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BackgroundSuboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and... more
BackgroundSuboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.MethodsWe systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24andCmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geome...
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Globally, deaths around the time of birth are unacceptably high of which there are about 2.7 million neonatal deaths and 2.6 million stillborn annually. Perinatal mortality accounts for deaths after 28 weeks of gestation to seven days... more
Globally, deaths around the time of birth are unacceptably high of which there are about 2.7 million neonatal deaths and 2.6 million stillborn annually. Perinatal mortality accounts for deaths after 28 weeks of gestation to seven days after birth. Perinatal mortality is a public health concern with a huge impact on the health, social and economic well being affecting both family and society. The burden of perinatal mortality is obvious in the low and middle-income countries, and more on the countries south of sub-Sahara Africa. East Africa being among the sub-Sahara countries is also experiencing a high rate of perinatal mortally, with Tanzania taking the lead. Almost half of stillborns are alive at the start of labor offering an opportunity for prevention. Likewise, 44% of the neonatal deaths occur on the first day of life and are predominantly the result of intrapartum events. Events during labor, including birth asphyxia (interruption of placental blood flow) account for one-quar...
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Research Interests: Microbiology, Biology, Developing Countries, Peru, Bangladesh, and 15 moreMedicine, Clinical Microbiology, Diarrhea, Biological Sciences, Humans, Campylobacter, Female, Male, Polymerase Chain Reaction, Infant, Feces, Campylobacter jejuni, Enzyme Linked Immunosorbent Assay, Campylobacter coli, and Medical and Health Sciences
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ABSTRACTBackgroundEnvironmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation.ObjectiveWe tested whether EED is associated... more
ABSTRACTBackgroundEnvironmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation.ObjectiveWe tested whether EED is associated with micronutrient deficiency risk independent of diet and systemic inflammation, and whether it mediates the relation between intake and micronutrient status.MethodsUsing data from 1283 children in the MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health) birth cohort we evaluated the risk of anemia, low retinol, zinc, and ferritin, and high transferrin receptor (TfR) at 15 mo. We characterized gut inflammation and permeability by myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT) concentrations from asymptomatic fecal samples averaged from 9 to 15 mo, and averaged the lactulose:mannitol ratio z-score (LMZ) at 9 and 15 mo. Nutrient intakes from complementary foods ...
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Background: SaferBirths Bundle of Care (SBBC) is a package of innovative clinical and training tools coupled with low-dose high-frequency simulation-based on-job training guided by local data. This bundle of care is a new initiative being... more
Background: SaferBirths Bundle of Care (SBBC) is a package of innovative clinical and training tools coupled with low-dose high-frequency simulation-based on-job training guided by local data. This bundle of care is a new initiative being implemented in 30 health facilities from five regions of Tanzania aiming at improving birth outcomes. Objective: To assess the perception of healthcare workers and facility leaders on the “SaferBirths Bundle of Care” towards saving women’s and newborns’ lives at birth. Method: We used a qualitative approach using focused group discussion (FGD) and individual interviews. A total of 21 FGD and 43 individual interviews were conducted between August and November 2022. In total, 94 midwives and 12 doctors were involved, some of whom were in leadership roles. The framework method for the analysis of qualitative data was used for analysis. Results: Healthcare workers and facility leaders received the bundle well and regarded it as effective in saving live...
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Giardia lamblia (Giardia) is among the most common intestinal pathogens in children in low- and middle-income countries (LMICs). Although Giardia associates with early-life linear growth restriction, mechanistic explanations for... more
Giardia lamblia (Giardia) is among the most common intestinal pathogens in children in low- and middle-income countries (LMICs). Although Giardia associates with early-life linear growth restriction, mechanistic explanations for Giardia-associated growth impairments remain elusive. Unlike other intestinal pathogens associated with constrained linear growth that cause intestinal or systemic inflammation or both, Giardia seldom associates with chronic inflammation in these children. Here we leverage the MAL-ED longitudinal birth cohort and a model of Giardia mono-association in gnotobiotic and immunodeficient mice to propose an alternative pathogenesis of this parasite. In children, Giardia results in linear growth deficits and gut permeability that are dose-dependent and independent of intestinal markers of inflammation. The estimates of these findings vary between children in different MAL-ED sites. In a representative site, where Giardia associates with growth restriction, infected...
