Bill Gates Research Articles

Sociodemographic characteristics of women who died by suicide in India from 2014 to 2020: findings from surveillance data

Women in India have twice the suicide death rate (SDR) compared with the global average for women. The aim of this study is to present a systematic understanding of sociodemographic risk factors, reasons for suicide deaths, and methods of suicide among women in India at the state level over time. Administrative data on suicide deaths among women by education level, marital status, and occupation, and reason for and method of suicide were extracted from the National Crimes Record Bureau reports for years 2014 to 2020. We extrapolated SDR at the population level for Indian women by education, marital status, and occupation to understand the sociodemography of these suicide deaths for India and its states. We reported the reasons for and methods of suicide deaths among Indian women at the state level over this period. SDR was higher among women with education of class 6 or more (10·2; 95% CI 10·1-10·4) than those with no education (3·8; 3·7-3·9) or education until class 5 (5·4; 5·2-5·5) in India in 2020, with similar patterns in most states. SDR declined between 2014 and 2020 for women with education until class 5. Women currently married accounted for 28 085 (63·1%) of 44 498 suicide deaths in India, 8336 (56·2%) of 14 840 in less developed states, and 19 661 (66·9%) of 29 407 in more developed states in 2020. For India, women currently married had a significantly higher SDR (8·1; 8·0-8·2) than those never married in 2014. However, women who never married had a significantly higher SDR (8·4; 8·2-8·5) in 2020 than those who were currently married. Many individual states in 2020 had similar SDR for women who never married and those who are currently married. Housewife as an occupation accounted for 50% or more of suicide deaths from 2014 to 2020 in India and its states. Family problems was the most common reason for suicide from 2014 to 2020, accounting for 16 140 (36·3%) of 44 498 suicide deaths in India, 5268 (35·5%) of 14 840 in less developed states, and 10 803 (36·7%) of 29 407 in more developed states in 2020. Hanging was the leading mean of suicide from 2014 to 2020. Insecticide or poison consumption was the second leading cause of suicide, accounting for 2228 (15·0%) of all 14 840 suicide deaths in less developed states and 5753 (19·6%) of 29 407 in more developed states, with a near 70·0% increase in the use of this method from 2014 to 2020. The higher SDR among women who have received an education, similar SDR between women currently married and never married, and variations in the reasons for and means of suicide at the state level highlight the need to incorporate sociological insights into how the external social environment can matter for women to better understand the complexity of suicide and determine how to effectively intervene. Bill & Melinda Gates Foundation.

Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers

BackgroundThe bacille Calmette–Guérin (BCG) vaccine has immunomodulatory “off-target” effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19).MethodsIn this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline.ResultsA total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], −0.7 to 5.5; P=0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, −1.2 to 3.5; P=0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified.ConclusionsVaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.)

Ferric carboxymaltose versus standard-of-care oral iron to treat second-trimester anaemia in Malawian pregnant women: a randomised controlled trial

Anaemia affects 46% of pregnancies in Africa; oral iron is recommended by WHO but uptake and adherence are suboptimal. We tested a single dose of a modern intravenous iron formulation, ferric carboxymaltose, for anaemia treatment in Malawian pregnant women. In this open-label, individually randomised controlled trial, we enrolled women with a singleton pregnancy of 13-26 weeks' gestation in primary care and outpatient settings across two regions in southern Malawi. Women were eligible if they had capillary haemoglobin of less than 10·0 g/dL and negative malaria rapid diagnostic test. Participants were randomised by sealed envelope 1:1. Assessors for efficacy outcomes (laboratory parameters and birthweight) were masked to intervention; participants and study nurses were not masked. Participants were given ferric carboxymaltose up to 1000 mg (given once at enrolment in an outpatient primary care setting), or standard of care (60 mg elemental iron twice daily for 90 days), along with intermittent preventive malaria treatment. The primary maternal outcome was anaemia at 36 weeks' gestation. The primary neonatal outcome was birthweight. Analyses were performed in the intention-to-treat population for mothers and liveborn neonates, according to their randomisation group. Safety outcomes included incidence of adverse events during infusion and all adverse events from randomisation to 4 weeks' post partum. The trial is registered with ANZCTR, ACTRN12618001268235. The trial has completed follow-up. Between Nov 12, 2018, and March 2, 2021, 21 258 women were screened, and 862 randomly assigned to ferric carboxymaltose (n=430) or standard of care (n=432). Ferric carboxymaltose did not reduce anaemia prevalence at 36 weeks' gestation compared with standard of care (179 [52%] of 341 in the ferric carboxymaltose group vs 189 [57%] of 333 in the standard of care group; prevalence ratio [PR] 0·92, 95% CI 0·81 to 1·06; p=0·27). Anaemia prevalence was numerically lower in mothers randomly assigned to ferric carboxymaltose compared with standard of care at all timepoints, although significance was only observed at 4 weeks' post-treatment (PR 0·91 [0·85 to 0·97]). Birthweight did not differ between groups (mean difference -3·1 g [-75·0 to 68·9, p=0·93). There were no infusion-related serious adverse events or differences in adverse events by any organ class (including malaria; ≥1 adverse event: ferric carboxymaltose 183 [43%] of 430 vs standard of care 170 [39%] of 432; risk ratio 1·08 [0·92 to 1·27]; p=0·34). In this malaria-endemic sub-Saharan African setting, treatment of anaemic pregnant women with ferric carboxymaltose was safe but did not reduce anaemia prevalence at 36 weeks' gestation or increase birthweight. Bill & Melinda Gates Foundation (INV-010612).

