Department For International Development Research Articles

Arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a single-centre, open-label, randomised, non-inferiority trial

SummaryBackgroundTriple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children.MethodsIn this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2–12 years and had an asexual parasitaemia of 5000–250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane–piperaquine, arterolane–piperaquine–mefloquine, or artemether–lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether–lumefantrine was administered twice daily (target dose 5–24 mg/kg of bodyweight of artemether and 29–144 mg/kg of bodyweight of lumefantrine), and oral arterolane–piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane–piperaquine–mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane–piperaquine–mefloquine versus artemether–lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was −7%. The study is registered in ClinicalTrials.gov, NCT03452475, and is completed.FindingsBetween March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane–piperaquine (n=73), arterolane–piperaquine–mefloquine (n=72), or artemether–lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane–piperaquine–mefloquine (100%, 95% CI 95–100; 72/72) was non-inferior to that after treatment with artemether–lumefantrine (96%, 95% CI 88–99; 69/72; risk difference 4%, 95% CI 0–9; p=0·25). The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine was non-inferior to that of arterolane–piperaquine (100%, 95% CI 95–100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane–piperaquine (5%, 95% CI 2–9; ten of 203 drug administrations; p=0·0013) or arterolane–piperaquine–mefloquine (5%, 3–9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether–lumefantrine (1%, 0–2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether–lumefantrine; n=19 for arterolane–piperaquine–mefloquine; n=23 for arterolane–piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths.InterpretationThis study shows that arterolane–piperaquine–mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance.FundingUK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries

Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study

SummaryBackgroundMicrobiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19.MethodsThe International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded.FindingsWe analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59–84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus. Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives.InterpretationIn patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist.FundingNational Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London.

Impact of a Homestead Food Production Program on Dietary Diversity: Seasonal and Annual Results from the FAARM Trial in Sylhet, Bangladesh

ObjectivesWe examine the impact of a nutrition-sensitive agricultural program on the dietary diversity of women and children enrolled in the Food and Agricultural Approaches to Reducing Malnutrition (FAARM) cluster-randomized controlled trial in rural Habiganj, Sylhet, Bangladesh. The homestead food production intervention, implemented by Helen Keller International, began in mid-2015 and ended in December 2018. MethodsWe use four data sources: 1) baseline data (all women and their youngest child, March-May 2015); 2) surveillance data (every two months - all children 6–18m and a rotating random third of women and children 19–37m, September 2015-August 2019); 3) endline data (all women and children 6–23m, September 2019-February 2020); 4) phone survey during the COVID-19 lockdown (a random two-thirds of women, May-June 2020). We calculated dietary diversity for women (MDDW-10) and children (WHO IYCF). Our analysis included 24,931 observations of 2,701 women and 17,445 observations of 2,162 children (6–37m). We estimate the impact of the intervention on dietary diversity using multi-level regression, controlling for clustering by settlement and repeated measures. ResultsDietary diversity scores and the proportion of women and children classified as consuming adequate diets varied greatly over the year, peaking in May/June with 5.3 food groups for women (out of ten) and 3.8 food groups for children (out of seven). Over all program years, intervention women had 1.8 higher odds of consuming an adequate diet compared to control women (p < 0.001). However, this benefit varied from 1.3 in the first year of the intervention (p = 0.015) to 2.3 in the last year (p < 0.001), before falling to around 1.9 in the post-intervention years (p < 0.001). We saw a nearly identical pattern in children. Dietary improvement was driven through incremental increases in nearly all food groups. ConclusionsThe intervention successfully increased dietary diversity in women and children, and these impacts persisted after the project closed, including during the COVID-19 lockdown period. Funding SourcesThe German Ministry for Education and Research (BMBF) is the primary funder for the FAARM trial. The U.K. Department for International Development (DFID) supported the design of the surveillance system.