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At least a third of tuberculosis (TB) cases remain undiagnosed, disproportionately so in children and adolescents, which is hampering global elimination goals. Prolonged symptom duration presents a high-risk scenario for childhood TB in... more
At least a third of tuberculosis (TB) cases remain undiagnosed, disproportionately so in children and adolescents, which is hampering global elimination goals. Prolonged symptom duration presents a high-risk scenario for childhood TB in endemic areas, but the prolonged period of symptoms and its impact on educational attainment are rarely documented. Using a mixed method approach, we aimed to quantify the duration of respiratory symptoms and describe their impact on education among children from a rural area of Tanzania. We used data from a prospectively enrolled cohort of children and adolescents aged 4–17 years in rural Tanzania at the start of active TB treatment. We report on the cohort’s baseline characteristics and explore the correlation between duration of symptoms and other variables. In-depth qualitative interviews were designed on the basis of a grounded theory approach to explore the impact of TB on educational attainment among school-aged children. In this cohort, child...
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<p>Performance of TaqMan array card (TAC) compared with 384 well PCR plate for AMR detection in direct stool and cultured isolates (N = 122).</p
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<p>The TaqMan array card includes 8 sample ports. Each well was configured and grouped according to antimicrobial resistance associated with those gene targets. Two wells were used for bacterial species/genera detection. The symbol... more
<p>The TaqMan array card includes 8 sample ports. Each well was configured and grouped according to antimicrobial resistance associated with those gene targets. Two wells were used for bacterial species/genera detection. The symbol “/” indicates a duplex assay. Because we amplified 42 duplex, 1 singleplex (DHA), and 1 singleplex manufacturing control target, only 44 wells were used out of the 48 well TAC card.</p
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<p>Comparison of real time PCR results with conventional PCR results on 120 ETEC isolates and 74 <i>E</i>. <i>coli</i> pools.</p
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<p>(A) On culture (N = 194), the overall correlation R<sup>2</sup> = 0.78 (<i>P</i> < 0.001). Each symbol represents one CF type. (B) On stool, the Cq correlation between enterotoxin and primary/sole CF... more
<p>(A) On culture (N = 194), the overall correlation R<sup>2</sup> = 0.78 (<i>P</i> < 0.001). Each symbol represents one CF type. (B) On stool, the Cq correlation between enterotoxin and primary/sole CF (the most abundant CF type measured by Cq values), secondary CF (the second most abundant, if present), tertiary CF (the third most abundant, if present), and quaternary CF (the fourth abundant, if present) CF were all statistically significant (P < 0.05, with R<sup>2</sup> = 0.66 (N = 81), 0.45 (N = 39), 0.46 (N = 17), and 0.82 (N = 7), respectively. The dotted line shows the diagonal line.</p
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<p>Five lots of stool with different amount of inhibitors were prepared, then the mixture of target nucleic acid was spiked. Extraction and testing with TAC were performed, target copy numbers were calculated based on standard... more
<p>Five lots of stool with different amount of inhibitors were prepared, then the mixture of target nucleic acid was spiked. Extraction and testing with TAC were performed, target copy numbers were calculated based on standard curves and normalized to extrinsic controls. Target copy numbers (circles) were log2 transformed in order to be on the same scale as Cq.</p
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<p>Primer and probe sequences of the real time PCR panels.</p
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<p>Comparison of CF detection on randomly selected stool samples and the corresponding <i>E</i>. <i>coli</i> pools.</p
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<p>For the RNA derived targets below, we compared Cqs between nucleic acid extracted with QIAamp Stool DNA mini kit versus a 1:1 mixture of QIAamp stool DNA mini kit extract and FUJIfilm QuickGene RNA tissue kit or QIAamp viral RNA... more
<p>For the RNA derived targets below, we compared Cqs between nucleic acid extracted with QIAamp Stool DNA mini kit versus a 1:1 mixture of QIAamp stool DNA mini kit extract and FUJIfilm QuickGene RNA tissue kit or QIAamp viral RNA mini kit extract.</p
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<p>The assays are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0158199#pone.0158199.s001" target="_blank">S1 Table</a>.</p
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<p>Sensitivity and specificity of detection on swabs was calculated using the results from the corresponding stool as the reference.</p
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<p>Correlation between genotypic (AMR-PCR assay) and phenotypic AST of <i>E</i>. <i>coli</i> isolates (N = 239).</p
