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Personalised risk-prediction tools for cryptococcal meningitis mortality to guide treatment stratification in sub-Saharan Africa: a prognostic modelling study based on pooled analysis of two randomised controlled trials.
Get PDFBACKGROUND: Cryptococcal meningitis is a major driver of global HIV-related mortality, and validated approaches to stratify mortality risk could help to target effective treatment strategies. We aimed to develop and validate models to predict risk of all-cause mortality in people with HIV-associated cryptococcal meningitis in sub-Saharan African countries. METHODS: For this prediction modelling study, we pooled individual-level data from the ACTA (ISRCTN45035509) and AMBITION-cm (ISRCTN72509687) randomised controlled trials. Data in ACTA were collected between Feb 12, 2013, and Jan 10, 2017, and data in AMBITION-cm were collected between Jan 31, 2018, and June 11, 2021. Adults aged 18 years or older with a first episode of HIV-associated cryptococcal meningitis were recruited to both trials. Exclusion criteria included pregnancy or lactation; receipt of high-dose anti-fungal treatment doses before screening; and contraindications to trial medication. Participants were recruited from nine hospitals across Cameroon, Malawi, Tanzania, and Zambia in ACTA and eight hospitals across Botswana, Malawi, South Africa, Uganda, and Zimbabwe in AMBITION-cm. We developed two primary multivariable logistic-regression models for the primary outcome of 2-week mortality: a basic model for use in a resource-limited setting that contained only candidate predictors that are routinely, programmatically obtained at hospital admission and a research model for which all predefined candidate predictors were considered for inclusion. We used internal-external cross-validation to evaluate model performance across countries within the development cohort (ie, data from all countries except Malawi participants in AMBITION-cm), before validation of discrimination, calibration, and net benefit in held-out data from Malawi. FINDINGS: We included 674 eligible participants from ACTA and 814 from AMBITION-cm in the pooled analysis (total sample size 1488). 1263 participants were included in model development, with 225 from the Malawi site in AMBITION-cm held out for validation. 222 (17·6%) of 1263 participants in the development set and 21 (9·3%) of 225 participants in the validation set met the primary model outcome of 2-week mortality. We retained five predictors in the basic model and seven in the research model. Predictors in both models were Glasgow Coma Scale score, Eastern Cooperative Oncology Group performance status, haemoglobin, blood neutrophil count, and treatment. Additional predictors in the research model were cerebrospinal fluid opening pressure and log10 cerebrospinal fluid quantitative cryptococcal culture. Discrimination was relatively consistent between study sites for both models (pooled C statistic 0·75 [95% CI 0·68-0·82] for the basic model and 0·78 [0·75-0·82] for the research model), but calibration was more heterogeneous (pooled calibration slope 0·87 [95% CI 0·57 to 1·17] and 0·83 [0·69 to 0·97], pooled calibration in the large 0·00 [-0·54 to 0·55] and -0·02 [-0·46 to 0·42], for the basic and research models, respectively). In held-out validation, discrimination of both models was slightly higher than estimates from internal-external cross-validation (C statistic 0·78 [95% CI 0·70-0·87] in the basic model and 0·85 [0·79-0·92] in the research model). Calibration assessment suggested overestimation of risk, particularly in the high-risk range: calibration slope 1·04 (95% CI 0·54 to 1·55), calibration in the large -0·55 (-1·02 to -0·07). When comparing single, high-dose liposomal amphotericin B plus 14 days of flucytosine plus fluconazole with 1 week of amphotericin B plus flucytosine in AMBITION-cm, hazard ratios were 0·50 (95% CI 0·26-0·97) in the low-risk stratum and 0·96 (0·67-1·37) in the high-risk stratum for the basic model, and 0·61 (0·31-1·18) in the low-risk stratum and 1·03 (0·72-1·47) in the high-risk stratum for the research model. INTERPRETATION: Both models accurately predicted 2-week mortality in people with HIV and have the potential to be incorporated into future treatment-stratification approaches in low-income and middle-income countries. FUNDING: National Institute for Health Research
Epstein-Barr virus and cytomegalovirus co-infections and mortality risk in patients with HIV-associated cryptococcal meningitis: a post-hoc analysis of a prospective nested cohort in the AMBITION-cm randomised controlled trial.