Associations of Percent Energy Intake From Total, Animal and Plant Protein With Overweight/Obesity and Underweight Among Adults in Addis Ababa, Ethiopia

ObjectivesObesity and diet-related noncommunicable diseases are increasing in Ethiopia—often in the same communities where undernutrition remains prevalent. Increasing proportion of energy intake from protein could be a potential strategy to address this double burden; however, this potential has not been examined in sub-Saharan Africa. The objective of this study is to investigate associations of types and food sources of protein with overweight/obesity and underweight in Ethiopia. MethodsWe conducted a cross-sectional dietary survey including 992 women and 632 men aged 18–49 years in Addis Ababa, Ethiopia. Linear regression models were used to assess associations between body mass index (BMI) and % energy intake from total, animal, and plant protein. Logistic regression models were used to examine associations of % energy intake from total, animal, and plant protein and specific food sources of protein with underweight and overweight/obesity. ResultsNearly one third of the sample were overweight or obese. Only 2.5% of total energy intake was derived from animal protein. In multivariable-adjusted linear models in the full sample, BMI was not associated with % energy from total protein, plant protein or animal protein. Total protein and animal protein intake were both associated with lower odds of overweight/obesity (Odds Ratio [OR] per 1% energy increment of total protein 0.92; 95% CI: 0.86, 0.99; P = 0.02; OR per 1% energy increment of animal protein 0.89; 95% CI: 0.82, 0.96; P = 0.004) when substituted for carbohydrate and adjusted for sociodemographic covariates. In food-based analyses, a greater % energy from milk was related to lower odds of underweight but with wide confidence intervals (OR per 5% energy increment 0.54; 95% CI: 0.30, 1.00; P = 0.05). ConclusionsIncreasing the proportion of energy intake from total protein or animal protein in place of carbohydrate could be a strategy to address overweight and obesity in Ethiopia; longitudinal studies are needed to further examine this potential. Funding SourcesUnited Kingdom Economic and Social Research Council (ESRC) and Department for International Development (DFID) Joint Fund for Poverty Alleviation Research.

Mental health, physical impairment and violence among FSWS in North Karnataka, South India: a story of intersecting vulnerabilities

AimsThis study examines the prevalence and associations between recent violence experience, mental health and physical health impairment among Female Sex Workers (FSWs) in north Karnataka, India.BackgroundMulti-morbidity, in particular the overlap between physical and mental health problems, is an important global health challenge to address. FSWs experience high levels of gender-based violence, which increases the risk of poor mental health, however there is limited information on the prevalence of physical health impairments and how this interacts with mental health and violence.MethodWe conducted secondary analysis of cross-sectional quantitative survey data collected in 2016 as part of a cluster-RCT with FSWs called Samvedana Plus. Bivariate and multivariate analyses were used to examine associations between physical impairment, recent (past 6 months) physical or sexual violence from any perpetrator, and mental health problems measured by PHQ-2 (depression), GAD-2 (anxiety), any common mental health problem (depression or anxiety), self-harm ever and suicidal ideation ever.Result511 FSWs participated. One fifth had symptoms of depression (21.5%) or anxiety (22.1%), one third (34.1%) reported symptoms of either, 4.5% had ever self-harmed and 5.5% reported suicidal ideation ever. Over half (58.1%) reported recent violence. A quarter (27.6%) reported one or more chronic physical impairments. Mental health problems such as depression were higher among those who reported recent violence (29%) compared to those who reported no recent violence (11%). There was a step-wise increase in the proportion of women with mental health problems as the number of physical impairments increased (e.g. depression 18.1% no impairment; 30.2% one impairment; 31.4% ≥ two impairments). In adjusted analyses, mental health problems were significantly more likely among women who reported recent violence (e.g. depression and violence AOR 2.42 (1.24–4.72) with rates highest among women reporting recent violence and one or more physical impairments (AOR 5.23 (2.49–10.97).ConclusionOur study suggests multi-morbidity of mental and physical health problems is a concern amongst FSWs and is associated with recent violence experience. Programmes working with FSWs need to be mindful of these intersecting vulnerabilities, inclusive of women with physical health impairments and include treatment for mental health problems as part of core-programming.Samvedana Plus was funded by UKaid through Department for International Development as part of STRIVE (structural drivers of HIV) led by London School of Hygiene and Tropical Medicine and the What Works to Prevent Violence Against Women and Girls Global Programme led by South African Medical Research Council

Maternal fecal microbiome predicts gestational age, birth weight and neonatal growth in rural Zimbabwe.

