Prevalence of Virulence Genes in Enteroaggregative Escherichia coli Isolates from Young Children from Rural South Africa.

In this study, we report on the prevalence of 19 virulence genes in enteroaggregative Escherichia coli (EAEC) isolates from northern South Africa. Stool samples obtained prospectively from 97 children from 1 to 12 months of age were analyzed, and EAEC isolates were confirmed based on the presence of aaiC or aatA genes. We investigated 177 enteroaggregative Escherichia coli isolates for the prevalence of virulence genes using multiplex polymerase chain reaction. The chromosomal gene aaiC was detected at higher frequency (48.0%) compared with aatA (26.0%). The gene encoding the open reading frame Orf61 was the most prevalent putative virulence trait detected among the isolates (150/177; 84.7%). None of the genes was statistically associated with diarrhea (P > 0.05). Detection rates were higher during 7-12 month of life with an association observed for the pic gene and the age group 7-12 months (P = 0.04). Winter was the season with the highest detection rates. Our data reveal a high prevalence of Orf61, Orf3, and astA in South African EAEC isolates. Specific genes may provide additional markers for the study of disease associations with age and season of sample collection.

Determinant Variables, Enteric Pathogen Burden, Gut Function and Immune-related Inflammatory Biomarkers Associated With Childhood Malnutrition: A Prospective Case-Control Study in Northeastern Brazil.

Malnutrition results in serious consequences for growth and cognitive development in children. We studied select child and maternal biologic factors, socioeconomic factors, enteric pathogenic burden and gut function biomarkers in 402 children 6-24 months of age in Northeastern Brazil. In this prospective case-control study, not being fed colostrum [odds ratio (OR): 3.29, 95% confidence interval (CI): 1.73-6.26], maternal age ≥18 years (OR: 1.88, 95% CI: 1.10-3.22) and no electric fan (OR: 2.46, 95% CI: 1.22-4.96) or bicycle (OR: 1.80, 95% CI: 1.10-2.95) in the household were positively associated, and higher birth weight (OR: 0.27, 95% CI: 0.19-0.38), larger head circumference (OR: 0.74, 95% CI: 0.66-0.82) and shortness of breath in the last 2 weeks (OR: 0.49, 95% CI: 0.27-0.90) were negatively associated with malnutrition. Subclinical enteric pathogen infections were common, and enteroaggregative Escherichia coli infections were more prevalent in malnourished children (P = 0.045). Biomarkers such as the lactulose-mannitol test, myeloperoxidase, neopterin and calprotectin were highly elevated in both malnourished and nourished children. Nourished children had a better systemic immune response than the malnourished children, as detected by elevated serum amyloid A-1 and soluble cluster of differentiation protein 14 biomarkers (P < 0.001). Serum amyloid A-1 and soluble cluster of differentiation protein 14 were also associated with better nutritional Z scores. Neonatal, maternal and socioeconomic factors were associated with malnutrition in children. There was a substantial subclinical enteric pathogen burden, particularly with enteroaggregative E. coli, in malnourished children.

Genome-Wide Analysis in Brazilians Reveals Highly Differentiated Native American Genome Regions.

Despite its population, geographic size, and emerging economic importance, disproportionately little genome-scale research exists into genetic factors that predispose Brazilians to disease, or the population genetics of risk. After identification of suitable proxy populations and careful analysis of tri-continental admixture in 1,538 North-Eastern Brazilians to estimate individual ancestry and ancestral allele frequencies, we computed 400,000 genome-wide locus-specific branch length (LSBL) Fst statistics of Brazilian Amerindian ancestry compared to European and African; and a similar set of differentiation statistics for their Amerindian component compared with the closest Asian 1000 Genomes population (surprisingly, Bengalis in Bangladesh). After ranking SNPs by these statistics, we identified the top 10 highly differentiated SNPs in five genome regions in the LSBL tests of Brazilian Amerindian ancestry compared to European and African; and the top 10 SNPs in eight regions comparing their Amerindian component to the closest Asian 1000 Genomes population. We found SNPs within or proximal to the genes CIITA (rs6498115), SMC6 (rs1834619), and KLHL29 (rs2288697) were most differentiated in the Amerindian-specific branch, while SNPs in the genes ADAMTS9 (rs7631391), DOCK2 (rs77594147), SLC28A1 (rs28649017), ARHGAP5 (rs7151991), and CIITA (rs45601437) were most highly differentiated in the Asian comparison. These genes are known to influence immune function, metabolic and anthropometry traits, and embryonic development. These analyses have identified candidate genes for selection within Amerindian ancestry, and by comparison of the two analyses, those for which the differentiation may have arisen during the migration from Asia to the Americas.