Health and economic impact of delaying large-scale HPV vaccination and screening implementation on cervical cancer in China: a modelling study

Current uptake of HPV vaccination and screening in China is far below World Health Organization 2030 targets for cervical cancer elimination. We quantified health and economic losses of delaying large-scale HPV vaccination and screening implementation in China. We used a previously validated transmission model to project lifetime health benefits, costs, effectiveness, and timeline for cervical cancer elimination of alternative scenarios, including combining HPV vaccination initiated from 2022 to 2030 with screening in different modalities and coverage increase rates, as well as screening alone. All women living or projected to be born in China during 2022-2100 were considered. We employed a societal perspective. Regardless of vaccine type, immediate large-scale vaccination initiated in 2022 and achieving 70% coverage of HPV-based screening in 2030 (no-delay scenario) would be the least costly and most effective. Compared with the no-delay scenario, delaying vaccination by eight years would result in 434,000-543,000 additional cervical cancer cases, 138,000-178,000 deaths, and $2863-4437 million costs, and delay elimination by 9-10 years. Even with immediate vaccination, the gradual scale-up of LBC-based screening to 70% coverage in 2070 would result in 2,530,000-3,060,000 additional cases, 909,000-1,040,000 deaths, and $5098-5714 million costs compared with no-delay scenario, and could not achieve elimination if domestic 2vHPV or 4vHPV vaccines are used (4.09-4.21 cases per 100,000 woman in 2100). Delaying large-scale HPV vaccination and/or high-performance screening implementation has detrimental consequences for cervical cancer morbidity, mortality, and expenditure. These findings should spur health authorities to expedite large-scale vaccine rollout and improve screening. Bill & Melinda Gates Foundation (INV-031449 and INV-003174) and CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-004).

Burden of Typhoid and Paratyphoid Fever in India

BackgroundIn 2017, more than half the cases of typhoid fever worldwide were projected to have occurred in India. In the absence of contemporary population-based data, it is unclear whether declining trends of hospitalization for typhoid in India reflect increased antibiotic treatment or a true reduction in infection.MethodsFrom 2017 through 2020, we conducted weekly surveillance for acute febrile illness and measured the incidence of typhoid fever (as confirmed on blood culture) in a prospective cohort of children between the ages of 6 months and 14 years at three urban sites and one rural site in India. At an additional urban site and five rural sites, we combined blood-culture testing of hospitalized patients who had a fever with survey data regarding health care use to estimate incidence in the community.ResultsA total of 24,062 children who were enrolled in four cohorts contributed 46,959 child-years of observation. Among these children, 299 culture-confirmed typhoid cases were recorded, with an incidence per 100,000 child-years of 576 to 1173 cases in urban sites and 35 in rural Pune. The estimated incidence of typhoid fever from hospital surveillance ranged from 12 to 1622 cases per 100,000 child-years among children between the ages of 6 months and 14 years and from 108 to 970 cases per 100,000 person-years among those who were 15 years of age or older. Salmonella enterica serovar Paratyphi was isolated from 33 children, for an overall incidence of 68 cases per 100,000 child-years after adjustment for age.ConclusionsThe incidence of typhoid fever in urban India remains high, with generally lower estimates of incidence in most rural areas. (Funded by the Bill and Melinda Gates Foundation; NSSEFI Clinical Trials Registry of India number, CTRI/2017/09/009719; ISRCTN registry number, ISRCTN72938224.)

Photosynthesis and food security: the evolving story of C4 rice.

Traditional "Green Revolution" cereal breeding strategies to improve yield are now reaching a plateau in our principal global food crop rice. Photosynthesis has now become a major target of international consortia to increase yield potential. Synthetic biology is being used across multiple large projects to improve photosynthetic efficiency. This review follows the genesis and progress of one of the first of these consortia projects, now in its 13th year; the Bill and Melinda Gates funded C4 Rice Project. This project seeks to install the biochemical and anatomical attributes necessary to support C4 photosynthesis in the C3 crop rice. Here we address the advances made thus far in installing the biochemical pathway and some of the key targets yet to be reached.

Digital adherence technologies to improve tuberculosis treatment outcomes in China: a cluster-randomised superiority trial

