboxes, compared with pill counts, reported sensitivity and specificity were 25%-99% and 69%-100%, respectively. For ingestible sensors, the sensitivity of dose detection was ≥95% compared with direct observation. Participant selection was the most frequent potential source of bias.
CONCLUSION: The limited number of studies available suggests suboptimal and variable performance of DATs for dose monitoring, with significant evidence gaps, notably in real-world programmatic settings. Future research should aim to improve understanding of the relationships of specific technologies, settings and user engagement with DAT performance and should measure and report performance in a more standardised manner
Cost-effectiveness of COVID rapid diagnostic tests for patients with severe/critical illness in low- and middle-income countries: A modeling study.
Get PDFBACKGROUND: Rapid diagnostic tests (RDTs) for coronavirus disease (COVID) are used in low- and middle-income countries (LMICs) to inform treatment decisions. However, to date, it is unclear when this use is cost-effective. Existing analyses are limited to a narrow set of countries and uses. The aim of this study is to assess the cost-effectiveness of COVID RDTs to inform the treatment of patients with severe illness in LMICs, considering real world practice.
METHODS AND FINDINGS: We assessed the cost-effectiveness of COVID testing across LMICs using a decision tree model, differentiating results by country income level, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) prevalence, and testing scenario (none, RDTs, polymerase chain reaction tests-PCRs and combinations). LMIC experts defined realistic care pathways and treatment options. Using a healthcare provider perspective and net monetary benefit approach, we assessed both intended (COVID symptom alleviation) and unintended (treatment side effects) health and economic impacts for each testing scenario. We included the side effects of corticosteroids, which are often the only available treatment for COVID. Because side effects depend both on the treatment and the patient's underlying illness (COVID or COVID-like illnesses, such as influenza), we considered the prevalence of COVID-like illnesses in our analyses. We found that SARS-CoV-2 testing of patients with severe COVID-like illness can be cost-effective in all LMICs, though only in some circumstances. High influenza prevalence among suspected COVID cases improves cost-effectiveness, since incorrectly provided corticosteroids may worsen influenza outcomes. In low- and some lower-middle-income countries, only patients with a high index of suspicion for COVID should be tested with RDTs, while other patients should be presumed to not have COVID. In some lower-middle-income and upper-middle-income countries, suspected severe COVID cases should almost always be tested. Further, in these settings, negative test results in patients with a high initial index of suspicion should be confirmed through PCR and, during influenza outbreaks, positive results in patients with a low initial index of suspicion should also be confirmed with a PCR. The use of interleukin-6 receptor blockers, when supported by testing, may also be cost-effective in higher-income LMICs. The cost at which they would be cost-effective in low-income countries (406 per treatment course) is below current prices. The primary limitation of our analysis is substantial uncertainty around some of the parameters in our model due to limited data, most notably on current COVID mortality with standard of care, and insufficient evidence on the impact of corticosteroids on patients with severe influenza.
CONCLUSIONS: COVID testing can be cost-effective to inform treatment of LMIC patients with severe COVID-like disease. The optimal algorithm is driven by country income level and health budgets, the level of suspicion that the patient may have COVID, and influenza prevalence. Further research to better characterize the unintended effects of corticosteroids, particularly on influenza cases, could improve decision making around the treatment of those with COVID-like symptoms in LMICs
Uncertainty in tuberculosis clinical decision-making: An umbrella review with systematic methods and thematic analysis.
Get PDFTuberculosis is a major infectious disease worldwide, but currently available diagnostics have suboptimal accuracy, particularly in patients unable to expectorate, and are often unavailable at the point-of-care in resource-limited settings. Test/treatment decision are, therefore, often made on clinical grounds. We hypothesized that contextual factors beyond disease probability may influence clinical decisions about when to test and when to treat for tuberculosis. This umbrella review aimed to identify such factors, and to develop a framework for uncertainty in tuberculosis clinical decision-making. Systematic reviews were searched in seven databases (MEDLINE, CINAHL Complete, Embase, Scopus, Cochrane, PROSPERO, Epistemonikos) using predetermined search criteria. Findings were classified as barriers and facilitators for testing or treatment decisions, and thematically analysed based on a multi-level model of uncertainty in health care. We included 27 reviews. Study designs and primary aims were heterogeneous, with seven meta-analyses and three qualitative evidence syntheses. Facilitators for decisions to test included providers' advanced professional qualification and confidence in tests results, availability of automated diagnostics with quick turnaround times. Common barriers for requesting a diagnostic test included: poor provider tuberculosis knowledge, fear of acquiring tuberculosis through respiratory sampling, scarcity of healthcare resources, and complexity of specimen collection. Facilitators for empiric treatment included patients' young age, severe sickness, and test inaccessibility. Main barriers to treatment included communication obstacles, providers' high confidence in negative test results (irrespective of negative predictive value). Multiple sources of uncertainty were identified at the patient, provider, diagnostic test, and healthcare system levels. Complex determinants of uncertainty influenced decision-making. This could result in delayed or missed diagnosis and treatment opportunities. It is important to understand the variability associated with patient-provider clinical encounters and healthcare settings, clinicians' attitudes, and experiences, as well as diagnostic test characteristics, to improve clinical practices, and allow an impactful introduction of novel diagnostics
Postpartum haemorrhage and risk of cardiovascular disease in later life: A population-based record linkage cohort study.
Get PDFOBJECTIVE: To investigate the association between postpartum haemorrhage (PPH) and subsequent cardiovascular disease. DESIGN: Population-based retrospective cohort study, using record linkage between Aberdeen Maternity and Neonatal Databank (AMND) and Scottish healthcare data sets.
SETTING: Grampian region, Scotland.
POPULATION: A cohort of 70 904 women who gave birth after 24 weeks of gestation in the period 1986-2016.