Systemic inflammation, growth factors, and linear growth in the setting of infection and malnutrition.

OBJECTIVES: Deficits in weight gain and linear growth are seen frequently among children in areas where malnutrition and recurrent infections are common. Although both inflammation and malnutrition can result in growth hormone (GH) resistance, the interrelationships of infection, inflammation, and growth deficits in developing areas remain unclear. The aim of this study was to evaluate relationships between low levels of systemic inflammation, growth factors, and anthropometry in a case-control cohort of underweight and normal weight children in northern Brazil. METHODS: We evaluated data from 147 children ages 6 to 24 mo evaluated in the MAL-ED (Interactions of Malnutrition and Enteric Disease) case-control study following recruitment from a nutrition clinic for impoverished families in Fortaleza, Brazil. We used nonparametric tests and linear regression to evaluate relationships between current symptoms of infections (assessed by questionnaire), systemic inflammation (assessed by high-sensitivity C-reactive protein [hsCRP]), the GH insulin-like growth factor-1 (IGF-1) axis, and measures of anthropometry. All models were adjusted for age and sex. RESULTS: Children with recent symptoms of diarrhea, cough, and fever (compared with those without symptoms) had higher hsCRP levels; those with recent diarrhea and fever also had lower IGF-1 and higher GH levels. Stool myeloperoxidase was positively associated with serum hsCRP. hsCRP was in turn positively associated with GH and negatively associated with IGF-1 and IGF-binding protein-3 (IGFBP-3), suggesting a state of GH resistance. After adjustment for hsCRP, IGF-1 and IGFBP-3 were positively and GH was negatively associated with Z scores for height and weight. CONCLUSIONS: Infection and inflammation were linked to evidence of GH resistance, whereas levels of GH, IGF-1, and IGFBP-3 were associated with growth indices independent of hsCRP. These data implicate complex interrelationships between infection, nutritional status, GH axis, and linear growth in children from a developing area.

Biomarkers of Environmental Enteropathy, Inflammation, Stunting, and Impaired Growth in Children in Northeast Brazil.

Critical to the design and assessment of interventions for enteropathy and its developmental consequences in children living in impoverished conditions are non-invasive biomarkers that can detect intestinal damage and predict its effects on growth and development. We therefore assessed fecal, urinary and systemic biomarkers of enteropathy and growth predictors in 375 6-26 month-old children with varying degrees of malnutrition (stunting or wasting) in Northeast Brazil. 301 of these children returned for followup anthropometry after 2-6m. Biomarkers that correlated with stunting included plasma IgA anti-LPS and anti-FliC, zonulin (if >12m old), and intestinal FABP (I-FABP, suggesting prior barrier disruption); and with citrulline, tryptophan and with lower serum amyloid A (SAA) (suggesting impaired defenses). In contrast, subsequent growth was predicted in those with higher fecal MPO or A1AT and also by higher L/M, plasma LPS, I-FABP and SAA (showing intestinal barrier disruption and inflammation). Better growth was predicted in girls with higher plasma citrulline and in boys with higher plasma tryptophan. Interactions were also seen with fecal MPO and neopterin in predicting subsequent growth impairment. Biomarkers clustered into markers of 1) functional intestinal barrier disruption and translocation, 2) structural intestinal barrier disruption and inflammation and 3) systemic inflammation. Principle components pathway analyses also showed that L/M with %L, I-FABP and MPO associate with impaired growth, while also (like MPO) associating with a systemic inflammation cluster of kynurenine, LBP, sCD14, SAA and K/T. Systemic evidence of LPS translocation associated with stunting, while markers of barrier disruption or repair (A1AT and Reg1 with low zonulin) associated with fecal MPO and neopterin. We conclude that key noninvasive biomarkers of intestinal barrier disruption, LPS translocation and of intestinal and systemic inflammation can help elucidate how we recognize, understand, and assess effective interventions for enteropathy and its growth and developmental consequences in children in impoverished settings.

