Gradient-Descent Quantum Process Tomography by Learning Kraus Operators.

We perform quantum process tomography (QPT) for both discrete- and continuous-variable quantum systems by learning a process representation using Kraus operators. The Kraus form ensures that the reconstructed process is completely positive. To make the process trace preserving, we use a constrained gradient-descent (GD) approach on the so-called Stiefel manifold during optimization to obtain the Kraus operators. Our ansatz uses a few Kraus operators to avoid direct estimation of large process matrices, e.g., the Choi matrix, for low-rank quantum processes. The GD-QPT matches the performance of both compressed-sensing (CS) and projected least-squares (PLS) QPT in benchmarks with two-qubit random processes, but shines by combining the best features of these two methods. Similar to CS (but unlike PLS), GD-QPT can reconstruct a process from just a small number of random measurements, and similar to PLS (but unlike CS) it also works for larger system sizes, up to at least five qubits. We envisage that the data-driven approach of GD-QPT can become a practical tool that greatly reduces the cost and computational effort for QPT in intermediate-scale quantum systems.

Pathogens Associated With Linear Growth Faltering in Children With Diarrhea and Impact of Antibiotic Treatment: The Global Enteric Multicenter Study.

BACKGROUND: The association between childhood diarrheal disease and linear growth faltering in developing countries is well described. However, the impact attributed to specific pathogens has not been elucidated, nor has the impact of recommended antibiotic treatment. METHODS: The Global Enteric Multicenter Study enrolled children with moderate to severe diarrhea (MSD) seeking healthcare at 7 sites in sub-Saharan Africa and South Asia. At enrollment, we collected stool samples to identify enteropathogens. Length/height was measured at enrollment and follow-up, approximately 60 days later, to calculate change in height-for-age z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested using linear mixed effects regression models. RESULTS: Among 8077 MSD cases analyzed, the proportion with stunting (HAZ below -1) increased from 59% at enrollment to 65% at follow-up (P < .0001). Pathogens significantly associated with linear growth decline included Cryptosporidium (P < .001), typical enteropathogenic Escherichia coli (P = .01), and untreated Shigella (P = .009) among infants (aged 0-11 months) and enterotoxigenic E. coli encoding heat-stable toxin (P < .001) and Cryptosporidium (P = .03) among toddlers (aged 12-23 months). Shigella-infected toddlers given antibiotics had improved linear growth (P = .02). CONCLUSIONS: Linear growth faltering among children aged 0-23 months with MSD is associated with specific pathogens and can be mitigated with targeted treatment strategies, as demonstrated for Shigella.

The Clinical Presentation of Culture-positive and Culture-negative, Quantitative Polymerase Chain Reaction (qPCR)-Attributable Shigellosis in the Global Enteric Multicenter Study and Derivation of a Shigella Severity Score: Implications for Pediatric Shigella Vaccine Trials.

BACKGROUND: Shigella is a leading cause of childhood diarrhea and target for vaccine development. Microbiologic and clinical case definitions are needed for pediatric field vaccine efficacy trials. METHODS: We compared characteristics of moderate to severe diarrhea (MSD) cases in the Global Enteric Multicenter Study (GEMS) between children with culture positive Shigella to those with culture-negative, quantitative polymerase chain reaction (qPCR)-attributable Shigella (defined by an ipaH gene cycle threshold <27.9). Among Shigella MSD cases, we determined risk factors for death and derived a clinical severity score. RESULTS: Compared to culture-positive Shigella MSD cases (n = 745), culture-negative/qPCR-attributable Shigella cases (n = 852) were more likely to be under 12 months, stunted, have a longer duration of diarrhea, and less likely to have high stool frequency or a fever. There was no difference in dehydration, hospitalization, or severe classification from a modified Vesikari score. Twenty-two (1.8%) Shigella MSD cases died within the 14-days after presentation to health facilities, and 59.1% of these deaths were in culture-negative cases. Age <12 months, diarrhea duration prior to presentation, vomiting, stunting, wasting, and hospitalization were associated with mortality. A model-derived score assigned points for dehydration, hospital admission, and longer diarrhea duration but was not significantly better at predicting 14-day mortality than a modified Vesikari score. CONCLUSIONS: A composite severity score consistent with severe disease or dysentery may be a pragmatic clinical endpoint for severe shigellosis in vaccine trials. Reliance on culture for microbiologic confirmation may miss a substantial number of Shigella cases but is currently required to measure serotype specific immunity.