BackgroundPreterm birth and low birth weight (LBW) affect one in ten and one in seven livebirths, respectively, primarily in low-income and middle-income countries (LMIC) and are major predictors of poor child health outcomes. However, both have been recalcitrant to public health intervention. The maternal intestinal microbiome may undergo substantial changes during pregnancy and may influence fetal and neonatal health in LMIC populations.MethodsWithin a subgroup of 207 mothers and infants enrolled in the SHINE trial in rural Zimbabwe, we performed shotgun metagenomics on 351 fecal specimens provided during pregnancy and at 1-month post-partum to investigate the relationship between the pregnancy gut microbiome and infant gestational age, birth weight, 1-month length-, and weight-for-age z-scores using extreme gradient boosting machines.FindingsPregnancy gut microbiome taxa and metabolic functions predicted birth weight and WAZ at 1 month more accurately than gestational age and LAZ. Blastoscystis sp, Brachyspira sp and Treponeme carriage were high compared to Western populations. Resistant starch-degraders were important predictors of birth outcomes. Microbiome capacity for environmental sensing, vitamin B metabolism, and signalling predicted increased infant birth weight and neonatal growth; while functions involved in biofilm formation in response to nutrient starvation predicted reduced birth weight and growth.InterpretationThe pregnancy gut microbiome in rural Zimbabwe is characterized by resistant starch-degraders and may be an important metabolic target to improve birth weight.FundingBill and Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Agency for Development and Cooperation, US National Institutes of Health, and UNICEF.

Livelihood Asset Maps: Livelihood Assets Concerning The Echo-Agro-Tourism Community-Based Management of The Komunitas Cengkih Afo in Tongole Ternate-North Maluku

Humans need livelihood assets for their survival which particularly are related to the resources that are available in their environment and/or can be accessed to meet their needs. Livelihoods assets which are including capabilities, assets, and activities that carry out to support the fulfillment of basic life needs. The Department for International Development (DFID) identifies 5 categories of assets used for livelihoods which consist of human, natural, financial, physical, and social capitals. The majority of people who live in Tongole Village work as farmers, and therefore by the presence of the echo-agro tourism activities, the livelihood assets of the community can increase and/or vary because there are other possible options to increase the economic income earned. The research is aiming to identify the use of livelihood assets by the farmer groups in Komunitas Cengkih Afo. The study has taken place in Tongole village, where the Komunitas Cengkih afo is located. Collecting data is using a purposive sampling method, which refers only to the member of the Komunitas Cengkih Afo. Data on livelihood assets is taken base on the criteria set out according to the pentagon diagram which consists of human, natural, financial, physical, and social capitals. Livelihood assets are categorized in high, medium, and low categories from each respondent. The influence of livelihood assets was analyzed using a scoring method and presented in a pentagon diagram for each capital. Results showed that human, natural, and social capital were the most utilized for all the members, while physical and financial capital was less utilized and/or at the moderate level.

Influence Networks Relating to Health Knowledge Among Nairobi’s Micro-Retailers and Their Clients

TRANSFORM, founded in 2015 by Unilever and the UK’s Department for International Development, supports several social enterprises by combining public sector resources with private sector technical capabilities and networks to support innovative social enterprises. Digital programs have enabled social enterprise partnerships to expand the reach of their initiatives to broader audiences including specifically defined groups that hitherto were untapped or difficult to reach. Unilever partnered with TRANSFORM and Every1Mobile to develop UJoin and UAfya in informal settlements of Nairobi, Kenya. UJoin is a social enterprise initiative for promoting business growth among underserved neighborhood shops called dukas. UAfya focuses on young expectant and new mothers, and women interested in family and maternal health topics. Each initiative uses an online community network to discuss and improve knowledge and behaviors regarding livelihoods and health. Online communities provide opportunities to reach specific groups with targeted behavior change messages and campaigns. However, little systematic knowledge is currently available on how to develop, and scale-up effective behavior change programs for digital communities in low-income markets. There is also little information about key guiding principles and best practices that underlie successful digital and online, social networking models. A systematic and participatory tool known as Net-Map was used to explore and understand potential frameworks for establishing digital-based community-driven partnerships with the private sector for health promotion through behavior change. The Net-Map approach was used to help individuals and groups clarify their view of a situation (including networks and power structures), foster discussion, and develop a strategic approach to their networking activities. Eight Net-Maps were constructed, stratified by groups based on location and digital platform. Each map was constructed by an average of 9-10 people for a total of 76 participants. Seventy-six participants identified actors – stakeholders and groups of people involved - and influential links – ways actors are connected - through the Net-Map activity. Among UAfya participants, local government, family, and friends, and the media were identified as the most important actor types. A comparison of the discussions associated with the creation of the maps by UAfya members shows that the two most important link types are conflict, and collaboration/partnership. Among UJoin participants, the three most important actor types were local government, business and financial institutions, and customers. UJoin members identified regulation, and conflict and competition, collaboration and, information sharing as key links between actors. Recommendations based on findings support a vision for scale-up of the UJoin and UAfya programs through accreditation and branding of a novel type of duka. Shop keepers would be trained and knowledgeable to provide high-quality services to improve customer health while also selling health products that benefit the bottom line.

Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT.

Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. Randomised trial and economic evaluation. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers and those assessing outcomes were masked to allocation. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. 175 hospitals in 29 countries. Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. Time to treatment may have been underestimated. Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme.

Faith Osier: inspirational immunologist

Faith Osier: inspirational immunologist

Improved housing versus usual practice for additional protection against clinical malaria in The Gambia (RooPfs): a household-randomised controlled trial

SummaryBackgroundIn malaria-endemic areas, residents of modern houses have less malaria than those living in traditional houses. We aimed to assess whether children in The Gambia received an incremental benefit from improved housing, where current best practice of insecticide-treated nets, indoor residual spraying, seasonal malaria chemoprevention in children younger than 5 years, and prompt treatment against clinical malaria was in place.MethodsIn this randomised controlled study, 800 households with traditional thatched-roofed houses were randomly selected from 91 villages in the Upper River Region of The Gambia. Within each village, equal numbers of houses were randomly allocated to the control and intervention groups using a sampling frame. Houses in the intervention group were modified with metal roofs and screened doors and windows, whereas houses in the control group received no modifications. In each group, clinical malaria in children aged 6 months to 13 years was monitored by active case detection over 2 years (2016–17). We did monthly collections from indoor light traps to estimate vector densities. Primary endpoints were the incidence of clinical malaria in study children with more than 50% of observations each year and household vector density. The trial is registered at ISRCTN02622179.FindingsIn June, 2016, 785 houses had one child each recruited into the study (398 in unmodified houses and 402 in modified houses). 26 children in unmodified houses and 28 children in modified houses did not have at least 50% of visits in a year and so were excluded from analysis. 38 children in unmodified houses were recruited after study commencement, as were 21 children in modified houses, meaning 410 children in unmodified houses and 395 in modified houses were included in the parasitological analyses. At the end of the study, 659 (94%) of 702 children were reported to have slept under an insecticide-treated net; 662 (88%) of 755 children lived in houses that received indoor residual spraying; and 151 (90%) of 168 children younger than 5 years had seasonal malaria chemoprevention. Incidence of clinical malaria was 0·12 episodes per child-year in children in the unmodified houses and 0·20 episodes per child-year in the modified houses (unadjusted incidence rate ratio [RR] 1·68 [95% CI 1·11–2·55], p=0·014). Household vector density was 3·30 Anopheles gambiae per house per night in the unmodified houses compared with 3·60 in modified houses (unadjusted RR 1·28 [0·87–1·89], p=0·21).InterpretationImproved housing did not provide protection against clinical malaria in this area of low seasonal transmission with high coverage of insecticide-treated nets, indoor residual spraying, and seasonal malaria chemoprevention.FundingGlobal Health Trials funded by Medical Research Council, UK Department for International Development, and Wellcome Trust.