Early Childhood Diarrhea Predicts Cognitive Delays in Later Childhood Independently of Malnutrition.

Understanding the complex relationship between early childhood infectious diseases, nutritional status, poverty, and cognitive development is significantly hindered by the lack of studies that adequately address confounding between these variables. This study assesses the independent contributions of early childhood diarrhea (ECD) and malnutrition on cognitive impairment in later childhood. A cohort of 131 children from a shantytown community in northeast Brazil was monitored from birth to 24 months for diarrhea and anthropometric status. Cognitive assessments including Test of Nonverbal Intelligence (TONI), coding tasks (WISC-III), and verbal fluency (NEPSY) were completed when children were an average of 8.4 years of age (range = 5.6-12.7 years). Multivariate analysis of variance models were used to assess the individual as well as combined effects of ECD and stunting on later childhood cognitive performance. ECD, height for age (HAZ) at 24 months, and weight for age (WAZ) at 24 months were significant univariate predictors of the studies three cognitive outcomes: TONI, coding, and verbal performance (P < 0.05). Multivariate models showed that ECD remained a significant predictor, after adjusting for the effect of 24 months HAZ and WAZ, for both TONI (HAZ, P = 0.029 and WAZ, P = 0.006) and coding (HAZ, P = 0.025 and WAZ, P = 0.036) scores. WAZ and HAZ were also significant predictors after adjusting for ECD. ECD remained a significant predictor of coding (WISC III) after number of household income was considered (P = 0.006). This study provides evidence that ECD and stunting may have independent effects on children's intellectual function well into later childhood.

Urinary N-methylnicotinamide and ß-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children.

Enteric infections, enteropathy and undernutrition in early childhood are preventable risk factors for child deaths, impaired neurodevelopment, and later life metabolic diseases. However, the mechanisms linking these exposures and outcomes remain to be elucidated, as do biomarkers for identifying children at risk. By examining the urinary metabolic phenotypes of nourished and undernourished children participating in a case-control study in Semi-Arid Brazil, we identified key differences with potential relevance to mechanisms, biomarkers and outcomes. Undernutrition was found to perturb several biochemical pathways, including choline and tryptophan metabolism, while also increasing the proteolytic activity of the gut microbiome. Furthermore, a metabolic adaptation was observed in the undernourished children to reduce energy expenditure, reflected by increased N-methylnicotinamide and reduced ß-aminoisobutyric acid excretion. Interestingly, accelerated catch-up growth was observed in those undernourished children displaying a more robust metabolic adaptation several months earlier. Hence, urinary N-methylnicotinamide and ß-aminoisobutyric acid represent promising biomarkers for predicting short-term growth outcomes in undernourished children and for identifying children destined for further growth shortfalls. These findings have important implications for understanding contributors to long-term sequelae of early undernutrition, including cognitive, growth, and metabolic functions.

Effects of recent Virginia AIDS Drug Assistance Program policy changes on diabetes and hyperlipidemia control in people living with HIV.

