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1.
Proc Natl Acad Sci U S A ; 117(34): 20717-20728, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32788367

RESUMO

Mucosal-associated invariant T (MAIT) cells are innate T lymphocytes activated by bacteria that produce vitamin B2 metabolites. Mouse models of infection have demonstrated a role for MAIT cells in antimicrobial defense. However, proposed protective roles of MAIT cells in human infections remain unproven and clinical conditions associated with selective absence of MAIT cells have not been identified. We report that typhoidal and nontyphoidal Salmonella enterica strains activate MAIT cells. However, S. Typhimurium sequence type 313 (ST313) lineage 2 strains, which are responsible for the burden of multidrug-resistant nontyphoidal invasive disease in Africa, escape MAIT cell recognition through overexpression of ribB This bacterial gene encodes the 4-dihydroxy-2-butanone-4-phosphate synthase enzyme of the riboflavin biosynthetic pathway. The MAIT cell-specific phenotype did not extend to other innate lymphocytes. We propose that ribB overexpression is an evolved trait that facilitates evasion from immune recognition by MAIT cells and contributes to the invasive pathogenesis of S. Typhimurium ST313 lineage 2.


Assuntos
Células T Invariáveis Associadas à Mucosa/imunologia , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , África ao Sul do Saara , Antibacterianos , Diarreia/microbiologia , Diarreia/mortalidade , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/fisiologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Infecções por Salmonella/imunologia , Salmonella typhimurium/patogenicidade
2.
Lancet ; 395(10239): 1779-1801, 2020 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-32513411

RESUMO

BACKGROUND: Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. METHODS: We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. FINDINGS: The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1-65·8), 17·4% (7·7-28·4), and 59·5% (34·2-86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. INTERPRETATION: By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Países em Desenvolvimento/estatística & dados numéricos , Diarreia/epidemiologia , Diarreia/mortalidade , Carga Global da Doença/estatística & dados numéricos , Saúde Global/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Teorema de Bayes , Pré-Escolar , Diarreia/prevenção & controle , Humanos , Incidência , Prevalência
3.
PLoS One ; 15(5): e0220164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32433685

RESUMO

Acute respiratory infection (ARI) and diarrhoea are two major causes of child morbidity and mortality in Bangladesh. National and regional level prevalence of ARI and diarrhoea are calculated from nationwide surveys; however, prevalence at micro-level administrative units (say, district and sub-district) is not possible due to lack of sufficient data at those levels. In such a case, small area estimation (SAE) methods can be applied by combining survey data with census data. Using an SAE method for the dichotomous response variable, this study aims to estimate the proportions of under-5 children experienced with ARI and diarrhoea separately as well as either ARI or diarrhoea within a period of two-week preceding the survey. The ARI and diarrhoea data extracted from Bangladesh Demographic and Health Survey 2011 are used to develop a random effect logistic model for each of the indicators, and then the prevalence is estimated adapting the World Bank SAE approach for the dichotomous response variable using a 5% sample of the Census 2011. The estimated prevalence of each indicator significantly varied by district and sub-district (1.4-11.3% for diarrhoea, 2.2-11.8% for ARI and 4.3-16.5% for ARI/diarrhoea at sub-district level). In many sub-districts, the proportions are found double of the national level. District and sub-district levels spatial distributions of the indicators might help the policymakers to identify the vulnerable disaggregated and remote hotspots. Particularly, aid industries can provide effective interventions at the highly vulnerable spots to overcome the gaps between micro and macro level administrative units.


Assuntos
Diarreia/epidemiologia , Infecções Respiratórias/epidemiologia , Bangladesh/epidemiologia , Censos , Criança , Pré-Escolar , Diarreia/mortalidade , Inquéritos Epidemiológicos/métodos , Humanos , Modelos Logísticos , Prevalência , Infecções Respiratórias/mortalidade
4.
BMC Public Health ; 20(1): 759, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448276

RESUMO

BACKGROUND: Oshikhandass is a rural village in northern Pakistan where a 1989-1991 verbal autopsy study showed that diarrhea and pneumonia were the top causes of under-5 mortality. Intensive surveillance, active community health education and child health interventions were delivered in 1989-1996; here we assess improvements in under-5 mortality, diarrhea, and pneumonia over this period and 15 years later. METHODS: Two prospective open-cohort studies in Oshikhandass from 1989 to 1996 (Study 1) and 2011-2014 (Study 2) enrolled all children under age 60 months. Study staff trained using WHO guidelines, conducted weekly household surveillance and promoted knowledge on causes and management of diarrhea and pneumonia. Information about household characteristics and socioeconomic status was collected. Hurdle models were constructed to examine putative risk factors for diarrhea and pneumonia. RESULTS: Against a backdrop of considerable change in the socioeconomic status of the community, under-5 mortality, which declined over the course of Study 1 (from 114.3 to 79.5 deaths/1000 live births (LB) between 1989 and 1996), exceeded Sustainable Development Goal 3 by Study 2 (19.8 deaths/ 1000 LB). Reductions in diarrhea prevalence (20.3 to 2.2 days/ Child Year [CY]), incidence (2.1 to 0.5 episodes/ CY), and number of bloody diarrhea episodes (18.6 to 5.2%) seen during Study 1, were sustained in Study 2. Pneumonia incidence was 0.5 episodes /CY in Study 1 and 0.2/CY in Study 2; only 5% of episodes were categorized as severe or very severe in both studies. While no individual factors predicted a statistically significant difference in diarrhea or pneumonia episodes, the combined effect of water, toilet and housing materials was associated with a significant decrease in diarrhea; higher household income was the most protective factor for pneumonia in Study 1. CONCLUSIONS: We report a 4-fold decrease in overall childhood mortality, and a 2-fold decrease in childhood morbidity from diarrhea and pneumonia in a remote rural village in Pakistan between 1989 and 2014. We conclude that significant, sustainable improvements in child health may be achieved through improved socioeconomic status and promoting interactions between locally engaged health workers and the community, but that continued efforts are needed to improve health worker training, supervision, and the rational use of medications. TRIAL REGISTRATION: Not Applicable.