Assessing the impact of the adoption of agroforestry technology on food production and poverty reduction among farming households in Oyo State, Nigeria

Assessing the impact of the adoption of agroforestry technology on food production and poverty reduction among farming households in Oyo State, Nigeria

Lassa fever outcomes and prognostic factors in Nigeria (LASCOPE): a prospective cohort study

SummaryBackgroundLassa fever is a viral haemorrhagic fever endemic in parts of west Africa. New treatments are needed to decrease mortality, but pretrial reference data on the disease characteristics are scarce. We aimed to document baseline characteristics and outcomes for patients hospitalised with Lassa fever in Nigeria.MethodsWe did a prospective cohort study (LASCOPE) at the Federal Medical Centre in Owo, Nigeria. All patients admitted with confirmed Lassa fever were invited to participate and asked to give informed consent. Patients of all ages, including newborn infants, were eligible for inclusion, as were pregnant women. All participants received standard supportive care and intravenous ribavirin according to Nigeria Centre for Disease Control guidelines and underwent systematic biological monitoring for 30 days. Patients' characteristics, care received, mortality, and associated factors were recorded using standard WHO forms. We used univariable and multivariable logistic regression models to investigate an association between baseline characteristics and mortality at day 30.FindingsBetween April 5, 2018, and March 15, 2020, 534 patients with confirmed Lassa fever were admitted to hospital, of whom 510 (96%) gave consent and were included in the analysis. The cohort included 258 (51%) male patients, 252 (49%) female patients, 426 (84%) adults, and 84 (16%) children (younger than 18 years). The median time between first symptoms and hospital admission was 8 days (IQR 7–13). At baseline, 176 (38%) of 466 patients had a Lassa fever RT-PCR cycle threshold (Ct) lower than 30. From admission to end of follow-up, 120 (25%) of 484 reached a National Early Warning Score (second version; NEWS2) of 7 or higher, 67 (14%) of 495 reached a Kidney Disease–Improving Global Outcome (KDIGO) stage of 2 or higher, and 41 (8%) of 510 underwent dialysis. All patients received ribavirin for a median of 10 days (IQR 9–13). 62 (12%) patients died (57 [13%] adults and five [6%] children). The median time to death was 3 days (1–6). The baseline factors independently associated with mortality were the following: age 45 years or older (adjusted odds ratio 16·30, 95% CI 5·31–50·30), NEWS2 of 7 or higher (4·79, 1·75–13·10), KDIGO grade 2 or higher (7·52, 2·66–21·20), plasma alanine aminotransferase 3 or more times the upper limit of normal (4·96, 1·69–14·60), and Lassa fever RT-PCR Ct value lower than 30 (4·65, 1·50–14·50).InterpretationOur findings comprehensively document clinical and biological characteristics of patients with Lassa fever and their relationship with mortality, providing prospective estimates that could be useful for designing future therapeutic trials. Such trials comparing new Lassa fever treatments to a standard of care should take no more than 15% as the reference mortality rate and consider adopting a combination of mortality and need for dialysis as the primary endpoint.FundingInstitut National de la Santé et de la Recherche Médicale, University of Oxford, EU, UK Department for International Development, Wellcome Trust, French Ministry of Foreign Affairs, Agence Nationale de Recherches sur le SIDA et les hépatites virales, French National Research Institute for Sustainable Development.

Quantifying the global number of tuberculosis survivors: a modelling study

People who survive tuberculosis face clinical and societal consequences after recovery, including increased risks of recurrent tuberculosis, premature death, reduced lung function, and ongoing stigma. To describe the size of this issue, we aimed to estimate the number of individuals who developed first-episode tuberculosis between 1980 and 2019, the number who survived to 2020, and the number who have been treated within the past 5 years or 2 years. In this modelling study, we estimated the number of people who survived treated tuberculosis using country-level WHO data on tuberculosis case notifications, excluding those who died during treatment. We estimated the number of individuals surviving untreated tuberculosis using the difference between WHO country-level incidence estimates and notifications, applying published age-stratified and HIV-stratified case fatality ratios. To estimate survival with time, post-tuberculosis life tables were developed for each country-year by use of UN World Population Prospects 2019 mortality rates and published post-tuberculosis mortality hazard ratios. Between 1980 and 2019, we estimate that 363 million people (95% uncertainty interval [UI] 287 million-438 million) developed tuberculosis, of whom 172 million (169 million-174 million) were treated. Individuals who developed tuberculosis between 1980 and 2019 had lived 3480 million life-years (95% UI 3040 million-3920 million) after tuberculosis by 2020, with survivors younger than 15 years at the time of tuberculosis development contributing 12% (95% UI 7-17) of these life-years. We estimate that 155 million tuberculosis survivors (95% UI 138 million-171 million) were alive in 2020, the largest proportion (47% [37-57]) of whom were in the WHO South-East Asia region. Of the tuberculosis survivors who were alive in 2020, we estimate that 18% (95% UI 16-20) were treated in the past 5 years and 8% (7-9) were treated in the past 2 years. The number of tuberculosis survivors alive in 2020 is more than ten times the estimated annual tuberculosis incidence. Interventions to alleviate respiratory morbidity, screen for and prevent recurrent tuberculosis, and reduce stigma should be immediately prioritised for recently treated tuberculosis survivors. UK Medical Research Council, the UK Department for International Development, the National Institute for Health Research, and the European and Developing Countries Clinical Trials Partnership.