OBJECTIVES: To describe the impacts of Virginia AIDS Drug Assistance Program's elimination of diabetes and hyperlipidemia medication on disease outcomes in people living with HIV. METHODS: Data were collected on two groups of people living with HIV who were prescribed medications for diabetes and/or hyperlipidemia; one group received medications from AIDS Drug Assistance Program (ADAP) and the other group received medications from another source. Data were collected for 13 months before and after the policy change. Diabetes, hyperlipidemia, and HIV control were compared using standard laboratory measures. RESULTS: During the pre-policy-change time period, non-ADAP patients had better diabetes control than ADAP patients, but with multivariate analysis, ADAP status was no longer a statistically significant predictor. Otherwise, no significant differences between groups were identified. DISCUSSION: ADAP patients had worse diabetes control compared to the non-ADAP group before the policy change. It is possible that this is due to the AIDS Drug Assistance Program population's poor access to non-HIV primary care, including care for diabetes. It is reassuring that, even during a time of flux in AIDS Drug Assistance Program resources, the AIDS Drug Assistance Program patients' co-morbid and HIV outcomes were not negatively impacted.

Enteric parasites and enteroaggregative Escherichia coli in children from Cañazas County, Veraguas Province, Panama.

This study was designed to examine the height-for-age z-scores (HAZ), and the prevalence of intestinal inflammation, gastrointestinal infections with parasites, and enteroaggregative Escherichia coli (EAEC) in rural Panamanian children. Stool microscopy and polymerase chain reaction (PCR) testing for EAEC detected Giardia lamblia (32%, 32 of 100) and EAEC (13%, 11 of 87) in the study participants, respectively. Anthropometric analyses showed that those children who were > 12 months of age had lower HAZ scores (mean of -1.449) than the reference population. As a group, the children in the study 1 to 5 years of age did not show recovery from the previously mentioned decline in terms of their HAZ. The HAZ means of the children infected with G. lamblia, EAEC, and Ascaris lumbricoides were -1.49, -1.67, and -2.11, respectively. Furthermore, the study participants with A. lumbricoides and EAEC infections in the presence of lactoferrin showed another decrease of 0.19 and 0.13, respectively, in their HAZ means.

Apolipoprotein E plays a key role against cryptosporidial infection in transgenic undernourished mice.

Apolipoliprotein E (apoE), a critical targeting protein in lipid homeostasis, has been found to have immunoinflammatory effects on murine models of infection and malnutrition. The effects of apoE in undernourished and Cryptosporidium parvum-infected mice have not been investigated. In order to study the role of apoE in a model of C. parvum infection, we used the following C57BL6J mouse genetic strains: APOE-deficient, wild-type controls, and APOE targeted replacement (TR) mice expressing human APOE genes (E3/3; E4/4). Experimental mice were orally infected with 10(7)-unexcysted-C. parvum oocysts between post-natal days 34-35 followed by malnutrition induced with a low-protein diet. Mice were euthanized seven days after C. parvum-challenge to investigate ileal morphology, cytokines, and cationic arginine transporter (CAT-1), arginase 1, Toll-like receptor 9 (TLR9), and inducible nitric oxide synthase (iNOS) expression. In addition, we analyzed stool oocyst shedding by qRT-PCR and serum lipids. APOE4/4-TR mice had better weight gains after infection plus malnutrition compared with APOE3/3-TR and wild-type mice. APOE4/4-TR and APOE knockout mice had lower oocyst shedding, however the latter exhibited with villus blunting and higher ileal pro-inflammatory cytokines and iNOS transcripts. APOE4/4-TR mice had increased ileal CAT-1, arginase-1, and TLR9 transcripts relative to APOE knockout. Although with anti-parasitic effects, APOE deficiency exacerbates intestinal inflammatory responses and mucosal damage in undernourished and C. parvum-infected mice. In addition, the human APOE4 gene was found to be protective against the compounded insult of Cryptosporidium infection plus malnutrition, thus extending our previous findings of the protection against diarrhea in APOE4 children. Altogether our findings suggest that apoE plays a key role in the intestinal restitution and immunoinflammatory responses with Cryptosporidium infection and malnutrition.

