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How mathematical modelling can inform outbreak response vaccination.
Get PDFMathematical models are established tools to assist in outbreak response. They help characterise complex patterns in disease spread, simulate control options to assist public health authorities in decision-making, and longer-term operational and financial planning. In the context of vaccine-preventable diseases (VPDs), vaccines are one of the most-cost effective outbreak response interventions, with the potential to avert significant morbidity and mortality through timely delivery. Models can contribute to the design of vaccine response by investigating the importance of timeliness, identifying high-risk areas, prioritising the use of limited vaccine supply, highlighting surveillance gaps and reporting, and determining the short- and long-term benefits. In this review, we examine how models have been used to inform vaccine response for 10 VPDs, and provide additional insights into the challenges of outbreak response modelling, such as data gaps, key vaccine-specific considerations, and communication between modellers and stakeholders. We illustrate that while models are key to policy-oriented outbreak vaccine response, they can only be as good as the surveillance data that inform them
School-age growth and development following infant feeding and/or water, sanitation, and hygiene interventions in rural Zimbabwe: long-term follow-up of a cluster-randomised trial.
Get PDFBACKGROUND: Few trials have explored long-term effects of interventions designed to reduce child stunting. We evaluated school-age outcomes in rural Zimbabwean children who received cluster-randomised water, sanitation and hygiene (WASH) and/or infant and young child feeding (IYCF) interventions from pregnancy up to 18 months of age.
METHODS: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial enrolled pregnant women from two rural Zimbabwean districts (Chirumanzu and Shurugwi) between 2012 and 2015, and cluster-randomised them using a 2 × 2 factorial design to standard-of-care, WASH, IYCF, or combined WASH & IYCF, with a co-primary outcome of height-for-age Z-score and haemoglobin at 18 months (clinicaltrials.govNCT01824940). Children who were HIV-unexposed, age 7 years, and still living in Shurugwi district were eligible for this follow-up study (registered at PACTR 202201828512110) and measured between 1st April 2021 and 30th September 2022. The primary outcome at 7 years was cognitive function using the Kaufman Assessment Battery for Children (KABC-II). Secondary outcomes were executive function, literacy and numeracy, fine motor skills, socioemotional function, handgrip strength, broad jump distance, shuttle-run test distance, anthropometry, lean mass index, and skinfold thicknesses. Study nurses conducting assessments were blinded to intervention arm. Analysis followed a pre-registered statistical analysis plan. Intention-to-treat analyses using generalized estimating equations were used to assess the long-term effects of WASH and IYCF on each outcome, leveraging the factorial trial design. A pre-specified subgroup analysis by child sex was also performed.
FINDINGS: Among 3989 HIV-negative women, 3676 children were assessed at age 18 months; of these, 1002 (510 female) were assessed at mean (SD) age 7.3 (0.2) years. There was no effect of IYCF or WASH on the KABC-II score or secondary cognitive outcomes, except a small improvement in socioemotional function in WASH arms (-0.98 points, 95% CI -1.73, -0.22, p = 0.01). Children in IYCF arms had higher handgrip strength (0.28 Kg, 95% CI 0.02, 0.53, p = 0.03); however, in the pre-specified subgroup analysis, improved handgrip strength was seen only in boys (0.53 Kg, 95% CI 0.19, 0.87 p = 0.002). There were no significant effects of either intervention on other outcomes.
INTERPRETATION: Early-life IYCF and WASH led to few functional benefits by school-age. Interventions that are more comprehensive, delivered for longer, and include nurturing care should be considered to improve long-term cognitive and physical function. FUNDING: Wellcome [220671/Z/20/Z, 108065/Z/15/Z]; NIH [R61HD103101]; Thrasher [15250]; and IMMANA [3.02]
Methods for measuring body composition in Zambian adolescents living with HIV.