Epidemiology and genetic characterization of human sapovirus among hospitalized acute diarrhea patients in Bangladesh, 2012-2015.

Human sapovirus, which causes acute gastroenteritis, is not well studied and poorly understood. This study aims to investigate the contribution of sapovirus in diarrhea, their clinical association, and genotypic diversity. Fecal specimens (n = 871) were randomly selected from diarrheal patients who attended International Centre for Diarrhoeal Disease Research, Bangladesh hospital in Dhaka, Bangladesh during January 2012-December 2015 and tested for the presence of sapovirus RNA using real-time polymerase chain reaction. Sapovirus RNA was identified in 2.3% (n = 20) of the samples. Seventy-five percent of the sapovirus positive cases were coinfected with other pathogens, such as rotavirus, norovirus, enterotoxigenic Escherichia coli, adenovirus, Shigella spp., and Vibrio cholerae. A vast genetic diversity was observed among sapovirus with at least seven common genotypes (GI.1, GI.2, GI.7, GII.1, GII.4, GII.6, and GIV), and a new genotype GII.NA1. Some of the GI.1 strains detected were similar to GI.4 in the polymerase region sequence and were confirmed as recombinant strains. Our findings suggest that the overall contribution of sapovirus in hospitalized diarrheal illness is low but highlight enormous genetic diversity.

Quantum State Tomography with Conditional Generative Adversarial Networks.

Quantum state tomography (QST) is a challenging task in intermediate-scale quantum devices. Here, we apply conditional generative adversarial networks (CGANs) to QST. In the CGAN framework, two dueling neural networks, a generator and a discriminator, learn multimodal models from data. We augment a CGAN with custom neural-network layers that enable conversion of output from any standard neural network into a physical density matrix. To reconstruct the density matrix, the generator and discriminator networks train each other on data using standard gradient-based methods. We demonstrate that our QST-CGAN reconstructs optical quantum states with high fidelity, using orders of magnitude fewer iterative steps, and less data, than both accelerated projected-gradient-based and iterative maximum-likelihood estimation. We also show that the QST-CGAN can reconstruct a quantum state in a single evaluation of the generator network if it has been pretrained on similar quantum states.

Pathogen-specific risk of seizure in children with moderate-to-severe diarrhoea: Case control study with follow-up.

OBJECTIVE: To determine the pathogen-specific risk of seizure in under-five children hospitalised with moderate-to-severe diarrhoea (MSD) in rural settings. METHOD: This was a prospective case-control study with follow-up, conducted in a sentinel facility of Global Enteric Multicenter Study in Mirzapur, a rural community of Bangladesh between 2007 and 2010. Children aged 0-59 months who presented with MSD and seizure constituted the cases whereas those who did not have seizure comprised the controls. MSD was defined if the episodes were associated with dehydration or dysentery or required hospitalisation with diarrhoea or dysentery. All enrolled children were followed up at home within 50-90 days of enrolment. A total of 64 cases and 128 randomly selected controls formed the analysable dataset. RESULTS: The result of logistic regression analysis after adjusting for potential confounders revealed that shigellosis (Shigella species, OR = 5.34, 95% CI = 2.37-12.04) particularly S. flexneri (OR = 3.34, 95% CI = 1.48-7.57), S. flexneri 6 (OR = 23.24, 95% CI = 2.79-193.85), S. sonnei (OR = 6.90, 95% CI = 2.34-19.85); norovirus (OR = 6.77, 95% CI = 1.69-27.11), fever (OR = 16.75, 95% CI = 1.81-154.70) and loss of consciousness (OR = 35.25, 95% CI = 1.71-726.20) were the independent risk factors for seizure in MSD children. At enrolment, cases had lower WHZ (P = 0.006) compared to their peers, follow-up anthropometrics showed significant improvement in WHZ (P < 0.001) and WAZ (P < 0.05), whereas deterioration in HAZ (P < 0.001) in both cases and controls. CONCLUSION: Childhood MSD episodes particularly due to Shigella and norovirus are often associated with seizure. Prompt identification and appropriate management of children with shigellosis may reduce occurrence and adverse consequences of seizure linked with MSD.