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<p>Comparison of AMR-PCR assays versus sequencing on bacterial isolates (N = 236).</p
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<p>Comparison of AMR-PCR assay detection in direct stool and paired <i>E</i>.<i>coli</i> isolates (N = 220).</p
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Background The purpose of this project was to improve perinatal survival by introducing Moyo Fetal Heart Rate (FHR) Monitor coupled with neonatal resuscitation simulation training. Methods The implementation was done at three district... more
Background The purpose of this project was to improve perinatal survival by introducing Moyo Fetal Heart Rate (FHR) Monitor coupled with neonatal resuscitation simulation training. Methods The implementation was done at three district hospitals. We assessed health care workers’ (HCW’s) skills and perinatal death trends during implementation. Baseline data were collected from the hospitals before implementation. Newborn resuscitation (NR) skills were assessed before and after simulation training. Assessment of perinatal outcomes was done over 2 years of implementation. We used descriptive analysis; a t-test (paired and independent two-sample) and a one-way Anova test to report the findings. Results A total of 107 HCW’s were trained on FHR monitoring using Moyo and NR knowledge and skills using NeoNatalie simulators. The knowledge increased post-training by 13.6% (p
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Background Serious invasive infections in newborns are a major cause of death. Lack of data on etiological causes hampers progress towards reduction of mortality. This study aimed to identify pathogens responsible for such infections in... more
Background Serious invasive infections in newborns are a major cause of death. Lack of data on etiological causes hampers progress towards reduction of mortality. This study aimed to identify pathogens responsible for such infections in young infants in sub-Saharan Africa and to describe their antibiotics resistance profile. Methods Between September 2016 and April 2018 we implemented an observational study in two rural sites in Burkina Faso and Tanzania enrolling young infants aged 0–59 days old with serious invasive infection. Blood samples underwent blood culture and molecular biology. Results In total 634 infants with clinical diagnosis of serious invasive infection were enrolled and 4.2% of the infants had a positive blood culture. The most frequent pathogens identified by blood culture were Klebsiella pneumonia and Staphylococcus aureus, followed by Escherichia coli. Gram-negative isolates were only partially susceptible to first line WHO recommended treatment for neonatal sep...
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ABSTRACT. We identified the determinants of positive (children who had a birth weight < 2.5 kg and/or maternal height < 145 cm but were nonstunted at 24 months of age) and negative (children who had a birth weight ≥ 2.5 kg and... more
ABSTRACT. We identified the determinants of positive (children who had a birth weight < 2.5 kg and/or maternal height < 145 cm but were nonstunted at 24 months of age) and negative (children who had a birth weight ≥ 2.5 kg and maternal height ≥ 145 cm but were stunted at 24 months of age) deviance in childhood linear growth. We found that socioeconomic status (β = 1.54, P < 0.01), serum retinol (β = 0.05, P < 0.01), hemoglobin (β = 0.36, P < 0.01), length-for-age Z-score (LAZ) at birth (β = 0.47, P < 0.01), and tetanus vaccine titer (β = 0.182, P < 0.05) were positively and maternal depressive symptom (β = –0.05, P < 0.01), serum ferritin (β = –0.03, P < 0.01), male sex (β = –1.08, P < 0.01), and α1-antitrypsin (β = –0.81, P < 0.01) were negatively associated with positive deviance. Further, diarrhea episodes (β = 0.02, P < 0.01), male sex (β = 0.72, P < 0.01), and α1-antitrypsin (β = 0.67, P < 0.01) were positively and hemoglobin (β= –0.28,...
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Culture-independent diagnostics have revealed a larger burden of Shigella among children in low-resource settings than previously recognized. We further characterized the epidemiology of Shigella in the first two years of life in a... more
Culture-independent diagnostics have revealed a larger burden of Shigella among children in low-resource settings than previously recognized. We further characterized the epidemiology of Shigella in the first two years of life in a multisite birth cohort. We tested 41,405 diar-rheal and monthly non-diarrheal stools from 1,715 children for Shigella by quantitative PCR. To assess risk factors, clinical factors related to age and culture positivity, and associations with inflammatory biomarkers, we used log-binomial regression with generalized estimating equations. The prevalence of Shigella varied from 4.9%-17.8% in non-diarrheal stools across sites, and the incidence of Shigella-attributable diarrhea was 31.8 cases (95% CI: 29.6, 34.2) per 100 child-years. The sensitivity of culture compared to qPCR was 6.6% and increased to 27.8% in Shigella-attributable dysentery. Shigella diarrhea episodes were more likely to be severe and less likely to be culture positive in younger children. Ol...