Zinc, vitamin A, and glutamine supplementation in Brazilian shantytown children at risk for diarrhea results in sex-specific improvements in verbal learning.

OBJECTIVE: To identify the impact of supplemental zinc, vitamin A, and glutamine, alone or in combination, on long-term cognitive outcomes among Brazilian shantytown children with low median height-for-age z-scores. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in children aged three months to nine years old from the urban shanty compound community of Fortaleza, Brazil. Demographic and anthropometric information was assessed. The random treatment groups available for cognitive testing (total of 167 children) were: (1) placebo, n = 25; (2) glutamine, n = 23; (3) zinc, n = 18; (4) vitamin A, n = 19; (5) glutamine+zinc, n = 20; (6) glutamine+vitamin A, n = 21; (7) zinc+vitamin A, n = 23; and (8) glutamine+zinc+vitamin A, n = 18. Neuropsychological tests were administered for the cognitive domains of non-verbal intelligence and abstraction, psychomotor speed, verbal memory and recall ability, and semantic and phonetic verbal fluency. Statistical analyses were performed using SPSS, version 16.0. ClinicalTrials.gov: NCT00133406. RESULTS: Girls receiving a combination of glutamine, zinc, and vitamin A had higher mean age-adjusted verbal learning scores than girls receiving only placebo (9.5 versus 6.4, p = 0.007) and girls receiving zinc+vitamin A (9.5 versus 6.5, p = 0.006). Similar group differences were not found between male study children. CONCLUSIONS: The findings suggest that combination therapy offers a sex-specific advantage on tests of verbal learning, similar to that seen among female patients following traumatic brain injury.

Handheld point-of-care cerebrospinal fluid lactate testing predicts bacterial meningitis in Uganda.

We validated a handheld point-of-care lactate (POCL) monitor's ability to measure lactate in cerebrospinal fluid (CSF) and diagnose bacterial meningitis in Uganda. There was a strong linear correspondence between POCL and standard laboratory lactate test results (R(2) = 0.86; P < 0.001). For 145 patients with clinical meningitis, the area under the receiver operating characteristic curve for the prediction of bacterial meningitis by CSF POCL was 0.92 (95% confidence interval = 0.85-0.99, P < 0.001). A CSF POCL concentration of 7.7 mmol/L provided 88% sensitivity and 90% specificity for the diagnosis of bacterial meningitis. CSF POCL testing had excellent use in the diagnosis of bacterial meningitis, and it may be useful where CSF analyses are delayed or laboratory infrastructure is limited.

Zinc, vitamin A, and glutamine supplementation in Brazilian shantytown children at risk for diarrhea results in sex-specific improvements in verbal learning

OBJECTIVE: To identify the impact of supplemental zinc, vitamin A, and glutamine, alone or in combination, on long-term cognitive outcomes among Brazilian shantytown children with low median height-for-age z-scores. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in children aged three months to nine years old from the urban shanty compound community of Fortaleza, Brazil. Demographic and anthropometric information was assessed. The random treatment groups available for cognitive testing (total of 167 children) were: (1) placebo, n = 25; (2) glutamine, n = 23; (3) zinc, n = 18; (4) vitamin A, n = 19; (5) glutamine+zinc, n = 20; (6) glutamine+vitamin A, n = 21; (7) zinc+vitamin A, n = 23; and (8) glutamine+zinc+vitamin A, n = 18. Neuropsychological tests were administered for the cognitive domains of non-verbal intelligence and abstraction, psychomotor speed, verbal memory and recall ability, and semantic and phonetic verbal fluency. Statistical analyses were performed using SPSS, version 16.0. ClinicalTrials.gov: NCT00133406. RESULTS: Girls receiving a combination of glutamine, zinc, and vitamin A had higher mean age-adjusted verbal learning scores than girls receiving only placebo (9.5 versus 6.4, p = 0.007) and girls receiving zinc+vitamin A (9.5 versus 6.5, p = 0.006). Similar group differences were not found between male study children. CONCLUSIONS: The findings suggest that combination therapy offers a sex-specific advantage on tests of verbal learning, similar to that seen among female patients following traumatic brain injury.