OBJECTIF: Déterminer le risque spécifique de convulsions chez les enfants de moins de cinq ans hospitalisés pour une diarrhée modérée à sévère (DMS) en milieu rural. MÉTHODE: Il s'agissait d'une étude prospective cas-témoins avec suivi, menée dans un établissement sentinelle de l'Etude Globale Multicentrique Entérique à Mirzapur, une communauté rurale du Bangladesh entre 2007 et 2010. Les enfants âgés de 0 à 59 mois qui se sont présentés avec une DMS et des convulsions constituaient les cas, tandis que ceux qui n'avaient pas des convulsions constituaient les témoins. La DMS a été définie si les épisodes étaient associés à une déshydratation ou à une dysenterie ou nécessitaient une hospitalisation pour diarrhée ou dysenterie. Tous les enfants recrutés ont été suivis à domicile dans les 50 à 90 jours suivant le recrutement. Un total de 64 cas et 128 témoins sélectionnés au hasard ont constitué l'ensemble de données analysables. RÉSULTATS: Le résultat de l'analyse de régression logistique après ajustement des facteurs de confusion potentiels a révélé que la shigellose (espèce Shigella, OR = 5,34 ; IC95%: 2,37-12,04) en particulier S. flexneri (OR = 3,34 ; IC95%: 1,48-7,57), S. flexneri 6 (OR = 23,24 ; IC95%: 2.79-193,85), S. sonnei (OR = 6,90 ; IC95%: 2,34-19,85) ; les norovirus (OR = 6,77 ; IC95%: 1,69-27,11), la fièvre (OR = 16,75 ; IC95%: 1,81-154,70) et la perte de conscience (OR = 35,25 ; IC95%: 1,71-726,20) étaient les facteurs de risque indépendants de convulsions chez les enfants souffrant de DMS. Lors du recrutement, les cas avaient un score Z poids pour la taille (ZPT) plus faible (P = 0,006) que leurs pairs, les anthropométries de suivi ont montré une amélioration significative du ZPT (P < 0,001) et du score Z poids pour l'âge (P < 0,05); tandis que le score Z taille pour l'âge (p < 0,001) s'est détérioré chez cas et chez les témoins. CONCLUSION: Les épisodes de DMS de l'enfance, notamment due à Shigella et aux norovirus, sont souvent associés à des convulsions. L'identification rapide et la prise en charge appropriée des enfants atteints de shigellose peuvent réduire la survenue et les conséquences négatives des crises liées aux DMS.

Epidemiologic and Genotypic Distribution of Noroviruses Among Children With Acute Diarrhea and Healthy Controls in a Low-income Rural Setting.

BACKGROUND: Noroviruses are the most common cause of epidemic and endemic acute gastroenteritis (AGE) worldwide. The burden of norovirus disease in low-income settings is poorly understood. METHODS: We tested stool samples from children less than 5 years of age with diarrhea who were admitted in a rural hospital in Bangladesh from 2010-2012 and from matched, healthy controls from the same catchment area. RESULTS: Norovirus was detected in 109 (18%) of 613 children with diarrhea and in 30 (15%) of 206 healthy controls. Most (n = 118; 85%) norovirus infections belonged to genogroup II (GII). Of these, GII.4 viruses were identified in 36 (33%) of the cases and in 6 (21%) of the controls. Other major genotypes included GII.3 (13%), GII.6 (11%), and GII.13 (11%) in the cases and GII.6 (17%) and GII.2 (14%) in the controls. The greatest risk of severe norovirus disease (Vesikari score ≥11) was associated with GII.4 infections. GII.4 viruses were the predominant genotype detected during the winter (55%) and rainy season (23%), while GII.3 (19%) and GII.13 (19%) viruses were the most prevalent genotypes during the summer. Vomiting was significantly associated with GII.4 infections, while longer durations of diarrhea were associated with GI.3 infections. CONCLUSIONS: Future studies are needed to understand the high rates of virus shedding in children without AGE symptoms.

Case-Control Study of Cryptosporidium Transmission in Bangladeshi Households.