METHODS: We used extended Cox regression models to investigate the association between having had one or more occurrences of PPH in any (first or subsequent) births (exposure) and subsequent cardiovascular disease, adjusted for sociodemographic, medical, and pregnancy and birth-related factors.
MAIN OUTCOME MEASURES: Cardiovascular disease identified from the prescription of selected cardiovascular medications, hospital discharge records or death from cardiovascular disease.
RESULTS: In our cohort of 70 904 women (with 124 795 birth records), 25 177 women (36%) had at least one PPH. Compared with not having a PPH, having at least one PPH was associated with an increased risk of developing cardiovascular disease, as defined above, in the first year after birth (adjusted hazard ratio, aHR 1.96; 95% confidence interval, 95% CI 1.51-2.53; p < 0.001). The association was attenuated over time, but strong evidence of increased risk remained at 2-5 years (aHR 1.19, 95% CI 1.11-1.30, P < 0.001) and at 6-15 years after giving birth (aHR 1.17, 95% CI 1.05-1.30, p = 0.005).
CONCLUSIONS: Compared with women who have never had a PPH, women who have had at least one episode of PPH are twice as likely to develop cardiovascular disease in the first year after birth, and some increased risk persists for up to 15 years
Comparison of oral anticoagulants for stroke prevention in atrial fibrillation using the UK clinical practice research Datalink Aurum: A reference trial (ARISTOTLE) emulation study.
Get PDFBACKGROUND: Stroke prevention guidance for patients with atrial fibrillation (AF) uses evidence generated from randomised controlled trials (RCTs). However, applicability to patient groups excluded from trials remains unknown. Real-world patient data provide an opportunity to evaluate outcomes in a trial analogous population of direct oral anticoagulants (DOACs) users and in patients otherwise excluded from RCTs; however, there remains uncertainty on the validity of methods and suitability of the data. Successful reference trial emulation can support the generation of evidence around treatment effects in groups excluded or underrepresented in trials. We used linked United Kingdom primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban versus warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results.
METHODS AND FINDINGS: Patients with AF in the UK Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 January 2013 to 31 July 2019 were selected. ARISTOTLE eligibility criteria were applied to this population and matched to the RCT apixaban arm on baseline characteristics creating a trial-analogous apixaban cohort; this was propensity-score matched to warfarin users in the CPRD Aurum. ARISTOTLE outcomes were assessed using Cox proportional hazards regression stratified by prior warfarin exposure status during 2.5 years of patient follow-up and results benchmarked against the trial results before treatment effectiveness was further evaluated based on (warfarin) TTR. The dataset comprised 8,734 apixaban users and propensity-score matched 8,734 warfarin users. Results [hazard ratio (95% confidence interval)] confirmed apixaban noninferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) versus trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) versus trial 0.89 (0.80,0.998)] but did not indicate apixaban superiority. Absolute event rates for stroke/SE were similar for apixaban in CPRD Aurum and ARISTOTLE (1.27%/year), whereas a lower event rate was observed for warfarin (CPRD Aurum 1.29%/year, ARISTOTLE 1.60%/year). Analysis by TTR suggested similar effectiveness of apixaban compared with poorly controlled warfarin (TTR < 0.75) for stroke/SE [0.91 (0.73, 1.14)], all-cause death [0.94 (0.84, 1.06)], and superiority for major bleeding [0.74 (0.63, 0.86)]. However, when compared with well-controlled warfarin (TTR ≥ 0.75), apixaban was associated with an increased hazard for all-cause death [1.20 (1.04, 1.37)], and there was no significant benefit for major bleeding [1.08 (0.90, 1.30)]. The main limitation of the study's methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm, and selection bias and misclassification in the analysis by TTR.
CONCLUSIONS: Analysis of noninterventional data generated results demonstrating noninferiority of apixaban versus warfarin consistent with prespecified benchmarking criteria. Unlike in ARISTOTLE, superiority of apixaban versus warfarin was not seen, possible due to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. This methodological template can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or underrepresented in trials and provides a framework that can be adapted to investigate treatment effects for other conditions
Factors shaping network emergence: A cross-country comparison of quality of care networks in Bangladesh, Ethiopia, Malawi, and Uganda.
Get PDFThe Quality-of-Care Network (QCN) was conceptualized by the World Health Organization (WHO) and other global partners to facilitate learning on and improve quality of care for maternal and newborn health within and across low and middle-income countries. However, there was significant variance in the speed and extent to which QCN formed in the involved countries. This paper investigates the factors that shaped QCN's differential emergence in Bangladesh, Ethiopia, Malawi, and Uganda. Drawing on network scholarship, we conducted a replicated case study of the four country cases and triangulated several sources of data, including a document review, observations of national-level and district level meetings, and key informant interviews in each country and at the global level. Thematic coding was performed in NVivo 12. We find that QCN emerged most quickly and robustly in Bangladesh, followed by Ethiopia, then Uganda, and slowest and with least institutionalization in Malawi. Factors connected to the policy environment and network features explained variance in network emergence. With respect to the policy environment, pre-existing resources and initiatives dedicated to maternal and newborn health and quality improvement, strong data and health system capacity, and national commitment to advancing on synergistic goals were crucial drivers to QCN's emergence. With respect to the features of the network itself, the embedding of QCN leadership in powerful agencies with pre-existing coordination structures and trusting relationships with key stakeholders, inclusive network membership, and effective individual national and local leadership were also crucial in explaining QCN's speed and quality of emergence across countries. Studying QCN emergence provides critical insights as to why well-intentioned top-down global health networks may not materialize in some country contexts and have relatively quick uptake in others, and has implications for a network's perceived legitimacy and ultimate effectiveness in producing stated objectives