Get PDFBACKGROUND: HIV-associated cryptococcal meningitis case fatality remains greater than 25%. Co-prevalent infections might contribute to poor outcomes. We aimed to ascertain the prevalence and the clinical significance of Epstein-Barr virus (EBV) and cytomegalovirus co-infections in patients with cryptococcal meningitis to guide potential therapeutic interventions. METHODS: We conducted a post-hoc analysis of a prospective cohort using plasma and cerebrospinal fluid (CSF) samples collected in the AMBITION-cm randomised trial. AMBITION-cm was done at seven hospital sites across five African countries (Botswana, Malawi, South Africa, Uganda, and Zimbabwe). The primary endpoint of the trial was all-cause mortality at 10 weeks. Quantitative PCR (qPCR) was used to measure baseline cytomegalovirus and EBV viral loads in these samples. Baseline demographic and clinical data including antiretroviral therapy status, and laboratory data including CD4 cell count, CSF white cell count, protein, glucose, and quantitative cryptococcal culture were captured in real time via an electronic medical records system. We assessed the prevalence of cytomegalovirus plasma viraemia and EBV plasma viraemia, and CNS co-infections, associations between cytomegalovirus and EBV co-infection status and baseline covariates, and associations with 2-week and 10-week mortality. FINDINGS: Between Jan 31, 2018, and Feb 18, 2021, among 811 participants enrolled, 60% were male, median age was 37 years (IQR 32-43), and median baseline CD4 count was 27 cells per μL (IQR 10-58). Cytomegalovirus plasma viraemia was present in 395 (49%) of 804 participants and EBV plasma viraemia was present in 585 (73%) participants. 39 (5%) of 707 participants had detectable cytomegalovirus in the CSF and 191 (27%) of 708 participants had detectable EBV. Cytomegalovirus plasma viraemia was associated with lower CD4 cell counts, less CSF inflammation, and higher CSF fungal burdens. Conversely, EBV plasma viraemia was associated with higher CD4 cell counts and more CSF inflammation. At 2 and 10 weeks, the risk of mortality was two times higher in participants with high-level cytomegalovirus plasma viraemia (≥1000 copies per mL) than in participants without cytomegalovirus plasma viraemia (adjusted odds ratio 2·31 [95% CI 1·12-4·75] at 2 weeks; 2·44 [1·33-4·45] at 10 weeks). EBV coinfections were not associated with increased mortality. INTERPRETATION: These data indicate that cytomegalovirus might be an important copathogen in this context, and that cytomegalovirus viraemia represents a potentially modifiable risk factor to reduce mortality among adults with HIV-associated cryptococcal meningitis. Interventional trials are now required and planned to determine whether treatment of cytomegalovirus viraemia improves outcomes in advanced HIV disease. FUNDING: National Institute for Health and Care Research, European and Developing Countries Clinical Trials Partnership, Medical Research Council, and Wellcome Trust
Stillbirths: Contribution of preterm birth and size-for-gestational age for 125.4 million total births from nationwide records in 13 countries, 2000-2020.
Get PDFOBJECTIVE: To examine the contribution of preterm birth and size-for-gestational age in stillbirths using six 'newborn types'. DESIGN: Population-based multi-country analyses.
SETTING: Births collected through routine data systems in 13 countries. SAMPLE: 125 419 255 total births from 22+0 to 44+6 weeks' gestation identified from 2000 to 2020.
METHODS: We included 635 107 stillbirths from 22+0 weeks' gestation from 13 countries. We classified all births, including stillbirths, into six 'newborn types' based on gestational age information (preterm, PT, 90th centile) for gestational age, according to the international newborn size for gestational age and sex INTERGROWTH-21st standards. MAIN
OUTCOME MEASURES: Distribution of stillbirths, stillbirth rates and rate ratios according to six newborn types.
RESULTS: 635 107 (0.5%) of the 125 419 255 total births resulted in stillbirth after 22+0 weeks. Most stillbirths (74.3%) were preterm. Around 21.2% were SGA types (PT + SGA [16.2%], PT + AGA [48.3%], T + SGA [5.0%]) and 14.1% were LGA types (PT + LGA [9.9%], T + LGA [4.2%]). The median rate ratio (RR) for stillbirth was highest in PT + SGA babies (RR 81.1, interquartile range [IQR], 68.8-118.8) followed by PT + AGA (RR 25.0, IQR, 20.0-34.3), PT + LGA (RR 25.9, IQR, 13.8-28.7) and T + SGA (RR 5.6, IQR, 5.1-6.0) compared with T + AGA. Stillbirth rate ratios were similar for T + LGA versus T + AGA (RR 0.7, IQR, 0.7-1.1). At the population level, 25% of stillbirths were attributable to small-for-gestational-age.