Preterm care during the COVID-19 pandemic: A comparative risk analysis of neonatal deaths averted by kangaroo mother care versus mortality due to SARS-CoV-2 infection.

BackgroundCOVID-19 is disrupting health services for mothers and newborns, particularly in low- and middle-income countries (LMIC). Preterm newborns are particularly vulnerable. We undertook analyses of the benefits of kangaroo mother care (KMC) on survival among neonates weighing ≤2000 g compared with the risk of SARS-CoV-2 acquired from infected mothers/caregivers.MethodsWe modelled two scenarios over 12 months. Scenario 1 compared the survival benefits of KMC with universal coverage (99%) and mortality risk due to COVID-19. Scenario 2 estimated incremental deaths from reduced coverage and complete disruption of KMC. Projections were based on the most recent data for 127 LMICs (~90% of global births), with results aggregated into five regions.FindingsOur worst-case scenario (100% transmission) could result in 1,950 neonatal deaths from COVID-19. Conversely, 125,680 neonatal lives could be saved with universal KMC coverage. Hence, the benefit of KMC is 65-fold higher than the mortality risk of COVID-19. If recent evidence of 10% transmission was applied, the ratio would be 630-fold. We estimated a 50% reduction in KMC coverage could result in 12,570 incremental deaths and full disruption could result in 25,140 incremental deaths, representing a 2·3–4·6% increase in neonatal mortality across the 127 countries.InterpretationThe survival benefit of KMC far outweighs the small risk of death due to COVID-19. Preterm newborns are at risk, especially in LMICs where the consequences of disruptions are substantial. Policymakers and healthcare professionals need to protect services and ensure clearer messaging to keep mothers and newborns together, even if the mother is SARS-CoV-2-positive.FundingEunice Kennedy Shriver National Institute of Child Health & Human Development; Bill & Melinda Gates Foundation; Elma Philanthropies; Wellcome Trust; and Joint Global Health Trials scheme of Department of Health and Social Care, Department for International Development, Medical Research Council, and Wellcome Trust.

Fighting corruption in Nigeria: excessive rhetoric and indeterminate bureaucratic practices in the implementation of SERVICOM

ABSTRACT This paper explores the SERVICOM reform, which was instituted in 2004 to fight the corruption and inefficiency considered to plague the Nigerian Civil Service. Using the method of ‘following the policy’, the paper demonstrates the meaning of SERVICOM for its various stakeholders: United Kingdom Department for International Development (DFID) officers, Nigerian bureaucrats, SERVICOM officers and citizens. The paper also shows how SERVICOM is made in the indeterminate bodily movements and social interactions of street-level bureaucrats rather than in the policy models crafted by experts. Not only has SERVICOM been incoherently implemented, it has also has been characterised by excessive rhetoric, which has constructed the idea of a good-willed technocratic state, eliciting ambivalence and catharsis in public discourse. Further, DFID officers have construed the reform as a success. This research provides an ethnographic perspective on how transnational ‘good governance’ initiatives in Africa are translated on the ground.