Assuntos
Diarreia/mortalidade , Mortalidade/tendências , Pneumonia/mortalidade , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Estudos Longitudinais , Masculino , Paquistão/epidemiologia , Vigilância da População/métodos , Estudos Prospectivos , Fatores de Risco , População Rural , Classe Social
5.
Am J Trop Med Hyg ; 103(3): 1319-1328, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32342837

RESUMO

Recent evidence indicates mass drug administration with azithromycin may reduce child mortality. This study uses verbal autopsy (VA) to investigate the causes of individual deaths during the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial in Malawi. Cluster randomization was performed as part of MORDOR. Biannual household visits were conducted to distribute azithromycin or placebo to children aged 1-59 months and update the census to identify deaths for VA. MORDOR was not powered to investigate mortality effects at individual sites, but the available evidence is presented here for hypothesis generation regarding the mechanism through which azithromycin may reduce child mortality. Automated VA analysis was performed to infer the likely cause of death using two major analysis programs, InterVA and SmartVA. A total of 334 communities were randomized to azithromycin or placebo, with more than 130,000 person-years of follow-up. During the study, there were 1,184 deaths, of which 1,131 were followed up with VA. Mortality was 9% lower in azithromycin-treated communities than in placebo communities (rate ratio 0.91 [95% CI: 0.79-1.05]; P = 0.20). The intention-to-treat analysis by cause using InterVA suggested fewer HIV/AIDS deaths in azithromycin-treated communities (rate ratio 0.70 [95% CI: 0.50-0.97]; P = 0.03) and fewer pneumonia deaths (rate ratio 0.82 [95% CI: 0.60-1.12]; P = 0.22). The use of the SmartVA algorithm suggested fewer diarrhea deaths (rate ratio 0.71 [95% CI: 0.51-1.00]; P = 0.05) and fewer pneumonia deaths (rate ratio 0.58 [95% CI: 0.33-1.00]; P = 0.05). Although this study is not able to provide strong evidence, the data suggest that the mortality reduction during MORDOR in Malawi may have been due to effects on pneumonia and diarrhea or HIV/AIDS mortality.


Assuntos
Síndrome de Imunodeficiência Adquirida/mortalidade , Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Causas de Morte , Infecções por HIV/mortalidade , Pneumonia/mortalidade , Autopsia , Mortalidade da Criança , Pré-Escolar , Diarreia/mortalidade , Feminino , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Macrolídeos/administração & dosagem , Malaui/epidemiologia , Masculino , Administração Massiva de Medicamentos
6.
Clin Sci (Lond) ; 134(8): 941-953, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227118

RESUMO

The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid-base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid-base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.


Assuntos
Anormalidades Múltiplas/genética , Diarreia/congênito , Células Epiteliais/metabolismo , Erros Inatos do Metabolismo/genética , Trocador 3 de Sódio-Hidrogênio/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Animais , Diarreia/genética , Diarreia/metabolismo , Diarreia/mortalidade , Diarreia/patologia , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/mortalidade , Erros Inatos do Metabolismo/patologia , Camundongos , Camundongos Knockout , Mutação , Trocador 3 de Sódio-Hidrogênio/metabolismo
7.
PLoS Med ; 17(3): e1003055, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32203504