CONCLUSIONS: In these high-quality data from high/middle income countries, almost three-quarters of stillbirths were born preterm and a fifth small-for-gestational age, with the highest stillbirth rates associated with the coexistence of preterm and SGA. Further analyses are needed to better understand patterns of gestation-specific risk in these populations, as well as patterns in lower-income contexts, especially those with higher rates of intrapartum stillbirth and SGA
Factors shaping evidence use in education policy: Findings from a systematic review
Get PDFThis chapter examines a subset of 85 education papers drawn from an external systematic review of barriers to and facilitators of the use of evidence by policy makers. It also presents the latest trends in research on factors shaping evidence use in education policy. It analyses the main trends in the education subset, draws comparisons with trends in other knowledge domains, and situates these findings within broader OECD research on knowledge mobilisation in education
Infections, Animal-Source Foods, and Micronutrient Status as Correlates of Serum IGF-1 in Children with Stunting: A Cross-sectional Study in Uganda.
Get PDFBACKGROUND: Serum insulin-like growth factor-1 (serum IGF-1) is important for growth in childhood. Inflammation downregulates serum IGF-1, but the roles of intake of animal-source foods and micronutrient status are not well known. OBJECTIVES: We assessed the associations of infections, intake of animal-source foods, iron, B12, folate, and vitamin A status with serum IGF-1 among stunted children. METHODS: We conducted a cross-sectional study, using data from a nutrition trial among 12-59-mo-old stunted Ugandan children. Data on sociodemography, anthropometry, breastfeeding, dietary intake, and morbidity were collected. Serum IGF-1 and markers of micronutrient status and inflammation were determined. A rapid malaria test was done. Fat and fat-free mass were measured using bioimpedance. Tobit regression was used to assess correlates of serum IGF-1. RESULTS: Of 750 children, 45.1% (n = 338) were girls and 29.6% (n = 222) were 1.05 μmol/L was associated with 14.3 (95% CI: 9.6, 19.1) and 6.1 (95% CI: 1.6, 10.6) μg/L lower serum IGF-1 after adjustments for age, sex, and inflammation. Markers of other micronutrients were not. Intake of milk, but not meat or eggs, was associated with 3.9 (95% CI: 0.7, 7.1) μg/L higher serum IGF-1. CONCLUSIONS: Milk intake and vitamin A status were positively associated with serum IGF-1. In contrast to milk, vitamin A has not consistently been associated with growth. This requires further investigation
Money for health: handling the costs of climate change to African health systems.
Get PDFThe manifold impacts of climate change are also seen in the field of health in most countries. It is particularly so in Africa, whose health systems are amongst the most fragile in the world. This Commentary showcases the degree of vulnerability of the health systems of African countries to climate change, and describes some measures aimed at increasing their resilience to climate shocks. African health systems face significant challenges due to climate change, necessitating a comprehensive approach to enhance resilience
Introduction, establishment, and distribution of Aedes aegypti and dengue in a temperate capital of Brazil: a retrospective surveillance-based study.