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To describe changes in intestinal permeability in early childhood in diverse epidemiologic settings. In a birth cohort study the lactulose:mannitol (LM) test was administered to 1,980 children at four time points in the first 24 months of... more
To describe changes in intestinal permeability in early childhood in diverse epidemiologic settings. In a birth cohort study the lactulose:mannitol (LM) test was administered to 1,980 children at four time points in the first 24 months of life in eight countries. Data from the Brazil site with an incidence of diarrhea similar to that seen in the U.S. and no growth faltering was used as an internal study reference to derive age- and sex-specific Z-scores for mannitol and lactulose recoveries and the lactulose mannitol ratio. 6,602 tests demonstrated mannitol recovery, lactulose recovery, and the L:M ratio were associated with country, sex, and age. There was heterogeneity in the recovery of both probes between sites with mean mannitol recovery ranging for 1.34%-to 5.88%, lactulose recovery of 0.19%-0.58%, and L:M ratios 0.10-0.17 in boys of 3 months of age across different sites. We observed strong sex-specific differences in both mannitol and lactulose recovery, with boys having hig...
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Diarrheal disease remains a major cause of childhood mortality and morbidity causing poor health and economic outcomes. In low-resource settings, young children are exposed to numerous risk factors for enteric pathogen transmission within... more
Diarrheal disease remains a major cause of childhood mortality and morbidity causing poor health and economic outcomes. In low-resource settings, young children are exposed to numerous risk factors for enteric pathogen transmission within their dwellings, though the relative importance of different transmission pathways varies by pathogen species. The objective of this analysis was to model associations between five household-level risk factors—water, sanitation, flooring, caregiver education, and crowding—and infection status for endemic enteric pathogens in children in five surveillance studies. Data were combined from 22 sites in which a total of 58,000 stool samples were tested for 16 specific enteropathogens using qPCR. Risk ratios for pathogen- and taxon-specific infection status were modeled using generalized linear models along with hazard ratios for all-cause diarrhea in proportional hazard models, with the five household-level variables as primary exposures adjusting for c...
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Background: Growth trajectories are highly variable between children, making epidemiological analyses challenging both to the identification of malnutrition interventions at the population level and also risk assessment at individual... more
Background: Growth trajectories are highly variable between children, making epidemiological analyses challenging both to the identification of malnutrition interventions at the population level and also risk assessment at individual level. We introduce stochastic differential equation (SDE) models into child growth research. SDEs describe flexible dynamic processes comprising: drift - gradual smooth changes – such as physiology or gut microbiome, and diffusion - sudden perturbations, such as illness or infection. Methods: We present a case study applying SDE models to child growth trajectory data from the Haydom, Tanzania and Venda, South Africa sites within the MAL-ED cohort. These data comprise n=460 children aged 0-24 months. A comparison with classical curve fitting (linear mixed models) is also presented. Results: The SDE models offered a wide range of new flexible shapes and parameterizations compared to classical additive models, with performance as good or better than stand...
Background Few studies have focused on quantitatively analyzing nutrients from infant diets, compromising complementary feeding evaluation and health promotion worldwide. Objectives This study aimed to describe dietary intake in infants... more
Background Few studies have focused on quantitatively analyzing nutrients from infant diets, compromising complementary feeding evaluation and health promotion worldwide. Objectives This study aimed to describe dietary intake in infants from 9 to 24 mo of age, determining nutrient intakes associated with the risk of underweight, wasting, and stunting. Methods Usual nutrient intakes from complementary feeding were determined by 24-h recalls collected when infants were 9–24 mo of age in communities from 7 low- and middle-income countries: Brazil (n = 169), Peru (n = 199), South Africa (n = 221), Tanzania (n = 210), Bangladesh (n = 208), India (n = 227), and Nepal (n = 229), totaling 1463 children and 22,282 food recalls. Intakes were corrected for within- and between-person variance and energy intake. Multivariable regression models were constructed to determine nutrient intakes associated with the development of underweight, wasting, and stunting at 12, 18, and 24 mo of age. Results ...