RESUMO

BACKGROUND: Housing is essential to human well-being but neglected in global health. Today, housing in Africa is rapidly improving alongside economic development, creating an urgent need to understand how these changes can benefit health. We hypothesised that improved housing is associated with better health in children living in sub-Saharan Africa (SSA). We conducted a cross-sectional analysis of housing conditions relative to a range of child health outcomes in SSA. METHODS AND FINDINGS: Cross-sectional data were analysed for 824,694 children surveyed in 54 Demographic and Health Surveys, 21 Malaria Indicator Surveys, and two AIDS Indicator Surveys conducted in 33 countries between 2001 and 2017 that measured malaria infection by microscopy or rapid diagnostic test (RDT), diarrhoea, acute respiratory infections (ARIs), stunting, wasting, underweight, or anaemia in children aged 0-5 years. The mean age of children was 2.5 years, and 49.7% were female. Housing was categorised into a binary variable based on a United Nations definition comparing improved housing (with improved drinking water, improved sanitation, sufficient living area, and finished building materials) versus unimproved housing (all other houses). Associations between house type and child health outcomes were determined using conditional logistic regression within surveys, adjusting for prespecified covariables including age, sex, household wealth, insecticide-treated bed net use, and vaccination status. Individual survey odds ratios (ORs) were pooled using random-effects meta-analysis. Across surveys, improved housing was associated with 8%-18% lower odds of all outcomes except ARI (malaria infection by microscopy: adjusted OR [aOR] 0.88, 95% confidence intervals [CIs] 0.80-0.97, p = 0.01; malaria infection by RDT: aOR 0.82, 95% CI 0.77-0.88, p < 0.001; diarrhoea: aOR 0.92, 95% CI 0.88-0.97, p = 0.001; ARI: aOR 0.96, 95% CI 0.87-1.07, p = 0.49; stunting: aOR 0.83, 95% CI 0.77-0.88, p < 0.001; wasting: aOR 0.90, 95% CI 0.83-0.99, p = 0.03; underweight: aOR 0.85, 95% CI 0.80-0.90, p < 0.001; any anaemia: aOR 0.87, 95% CI 0.82-0.92, p < 0.001; severe anaemia: aOR 0.89, 95% CI 0.84-0.95, p < 0.001). In comparison, insecticide-treated net use was associated with 16%-17% lower odds of malaria infection (microscopy: aOR 0.83, 95% CI 0.78-0.88, p < 0.001; RDT: aOR 0.84, 95% CI 0.79-0.88, p < 0.001). Drinking water source and sanitation facility alone were not associated with diarrhoea. The main study limitations are the use of self-reported diarrhoea and ARI, as well as potential residual confounding by socioeconomic position, despite adjustments for household wealth and education. CONCLUSIONS: In this study, we observed that poor housing, which includes inadequate drinking water and sanitation facility, is associated with health outcomes known to increase child mortality in SSA. Improvements to housing may be protective against a number of important childhood infectious diseases as well as poor growth outcomes, with major potential to improve children's health and survival across SSA.


Assuntos
Anemia/epidemiologia , Saúde da Criança , Transtornos da Nutrição Infantil/epidemiologia , Diarreia/epidemiologia , Habitação , Malária/epidemiologia , Determinantes Sociais da Saúde , África ao Sul do Saara/epidemiologia , Fatores Etários , Anemia/diagnóstico , Anemia/mortalidade , Anemia/prevenção & controle , Transtornos da Nutrição Infantil/diagnóstico , Transtornos da Nutrição Infantil/mortalidade , Transtornos da Nutrição Infantil/prevenção & controle , Pré-Escolar , Estudos Transversais , Diarreia/diagnóstico , Diarreia/mortalidade , Diarreia/prevenção & controle , Água Potável , Feminino , Nível de Saúde , Inquéritos Epidemiológicos , Humanos , Lactente , Recém-Nascido , Mosquiteiros Tratados com Inseticida , Malária/diagnóstico , Malária/mortalidade , Malária/prevenção & controle , Masculino , Estudos Prospectivos , Fatores de Proteção , Medição de Risco , Fatores de Risco , Saneamento
8.
BMC Infect Dis ; 20(1): 207, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164562

RESUMO

BACKGROUND: Kiribati introduced rotavirus vaccine in 2015. To estimate the impact of rotavirus vaccine on acute gastroenteritis (AGE) and severe acute malnutrition (SAM) among children under 5 in Kiribati, a retrospective review of inpatient and outpatient AGE and hospitalized SAM was undertaken. METHODS: Inpatient data for admissions and hospital deaths due to AGE, SAM and all-causes were collected for children under 5 from all hospitals on the main island, Tarawa, from January 2010-December 2013 (pre-rotavirus vaccine) and January 2016-September 2017 (post-rotavirus vaccine). National outpatient diarrhea data were collected from January 2010 to August 2017 for under 5. An interrupted time-series analysis was undertaken to estimate the effect of rotavirus vaccine on the rates of inpatient and outpatient AGE, inpatient SAM; and inpatient case fatality rates for AGE and SAM, were calculated pre- and post-rotavirus vaccine introduction. RESULTS: The incidence rate of AGE admissions from Tarawa and national AGE outpatient presentations significantly declined by 37 and 44%, respectively, 2 years following rotavirus vaccine introduction. There was a significant decline in the percentage of AGE contributing to all-cause under 5 admissions (12·8% vs. 7·2%, p < 0·001) and all-cause under-five mortality (15·9% vs. 5·7%, p = 0·006) pre- and post-rotavirus vaccine introduction. The estimated incidence rate of inpatient SAM decreased by 24% in under 5 s, 2 years following rotavirus vaccine introduction. CONCLUSIONS: AGE morbidity and mortality and hospitalized SAM rates have declined following rotavirus vaccine introduction in Kiribati children.


Assuntos
Diarreia/epidemiologia , Gastroenterite/epidemiologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/uso terapêutico , Desnutrição Aguda Grave/epidemiologia , Pré-Escolar , Diarreia/mortalidade , Fezes/virologia , Feminino , Gastroenterite/mortalidade , Gastroenterite/virologia , Hospitais/estatística & dados numéricos , Humanos , Lactente , Análise de Séries Temporais Interrompida , Masculino , Micronésia/epidemiologia , Morbidade , Estudos Retrospectivos , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/mortalidade , Vacinas contra Rotavirus/imunologia
9.
J Glob Health ; 10(1): 010601, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32082546