Does childhood diarrhea influence cognition beyond the diarrhea-stunting pathway?

BACKGROUND: Diarrhea is a leading cause of morbidity among children under 5 years of age in low- and middle-income countries yet the additional effects and sequelae, such as cognitive impairment associated with diarrhea, have not been quantified. METHODS: We quantified the association between diarrhea prevalence and cognitive outcomes while controlling for linear growth in 4 study populations. Cognition was assessed using different methods across sites and was expressed in standardized units. We built linear regression models for each study with standardized cognitive score as the outcome and diarrhea prevalence as the main predictor variable. We then conducted meta-analyses of the regression coefficients to generate pooled estimates of the association between diarrhea prevalence and cognition whilst controlling for anthropometric status and other covariates. RESULTS: Diarrhea was not a significant predictor of cognitive score in any site in the regression models or in the meta-analyses (Coefficient = 0.07; 95% CI: -0.1, 0.2). The length for age Z- score was negatively related to cognition in all sites (0.18; 95% CI: 0.14, 0.21), with coefficients remarkably similar across sites (Coefficient Range: 0.168-0.186). CONCLUSIONS: We did not demonstrate an association between diarrhea and cognition with stunting included in the model. The links between diarrhea, stunting, and cognition provide additional rationale for accelerating interventions to reduce diarrhea.

Intimate partner violence: a predictor of worse HIV outcomes and engagement in care.

For HIV-infected patients, experiencing multiple traumas is associated with AIDS-related and all-cause mortality, increased opportunistic infections, progression to AIDS, and decreased adherence to therapy. The impact of intimate partner violence (IPV) on adherence and HIV outcomes is unknown. HIV-infected patients recruited from a public HIV clinic participated in this observational cohort study (n=251). Participants completed interviews evaluating IPV and covariates. CD4 count <200 (CD4<200), detectable HIV viral load (VL), and engagement in care ("no show rate" [NSR]) were the outcomes of interest. Medication adherence was not measured. Univariate and multivariate regression analyses were performed with covariates included if p<0.3 in the univariate phase. Seventy-four percent of the participants were male, 55% Caucasian, and 52.2% self-identified as "men who have sex with men." IPV prevalence was 33.1% with no difference by gender or sexual orientation. In univariate analysis, IPV exposure predicted having a CD4<200 (p=0.005) and a detectable VL (p=0.04) but trended toward significance with a high NSR (p=0.077). Being threatened by a partner was associated with a CD4<200 (p=0.005), a detectable VL (p=0.011), and high NSR (p=0.019) in univariate analysis. In multivariate analysis, IPV predicted having a CD4<200 (p=0.005) and detectable VL (p=0.035). Being threatened by a partner predicted having a CD4<200 (p=0.020), a detectable VL (p=0.007), and a high NSR (p=0.020). Our results suggest IPV impacts biologic outcomes and engagement in care for HIV-infected patients. IPV alone predicts worse biologic outcomes, whereas the specific experience of being threatened by a partner was associated with all three outcomes in univariate and multivariate analyses.

Evidence for genetic susceptibility to developing early childhood diarrhea among shantytown children living in northeastern Brazil.