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Objectives: To measure the role of water, sanitation and hygiene (WASH) practices on recovery from stunting and assess the role of timing of stunting on the reversal of this phenomenon Design: Data from the MAL-ED multi-country birth... more
Objectives: To measure the role of water, sanitation and hygiene (WASH) practices on recovery from stunting and assess the role of timing of stunting on the reversal of this phenomenon Design: Data from the MAL-ED multi-country birth cohort study was used for the current analysis. Generalised linear mixed-effects models were used to estimate the probability of reversal of stunting with WASH practice and timing of stunting as the exposures of interest. Setting: Seven different countries across three continents. Participants: A total of 612 children <2 years of age. Results: We found that not WASH practice but timing of stunting had statistically significant association with recovery from stunting. In comparison with the children who were stunted at 6 months, children who were stunted at 12 months had 1·9 times (β = 0·63, P = 0·03) more chance of recovery at 24 months of age. And, children who were stunted at 18 months of age even had higher odds (adjusted OR = 3·01, β = 1·10, P &l...
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Extreme floods pose multiple direct and indirect health risks. These risks include contamination of water, food, and the environment, often causing outbreaks of diarrheal disease. Evidence regarding the effects of flooding on individual... more
Extreme floods pose multiple direct and indirect health risks. These risks include contamination of water, food, and the environment, often causing outbreaks of diarrheal disease. Evidence regarding the effects of flooding on individual diarrhea-causing pathogens is limited, but is urgently needed in order to plan and implement interventions and prioritize resources before climate-related disasters strike. This study applied a causal inference approach to data from a multisite study that deployed broadly inclusive diagnostics for numerous high-burden common enteropathogens. Relative risks (RRs) of infection with each pathogen during a flooding disaster that occurred at one of the sites—Loreto, Peru—were calculated from generalized linear models using a comparative interrupted time series framework with the other sites as a comparison group and adjusting for background seasonality. During the early period of the flood, increased risk of heat-stable enterotoxigenic E. coli (ST-ETEC) w...
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Campylobacter species infections have been associated with malnutrition and intestinal inflammation among children in low-resource settings. However, it remains unclear whether that association is specific to Campylobacter jejuni/coli.... more
Campylobacter species infections have been associated with malnutrition and intestinal inflammation among children in low-resource settings. However, it remains unclear whether that association is specific to Campylobacter jejuni/coli. The aim of this study was to assess the association between both all Campylobacter species infections and Campylobacter jejuni/coli infections on growth and enteric inflammation in children aged 1–24 months. We analyzed data from 1715 children followed from birth until 24 months of age in the MAL-ED birth cohort study, including detection of Campylobacter species by enzyme immunoassay and Campylobacter jejuni/coli by quantitative PCR in stool samples. Myeloperoxidase (MPO) concentration in stool, used as a quantitative index of enteric inflammation, was measured. The incidence rate per 100 child-months of infections with Campylobacter jejuni/coli and Campylobacter species during 1–24 month follow up were 17.7 and 29.6 respectively. Female sex of child...
ObjectivesGlobally, perinatal mortality remains high, especially in sub-Saharan countries, mainly because of inadequate obstetric and newborn care. Helping Babies Breathe (HBB) resuscitation training as part of a continuous quality... more
ObjectivesGlobally, perinatal mortality remains high, especially in sub-Saharan countries, mainly because of inadequate obstetric and newborn care. Helping Babies Breathe (HBB) resuscitation training as part of a continuous quality improvement (CQI) programme may improve outcomes. The aim of this study was to describe observed changes in perinatal survival during a 6-year period, while adjusting for relevant perinatal risk factors.SettingDelivery rooms and operating theatre in a rural referral hospital in northern-central Tanzania providing comprehensive obstetric and basic newborn care 24 hours a day. The hospital serves approximately 2 million people comprising low social-economic status.ParticipantsAll newborns (n=31 122) born in the hospital from February 2010 through January 2017; 4893 were born in the 1-year baseline period (February 2010 through January 2011), 26 229 in the following CQI period.InterventionsThe HBB CQI project, including frequent HBB training, was implemented...