RESUMO

Background: An estimated 1.2 million children under five years of age die each year in India, with pneumonia and diarrhea among the leading causes. Increasing care-seeking is important to reduce mortality and morbidity from these causes. This paper explores the determinants and patterns of care-seeking for childhood illness in rural Pune district, India. Methods: Mothers having at least one child <5 years from the study area of the Vadu Health and Demographic Surveillance System were enrolled in a prospective cohort study. Household sociodemographic information was collected through a baseline questionnaire administered at enrollment. Participants were visited up to six times between July 2015 and February 2016 to collect information on recent childhood acute illness and associated care-seeking behavior. Multivariate logistic regression explored the associations between care-seeking and child, participant, and household characteristics. Results: We enrolled 743 mothers with 1066 eligible children, completing 2585 follow-up interviews (90% completion). Overall acute illness prevalence in children was 26% with care sought from a health facility during 71% of episodes. Multivariable logistic regression showed care-seeking was associated with the number of reported symptoms (Odds ratio (OR) = 2.4, 95% confidence interval (CI) = 1.5-3.9) and household insurance coverage (OR = 2.2, 95% CI = 1.1-4.3). We observed an interaction between the associations of illness severity and maternal employment on care-seeking. Somewhat-to-very severe illness was associated with increased care-seeking among both employed (OR = 5.0, 95% CI = 2.2-11.1) and currently unemployed mothers (OR = 7.0, 95% CI = 3.9-12.6). Maternal employment was associated with reduced care-seeking for non-severe illness (OR = 0.3, 95% CI = 0.1-0.7), but not associated with care-seeking for somewhat-to-very severe illness. Child sex was not associated with care-seeking. Conclusions: This study demonstrates the importance of illness characteristics in determining facility-based care-seeking while also suggesting that maternal employment resulted in decreased care-seeking among non-severe illness episodes. The nature of the association between maternal employment and care-seeking is unclear and should be explored through additional studies. Similarly, the absence of male bias in care-seeking should be examined to assess for potential bias at other stages in the management of childhood illness.


Assuntos
Diarreia/terapia , Mães/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Pneumonia/terapia , População Rural , Adulto , Pré-Escolar , Diarreia/epidemiologia , Diarreia/mortalidade , Emprego/estatística & dados numéricos , Feminino , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Masculino , Mães/estatística & dados numéricos , Pneumonia/epidemiologia , Pneumonia/mortalidade , Estudos Prospectivos , População Rural/estatística & dados numéricos , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto Jovem
10.
Trials ; 21(1): 71, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931848

RESUMO

BACKGROUND: Acute diarrhoea is a common cause of illness and death among children in low- to middle-income settings. World Health Organization guidelines for the clinical management of acute watery diarrhoea in children focus on oral rehydration, supplemental zinc and feeding advice. Routine use of antibiotics is not recommended except when diarrhoea is bloody or cholera is suspected. Young children who are undernourished or have a dehydrating diarrhoea are more susceptible to death at 90 days after onset of diarrhoea. Given the mortality risk associated with diarrhoea in children with malnutrition or dehydrating diarrhoea, expanding the use of antibiotics for this subset of children could be an important intervention to reduce diarrhoea-associated mortality and morbidity. We designed the Antibiotics for Childhood Diarrhoea (ABCD) trial to test this intervention. METHODS: ABCD is a double-blind, randomised trial recruiting 11,500 children aged 2-23 months presenting with acute non-bloody diarrhoea who are dehydrated and/or undernourished (i.e. have a high risk for mortality). Enrolled children in Bangladesh, India, Kenya, Malawi, Mali, Pakistan and Tanzania are randomised (1:1) to oral azithromycin 10 mg/kg or placebo once daily for 3 days and followed-up for 180 days. Primary efficacy endpoints are all-cause mortality during the 180 days post-enrolment and change in linear growth 90 days post-enrolment. DISCUSSION: Expanding the treatment of acute watery diarrhoea in high-risk children to include an antibiotic may offer an opportunity to reduce deaths. These benefits may result from direct antimicrobial effects on pathogens or other incompletely understood mechanisms including improved nutrition, alterations in immune responsiveness or improved enteric function. The expansion of indications for antibiotic use raises concerns about the emergence of antimicrobial resistance both within treated children and the communities in which they live. ABCD will monitor antimicrobial resistance. The ABCD trial has important policy implications. If the trial shows significant benefits of azithromycin use, this may provide evidence to support reconsideration of antibiotic indications in the present World Health Organization diarrhoea management guidelines. Conversely, if there is no evidence of benefit, these results will support the current avoidance of antibiotics except in dysentery or cholera, thereby avoiding inappropriate use of antibiotics and reaffirming the current guidelines. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03130114. Registered on April 26 2017.


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Desenvolvimento Infantil , Desidratação/fisiopatologia , Países em Desenvolvimento , Diarreia/tratamento farmacológico , Transtornos da Nutrição do Lactente/fisiopatologia , Desnutrição/fisiopatologia , África ao Sul do Saara , Fatores Etários , Antibacterianos/efeitos adversos , Ásia Ocidental , Azitromicina/efeitos adversos , Desidratação/diagnóstico , Desidratação/mortalidade , Diarreia/diagnóstico , Diarreia/mortalidade , Diarreia/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Lactente , Mortalidade Infantil , Transtornos da Nutrição do Lactente/diagnóstico , Transtornos da Nutrição do Lactente/mortalidade , Fenômenos Fisiológicos da Nutrição do Lactente , Masculino , Desnutrição/diagnóstico , Desnutrição/mortalidade , Estudos Multicêntricos como Assunto , Estado Nutricional , Estado de Hidratação do Organismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Equilíbrio Hidroeletrolítico
11.
Lancet Glob Health ; 8(2): e215-e224, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31981554