Drug-sensitive tuberculosis treatment requires 6 months of therapy, so adherence problems are common. Digital adherence technologies might improve tuberculosis treatment outcomes. We aimed to evaluate the effect of a daily reminder medication monitor, monthly review of adherence data by the health-care provider, and differentiated care for patients with adherence issues, on tuberculosis treatment adherence and outcomes. We did a cluster-randomised superiority trial across four prefectures in China. 24 counties or districts (clusters) were randomly assigned (1:1) to intervention or control groups. We enrolled patients aged 18 years or older with GeneXpert-positive, rifampicin-sensitive pulmonary tuberculosis, who were receiving daily fixed-dose combination treatment. Patients in the intervention group received a medication monitor for daily drug-dosing reminders, monthly review of adherence data by health-care provider, and management of poor adherence; and patients in the control group received routine care (silent-mode monitor-measured adherence). Only the independent endpoints review committee who assessed endpoint data for some participants were masked to study group assignment. Patients were followed up (with sputum solid culture) at 12 and 18 months. The primary outcome was a composite of death, loss to follow-up, treatment failure, switch to multidrug-resistant tuberculosis treatment, or tuberculosis recurrence by 18 months from treatment start, analysed in the intention-to-treat population. Analysis accounted for study design with multiple imputation for the primary outcome. This trial is now complete and is registered with ISRCTN, 35812455. Between Jan 26, 2017, and April 3, 2019, 15 257 patients were assessed for eligibility and 3074 were enrolled, 2686 (87%) of whom were included in the intention-to-treat population. 1909 (71%) of 2686 patients were male, 777 (29%) were female, and the median age was 44 years (IQR 29-58). By 18 months from treatment start, using multiple imputation for missing outcomes, 239 (16% [geometric mean of cluster-level proportion]) of 1388 patients in the control group and 224 (16%) of 1298 in the intervention group had a primary composite outcome event (289 [62%] of 463 events were loss to follow-up during treatment and 42 [9%] were tuberculosis recurrence). The intervention had no effect on risk of the primary composite outcome (adjusted risk ratio 1·01, 95% CI 0·73-1·40). Our digital medication monitor intervention had no effect on unfavourable outcomes, which included loss to follow-up during treatment, tuberculosis recurrence, death, and treatment failure. There was a failure to change patient management following identification of treatment non-adherence at monthly reviews. A better understanding of adherence patterns and how they relate to poor outcomes, coupled with a more timely review of adherence data and improved implementation of differentiated care, may be required. Bill & Melinda Gates Foundation.

Efficacy against pneumococcal carriage and the immunogenicity of reduced-dose (0 + 1 and 1 + 1) PCV10 and PCV13 schedules in Ho Chi Minh City, Viet Nam: a parallel, single-blind, randomised controlled trial

Interest in reduced-dose pneumococcal conjugate vaccine (PCV) schedules is growing, but data on their ability to provide direct and indirect protection are scarce. We evaluated 1 + 1 (at 2 months and 12 months) and 0 + 1 (at 12 months) schedules of PCV10 or PCV13 in a predominately unvaccinated population. In this parallel, single-blind, randomised controlled trial, healthy infants aged 2 months were recruited from birth records in three districts in Ho Chi Minh City, Vietnam, and assigned (4:4:4:4:9) to one of five groups: PCV10 at 12 months of age (0 + 1 PCV10), PCV13 at 12 months of age (0 + 1 PCV13), PCV10 at 2 months and 12 months of age (1 + 1 PCV10), PCV13 at 2 months and 12 months of age (1 + 1 PCV13), and unvaccinated control. Outcome assessors were masked to group allocation, and the infants' caregivers and those administering vaccines were not. Nasopharyngeal swabs collected at 6 months, 12 months, 18 months, and 24 months were analysed for pneumococcal carriage. Blood samples collected from a subset of participants (200 per group) at various timepoints were analysed by ELISA and opsonophagocytic assay. The primary outcome was the efficacy of each schedule against vaccine-type carriage at 24 months, analysed by intention to treat for all those with a nasopharyngeal swab available. This trial is registered at ClinicalTrials.gov, NCT03098628. 2501 infants were enrolled between March 8, 2017, and July 24, 2018 and randomly assigned to study groups (400 to 0 + 1 PCV10, 400 to 0 + 1 PCV13, 402 to 1 + 1 PCV10, 401 to 1 + 1 PCV13, and 898 to control). Analysis of the primary endpoint included 341 participants for 0 + 1 PCV10, 356 0 + 1 PCV13, 358 1 + 1 PCV10, 350 1 + 1 PCV13, and 758 control. At 24 months, a 1 + 1 PCV10 schedule reduced PCV10-type carriage by 58% (95% CI 25 to 77), a 1 + 1 PCV13 schedule reduced PCV13-type carriage by 65% (42 to 79), a 0 + 1 PCV10 schedule reduced PCV10-type carriage by 53% (17 to 73), and a 0 + 1 PCV13 schedule non-significantly reduced PCV13-type carriage by 25% (-7 to 48) compared with the unvaccinated control group. Reactogenicity and serious adverse events were similar across groups. A 1 + 1 PCV schedule greatly reduces vaccine-type carriage and is likely to generate substantial herd protection and provide some degree of individual protection during the first year of life. Such a schedule is suitable for mature PCV programmes or for introduction in conjunction with a comprehensive catch-up campaign, and potentially could be most effective given as a mixed regimen (PCV10 then PCV13). A 0 + 1 PCV schedule has some effect on carriage along with a reasonable immune response and could be considered for use in humanitarian crises or remote settings. Bill & Melinda Gates Foundation. For the Vietnamese translation of the abstract see Supplementary Materials section.