Get PDFAssessment of body composition can be useful in managing many clinical or public health conditions, including HIV. Most people living with HIV infection are in Africa where clinics may lack equipment, utilities or staff time for optimal body composition assessment. Thus, it is important to determine whether less expensive and more available and scalable methods can provide adequate information. We estimated body composition of 420 perinatally HIV-infected Zambian adolescents, aged 11-19 years, using dual-energy X-ray absorptiometry (DXA), bioelectrical impedance (BIA) and anthropometry: body mass index (BMI), waist circumference, and subscapular and suprailiac skinfolds. Data were converted to internal population Z-scores in order to compare measures. BIA and DXA were compared for total fat and fat-free mass, BMI was compared to DXA fat mass, and waist circumference and skinfolds were compared to DXA trunk (central) fat. Neither anthropometry nor BIA adequately reflected total fat or trunk fat as measured by DXA. Although mean bias was generally small, especially for females, the limits of agreement were wide for all comparisons. In addition, for central fat in males, the bias was larger at higher mean Z-score values. BMI had similar agreement with DXA fat mass, as did BIA in females, though not males. We conclude that, because of wide limits of agreement and bias in some measures, none of the simpler methods examined are adequate for assessing longitudinal changes in body composition in order to monitor children's health. However, where BIA is available and DXA is not, BIA may still be able to describe broad trends in body composition of African adolescents living with HIV
Association of the humoral immune response with the inflammatory profile in Plasmodium vivax infections in pregnant women.
Get PDFBACKGROUND: Plasmodium vivax infection, when it occurs during pregnancy, has often been associated with serious adverse pregnancy outcomes. However, immunological alterations in pregnancy and their consequences have been little explored. We characterized the humoral immune response in pregnant women exposed to malaria by P. vivax antigens and its association with the maternal inflammatory profile and poor pregnancy outcomes.
METHODS: An observational cohort study in the Brazilian Amazon was conducted between 2013 and 2015. After applying exclusion criteria, 242 mother-child pairs were included in the analysis. Data on maternal infection, gestational outcomes, and inflammatory factors were evaluated in the maternal peripheral plasma. In samples from the first infection, the presence of total IgG and its subclasses in plasma against PvMSP119 protein were also quantified.
RESULTS: Previous exposure to malaria, observed by anti-total IgG antibodies to the PvMSP119 antigen, increased the inflammatory response to infection when the pregnant woman had malaria during pregnancy. IL-6 and IL-10 levels were positively correlated with parasitemia and with total IgG levels; but they were negatively correlated with the gestational age at delivery from Pv-infected woman. In multivariate linear regression analyses, IgG 1, 2 and 4 was negatively and positively associated with cytokines IL-6 and IL-10, respectively, in P. vivax-infection.
CONCLUSIONS: An association between the humoral immune response and the peripheral inflammatory cytokine profile with the adverse outcomes in malaria in pregnancy by P. vivax was observed. Previous exposure to the parasite can influence the IL-6 and IL-10 response, which is associated with increased parasitemia, reduced maternal weight gain and premature delivery
Combination of computational techniques and RNAi reveal targets in Anopheles gambiae for malaria vector control.