RESUMO

BACKGROUND: Host vulnerabilities associated with acute malnutrition could facilitate the ability of specific enteric pathogens to cause diarrhoea and associated mortality. Using data from the Global Enteric Multicenter Study, we assessed whether acute malnutrition modifies the association between common enteric pathogens and moderate-to-severe diarrhoea, and whether associations between enteric pathogens and death were modified by acute malnutrition. METHODS: Children with moderate-to-severe diarrhoea and age-matched and community-matched controls were included in this post-hoc analysis if their mid-upper arm circumference had been measured and if they were older than 6 months of age. Acute malnutrition was defined as mid-upper arm circumference below 12·5 cm, capturing both severe acute malnutrition (<11·5 cm) and moderate acute malnutrition (≥11·5 cm and <12·5 cm). We tested whether acute malnutrition modified associations between enteric pathogens and moderate-to-severe diarrhoea in conditional logistic regression models. Among children with moderate-to-severe diarrhoea, Cox proportional hazards regression evaluated the modifying effect of acute malnutrition on the relationship between pathogens and 60-day fatality rate. FINDINGS: The age, site, and co-infection adjusted odds ratios (aORs) for moderate-to-severe diarrhoea associated with typical enteropathogenic Escherichia coli among children aged 6-11 months was 2·08 (95% CI 1·14-3·79) in children with acute malnutrition, and 0·97 (0·77-1·23) in children with better nutritional status, compared with healthy controls. Enterotoxigenic E coli producing heat-stable toxin among children aged 12-23 months also had a stronger association with moderate-to-severe diarrhoea in children with acute malnutrition (aOR 7·60 [2·63-21·95]) than among similarly aged children with better nutritional status (aOR 2·39 [1·76-3·25]). Results for Shigella spp, norovirus, and sapovirus suggested they had a stronger association with moderate-to-severe diarrhoea than other pathogens among children with better nutritional status, although Shigella spp remained associated with moderate-to-severe diarrhoea in both nutritional groups. 92 (64%) of 144 children with moderate-to-severe diarrhoea who died had acute malnutrition. Pathogen-specific 60-day fatality rates for all pathogens were higher among children with acute malnutrition, but no individual pathogen had a significantly larger increase in its relative association with mortality. INTERPRETATION: Acute malnutrition might strengthen associations between specific pathogens and moderate-to-severe diarrhoea. However, the strong link between acute malnutrition and mortality during moderate-to-severe diarrhoea in children is not limited to specific infections, and affects a broad spectrum of enteric pathogens. Interventions addressing acute malnutrition could be an effective way to lower the mortality of both childhood malnutrition and diarrhoea. FUNDING: The Bill & Melinda Gates Foundation.


Assuntos
Causas de Morte , Coinfecção/mortalidade , Diarreia/etiologia , Diarreia/mortalidade , Mortalidade , Desnutrição Aguda Grave/complicações , Desnutrição Aguda Grave/mortalidade , Bangladesh/epidemiologia , Estudos de Casos e Controles , Pré-Escolar , Estudos de Coortes , Diarreia/epidemiologia , Feminino , Gâmbia/epidemiologia , Humanos , Índia/epidemiologia , Lactente , Quênia/epidemiologia , Masculino , Mali/epidemiologia , Moçambique/epidemiologia , Estado Nutricional , Paquistão/epidemiologia , Desnutrição Aguda Grave/epidemiologia
12.
Lancet Glob Health ; 8(2): e204-e214, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31864916

RESUMO

BACKGROUND: The Global Enteric Multicenter Study (GEMS) was a 3-year case-control study that measured the burden, aetiology, and consequences of moderate-to-severe diarrhoea (MSD) in children aged 0-59 months. GEMS-1A, a 12-month follow-on study, comprised two parallel case-control studies, one assessing MSD and the other less-severe diarrhoea (LSD). In this report, we analyse the risk of death with each diarrhoea type and the specific pathogens associated with fatal outcomes. METHODS: GEMS was a prospective, age-stratified, matched case-control study done at seven sites in Africa and Asia. Children aged 0-59 months with MSD seeking care at sentinel health centres were recruited along with one to three randomly selected matched community control children without diarrhoea. In the 12-month GEMS-1A follow-on study, children with LSD and matched controls, in addition to children with MSD and matched controls, were recruited at six of the seven sites; only cases of MSD and controls were enrolled at the seventh site. We compared risk of death during the period between enrolment and one follow-up household visit done about 60 days later (range 50-90 days) in children with MSD and LSD and in their respective controls. Approximately 50 pathogens were detected using, as appropriate, classic bacteriology, immunoassays, gel-based PCR and reverse transcriptase PCR, and quantitative real-time PCR (qPCR). Specimens from a subset of GEMS cases and controls were also tested by a TaqMan Array Card that compartmentalised probe-based qPCR for 32 enteropathogens. FINDINGS: 223 (2·0%) of 11 108 children with MSD and 43 (0·3%) of 16 369 matched controls died between study enrolment and the follow-up visit at about 60 days (hazard ratio [HR] 8·16, 95% CI 5·69-11·68, p<0·0001). 12 (0·4%) of 2962 children with LSD and seven (0·2%) of 4074 matched controls died during the follow-up period (HR 2·78, 95% CI 0·95-8·11, p=0·061). Risk of death was lower in children with dysenteric MSD than in children with non-dysenteric MSD (HR 0·20, 95% CI 0·05-0·87, p=0·032), and lower in children with LSD than in those with non-dysenteric MSD (HR 0·29, 0·14-0·59, p=0·0006). In children younger than 24 months with MSD, infection with typical enteropathogenic Escherichia coli, enterotoxigenic E coli encoding heat-stable toxin, enteroaggregative E coli, Shigella spp (non-dysentery cases), Aeromonas spp, Cryptosporidium spp, and Entamoeba histolytica increased risk of death. Of 61 deaths in children aged 12-59 months with non-dysenteric MSD, 31 occurred among 942 children qPCR-positive for Shigella spp and 30 deaths occurred in 1384 qPCR-negative children (HR 2·2, 95% CI 1·2-3·9, p=0·0090), showing that Shigella was strongly associated with increased risk of death. INTERPRETATION: Risk of death is increased following MSD and, to a lesser extent, LSD. Considering there are approximately three times more cases of LSD than MSD in the population, more deaths are expected among children with LSD than in those with MSD. Because the major attributable LSD-associated and MSD-associated pathogens are the same, implementing vaccines and rapid diagnosis and treatment interventions against these major pathogens are rational investments. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Países em Desenvolvimento/estatística & dados numéricos , Diarreia/epidemiologia , Diarreia/mortalidade , Carga Global da Doença/estatística & dados numéricos , Pobreza/estatística & dados numéricos , Estudos de Casos e Controles , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Mortalidade , Estudos Prospectivos
13.
Transbound Emerg Dis ; 67(1): 6-10, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31411792