Get PDFBACKGROUND: Dengue is spreading to southern latitudes in Brazil, where the temperate climate was once a barrier to the primary vector, Aedes aegypti. In this study, our objective was to reconstruct the introduction, establishment, and subsequent expansion of Ae. aegypti and dengue in Porto Alegre, the southernmost state capital of Brazil, located in Rio Grande do Sul state. METHODS: This ecological study used entomological and epidemiological surveillance data and official reports obtained from municipal health authorities of Porto Alegre, from 2001 to 2021. Descriptive analyses were employed, supplemented by space-time scan statistics to identify high-risk vector abundance and dengue case clusters. FINDINGS: Ae. aegypti was first detected in Porto Alegre in 2001, spreading citywide by 2016. The first autochthonous dengue case was recorded in 2010, and by 2021 the disease was detected in 78% of the neighbourhoods. DENV-1 was the dominant serotype and most cases occurred among people aged 20-59. Clusters of vectors and dengue cases were more frequent during summer and autumn, but a few were also identified during winter. High-risk clusters for vectors were more frequent in the Partenon and Northwest regions and for dengue in the East, Centre, Partenon and South. INTERPRETATION: Ae. aegypti successfully established and spread within a temperate city in Brazil. The presence of vectors, a susceptible population and socio-environmental characteristics conducive to mosquito proliferation resulted in autochthonous transmission of dengue fever after the continuous introduction of imported cases. The climatic barrier to dengue transmission in the south of Brazil has shifted southward, coinciding with the colonisation of Ae. aegypti and the emergence of dengue in recent years in Porto Alegre. FUNDING: Generalitat de Catalunya, European Commission, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
A scalable CRISPR-Cas9 gene editing system facilitates CRISPR screens in the malaria parasite Plasmodium berghei.
Get PDFMany Plasmodium genes remain uncharacterized due to low genetic tractability. Previous large-scale knockout screens have only been able to target about half of the genome in the more genetically tractable rodent malaria parasite Plasmodium berghei. To overcome this limitation, we have developed a scalable CRISPR system called P. berghei high-throughput (PbHiT), which uses a single cloning step to generate targeting vectors with 100-bp homology arms physically linked to a guide RNA (gRNA) that effectively integrate into the target locus. We show that PbHiT coupled with gRNA sequencing robustly recapitulates known knockout mutant phenotypes in pooled transfections. Furthermore, we provide an online resource of knockout and tagging designs to target the entire P. berghei genome and scale-up vector production using a pooled ligation approach. This work presents for the first time a tool for high-throughput CRISPR screens in Plasmodium for studying the parasite's biology at scale
ENSAIO SOBRE DEFICIÊNCIA, MIGRAÇÃO E PROTEÇÃO SOCIAL NO BRASIL
Get PDFO ensaio discute as relações entre regulação migratória e assistência social, no tocante aos migrantes internacionais com deficiência. Nos apoiamos em documentos normativos nacionais e internacionais que mencionam imigração e deficiência, investigando os sentidos de proteção social que deles emergem. Enfatizamos o caráter eugênico e capacitista das normativas brasileiras de longa duração, aspecto que conjuga com desafios atuais, como: pouca repercussão das orientações humanitárias sobre a gestão migratória brasileira; invisibilidade informacional e política dessa população; e limitações estruturantes da política socioassistencial, cuja atuação com imigrantes com deficiência ainda demanda maiores reflexões e mobilização dos mecanismos de justiça para efetivação, ampliação e universalização
Pilot project demonstrating the feasibility of HIV antiretroviral therapy waste bottle collection and recycling
Get PDFBackground HIV remains a leading cause of morbidity and mortality in Uganda. At current levels of antiretroviral therapy (ART) coverage, ART waste bottles are becoming a challenge to both patients and the environment in Uganda. Additionally, ART improperly disposed of in the environment can end up in the food chain and lead to antimicrobial resistance. We aimed to pilot a feasibility study of collecting and recycling the used ART pill bottles at a large urban HIV clinic in Kampala, Uganda. Methods Patients were first engaged randomly during their clinic visits and asked how they disposed of the waste medication bottles. Verbal information on proper disposal options of these medication containers was provided to patients. Patients and caretakers were then encouraged to return the waste medication bottles to the clinic at the time of their next appointment. Posters conveying information about bottle returns were displayed and information leaflets were distributed. Finally, recycling partners were engaged to explore options for the bottles. Results From the group oral engagements performed, patients reported that a means to discreetly dispose of pill bottles was welcome due to the stigma associated with these bottles in the community. They reported previously throwing these bottles in pit latrines, informal rubbish pits, nearby bushes and burning them, all methods that endanger the environment. The process of returning bottles was widely adopted. 53kg of returned bottles were recycled to make each bench that are used by patients in the clinic. Conclusions This pilot study showed a high willingness among people living with HIV to return their used pill bottles. Collecting, storing and recycling was feasible and successful at one large urban HIV clinic in Kampala, Uganda. We, therefore, recommend expanding this model to more HIV clinics country-wide to reduce the environmental impact of HIV programmes.</ns3:p