Get PDFIncreasing reports of insecticide resistance continue to hamper the gains of vector control strategies in curbing malaria transmission. This makes identifying new insecticide targets or alternative vector control strategies necessary. CLassifier of Essentiality AcRoss EukaRyote (CLEARER), a leave-one-organism-out cross-validation machine learning classifier for essential genes, was used to predict essential genes in Anopheles gambiae and selected predicted genes experimentally validated. The CLEARER algorithm was trained on six model organisms: Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Saccharomyces cerevisiae and Schizosaccharomyces pombe, and employed to identify essential genes in An. gambiae. Of the 10,426 genes in An. gambiae, 1,946 genes (18.7%) were predicted to be Cellular Essential Genes (CEGs), 1716 (16.5%) to be Organism Essential Genes (OEGs), and 852 genes (8.2%) to be essential as both OEGs and CEGs. RNA interference (RNAi) was used to validate the top three highly expressed non-ribosomal predictions as probable vector control targets, by determining the effect of these genes on the survival of An. gambiae G3 mosquitoes. In addition, the effect of knockdown of arginase (AGAP008783) on Plasmodium berghei infection in mosquitoes was evaluated, an enzyme we computationally inferred earlier to be essential based on chokepoint analysis. Arginase and the top three genes, AGAP007406 (Elongation factor 1-alpha, Elf1), AGAP002076 (Heat shock 70kDa protein 1/8, HSP), AGAP009441 (Elongation factor 2, Elf2), had knockdown efficiencies of 91%, 75%, 63%, and 61%, respectively. While knockdown of HSP or Elf2 significantly reduced longevity of the mosquitoes (p<0.0001) compared to control groups, Elf1 or arginase knockdown had no effect on survival. However, arginase knockdown significantly reduced P. berghei oocytes counts in the midgut of mosquitoes when compared to LacZ-injected controls. The study reveals HSP and Elf2 as important contributors to mosquito survival and arginase as important for parasite development, hence placing them as possible targets for vector control
Health impacts of takeaway management zones around schools in six different local authorities across England: a public health modelling study using PRIMEtime.
Get PDFBACKGROUND: In England, the number of takeaway food outlets ('takeaways') has been increasing for over two decades. Takeaway management zones around schools are an effective way to restrict the growth of new takeaways but their impacts on population health have not been estimated.
METHODS: To model the impact of takeaway management zones on health, we used estimates of change in and exposure to takeaways (across home, work, and commuting buffers) based on a previous evaluation suggesting that 50% of new outlets were prevented from opening because of management zones. Based on previous cross-sectional findings, we estimated changes in body mass index (BMI) from changes in takeaway exposure, from 2018 to 2040. We used PRIMEtime, a proportional multistate lifetable model, and BMI change to estimate the impact of the intervention, in a closed-cohort of adults (25-64 years), on incidence of 12 non-communicable diseases, obesity prevalence, quality-adjusted life years (QALYs), and healthcare costs saved by 2040 in six local authorities (LAs) across the rural-urban spectrum in England (Wandsworth, Manchester, Blackburn with Darwen, Sheffield, North Somerset, and Fenland).
RESULTS: By 2031, compared to no intervention, reductions in outlet exposure ranged from 3 outlets/person in Fenland to 28 outlets/person in Manchester. This corresponded to mean per person reductions in BMI of 0.08 and 0.68 kg/m2, respectively. Relative to no intervention, obesity prevalence was estimated to be reduced in both sexes in all LAs, including by 2.3 percentage points (PP) (95% uncertainty interval:2.9PP, 1.7PP) to 1.5PP (95%UI:1.9PP, 1.1PP) in males living in Manchester and Wandsworth by 2040, respectively. Model estimates showed reductions in incidence of disease, including type II diabetes (e.g. 964 (95% UI: 1565, 870) fewer cases/100,000 population for males in Manchester)), cardiovascular diseases, asthma, certain cancers, and low back pain. Savings in healthcare costs (millions) ranged from £1.65 (95% UI: £1.17, £2.25)/100,000 population in North Somerset to £2.02 (95% UI: £1.39, £2.83)/100,000 population in Wandsworth. Gains in QALYs/100,000 person were broadly similar across LAs.
CONCLUSIONS: Takeaway management zones in England have the potential to meaningfully contribute towards reducing obesity prevalence and associated healthcare burden in the adult population, at the local level and across the rural-urban spectrum
Is alcohol use disorder associated with higher rates of depression and anxiety among people with new onset type 2 diabetes? A cohort study using linked primary care data in England.
Get PDFINTRODUCTION: Depression and alcohol use disorder (AUD) in people living with Type 2 diabetes mellitus (T2DM) are associated with worse health outcomes. AUD is strongly associated with depression and anxiety, but it is not known how these conditions cluster in people with T2DM. We investigated rates of new episodes of depression and anxiety following T2DM diagnosis in people with and without prior AUD among an English primary care population.