BACKGROUND: Cryptosporidium is a leading contributor to diarrheal morbidity and mortality in under-5 children worldwide. As there is no vaccine and no effective drug therapy in young children for this infection, preventing infection is critical. We undertook a pilot case-control study to define the extent of person-to-person transmission of cryptosporidiosis within an urban and a rural community in Bangladesh. METHODS: We enrolled 48 case families with a Cryptosporidium-infected child aged 6-18 months. Controls were age- and sex-matched Cryptosporidium-negative children in 12 households. Children and household members were followed for 8 weeks with weekly illness survey and stool testing with quantitative polymerase chain reaction for Cryptosporidium. RESULTS: In the 24 urban case families, the secondary attack rate was 35.8% (19/53) vs 0% (0/11) in controls (P = .018, χ2 test). In contrast, in the 24 rural case families, the secondary attack rate was 7.8% (5/64) vs 0% (0/21) in controls (P = .19, χ2 test). Genotyping by gp60 demonstrated infection with the same subspecies in 5 families, and evidence of transmission in 2. Serologic response to Cryptosporidium infection was associated with younger age, longer duration of infection, and Cryptosporidium hominis gp60_IbA9G3R2 infection. CONCLUSIONS: In the urban site, the high rate of secondary infection and infection with the same subspecies within families suggests that person-to-person transmission is a major source of Cryptosporidium infection for young children living in this region. Molecular genotyping can be applied to determine transmission of Cryptosporidium in endemic regions. Further work is needed to understand the differences in parasite transmissibility and immunity to different genotypes.

Multiplex genomewide association analysis of breast milk fatty acid composition extends the phenotypic association and potential selection of FADS1 variants to arachidonic acid, a critical infant micronutrient.

BACKGROUND: Breast milk is the sole nutrition source during exclusive breastfeeding, and polyunsaturated fatty acids (FAs) are critical micronutrients in infant physical and cognitive development. There has been no prior genomewide association study of breast milk, hence our objective was to test for genetic association with breast milk FA composition. METHODS: We measured the fractional composition of 26 individual FAs in breast milk samples from three cohorts totalling 1142 Bangladeshi mothers whose infants were genotyped on the Illumina MEGA chip and replicated on a custom Affymetrix 30K SNP array (n=616). Maternal genotypes were imputed using IMPUTE. RESULTS: After running 33 separate FA fraction phenotypes, we found that SNPs known to be associated with serum FAs in the FADS1/2/3 region were also associated with breast milk FA composition (experiment-wise significance threshold 4.2×10-9). Hypothesis-neutral comparison of the 33 fractions showed that the most significant genetic association at the FADS1/2/3 locus was with fraction of arachidonic acid (AA) at SNP rs174556, with a very large per major allele effect size of 17% higher breast milk AA level. There was no evidence of independent association at FADS1/2/3 with any other FA or SNP after conditioning on AA and rs174556. We also found novel significant experiment-wise SNP associations with: polyunsaturated fatty acid (PUFA) 6/PUFA3 ratio (sorting nexin 29), eicosenoic (intergenic) and capric (component of oligomeric Golgi complex 3) acids; and six additional loci at genomewide significance (<5×10-8). CONCLUSIONS: AA is the primary FA in breast milk influenced by genetic variation at the FADS1/2/3 locus, extending the potential phenotypes under genetic selection to include breast milk composition, thereby possibly affecting infant growth or cognition. Breast milk FA composition is influenced by maternal genetics in addition to diet and body composition.

Genetic Diversity of Cryptosporidium hominis in a Bangladeshi Community as Revealed by Whole-Genome Sequencing.

We studied the genetic diversity of Cryptosporidium hominis infections in slum-dwelling infants from Dhaka over a 2-year period. Cryptosporidium hominis infections were common during the monsoon, and were genetically diverse as measured by gp60 genotyping and whole-genome resequencing. Recombination in the parasite was evidenced by the decay of linkage disequilibrium in the genome over <300 bp. Regions of the genome with high levels of polymorphism were also identified. Yet to be determined is if genomic diversity is responsible in part for the high rate of reinfection, seasonality, and varied clinical presentations of cryptosporidiosis in this population.

Giardia/Cryptosporidium QUIK CHEK Assay Is More Specific Than Quantitative Polymerase Chain Reaction for Rapid Point-of-care Diagnosis of Cryptosporidiosis in Infants in Bangladesh.