To explore the genetic components of susceptibility to early childhood diarrhea (ECD), we used a quantitative genetic approach to estimate the heritability of ECD among children from two Brazilian favelas. Shared environment was used to model common exposure to environmental factors. Genetic relatedness was determined from pedigree information collected by screening household participants (n = 3,267) from two geographically related favelas located in Fortaleza, Brazil. There were 277 children within these pedigrees for whom diarrheal episodes in the first two years of life were recorded. Data on environmental exposure and pedigree relationship were combined to quantitatively partition phenotypic variance in ECD into environmental and genetic components by using a variance components approach as implemented in Sequential Oligogenic Linkage Analysis Routines program. Heritability accounted for 54% of variance in ECD and proximity of residence effect accounted for 21% (P < 0.0001). These findings suggest a substantial genetic component to ECD susceptibility and the potential importance of future genetics studies.

Aggregate evaluable organ dysfunction predicts in-hospital mortality from sepsis in Uganda.

We evaluated the association between severity of sepsis and in-hospital mortality in 150 patients with non-surgical sepsis at a regional referral hospital in Uganda. In-hospital mortality occurred in 5 of 52 (9.6%) patients with sepsis, 24 of 71 (33.8%) patients with severe sepsis, and 16 of 27 (59.3%) patients with septic shock. In the multivariate analysis, the identification of severe sepsis (adjusted hazard ratio [AHR] = 2.9, 95% confidence interval [CI] = 1.0-8.2, P = 0.04), septic shock (AHR = 5.7, 95% CI = 1.6-20.3, P = 0.007), and dysfunction of three or more organs (AHR = 2.9, 95% CI = 1.1-7.3, P = 0.03) increased the risk of in-hospital mortality. Adding aggregate organ dysfunction to the multivariate equation that included the sepsis category statistically significantly improved the model, but the opposite did not. Predictors of mortality were easily measurable and could be used to risk stratify critically ill patients in resource-constrained settings.

Hypoglycemia at admission is associated with inhospital mortality in Ugandan patients with severe sepsis.

OBJECTIVE: Dysglycemia during sepsis is associated with poor outcomes in resource-rich settings. In resource-limited settings, hypoglycemia is often diagnosed clinically without the benefit of laboratory support. We studied the utility of point-of-care glucose monitoring to predict mortality in severely septic patients in Uganda. DESIGN: Prospective observational study. SETTING: One national and two regional referral hospitals in Uganda. PATIENTS: We enrolled 532 patients with sepsis at three hospitals in Uganda. The analysis included 418 patients from the three sites with inhospital mortality data, a documented admission blood glucose concentration, and evidence of organ dysfunction at admission (systolic blood pressure≤100 mm Hg, lactate>4 mmol/L, platelet number<100,000/µL, or altered mental status). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the association between admission point-of-care blood glucose concentration and inhospital mortality. We also assessed the accuracy of altered mental status as a predictor of hypoglycemia. Euglycemia occurred in 33.5% (140 of 418) of patients, whereas 16.3% (68 of 418) of patients were hypoglycemic and 50.2% (210 of 418) were hyperglycemic. Univariate Cox regression analyses comparing in-hospital mortality among hypoglycemic (35.3% [24 of 68], hazard ratio 2.0, 95% confidence interval 1.2-3.6, p=.013) and hyperglycemic (29.5% [62 of 210], hazard ratio 1.5, 95% confidence interval 0.96-2.4, p=.08) patients to euglycemic (19.3% [27 of 140]) patients showed statistically significantly higher rates of inhospital mortality for patients with hypoglycemia. Hypoglycemia (adjusted hazard ratio 1.9, 95% confidence interval 1.1-3.3, p=.03) remained significantly and independently associated with inhospital mortality in the multivariate model. The sensitivity and specificity of altered mental status for hypoglycemia were 25% and 86%, respectively. CONCLUSION: Hypoglycemia is an independent risk factor for inhospital mortality in patients with severe sepsis and cannot be adequately assessed by clinical examination. Correction of hypoglycemia may improve outcomes of critically ill patients in resource-limited settings.

Prolonged episodes of acute diarrhea reduce growth and increase risk of persistent diarrhea in children.