METHODS: The study population was people diagnosed with T2DM between 2004 and 2019. We used the Clinical Practice Research Datalink (CPRD) Aurum database and linked Hospital Episode Statistics Admitted Patient Care (HES APC) and Office for National Statistics (ONS) mortality data. We examined incidence of new episodes of anxiety or depression in people with T2DM with and without AUD. AUD was defined as any of i) clinical diagnosis; ii) alcohol withdrawal; or iii) chronic alcohol-related harm (physical or mental) using SNOMED-CT or ICD-10 codes. People were excluded if they had codes for depression/anxiety 12 months prior to T2DM diagnosis. Poisson regression models were fitted adjusting sequentially for a) age, gender, calendar time; b) region, Index of Multiple Deprivation, ethnicity, body mass index, smoking status, Charlson co-morbidity index; and c) history of a mental health condition.
RESULTS: Our study population was 479,447 people of whom 10,983 (2.3%) had an AUD code prior to T2DM diagnosis. After adjusting for all measured confounders except history of a mental health condition, IRR for depression was 2.00 (95% CI 1.93, 2.06) for people with AUD compared to without AUD. This reduced to 1.45 (95% CI 1.41, 1.50) after further adjustment for history of a mental health condition. Findings for anxiety were substantially similar to those for depression (adjusted for all measured confounders except history of a mental health condition, IRR 2.08 95% CI 1.99, 2.18 fully adjusted IRR 1.48 95% CI 1.41, 1.55).
CONCLUSIONS: People with AUD have over double the rates of depression and anxiety following T2DM diagnosis than those without AUD. This was only partially explained by pre-existing diagnoses of mental health conditions. A holistic approach incorporating mental health support is needed to improve health outcomes for people with AUD who develop T2DM.
TRIAL REGISTRATION: Not applicable
Incidence, prevalence and risk factors for comorbid mental illness among people with hypertension and type 2 diabetes in West Africa: protocol for a systematic review and meta-analysis.
Get PDFINTRODUCTION: Mental illness remains a significant global health concern that affects diverse populations, including individuals living with hypertension and/or type 2 diabetes, predominantly in lower-income to middle-income countries. The association between non-communicable diseases (NCDs) and mental illness is firmly established globally, however, this connection has yet to be comprehensively explored in West Africa. Our systematic review and meta-analysis aim to synthesise existing evidence on the prevalence, incidence, and risk factors for comorbid mental illness with hypertension and/or type 2 diabetes in West Africa. This effort seeks to contribute to bridging the knowledge gap and facilitating the implementation of interventions tailored to this context.
METHODS AND ANALYSIS: A comprehensive search will be conducted across multiple databases (PubMed, Google Scholar, PsycINFO, Carin Info and CINAHL), supplemented by searches on the websites of the WHO and various countries' ministries of health, and references cited in relevant papers. Inclusion criteria specify studies conducted in countries from the Economic Community of West African States, reported from January 2000 until date of search, focusing on adults with hypertension and/or type 2 diabetes and mental illness. Exclusion criteria encompass studies outside the specified time frame, involving pregnant women, or lacking relevant outcomes. There will be no language restrictions for inclusion. Study selection, data extraction and risk of bias assessment will be carried out independently by at least two reviewers. We will employ pooled proportions of OR, risk ratio and mean differences to assess prevalence, and incidence of mental illness and heterogeneity will be assessed.
ETHICS AND DISSEMINATION: This protocol does not require ethical approval; however, it is a part of a larger study on NCDs, which has received ethical clearance from the Ghana Health Service (ID NO: GHS-ERC 013/02/23). The results will be presented to stakeholders (policymakers and practitioners) and disseminated through conferences and peer-reviewed publications.
PROSPERO REGISTRATION NUMBER: CRD42023450732
Addressing data quality issues to assess clinical and epidemiological risk factors for COVID-19 among documented cases in Liberia: a single-centre, retrospective, observational study.