RESUMO

Circoviruses are found in many species, including mammals, birds, lower vertebrates and invertebrates. To date, there are no reports of circovirus-induced diseases in chickens. In this study, we identified a new strain of chicken circovirus (CCV) by PacBio third-generation sequencing samples from chickens with acute gastroenteritis in a Shandong commercial broiler farm in China. The complete genome of CCV was verified by inverse PCR. Genomic analysis revealed that CCV codes two inverse open reading frames (ORFs), and a potential stem-loop structure was present at the 5' end with a structure typical of a circular virus. Phylogenetic tree analysis showed that CCV formed an independent branch between mammalian and avian circovirus, and homology analysis indicated that the homology of CCV with 21 other known circoviruses was less than 40%. Thus, this CCV strain represents a new species in the genus Circovirus. The infection rate of CCV in 12 chickens with diarrhoea was 100%, but no CCV was found in healthy chickens, thereby indicating that the novel CCV strain is highly associated with acute infectious gastroenteritis in chickens. The emergence of a novel CCV in commercial broiler chickens is highly concerning for the broiler industry.


Assuntos
Galinhas/virologia , Infecções por Circoviridae/veterinária , Circovirus/isolamento & purificação , Diarreia/veterinária , Gastroenterite/veterinária , Genoma Viral/genética , Doenças das Aves Domésticas/virologia , Doença Aguda , Animais , China/epidemiologia , Infecções por Circoviridae/mortalidade , Infecções por Circoviridae/virologia , Circovirus/classificação , Circovirus/genética , Diarreia/mortalidade , Diarreia/virologia , Fezes/virologia , Gastroenterite/mortalidade , Gastroenterite/virologia , Fases de Leitura Aberta/genética , Filogenia , Reação em Cadeia da Polimerase/veterinária , Doenças das Aves Domésticas/mortalidade
14.
J Agric Food Chem ; 68(2): 441-450, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31736308

RESUMO

Absorption of glucose, via intestinal Na+/glucose cotransporter 1 (SGLT1), activates salt and water absorption and is an effective route for treating Escherichia coli (E. coli)-induced diarrhea. Activity and expression of SGLT1 is regulated by sensing of sugars and artificial/natural sweeteners by the intestinal sweet receptor T1R2-T1R3 expressed in enteroendocrine cells. Diarrhea, caused by the bacterial pathogen E. coli, is the most common post-weaning clinical feature in rabbits, leading to mortality. We demonstrate here that, in rabbits with experimentally E. coli-induced diarrhea, inclusion of a supplement containing stevia leaf extract (SL) in the feed decreases cumulative morbidity, improving clinical signs of disease (p < 0.01). We show that the rabbit intestine expresses T1R2-T1R3. Furthermore, intake of SL enhances activity and expression of SGLT1 and the intestinal capacity to absorb glucose (1.8-fold increase, p < 0.05). Thus, a natural plant extract sweetener can act as an effective feed additive for lessening the negative impact of enteric diseases in animals.


Assuntos
Diarreia/veterinária , Células Enteroendócrinas/metabolismo , Infecções por Escherichia coli/veterinária , Escherichia coli/fisiologia , Mucosa Intestinal/efeitos dos fármacos , Adoçantes não Calóricos/administração & dosagem , Extratos Vegetais/administração & dosagem , Coelhos/microbiologia , Transportador 1 de Glucose-Sódio/metabolismo , Stevia/química , Animais , Diarreia/tratamento farmacológico , Diarreia/microbiologia , Diarreia/mortalidade , Células Enteroendócrinas/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/mortalidade , Feminino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Folhas de Planta/química , Coelhos/metabolismo , Transportador 1 de Glucose-Sódio/genética
15.
Salud Publica Mex ; 62(1): 6-13, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-31869557

RESUMO

OBJECTIVE: To evaluate the impact of rotavirus (RV) vaccination after 10 years of it´s universalization on morbidity and mortality from Acute Diarrheal Disease (ADD) in mexican children under five years of age. MATERIALS AND METHODS: Annual median numbers for ADD new cases, hospitalizations and deaths were compared between pre and post universalization periods; absolute and relative reductions were calculated, considering p<0.05 values as significant. RESULTS: Mortality, hospitalizations and new cases from ADD in children under five decreased 52.6, 46, and 15.5% respectively, in the posuniversalization period. During rotavirus seasons, reduction in mortality, hospitalizations and new cases was 66.9, 64.7, and 28.7% respectively. CONCLUSIONS: As of the universal introduction of RV vaccination in Mexico, significant and sustained reductions are appreciated for mortality and hospitalizations from ADD, less so for incidence. A most prominent effect is observed during the winter season.