Background: Cryptosporidium is a major cause of childhood diarrhea. Current modes of cryptosporidiosis diagnosis involve procedures that are costly and require both a well-equipped laboratory and technical expertise. Therefore, a cost-effective, user-friendly, and rapid method for point-of-care detection of Cryptosporidium is desirable. Methods: A total of 832 diarrheal stool specimens collected from 200 children aged <2 years were tested by Giardia/Cryptosporidium QUIK CHEK, enzyme-linked immunosorbent assay (ELISA), and quantitative polymerase chain reaction (qPCR) to compare the performance of the individual techniques. We also tested for the presence of other diarrheal pathogens in qPCR-positive samples with a TaqMan Array Card (TAC) to assess whether Cryptosporidium was the sole causative agent for the diarrheal episodes. Results: Of 832 samples, 4.4% were found positive for Cryptosporidium by QUIK CHEK, 3.6% by ELISA, and 8.8% by qPCR. Using TAC-attributed Cryptosporidium diarrhea as the gold standard, the sensitivities of QUIK CHEK, ELISA, and qPCR were 92.3%, 71.8%, and 100%, respectively; the specificities were 97.1%, 94.3%, and 0%, respectively. Analysis of the qPCR-positive and QUIK CHEK-negative samples by TAC identified other enteropathogens as more likely than Cryptosporidium to be the causative agents of diarrhea. Conclusions: QUIK CHEK was more sensitive and specific than ELISA. While qPCR detected Cryptosporidium in more samples than QUIK CHEK, most of these were instances of qPCR detecting small quantities of Cryptosporidium DNA in a diarrheal episode caused by another enteropathogen. We concluded that QUIK CHEK was comparable in sensitivity and superior in specificity to qPCR for the diagnosis of Cryptosporidium diarrhea.

Species of Cryptosporidia Causing Subclinical Infection Associated With Growth Faltering in Rural and Urban Bangladesh: A Birth Cohort Study.

Background: Cryptosporidiosis is a major cause of childhood diarrhea in low- and middle-income countries and has been linked to impairment of child growth. This study investigated the burden of cryptosporidiosis and its impact on child growth in both a rural and an urban site in Bangladesh. Methods: Pregnant women in the second trimester were identified at 2 sites in Bangladesh, 1 urban and 1 rural. Their offspring were enrolled at birth into the study (urban, n = 250; rural, n = 258). For 2 years, the children were actively monitored for diarrhea and anthropometric measurements were obtained every 3 months. Stool samples were collected monthly and during diarrheal episodes with Cryptosporidium infection and causative species determined by quantitative polymerase chain reaction assays. Results: Cryptosporidium infections were common at both sites and mostly subclinical. In the urban site, 161 (64%) children were infected and 65 (26%) had ≥2 infections. In the rural site, 114 (44%) were infected and 24 (9%) had multiple infections. Adjusted for potential confounders, cryptosporidiosis was associated with a significantly greater drop in the length-for-age z score (LAZ) at 24 months from LAZ at enrollment (Δ-LAZ), an effect greatest in the children with multiple episodes of cryptosporidiosis. The most common species in Mirpur was Cryptosporidium hominis, whereas Cryptosporidium meleagridis predominated in Mirzapur. Conclusions: Cryptosporidiosis is common in early childhood and associated with early growth faltering in Bangladeshi children. Predominant Cryptosporidium species differed between the 2 sites, suggesting different exposures or modes of transmission but similar consequences for child growth. Clinical Trials Registration: NCT02764918.

Detection of enteric- and non-enteric adenoviruses in gastroenteritis patients, Bangladesh, 2012-2015.

Human adenoviruses (HAdVs) are common cause of nonbacterial acute gastroenteritis worldwide. Limited data exist on HAdVs molecular epidemiology associated with acute gastroenteritis in Bangladesh. We describe the genetic diversity and epidemiology of HAdVs among hospitalized diarrhea patients, including HAdV genotypes, clinical symptoms, and co-infecting enteric pathogens. Stool samples were collected from ongoing diarrhea surveillance during 2012-2015. HAdV was detected using PCR and genotyped by sequencing and phylogenetic analysis. Detailed socio-demographic and clinical information regarding each individual was recorded such as duration of diarrhea, dehydration status, vomiting, abdominal pain, fever, and severity. Of 871 fecal specimens, HAdV DNA was detected in 93 (10.7%). Among them 56% were co-infected with other known enteric viral and bacterial pathogens and 31.6% had severe gastroenteritis. The majority (55%) of HAdV positives were children <5 years of age. Two main clinical symptoms in HAdV infected patients were diarrhea and vomiting. HAdVs were detected throughout the year with low prevalence in winter (November-January). Five HAdV species (A, B, C, D, and F) including 17 different genotypes were identified during the study period, with enteric HAdV species F (HAdV-40/41) being the most dominant. However, non-enteric HAdV were also detected in substantial proportion of specimens (15% species C, 15% species D, 10.8% species A, and 4.3% species B). Our study demonstrates high genetic diversity of HAdVs including enteric and non-enteric HAdVs among diarrhea patients and provides a foundation for further clarification of the role of non-enteric HAdVs in diarrheal diseases.