Clinical Manifestations of Rift Valley Fever in Humans: Systematic Review and Meta-Analysis

Background: Rift Valley fever (RVF) is an emerging, neglected, mosquito-borne viral haemorrhagic zoonosis associated with severe morbidity, mortality and expanding geographical scope. Human symptoms have poor specificity and case definitions vary. We determined the clinical manifestations of RVF in humans. Methods: In this systematic review and meta-analysis we searched Medline, Embase, Global Health, and Web of Science databases from indexing inception to 15th October 2019. Studies published in English, reporting frequency of symptoms in humans, and laboratory confirmed RVF were included. Animals studies, those among asymptomatic volunteers and single case reports for which a proportion could not be estimated were excluded. Quality assessment was done, data extracted, and pooled frequency estimates calculated using random effects meta-analysis. Results: Of the 3765 articles retrieved, 32 were included in the systematic review and meta-analysis. Nine RVF clinical syndromes were reported including general febrile, gastrointestinal, hepatic, renal, neurological, haemorrhagic, obstetric, visual, and cardio-pulmonary syndromes. The most common clinical manifestations included fever (81%; 95% Confidence Interval (CI) 69-91), nausea (38%; 12-67), jaundice (26%; 16-36), renal failure (41%; 23-59), encephalitis (21%; 11-33), haemorrhagic disease (26%; 17-36), miscarriage (54%), partial blindness (24%; 7-45), and cough (4%; 0-17), respectively. Death occurred in 21% (95% CI 14-29) of cases. Interpretation: This study delineates the complex symptomatology of human RVF disease into syndromes. This approach is likely to improve case definitions and detection rates, impact outbreaks control, increase public awareness about RVF, and subsequently inform ‘one-health’ policies. Study protocol registration number: CRD42019128928. Funding: (UK Department of Health and Social care) The work was conducted at the MRC/UVRI and LSHTM Uganda Research Unit which is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordant agreement and is also part of the EDCTP2 programme supported by the European Union. This project was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the Medical Research Council (MRC)/Department of Health, through the UK Vaccines Network which is a Government Funding Stream (Grant no: 16/107/02). SL was supported by the PANDORA-ID-NET Consortium (EDCTP Reg/Grant RIA2016E-1609) funded by the European and Developing Countries Clinical Trials Partnership (EDCTP2) programme under the Horizon 2020, the European Union’s Framework Programme for Research and Innovation. GMW is supported by an Oak foundation fellowship and a Wellcome Trust grant (grant number 203077_Z_16_Z). Declaration of Interests: All authors declare no potential conflicts of interest.

Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study

SummaryBackgroundPrognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.MethodsWe developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).Findings74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [–0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model.InterpretationThe 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19.FundingNational Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London.

Spike Protein Cleavage-Activation Mediated by the SARS-CoV-2 P681R Mutation: A Case-Study From Its First Appearance in Variant of Interest (VOI) A.23.1 Identified in Uganda

The African continent like all other parts of the world with high infection/low vaccination rates can, and will, be a source of novel SARS-CoV-2 variants. The A.23 viral lineage, characterized by three spike mutations F157L, V367F and Q613H, was first identified in COVID-19 cases from a Ugandan prison in July 2020, and then was identified in the general population with the additional spike mutation P681R at the S1/S2 cleavage site to comprise lineage A.23.1 by September 2020 with subsequent spread to 26 other countries. The P681R spike substitution of A.23.1 is of note as it increases the number of basic residues in the sub-optimal SARS-CoV-2 spike protein furin cleavage site; as such, this substitution may affect viral replication, transmissibility, or pathogenic properties. The same P681R substitution has also subsequently appeared in B.1.617 variants, including B.1.617.2 (Delta). Here, we performed assays using fluorogenic peptides mimicking the S1/S2 from A.23.1 and B.1.617 and observed significantly increased cleavability with furin, compared to sequences derived from the original Wuhan-Hu1 S1/S2. We performed cell-cell fusion and functional infectivity assays using pseudotyped particles harboring SARS-CoV-2 spike proteins and observed an increase in transduction for A.23.1-pseudotyped particles compared to Wuhan-Hu-1. However, these changes in activity were not reproduced in the original Wuhan-Hu-1 spike bearing only the P681R substitution. Our findings suggest that while A.23.1 has increased furin-mediated cleavage linked to the P681R substitution—which may affect viral infection and transmissibility—this substitution alone needs to occur on the background of other spike protein changes to enable its full functional consequences.Funding: This work was funded in part by the National Institute of Health research grant R01AI35270 (to GW and SD). We thank the global SARS-CoV-2 sequencing groups for their open and rapid sharing of sequence data and GISAID for providing an effective platform to make these data available. DLB, MVTP and MC were funded by the UK Medical Research Council (MRC/UK Research and Innovation) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement (grant agreement no. NC_PC_19060) and Wellcome Trust, UK FCDO—Wellcome Epidemic Preparedness—Coronavirus (grant agreement no. 220977/Z/20/Z). TT was supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1650441 and the Samuel C. Fleming Family Graduate Fellowship. Declaration of Interests: The authors manifest no conflict of interest.