Assuntos
Diarreia/epidemiologia , Hospitalização/estatística & dados numéricos , Infecções por Rotavirus/epidemiologia , Vacinas contra Rotavirus/administração & dosagem , Doença Aguda , Pré-Escolar , Diarreia/mortalidade , Diarreia/prevenção & controle , Diarreia/virologia , Hospitalização/tendências , Humanos , Incidência , Lactente , Recém-Nascido , México/epidemiologia , Infecções por Rotavirus/mortalidade , Infecções por Rotavirus/prevenção & controle , Fatores de Tempo
16.
Can J Gastroenterol Hepatol ; 2019: 2576349, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815114

RESUMO

Background: Combination therapy of transarterial chemoembolization plus sorafenib (TACE-S) has been proven to be safe and effective for hepatocellular carcinoma (HCC); however, this combination therapy is associated with a high incidence of adverse events (AEs). Our study focused on the relationships between AEs and treatment outcomes and aimed to discover AE-based clinical markers that can predict the survival benefits of combination treatment. Methods: From January 2010 to June 2014, a total of 235 HCC patients treated with TACE-S were retrospectively enrolled. Major sorafenib-related AEs were prospectively recorded, and their correlations with overall survival (OS) were analysed using time-dependent covariate Cox regression analyses. Results: The majority of the patients (200, 85.1%) were male, and the median age was 51 years old. After two years of follow-up, the median OS of the study population reached 12.4 months. In all, 218 patients (92.8%) presented at least one AE, and 174 (74.0%) suffered AEs ≥2 grade. Based on time-dependent multivariate analyses, the development of hand-foot skin reaction (HFSR) ≥2 grade (HR = 0.43, 95% CI: 0.32-0.58, P < 0.001) and diarrhoea ≥1 grade (HR = 0.72, 95% CI: 0.53-0.97, P=0.029) were identified as independent predictors of prolonged OS. Moreover, patients who developed both HFSR ≥2 grade and diarrhoea ≥1 grade achieved better outcomes than those patients who developed either or neither of these AEs (HR = 1.51, 95% CI: 1.11-2.06, P=0.009). Conclusions: The development of HFSR ≥2 grade or diarrhoea ≥1 grade during TACE-S treatment indicated prolonged OS, and these AEs should be considered important clinical markers for predicting patient prognoses.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/efeitos adversos , Diarreia/etiologia , Neoplasias Hepáticas/terapia , Dermatopatias/etiologia , Sorafenibe/uso terapêutico , Adulto , Biomarcadores , Carcinoma Hepatocelular/mortalidade , Diarreia/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Dermatopatias/mortalidade , Taxa de Sobrevida , Resultado do Tratamento
17.
J Glob Health ; 9(2): 020801, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31673345

RESUMO

Background: Childhood diarrhea deaths have declined more than 80% from 1980 to 2015, in spite of an increase in the number of children in low- and middle-income countries (LMIC). Possible drivers of this remarkable accomplishment can guide the further reduction of the half million annual child deaths from diarrhea that still occur. Methods: We used the Lives Saved Tool, which models effects on mortality due to changes in coverage of preventive or therapeutic interventions or risk factors, for 50 LMIC to determine the proximal drivers of the diarrhea mortality reduction. Results: Diarrhea treatment (oral rehydration solution [ORS], zinc, antibiotics for dysentery and management of persistent diarrhea) and use of rotavirus vaccine accounted for 49.7% of the diarrhea mortality reduction from 1980 to 2015. Improvements in nutrition (stunting, wasting, breastfeeding practices, vitamin A) accounted for 38.8% and improvements in water, sanitation and handwashing for 11.5%. The contribution of ORS was greater from 1980 to 2000 (58.0% of the reduction) than from 2000 to 2015 (30.7%); coverage of ORS increased from zero in 1980 to 29.5% in 2000 and more slowly to 44.1% by 2015. To eliminate the remaining childhood diarrhea deaths globally, all these interventions will be needed. Scaling up diarrhea treatment and rotavirus vaccine, to 90% coverage could reduce global child diarrhea mortality by 74.1% from 2015 levels by 2030. Adding improved nutrition could increase that to 89.1%. Finally, adding increased use of improved water sources, sanitation and handwashing could result in a 92.8% reduction from the 2015 level. Conclusions: Employing the interventions that have resulted in such a large reduction in diarrhea mortality in the last 35 years can virtually eliminate remaining childhood diarrhea deaths by 2030.