Get PDFINTRODUCTION: Identification of risk factors for severe COVID-19 can help to inform case management in resource-constrained settings. We aimed to rigorously but retroactively address data issues to identify risk factors for COVID-19 morbidity and mortality among cases seeking care in Liberia. METHODS: Chart data on confirmed cases were extracted at the national COVID-19 treatment unit. Due to the use of paper charts, assignment of non-unique identifiers and incomplete documentation, data required cleaning to remove duplicates per three sets of predefined criteria. Associations between epidemiological, clinical and demographic variables and indicators of disease severity were assessed using multivariable logistic regression. RESULTS: The raw data set for patients classified between 15 March and 1 September 2020 included 2703 cases or 107% more than the 1303 cases reported by the national surveillance system during the same period. The median age of cases was found to be 38 years (IQR: 27-50); most cases were men (65%). The rates of continuous positive airway pressure (CPAP) use for breathing support and of case fatality were 5% (71/1330) and 5% (52/981), respectively. Increased odds of breathing assistance with CPAP use were associated with self-reported diabetes (aOR: 4.37; 95% CI: 1.72 to 10.4) and/or hypertension (aOR: 4.86; 95% CI: 1.81 to 12.2) and increasing age (aOR: 1.06; 95% CI: 1.04 to 1.08). Recent travel history (aOR: 5.13; 95% CI: 1.13 to 19.3) and residence outside of urban Montserrado County (aOR: 22.7; 95% CI: 8.08 to 76.4) were associated with increased odds of death. CONCLUSIONS: Results from this retrospective analysis highlight self-reported non-communicable diseases as well as residence outside of largely urbanised Montserrado County as factors associated with COVID-19 severity among presenting cases in Liberia. The findings, both in terms of analytical results and data quality concerns, offer insight into how access to the highly centralised health systems and processes in Liberia may have affected populations distant from the central response in terms not only of COVID-19 disease outcomes but also care-seeking behaviour and surveillance effectiveness. This has implications for surveillance and response across priority diseases
Impact of the 100 days mission for vaccines on COVID-19: a mathematical modelling study.
Get PDFBACKGROUND: The COVID-19 pandemic has underscored the beneficial impact of vaccines. It also highlighted the need for future investments to expedite an equitable vaccine distribution. The 100 Days Mission aims to develop and make available a new vaccine against a future pathogen with pandemic potential within 100 days of that pathogen threat being recognised. We assessed the value of this mission by estimating the impact that it could have had on the COVID-19 pandemic.
METHODS: Using a previously published model of SARS-CoV-2 transmission dynamics fitted to excess mortality during the COVID-19 pandemic, we projected scenarios for three different investment strategies: rapid development and manufacture of a vaccine, increasing manufacturing capacity to eliminate supply constraints, and strengthening health systems to enable faster vaccine roll-outs and global equity. Each scenario was compared against the observed COVID-19 pandemic to estimate the public health and health-economic impacts of each scenario.
FINDINGS: If countries implemented non-pharmaceutical interventions (NPIs) as they did historically, the 100 Days Mission could have averted an estimated 8·33 million deaths (95% credible interval [CrI] 7·70-8·68) globally, mostly in lower-middle income countries. This corresponds to a monetary saving of US$14·35 trillion (95% CrI 12·96-17·87) based on the value of statistical life-years saved. Investment in manufacturing and health systems further increases deaths averted to 11·01 million (95% CrI 10·60-11·49). Under an alternative scenario whereby NPIs are lifted earlier on the basis of vaccine coverage, the 100 Days Mission alone could have reduced restrictions by 12 600 days (95% CrI 12 300-13 100) globally while still averting 5·76 million deaths (95% CrI 4·91-6·81).
INTERPRETATION: Our findings show the value of the 100 Days Mission and how these can be amplified through improvements in manufacturing and health systems equity. However, these investments must be enhanced by prioritising a more equitable global vaccine distribution.
FUNDING: Schmidt Science Fellowship in partnership with the Rhodes Trust, WHO, UK Medical Research Council, Coalition for Epidemic Preparedness Innovations