Implementation of the 7-1-7 target for detection, notification, and response to public health threats in five countries: a retrospective, observational study

Suboptimal detection and response to recent outbreaks, including COVID-19 and mpox (formerly known as monkeypox), have shown that the world is insufficiently prepared for public health threats. Routine monitoring of detection and response performance of health emergency systems through timeliness metrics has been proposed to evaluate and improve outbreak preparedness and contain health threats early. We implemented 7-1-7 to measure the timeliness of detection (target of ≤7 days from emergence), notification (target of ≤1 day from detection), and completion of seven early response actions (target of ≤7 days from notification), and we identified bottlenecks to and enablers of system performance. In this retrospective, observational study, we conducted reviews of public health events in Brazil, Ethiopia, Liberia, Nigeria, and Uganda with staff from ministries of health and national public health institutes. For selected public health events occurring from Jan 1, 2018, to Dec 31, 2022, we calculated timeliness intervals for detection, notification, and early response actions, and synthesised identified bottlenecks and enablers. We mapped bottlenecks and enablers to Joint External Evaluation (second edition) indicators. Of 41 public health events assessed, 22 (54%) met a target of 7 days to detect (median 6 days [range 0-157]), 29 (71%) met a target of 1 day to notify (0 days [0-24]), and 20 (49%) met a target of 7 days to complete all early response actions (8 days [0-72]). 11 (27%) events met the complete 7-1-7 target, with variation among event types. 25 (61%) of 41 bottlenecks to and 27 (51%) of 53 enablers of detection were at the health facility level, with delays to notification (14 [44%] of 32 bottlenecks) and response (22 [39%] of 56 bottlenecks) most often at an intermediate public health (ie, municipal, district, county, state, or province) level. Rapid resource mobilisation for responses (six [9%] of 65 enablers) from the national level enabled faster responses. The 7-1-7 target is feasible to measure and to achieve, and assessment with this framework can identify areas for performance improvement and help prioritise national planning. Increased investments must be made at the health facility and intermediate public health levels for improved systems to detect, notify, and rapidly respond to emerging public health threats. Bill & Melinda Gates Foundation.

Risk and accuracy of outpatient-identified hypoxaemia for death among suspected child pneumonia cases in rural Bangladesh: a multifacility prospective cohort study

Hypoxaemic pneumonia mortality risk in low-income and middle-income countries is high in children who have been hospitalised, but unknown among outpatient children. We sought to establish the outpatient burden, mortality risk, and prognostic accuracy of death from hypoxaemia in children with suspected pneumonia in Bangladesh. We conducted a prospective community-based cohort study encompassing three upazila (subdistrict) health complex catchment areas in Sylhet, Bangladesh. Children aged 3-35 months participating in a community surveillance programme and presenting to one of three upazila health complex Integrated Management of Childhood Illness (IMCI) outpatient clinics with an acute illness and signs of difficult breathing (defined as suspected pneumonia) were enrolled in the study; because lower respiratory tract infection mortality mainly occurs in children younger than 1 year, the primary study population comprised children aged 3-11 months. Study physicians recorded WHO IMCI pneumonia guideline clinical signs and peripheral arterial oxyhaemoglobin saturations (SpO2) in room air. They treated children with pneumonia with antibiotics (oral amoxicillin [40 mg/kg per dose twice per day for 5-7 days, as per local practice]), and recommended oxygen, parenteral antibiotics, and hospitalisation for those with an SpO2 of less than 90%, WHO IMCI danger signs, or severe malnutrition. Community health workers documented the children's vital status and the date of any vital status changes during routine household surveillance (one visit to each household every 2 months). The primary outcome was death at 2 weeks after enrolment in children aged 3-11 months (primary study population) and 12-35 months (secondary study population). Primary analyses included estimating the outpatient prevalence, mortality risk, and prognostic accuracy of hypoxaemia for death in children aged 3-11 months with suspected pneumonia. Risk ratios were produced by fitting a multivariable model that regressed predefined SpO2 ranges (<90%, 90-93%, and 94-100%) on the primary 2-week mortality outcome (binary outcome) using Poisson models with robust variance estimation. We established the prognostic accuracy of WHO IMCI guidelines for death with and without varying SpO2 thresholds. Participants were recruited between Sept 1, 2015, to Aug 31, 2017. During the study period, a total of 7440 children aged 3-35 months with the first suspected pneumonia episode were enrolled, of whom 3848 (54·3%) with an attempted pulse oximeter measurement and 2-week outcome were included in our primary study population of children aged 3-11-months. Among children aged 3-11 months, an SpO2 of less than 90% occurred in 102 (2·7%) of 3848 children, an SpO2 of 90-93% occurred in 306 (8·0%) children, a failed SpO2 measurement occurred in 67 (1·7%) children, and 24 (0·6%) children with suspected pneumonia died. Compared with an SpO2 of 94-100% (3373 [87·7%] of 3848), the adjusted risk ratio for death was 10·3 (95% CI 3·2-32·3; p<0·001) for an SpO2 of less than 90%, 4·3 (1·5-11·8; p=0·005) for an SpO2 of 90-93%, and 11·4 (3·1-41·4; p<0·001) for a failed measurement. When not considering pulse oximetry, of the children who died, WHO IMCI guidelines identified only 25·0% (95% CI 9·7-46·7; six of 24 children) as eligible for referral to hospital. For identifying deaths, in children with an SpO2 of less than 90% WHO IMCI guidelines had a 41·7% sensitivity (95% CI 22·1-63·4) and 89·7% specificity (88·7-90·7); for children with an SpO2 of less than 90% or measurement failure the guidelines had a 54·2% sensitivity (32·8-74·4) and 88·3% specificity (87·2-89·3); and for children with an SpO2 of less than 94% or measurement failure the guidelines had a 62·5% sensitivity (40·6-81·2) and 81·3% specificity (80·0-82·5). These findings support pulse oximeter use during the outpatient care of young children with suspected pneumonia in Bangladesh as well as the re-evaluation of the WHO IMCI currently recommended threshold of an SpO2 less than 90% for hospital referral. Fogarty International Center of the National Institutes of Health (K01TW009988), The Bill & Melinda Gates Foundation (OPP1084286 and OPP1117483), and GlaxoSmithKline (90063241).