BACKGROUND & AIMS: Prolonged episodes of acute diarrhea (ProD; duration 7-13 days) or persistent diarrhea (PD; duration ≥14 days) are important causes of undernutrition, yet the epidemiology and nutritional impact of ProD are poorly understood. METHODS: We conducted a 10-year cohort study of 414 children from a Brazilian shantytown who were followed from birth; data were collected on diarrhea, enteric pathogens, and anthropometry. RESULTS: During 1276 child-years of observation, we recorded 3257 diarrheal episodes. ProD was twice as common as PD (12% and 5% of episodes, respectively); ProD and PD together accounted for 50% of all days with diarrhea. ProD was more common in infants whose mothers had not completed primary school (relative risk [RR], 2.1; 95% confidence interval: 1.02-2.78). Early weaning was associated with earlier onset of ProD (Spearman ρ = 0.309; P = .005). Infants with ProD were twice as likely to develop PD in later childhood (log rank, P = .002) compared with infants with only acute diarrhea (AD; duration <7 days), even after controlling for confounders. Children's growth was more severely stunted before their first episode of ProD, compared with AD (mean height-for-age Z score (HAZ) -0.81 vs -0.51, respectively, P < .05, unpaired t test). Following ProD, HAZ (ΔHAZ = -0.232) and weight-for-age (ΔWAZ = -0.26) significantly decreased (P < .005 in paired t tests). ProD was associated with Cryptosporidium and Shigella infections. CONCLUSIONS: ProD accounts for significant morbidity and identifies children at risk of a vicious cycle of diarrhea and malnutrition. Further studies are needed to address the recognition and control of ProD and its consequences in resource-limited settings and assess its role in PD pathogenesis.

Severe sepsis in two Ugandan hospitals: a prospective observational study of management and outcomes in a predominantly HIV-1 infected population.

BACKGROUND: Sepsis likely contributes to the high burden of infectious disease morbidity and mortality in low income countries. Data regarding sepsis management in sub-Saharan Africa are limited. We conducted a prospective observational study reporting the management and outcomes of severely septic patients in two Ugandan hospitals. We describe their epidemiology, management, and clinical correlates for mortality. METHODOLOGY/RESULTS: Three-hundred eighty-two patients fulfilled enrollment criteria for a severe sepsis syndrome. Vital signs, management and laboratory results were recorded. Outcomes measured included in-hospital and post-discharge mortality. Most patients were HIV-infected (320/377, 84.9%) with a median CD4+ T cell (CD4) count of 52 cells/mm(3) (IQR, 16-131 cells/mm(3)). Overall mortality was 43.0%, with 23.7% in-hospital mortality (90/380) and 22.3% post-discharge mortality (55/247). Significant predictors of in-hospital mortality included admission Glasgow Coma Scale and Karnofsky Performance Scale (KPS), tachypnea, leukocytosis and thrombocytopenia. Discharge KPS and early fluid resuscitation were significant predictors of post-discharge mortality. Among HIV-infected patients, CD4 count was a significant predictor of post-discharge mortality. Median volume of fluid resuscitation within the first 6 hours of presentation was 500 mLs (IQR 250-1000 mls). Fifty-two different empiric antibacterial regimens were used during the study. Bacteremic patients were more likely to die in hospital than non-bacteremic patients (OR 1.83, 95% CI = 1.01-3.33). Patients with Mycobacterium tuberculosis (MTB) bacteremia (25/249) had higher in-hospital mortality (OR 1.97, 95% CI = 1.19-327) and lower median CD4 counts (p = 0.001) than patients without MTB bacteremia. CONCLUSION: Patients presenting with sepsis syndromes to two Ugandan hospitals had late stage HIV infection and high mortality. Bacteremia, especially from MTB, was associated with increased in-hospital mortality. Most clinical predictors of in-hospital mortality were easily measurable and can be used for triaging patients in resource-constrained settings. Procurement of low cost and high impact treatments like intravenous fluids and empiric antibiotics may help decrease sepsis-associated mortality in resource-constrained settings.