Assuntos
Mortalidade da Criança/tendências , Diarreia/mortalidade , Diarreia/prevenção & controle , Mortalidade Infantil/tendências , Pré-Escolar , Países em Desenvolvimento/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido
18.
J Glob Health ; 9(2): 020802, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31673346

RESUMO

The Program for the Control of Diarrheal Diseases (CDD) of the World Health Organization (WHO) was created in 1978, the year the Health for All Strategy was launched at the Alma Ata International Conference on Primary Health Care. CDD quickly became one of the pillars of this strategy, with its primary goal of reducing diarrhea-associated mortality among infants and young children in developing countries. WHO expanded the previous cholera-focused unit into one that addressed all diarrheal diseases, and uniquely combined support to research and to national CDD Programs. We describe the history of the Program, summarize the results of the research it supported, and illustrate the outcome of the Program's control efforts at country and global levels. We then relate the subsequent evolution of the Program to an approach that was more technically broad and programmatically narrow and describe how this affected diarrheal diseases-related activities globally and in countries.


Assuntos
Diarreia/prevenção & controle , Desenvolvimento de Programas , Organização Mundial da Saúde/organização & administração , Pré-Escolar , Países em Desenvolvimento/estatística & dados numéricos , Diarreia/mortalidade , Objetivos , Humanos , Lactente , Recém-Nascido
19.
J Glob Health ; 9(2): 020803, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31673347

RESUMO

Background: Bangladesh had a large reduction in childhood deaths due to diarrhoeal disease in recent decades. This paper explores the preventive, promotive, curative and contextual drivers that helped Bangladesh achieve this exemplary success. Methods: Primary and secondary data collection approaches were used to document trends in reduction of Diarrhoea Specific Mortality Rate (DSMR) between 1980 and 2015, understand what policies and programmes played key roles, and estimate the contribution of specific interventions that were implemented during the period. Data acquisition involved relevant document reviews and in-depth interviews with key stake-holders. A systematic search of literature was undertaken to explore socio-economic, aetiological, behavioural, and nutritional drivers of diarrhoeal disease reduction in Bangladesh. Finally, we used LiST (Lives Saved Tool) to model the contributions of the relevant interventions during three time periods (1980-2015, 1980-2000 and 2000-2015), and to project the number of lives saved in 2030 (compared to 2015) if these interventions were implemented at near universal coverage (90%). Results: The factors which likely had the most impact on DSMR were the coordinated efforts of the Government of Bangladesh (GoB) with non-government organizations (NGOs) and the private sector that enabled swift implementation, at scale, of interventions like oral rehydration solution (ORS) and zinc, promotion of breastfeeding, handwashing and sanitary latrines (WASH), as well as improvements in female education and nutrition. Compared to 1980, we found ORS and reduction in stunting prevalence had the greatest impact on DSMR, saving roughly 70 000 lives combined in 2015. Until 2000, ORS had a higher contribution to DSMR reduction than reduction in stunting prevalence. This proportionate contribution was reversed during 2000-2015. At near universal coverage (90%) of combined direct diarrhoeal disease, nutrition and WASH interventions, we project that an additional 5356 deaths due to diarrhoea could be averted in 2030. Conclusion: Bangladesh's achievement in reduction of DSMR highlights the important role of an enabling policy environment that fostered coordinated efforts of the public and private sectors and NGOs for maximal impact. To maintain this momentum, evidence-based interventions should be scaled up at universal coverage.


Assuntos
Mortalidade da Criança/tendências , Diarreia/prevenção & controle , Mortalidade Infantil/tendências , Logro , Bangladesh/epidemiologia , Pré-Escolar , Diarreia/mortalidade , Humanos , Lactente , Recém-Nascido , Avaliação de Programas e Projetos de Saúde
20.
J Glob Health ; 9(2): 020804, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31673348

RESUMO

Background: India has achieved 86% reduction in the number of under-five diarrheal deaths from 1980 to 2015. Nonetheless diarrhea is still among the leading causes of under-five deaths. The aim of this analysis was to study the contribution of factors that led to decline in diarrheal deaths in the country and the effect of scaling up of intervention packages to address the remaining diarrheal deaths. Methods: We assessed the attribution of different factors and intervention packages such as direct diarrhea case management interventions, nutritional factors and WASH interventions which contributed to diarrhea specific under-five mortality reduction (DSMR) during 1980 to 2015 using the Lives Saved Tool (LiST). The potential impact of scaling up different packages of interventions to achieve universal coverage levels by year 2030 on reducing the number of remaining diarrheal deaths were estimated. Results: The major factors associated with DSMR reduction in under-fives during 1980 to 2015, were increase in ORS use, reduction in stunting prevalence, improved sanitation, changes in age appropriate breastfeeding practices, increase in the vitamin-A supplementation and persistent diarrhea treatment. ORS use and reduction in stunting were the two key interventions, each accounting for around 32% of the lives saved during this period. Scaling up the direct diarrhea case management interventions from the current coverage levels in 2015 to achieve universal coverage levels by 2030 can save around 82 000 additional lives. If the universal targets for nutritional factors and WASH interventions can be achieved, an additional 23 675 lives can potentially be saved. Conclusions: While it is crucial to improve the coverage and equity in ORS use, an integrated approach to promote nutrition, WASH and direct diarrhea interventions is likely to yield the highest impact on reducing the remaining diarrheal deaths in under-five children.


Assuntos
Mortalidade da Criança/tendências , Diarreia/mortalidade , Mortalidade Infantil/tendências , Pré-Escolar , Diarreia/prevenção & controle , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Fatores de Risco
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