Bill Gates and the ‘new normal’ COVID-19 conspiracy theories: ‘it’s a new thing’ or nothing new under the sun?

ABSTRACT The outbreak of SARS-CoV-2 in late 2019 and the subsequent lockdowns led to widespread conspiracy theories often involving one particular actor: Bill Gates. Adherents of these conspiracy theories believed Gates was behind the pandemic for some nefarious purpose, including chipping and/or eugenics. This was, however, no fringe sentiment: celebrities and other prominent voices articulated some iteration of the Gates-COVID-19 conspiracy theory beginning in 2020. Though the conspiracy theory appears to have come out of nowhere, it does have a (pre-)history. Some have tried to point to a single or recent origin, but it is in fact much older, more complex, and informed by real developments over the previous two decades. This article traces the origins of the conspiracy theory going back to its prehistory in the 1990s, describes the narrative in its various iterations and (per)mutations – along with Gates’s shifting role in them – and charts the dissemination of this dynamic conspiracy theory while examining some of its notable tropes.

Real-time sewage surveillance for SARS-CoV-2 in Dhaka, Bangladesh versus clinical COVID-19 surveillance: a longitudinal environmental surveillance study (December, 2019–December, 2021)

Clinical surveillance for COVID-19 has typically been challenging in low-income and middle-income settings. From December, 2019, to December, 2021, we implemented environmental surveillance in a converging informal sewage network in Dhaka, Bangladesh, to investigate SARS-CoV-2 transmission across different income levels of the city compared with clinical surveillance. All sewage lines were mapped, and sites were selected with estimated catchment populations of more than 1000 individuals. We analysed 2073 sewage samples, collected weekly from 37 sites, and 648 days of case data from eight wards with varying socioeconomic statuses. We assessed the correlations between the viral load in sewage samples and clinical cases. SARS-CoV-2 was consistently detected across all wards (low, middle, and high income) despite large differences in reported clinical cases and periods of no cases. The majority of COVID-19 cases (26 256 [55·1%] of 47 683) were reported from Ward 19, a high-income area with high levels of clinical testing (123 times the number of tests per 100 000 individuals compared with Ward 9 [middle-income] in November, 2020, and 70 times the number of tests per 100 000 individuals compared with Ward 5 [low-income] in November, 2021), despite containing only 19·4% of the study population (142 413 of 734 755 individuals). Conversely, a similar quantity of SARS-CoV-2 was detected in sewage across different income levels (median difference in high-income vs low-income areas: 0·23 log10 viral copies + 1). The correlation between the mean sewage viral load (log10 viral copies + 1) and the log10 clinical cases increased with time (r = 0·90 in July-December, 2021 and r=0·59 in July-December, 2020). Before major waves of infection, viral load quantity in sewage samples increased 1-2 weeks before the clinical cases. This study demonstrates the utility and importance of environmental surveillance for SARS-CoV-2 in a lower-middle-income country. We show that environmental surveillance provides an early warning of increases in transmission and reveals evidence of persistent circulation in poorer areas where access to clinical testing is limited. Bill & Melinda Gates Foundation.

Black-White disparities in maternal vulnerability and adverse pregnancy outcomes: an ecological population study in the United States, 2014–2018

Systematic information on the association between community-level determinants and maternal health outcomes and disparities is needed. We aimed to investigate multi-dimensional place-based contributions to Black-White maternal health disparities in the United States. We constructed the Maternal Vulnerability Index, a geospatial measure of vulnerability to poor maternal health. The index was linked to 13m live births and maternal deaths to mothers aged 10-44 for 2014-2018 in the United States. We quantified racial disparities in exposure to higher risk environments, and used logistic regression to estimate associations between race, vulnerability, and maternal death (n=3633), low birthweight (n=1.1m), and preterm birth (n=1.3m). Black mothers lived in disproportionately higher maternal vulnerability counties, when compared to White mothers (median of 55 vs 36/100 points). Giving birth in the highest-quartile MVI counties was associated with an increase in the odds of poor outcomes when compared to the lowest-quartile (aOR 1.43 [95% CI 1.20-1.71] for mortality, 1.39 [1.37-1.41] for low birthweight and 1.41 [1.39-1.43] for preterm birth, adjusted for age, educational attainment level and race/ethnicity). Racial disparities exist in low- and high-vulnerability counties: Black mothers in the least vulnerable counties remain at higher risk of maternal mortality, preterm birth, and low birthweight as White mothers in the most vulnerable. Exposure to community maternal vulnerability is associated with increased odds of adverse outcomes, but the Black-White gap in outcomes remained under all vulnerability levels. Our findings suggest that locally-informed precision health interventions and further research into racism are needed to achieve maternal health equity. Bill & Melinda Gates Foundation(grant number INV-024583).