Enteric Infections in Young Children are Associated with Environmental Enteropathy and Impaired Growth.

OBJECTIVE: To investigate the relationship between faecal contamination in child play spaces, enteric infections, environmental enteropathy (EE) and impaired growth among young children. METHODS: A prospective cohort study was conducted of 203 children 6-30 months of age in rural Bangladesh. Stool samples were analysed by quantitative PCR for Shigella, Enterotoxigenic Escherichia coli (ETEC), Campylobacter jejuni, Giardia intestinalis and Cryptosporidium spp. Four faecal markers of intestinal inflammation were also measured: alpha-1-antitrypsin, myeloperoxidase, neopterin and calprotectin. Child growth was measured at baseline and 9 months after enrolment. E. coli was measured in soil in child play spaces. RESULTS: Forty-seven percent of study children had three or more enteric pathogens in their stool. Thirty five percent (71/203) of children had Shigella, 30% (61/203) had ETEC, 73% (148/203) had C. jejuni, 79% (160/203) had Giardia intestinalis and none had Cryptosporidium. Children with ETEC had significantly higher calprotectin concentrations (Coefficient: 1.35, 95% Confidence Interval [CI]: 1.005, 1.82). Children with Shigella had a significantly higher odds of being stunted at our 9-month follow-up (OR: 2.01, 95% CI: 1.02, 3.93). Children with Giardia intestinalis had significantly higher E.coli counts in the soil collected from their play spaces (OR: 1.23, 95% CI: 1.02, 1.48). CONCLUSION: Enteric infections were significantly associated with EE and impaired growth in rural Bangladesh. These findings provide further evidence to support the hypothesis that contaminated soil in child play spaces can lead to enteric infections, many of which are likely subclinical, resulting in EE and impaired growth in young children.

The effect of a newly established urban diarrhea treatment facility in Bangladesh: Changing patient characteristics and etiologies.

BACKGROUND: Mirpur treatment centre (MTC), Dhaka of the International Centre for Diarrhoeal Disease Research, Bangladesh, was established as a consequence of an outbreak of diarrheal disease during the summer month of April 2007 in Mirpur area. OBJECTIVE: The present study aimed to evaluate the impact of this new facility on patient load, common etiology, and other characteristics of patient population who sought treatment at Dhaka Hospital. METHODS: As part of the Diarrheal Disease Surveillance System (DDSS), 10% patients (every 10th) seeking care irrespective of age, sex, sociodemographic background, and severity of disease were enrolled at MTC as opposed to 2% (every 50th) at Dhaka Hospital following identical methodology from 2010 to 2013. Moreover, enrolled DDSS patients from 2005 to 2009 at Dhaka Hospital were also included in analysis to further examine the impact of MTC on Dhaka Hospital. RESULTS: Patient load from Mirpur area attending the Dhaka Hospital reduced from 13% during epidemic in 2010 to 6% in 2013 (53% reduction), whereas attendance in MTC increased substantially by 33%. This changing trend was also observed among children <5 years old. A significant reduction of patients presenting with moderately severe disease from Mirpur area at Dhaka Hospital was observed (69% reduction); however, attendance at MTC increased by 26% during same period. CONCLUSION: The number of patients from Mirpur area in Dhaka Hospital reduced but increased at MTC explaining the need for establishment of a set up for early treatment and control of diarrheal disease when consistent increase in annual number of cases or at the time of upsurge of cases is observed.

Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study.