Effect of HIV Infection on Growth and Bone Density in Peripubertal Children in the Era of Antiretroviral Therapy: A Cross-Sectional Study in Zimbabwe

Background: Poor linear growth and pubertal delay, both common in children with HIV (CWH) in sub-Saharan Africa, may affect adolescent bone accrual and future fragility fracture risk. We investigated the association of HIV with size-adjusted bone density in peri-pubertal children in Zimbabwe. Methods: CWH aged 8-16 years taking ART for ≥2 years from public-sector HIV clinics in Harare, and HIV-uninfected children from schools in the same catchment area, were recruited into a cross-sectional study. Sociodemographic, clinical and anthropometric data were collected. Outcomes were dual-energy X-ray absorptiometry (DXA) measured total-body less-head bone mineral content-for-lean mass adjusted for height (TBLH-BMCLBM) and lumbar spine bone mineral apparent density (LS-BMAD). Linear regression models using multiple imputation for missing data, assessed relationships between risk factors and DXA measures by HIV status, and interaction by sex and pubertal (Tanner) stage. Findings: We recruited 303 CWH and 306 without HIV, mean (SD) age 12.5 (2.5) years and 50% female. Mean ART duration was 7.9 (2.6) years; for 34% ART included tenofovir disproxil fumarate (TDF). The prevalence of low TBLH-BMCLBM and LS-BMAD (Z-Score<-2) was higher in children with than without HIV (10.4% vs. 6.2%, p=0.066; 14.3% vs. 5.8%, p=0.001 respectively). HIV and male sex were associated with earlier Tanner stage. The negative effects of HIV on TBLH-BMCLBM and LS-BMAD were more pronounced with pubertal maturation, particularly in females. Among CWH, years of TDF exposure and orphanhood were strongly associated with lower TBLH-BMCLBM Z-Score in both unadjusted and adjusted analyses. Current TDF use was associated with 0.40 (95%CI 0.07, 0.73; p=0.018) and 0.31 (0.07, 0.69; p=0.110) lower TBLH-BMCLBM and LS-BMAD Z-Scores respectively. Interpretation: Despite ART, HIV is associated with substantial skeletal deficits by the end of puberty. The size of bone deficits associated with TDF and its widespread use in children in sub-Saharan Africa raise concern for future adult fracture risk. Funding Statement: Wellcome Trust. Declaration of Interests: RR (206764/Z/17/Z) RAF (206316/Z/17/Z) are funded by the Wellcome Trust. CK is funded by a National Institute of Health (NIH) Fogarty Trent Fellowship. AMR is partially supported by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement which is also part of the EDCTP2 programme supported by the European Union Grant Ref: MR/R010161/1. All other authors declare no competing interests. Ethics Approval Statement: Ethical and governance approvals were granted by the London School of Hygiene and Tropical Medicine Ethics Committee (Ref: 15333), the Institutional Review Board of the Biomedical Research and Training Institute in Harare (Ref: AP145/2018), the Joint Research Ethics Committee for University of Zimbabwe College of Health Sciences and the Parirenyatwa Group of Hospitals (Ref: 11/18), Harare Central Hospital Ethics Committee (Ref: 170118/04), the Medical Research Council of Zimbabwe (Ref: MRCZ/A/2297) and the Ministry of Primary and Secondary Education Zimbabwe (Ref: C/426/Harare). Guardians provided written informed consent and children provided written assent.