Prevalence of Zero-Food among infants and young children in India: patterns of change across the States and Union Territories of India, 1993–2021

The extent of food deprivation and insecurity among infants and young children-a critical phase for children's current and future health and well-being-in India is unknown. We estimate the prevalence of food deprivation among infants and young children in India and describe its evolution over time at sub-national levels. Data from five National Family Health Surveys (NFHS) conducted in 1993, 1999, 2006, 2016 and 2021 for the 36 states/Union Territories (UTs) of India were used. The study population consisted of the most recent children (6-23 months) born to mothers (aged 15-49 years), who were alive and living with the mother at the time of survey (n=175,614 after excluding observations that had no responses to the food question). Food deprivation was defined based on the mother's reporting of the child having not eaten any food of substantial calorific content (i.e., any solid/semi-solid/soft/mushy food types, infant formula and powdered/tinned/fresh milk) in the past 24hours (h), which we labelled as "Zero-Food". In this study, we analyzed Zero-Food in terms of percent prevalence as well as population headcount burden. We calculated the Absolute Change (AC) to quantify the change in the percentage points of Zero-Food across time periods for all-India and by states/UTs. The prevalence of Zero-Food in India marginally declined from 20.0% (95% CI: 19.3%-20.7%) in 1993 to 17.8% (95% CI: 17.5%-18.1%) in 2021. There were considerable differences in the trajectories of change in the prevalence of Zero-Food across states. Chhattisgarh, Mizoram, and Jammu and Kashmir experienced high increase in the prevalence of Zero-Food over this time period, while Nagaland, Odisha, Rajasthan and Madhya Pradesh witnessed a significant decline. In 2021, Uttar Pradesh (27.4%), Chhattisgarh (24.6%), Jharkhand (21%), Rajasthan (19.8%) and Assam (19.4%) were states with the highest prevalence of Zero-Food. As of 2021, the estimated number of Zero-Food children in India was 5,998,138, with the states of Uttar Pradesh (28.4%), Bihar (14.2%), Maharashtra (7.1%), Rajasthan (6.5%), and Madhya Pradesh (6%) accounting for nearly two-thirds of the total Zero-Food children in India. Zero-Food in 2021 was concerningly high among children aged 6-11 months (30.6%) and substantial even among children aged 18-23 months (8.5%). Overall, socioeconomically advantaged groups had lower prevalence of Zero-Food than disadvantaged groups. Concerted efforts at the national and state levels are required to further strengthen existing policies, and design and develop new ones to provide affordable food to children in a timely and equitable manner to ensure food security among infants and young children. This study was supported by a grant from the Bill & Melinda Gates Foundation INV-002992.

Nonhlanhla Yende-Zuma: “We are slowly and carefully changing our thinking”

Abstract Nonhlanhla Yende-Zuma is head of biostatistics at global research organisation CAPRISA in Durban, South Africa. She has been named one of Bill Gates's “Heroes in the Field” - those “putting in the real work to improve lives” - and has her sights set on a future in global policy-making. Anna Britten finds out more

THE TOXIC TURN? CONCEPTUAL AND METHODOLOGICAL ADVANCES ON PROBLEMATIC CONTENTS ON SOCIAL MEDIA

The ‘toxic turn’ in social media platforms continues unabated. Hate speech, mis- and disinformation, misogynistic and racist speech, images, memes and videos are all far too common on social media platforms and more broadly on the internet. While the diminishing popularity of populist politicians led to hopes for less social toxicity, the Covid-19 pandemic introduced new and more complex dimensions. Tensions have emerged around what constitutes problematic content and who gets to define it. Co-regulation models, such as for example the EC Code of Conduct against Illegal Hate Speech, focus on the legality of certain types of contents, while leaving other categories of problematic contents to be defined by platforms. In parallel, the social media ecosystem became more diverse, as new platforms with hands off moderation policies attracted users who felt too constrained by the policies of mainstream platforms. The proposed panel examines this complex and dynamic landscape by problematizing what is understood as toxic, deplatformed, removable and in general problematic content on platforms with the aim to probe the boundaries of what is constituted as acceptable discourse on platforms and to map its implications. In particular, this panel discusses the broad definition of ‘problematic content’ employed by social media platforms, a catch-all term that cuts across hate speech and propaganda, including more politically topical content such as mal-, mis-, and disinformation, hyperpartisan and polarising content, but also abusive, misogynistic, racist, and homophobic discourse. The term is also employed to refer to spam and content that infringes upon the Terms of Service or the Community Standards of social media platforms. As such, it is a broad category that resists a narrower classification given the operational scope of its use. Defining what constitutes problematic content is a key operation of platform content moderation policies but is also the subject of intense debates (de Gregorio, 2020; Gillespie, 2018; Gillespie et al., 2020; Gorwa et al., 2020). The panel interrogates the many definitions and applications of problematic content on social media platforms and applications through an empirically informed lens and focusing on deleted contents, complex mixed narratives, and grey areas, including hidden misinformation on voice applications. Problematic Content according to Twitter Compliance API presents ongoing work on the Twitter Compliance API and the Compliance Firehose, which allow researchers to identify content that has been deleted, deactivated, protected, or suspended from Twitter, a proxy for problematic content. In Multi-Part Narratives on Telegram Siapera presents ongoing research that probes the intersection between Covid-19 scepticism, far right and other political narratives in vaccine hesitant groups on Telegram. The third contribution, What if Bill Gates really is evil, people? Investigating the infodemic’s grey areas discusses the conceptual and methodological definitions of problematic content in relation to work on anti-vax and other conspiratorial narratives on Instagram and on Twitter. The fourth contribution, Misinformation and other Harmful Content in Third-Party Voice Applications focuses on problematic content that is yet to be identified on voice applications such as personal assistants. The article addresses the methodological challenges of identifying and defining such contents on applications that have currently no content moderation policies. All contributions foreground the difficulties and costs of identifying and dealing with problematic contents on social media. The panel fits with theme of decolonization in two ways: firstly, because it is concerned with the tensions around how toxic/problematic contents are defined and who gets to define them; and secondly, because of its focus on neo-colonial discourses or justifications for colonialism in both narratives hosted by platforms and in platforms’ attempts to regulate content. As some narratives are flagged for removal by social platforms, they also raise the question of who is deciding and what does problematic content mean, with far right discourses exploiting this tension and ironically denouncing any attempt to regulate the public discourse as ideological enforcement and justification for (neo)colonial practices performed by social media platforms. From this perspective, platforms' own claims about what constitutes acceptable content is uncomfortably close to colonial narratives of civilised discourse and brings to the fore the potential for neo-colonial narratives and practices in digital spaces.