BACKGROUND: Diarrhoea is the second leading cause of mortality in children worldwide, but establishing the cause can be complicated by diverse diagnostic approaches and varying test characteristics. We used quantitative molecular diagnostic methods to reassess causes of diarrhoea in the Global Enteric Multicenter Study (GEMS). METHODS: GEMS was a study of moderate to severe diarrhoea in children younger than 5 years in Africa and Asia. We used quantitative real-time PCR (qPCR) to test for 32 enteropathogens in stool samples from cases and matched asymptomatic controls from GEMS, and compared pathogen-specific attributable incidences with those found with the original GEMS microbiological methods, including culture, EIA, and reverse-transcriptase PCR. We calculated revised pathogen-specific burdens of disease and assessed causes in individual children. FINDINGS: We analysed 5304 sample pairs. For most pathogens, incidence was greater with qPCR than with the original methods, particularly for adenovirus 40/41 (around five times), Shigella spp or enteroinvasive Escherichia coli (EIEC) and Campylobactor jejuni o C coli (around two times), and heat-stable enterotoxin-producing E coli ([ST-ETEC] around 1·5 times). The six most attributable pathogens became, in descending order, Shigella spp, rotavirus, adenovirus 40/41, ST-ETEC, Cryptosporidium spp, and Campylobacter spp. Pathogen-attributable diarrhoeal burden was 89·3% (95% CI 83·2-96·0) at the population level, compared with 51·5% (48·0-55·0) in the original GEMS analysis. The top six pathogens accounted for 77·8% (74·6-80·9) of all attributable diarrhoea. With use of model-derived quantitative cutoffs to assess individual diarrhoeal cases, 2254 (42·5%) of 5304 cases had one diarrhoea-associated pathogen detected and 2063 (38·9%) had two or more, with Shigella spp and rotavirus being the pathogens most strongly associated with diarrhoea in children with mixed infections. INTERPRETATION: A quantitative molecular diagnostic approach improved population-level and case-level characterisation of the causes of diarrhoea and indicated a high burden of disease associated with six pathogens, for which targeted treatment should be prioritised. FUNDING: Bill & Melinda Gates Foundation.

Mouthing of Soil Contaminated Objects is Associated with Environmental Enteropathy in Young Children.

OBJECTIVE: To characterise childhood mouthing behaviours and to investigate the association between object-to-mouth and food-to-mouth contacts, diarrhoea prevalence and environmental enteropathy. METHODS: A prospective cohort study was conducted of 216 children ≤30 months of age in rural Bangladesh. Mouthing contacts with soil and food and objects with visible soil were assessed by 5-h structured observation. Stool was analysed for four faecal markers of intestinal inflammation: alpha-1-antitrypsin, myeloperoxidase, neopterin and calprotectin. RESULTS: Overall 82% of children were observed mouthing soil, objects with visible soil, or food with visible soil during the structured observation period. Sixty two percent of children were observed mouthing objects with visible soil, 63% were observed mouthing food with visible soil, and 18% were observed mouthing soil only. Children observed mouthing objects with visible soil had significantly elevated faecal calprotectin concentrations (206.81 µg/g, 95% confidence interval [CI]: 6.27, 407.36). There was also a marginally significant association between Escherichia coli counts in soil from a child's play space and the prevalence rate of diarrhoea (diarrhoea prevalence ratio: 2.03, 95% CI 0.97, 4.25). CONCLUSION: These findings provide further evidence to support the hypothesis that childhood mouthing behaviour in environments with faecal contamination can lead to environmental enteropathy in susceptible paediatric populations. Furthermore, these findings suggest that young children mouthing objects with soil, which occurred more frequently than soil directly (60% vs. 18%), was an important exposure route to faecal pathogens and a risk factor for environmental enteropathy.

Sanitation and Hygiene-Specific Risk Factors for Moderate-to-Severe Diarrhea in Young Children in the Global Enteric Multicenter Study, 2007-2011: Case-Control Study.