Bedaquiline and clofazimine resistance in Mycobacterium tuberculosis: an in-vitro and in-silico data analysis

Bedaquiline is a core drug for the treatment of multidrug-resistant tuberculosis; however, the understanding of resistance mechanisms is poor, which is hampering rapid molecular diagnostics. Some bedaquiline-resistant mutants are also cross-resistant to clofazimine. To decipher bedaquiline and clofazimine resistance determinants, we combined experimental evolution, protein modelling, genome sequencing, and phenotypic data. For this in-vitro and in-silico data analysis, we used a novel in-vitro evolutionary model using subinhibitory drug concentrations to select bedaquiline-resistant and clofazimine-resistant mutants. We determined bedaquiline and clofazimine minimum inhibitory concentrations and did Illumina and PacBio sequencing to characterise selected mutants and establish a mutation catalogue. This catalogue also includes phenotypic and genotypic data of a global collection of more than 14 000 clinical Mycobacterium tuberculosis complex isolates, and publicly available data. We investigated variants implicated in bedaquiline resistance by protein modelling and dynamic simulations. We discerned 265 genomic variants implicated in bedaquiline resistance, with 250 (94%) variants affecting the transcriptional repressor (Rv0678) of the MmpS5-MmpL5 efflux system. We identified 40 new variants in vitro, and a new bedaquiline resistance mechanism caused by a large-scale genomic rearrangement. Additionally, we identified in vitro 15 (7%) of 208 mutations found in clinical bedaquiline-resistant isolates. From our in-vitro work, we detected 14 (16%) of 88 mutations so far identified as being associated with clofazimine resistance and also seen in clinically resistant strains, and catalogued 35 new mutations. Structural modelling of Rv0678 showed four major mechanisms of bedaquiline resistance: impaired DNA binding, reduction in protein stability, disruption of protein dimerisation, and alteration in affinity for its fatty acid ligand. Our findings advance the understanding of drug resistance mechanisms in M tuberculosis complex strains. We have established an extended mutation catalogue, comprising variants implicated in resistance and susceptibility to bedaquiline and clofazimine. Our data emphasise that genotypic testing can delineate clinical isolates with borderline phenotypes, which is essential for the design of effective treatments. Leibniz ScienceCampus Evolutionary Medicine of the Lung, Deutsche Forschungsgemeinschaft, Research Training Group 2501 TransEvo, Rhodes Trust, Stanford University Medical Scientist Training Program, National Institute for Health and Care Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Bill & Melinda Gates Foundation, Wellcome Trust, and Marie Skłodowska-Curie Actions.

Implementation and outcomes of dolutegravir-based first-line antiretroviral therapy for people with HIV in South Africa: a retrospective cohort study

There are few data assessing the uptake of first-line dolutegravir among men and women living with HIV in low-income and middle-income countries, and subsequent clinical outcomes in non-trial settings. We aimed to determine dolutegravir uptake in women, and the effect of dolutegravir on clinical outcomes in routine care in South Africa. In this cohort study, we analysed deidentified data from adults receiving first-line antiretroviral therapy (ART) at 59 South African clinics from Dec 1, 2019, to Feb 28, 2022, using two distinct cohorts. In the initiator cohort, we used Poisson regression models to assess the outcome of initiation with dolutegravir-based ART by gender, and associations between dolutegravir use and the outcomes of 12-month retention in care and viral suppression at less than 50 copies per mL. In the transition cohort, comprising adults who received non-dolutegravir-based first-line ART in December, 2019, we used Cox proportional hazards models to assess the outcome of transition to first-line dolutegravir by gender. We then used time-dependent propensity score matching to compare the outcomes of subsequent 12-month retention in care and viral suppression between people who transitioned to dolutegravir and those who had not yet transitioned at the same timepoint. In both the initiation and transition cohort, the primary viral load analysis was an intention-to-treat analysis, with a secondary as-treated analysis that excluded people who changed their ART regimen after baseline. In the initiator cohort, between Dec 1, 2019, and Feb 28, 2022, 45 392 people were initiated on ART. 23 945 (52·8%) of 45 392 were non-pregnant women, 4780 (10·5%) were pregnant women, and 16 667 (36·7%) were men. The median participant age was 31·0 years (IQR 26·0-38·0) and 2401 (5·3%) were receiving tuberculosis treatment at time of ART initiation. 31 264 (68·9%) of 45 392 people were initiated on dolutegravir, 14 102 (31·1%) on efavirenz, and 26 (0·1%) on nevirapine. In a univariable Poisson regression model, pregnant women (risk ratio [RR] 0·57, 95% CI 0·49 to 0·66; risk difference -35·4%, 95% CI -42·3 to -28·5) and non-pregnant women (RR 0·78, 0·74 to 0·82; risk difference -18·4%, -21·6 to -15·2) were less likely to be initiated on dolutegravir than were men. In Poisson models adjusted for age, gender (including pregnancy), time, tuberculosis status, and initiation CD4 count, people initiated on dolutegravir were more likely to be retained in care at 12 months (adjusted RR 1·09, 95% CI 1·04 to 1·14; adjusted risk difference 5·2%, 2·2 to 8·4) and virally suppressed (adjusted RR 1·04, 95% CI 1·01 to 1·06; adjusted risk difference 3·1%, 1·2 to 5·1) compared with those initiated on non-dolutegravir-based regimens. For the transition cohort, on Dec 1, 2019, 180 956 people were receiving non-dolutegravir-based first-line ART at the study clinics, of whom 124 168 (68·6%) were women. The median age was 38 years (IQR 32-45), and the median time on ART was 3·9 years (2·0-6·4) years, with most people receiving efavirenz (178 624 [98·7%] people) and tenofovir (178 148 [98·4%]). By Feb 28, 2022, 121 174 (67·0%) of 180 956 people had transitioned to first-line dolutegravir at a median of 283 days (IQR 203-526). In a univariable Cox regression model the hazard of being transitioned to dolutegravir was lower in women than in men (hazard ratio 0·56, 95% CI 0·56 to 0·57). Among 92 318 propensity score matched people, the likelihood of retention in care was higher among the dolutegravir group compared with matched controls (adjusted RR 1·03, 95% CI 1·02 to 1·03; risk difference 2·5%, 95% CI 2·1 to 2·9). In the dolutegravir group, 33 423 (90·5%) of 36 920 people were suppressed at less than 50 copies per mL compared with 31 648 (89·7%) of 35 299 matched controls (adjusted RR 1·01, 95% CI 1·00 to 1·02; risk difference 0·8%, 95% CI 0·3 to 1·4). Women were less likely to receive dolutegravir than men. As dolutegravir was associated with improved outcomes, roll-out should continue, with a particular emphasis on inclusion of women. Wellcome Trust, Africa Oxford Initiative, International Association of Providers of AIDS Care, and Bill & Melinda Gates Foundation. For the isiZulu translation of the abstract see Supplementary Materials section.

Malaria temporal dynamic clustering for surveillance and intervention planning

BackgroundTargeting interventions where most needed and effective is crucial for public health. Malaria control and elimination strategies increasingly rely on stratification to guide surveillance, to allocate vector control campaigns, and to prioritize access to community-based early diagnosis and treatment (EDT). We developed an original approach of dynamic clustering to improve local discrimination between heterogeneous malaria transmission settings. MethodsWe analysed weekly malaria incidence records obtained from community-based EDT (malaria posts) in Karen/Kayin state, Myanmar. We smoothed longitudinal incidence series over multiple seasons using functional transformation. We regrouped village incidence series into clusters using a dynamic time warping clustering and compared them to the standard, 5-category annual incidence standard stratification. ResultsWe included 1115 villages from 2016 to 2020. We identified eleven P. falciparum and P. vivax incidence clusters which differed by amplitude, trends and seasonality. Specifically the 124 villages classified as “high transmission area” in the standard P. falciparum stratification belonged to the 11 distinct groups when accounting to inter-annual trends and intra-annual variations. Likewise for P. vivax, 399 “high transmission” villages actually corresponded to the 11 distinct dynamics. ConclusionOur temporal dynamic clustering methodology is easy to implement and extracts more information than standard malaria stratification. Our method exploits longitudinal surveillance data to distinguish local dynamics, such as increasing inter-annual trends or seasonal differences, providing key information for decision-making. It is relevant to malaria strategies in other settings and to other diseases, especially when many countries deploy health information systems and collect increasing amounts of health outcome data. FundingThe Bill & Melinda Gates Foundation, The Global Fund against AIDS, Tuberculosis and Malaria (the Regional Artemisinin Initiative) and the Wellcome Trust funded the METF program.

Successes and Opportunities during the Pandemic: Reflections and Revelations from a Vaccine Development Perspective.

The Centre of Regulatory Excellence (CoRE) launched an annual lecture series in 2021 in Singapore to honor the memory of the late Professor Sir Alasdair Breckenridge, CoRE's founding Chair, and foster dialogue on global biomedical and regulatory perspectives, challenges, and advances. The 2022 Sir Alasdair Breckenridge Lecture "Success and Opportunities in the Pandemic" was delivered by Dr Penny M Heaton, former CEO of the Bill & Melinda Gates Foundation Research Institute and current Global Therapeutics Lead for Vaccines at Johnson & Johnson. Dr Heaton highlighted key lessons on the importance of trust, collaboration, and transparency in the context of health care and vaccine production.