BACKGROUND: Diarrheal disease is the second leading cause of disease in children less than 5 y of age. Poor water, sanitation, and hygiene conditions are the primary routes of exposure and infection. Sanitation and hygiene interventions are estimated to generate a 36% and 48% reduction in diarrheal risk in young children, respectively. Little is known about whether the number of households sharing a sanitation facility affects a child's risk of diarrhea. The objective of this study was to describe sanitation and hygiene access across the Global Enteric Multicenter Study (GEMS) sites in Africa and South Asia and to assess sanitation and hygiene exposures, including shared sanitation access, as risk factors for moderate-to-severe diarrhea (MSD) in children less than 5 y of age. METHODS/FINDINGS: The GEMS matched case-control study was conducted between December 1, 2007, and March 3, 2011, at seven sites in Basse, The Gambia; Nyanza Province, Kenya; Bamako, Mali; Manhiça, Mozambique; Mirzapur, Bangladesh; Kolkata, India; and Karachi, Pakistan. Data was collected for 8,592 case children aged <5 y old experiencing MSD and for 12,390 asymptomatic age, gender, and neighborhood-matched controls. An MSD case was defined as a child with a diarrheal illness <7 d duration comprising ≥3 loose stools in 24 h and ≥1 of the following: sunken eyes, skin tenting, dysentery, intravenous (IV) rehydration, or hospitalization. Site-specific conditional logistic regression models were used to explore the association between sanitation and hygiene exposures and MSD. Most households at six sites (>93%) had access to a sanitation facility, while 70% of households in rural Kenya had access to a facility. Practicing open defecation was a risk factor for MSD in children <5 y old in Kenya. Sharing sanitation facilities with 1-2 or ≥3 other households was a statistically significant risk factor for MSD in Kenya, Mali, Mozambique, and Pakistan. Among those with a designated handwashing area near the home, soap or ash were more frequently observed at control households and were significantly protective against MSD in Mozambique and India. CONCLUSIONS: This study suggests that sharing a sanitation facility with just one to two other households can increase the risk of MSD in young children, compared to using a private facility. Interventions aimed at increasing access to private household sanitation facilities may reduce the burden of MSD in children. These findings support the current World Health Organization/ United Nations Children's Emergency Fund (UNICEF) system that categorizes shared sanitation as unimproved.

Unsafe Child Feces Disposal is Associated with Environmental Enteropathy and Impaired Growth.

OBJECTIVE: To investigate the relationship between unsafe child feces disposal, environmental enteropathy, and impaired growth, we conducted a prospective cohort study of 216 young children in rural Bangladesh. STUDY DESIGN: Using a prospective cohort study design in rural Bangladesh, unsafe child feces disposal, using the Joint Monitoring Program definition, was assessed using 5-hour structured observation by trained study personnel as well as caregiver reports. Anthropometric measurements were collected at baseline and at a 9-month follow-up. Stool was analyzed for fecal markers of environmental enteropathy: alpha-1-antitrypsin, myeloperoxidase, neopterin (combined to form an environmental enteropathy disease activity score), and calprotectin. FINDINGS: Among 216 households with young children, 84% had an unsafe child feces disposal event during structured observation and 75% had caregiver reported events. There was no significant difference in observed unsafe child feces disposal events for households with or without an improved sanitation option (82% vs 85%, P = .72) or by child's age (P = .96). Children in households where caregivers reported unsafe child feces disposal had significantly higher environmental enteropathy scores (0.82-point difference, 95% CI 0.11-1.53), and significantly greater odds of being wasted (weight-for-height z score <-2 SDs) (9% vs 0%, P = .024). In addition, children in households with observed unsafe feces disposal had significantly reduced change in weight-for-age z-score (-0.34 [95% CI -0.68, -0.01] and weight-for-height z score (-0.52 [95% CI -0.98, -0.06]). CONCLUSION: Unsafe child feces disposal was significantly associated with environmental enteropathy and impaired growth in a pediatric population in rural Bangladesh. Interventions are needed to reduce this high-risk behavior to protect the health of susceptible pediatric populations.

Geophagy Is Associated with Growth Faltering in Children in Rural Bangladesh.

OBJECTIVE: To determine the relationship between geophagy (mouthing of dirt, sand, clay, or mud) and growth faltering in young children. STUDY DESIGN: We examined linear growth as height and weight standardized by age and sex, and weight standardized by height, in a cohort of children aged 6-36 months in rural Mirzapur, Bangladesh. We determined geophagy behavior at baseline through caregiver report. Anthropometric measurements were assessed at baseline and at a 1-year follow-up. RESULTS: We found that among children not stunted at baseline, those with caregiver-reported geophagy at baseline grew less over 1 year compared with their peers, with a difference in the change of standardized height for age and sex of -0.31 (95% CI, -0.61 to -0.01). CONCLUSION: These findings show that caregiver-reported geophagy was associated with growth faltering in a pediatric population in rural Bangladesh. Future studies are needed to learn more about this exposure pathway and its relevance to child growth.