The combined pioglitazone and topiramate therapy for management of pediatric patients with severe MASLD.

BACKGROUND: Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common cause of chronic hepatitis in adult and pediatric patients. Adolescents with severe MASLD can demonstrate a more aggressive disease phenotype as they more commonly develop liver fibrosis than BMI matched adults. Therefore, MASLD is the fastest growing indication for liver transplants in young adults. METHODS: Pioglitazone has been shown to improve liver histology in adult patients with MASLD, and in some studies, it attenuated liver fibrosis. Despite its perceived efficacy, pioglitazone is not widely used, likely due to its side effect profile, specifically increased weight gain. Topiramate lowers body weight in adolescents and in combination with phentermine, is one of the few FDA-approved medications for the management of obesity in children over 12 years of age. We performed a retrospective review of the outcomes in pediatric patients with severe MASLD, treated with the combined pioglitazone and topiramate therapy. RESULTS: Here, we report a case series of seven adolescents with severe MASLD and ≥F2 liver fibrosis treated with the combined pioglitazone and topiramate therapy. The combined therapy improved mean serum ALT from 165 ± 80 U/L to 89 ± 62 U/L after 12 months mean duration of treatment. One patient who completed 24 months of the combined therapy demonstrated a decrease in liver stiffness from 8.9 kPa to 5.6 kPa, as assessed by FibroScan elastography. There was a significant increase in body weight during this time, however, body mass index as a percentage of the 95th percentile adjusted for age and gender did not increase significantly, 151 ± 29% vs. 152 ± 28%. Moreover, waist circumference, mid-upper arm circumference, percent body fat, and muscle mass were not significantly different before and after treatment. Serum lipid levels and hemoglobin A1c also did not change with the treatment. CONCLUSION: In summary, this case series provides encouraging results about the efficacy of the combined pioglitazone and topiramate therapy for the management of adolescents with severe MASLD, which should be further explored in clinical studies.

Cardiometabolic risk factors in South American children: A systematic review and meta-analysis.

BACKGROUND: Cardiometabolic risk factors (impaired fasting glucose, abdominal obesity, high blood pressure, dyslipidemia) cluster in children, may predict adult disease burden, and are inadequately characterized in South American children. OBJECTIVES: To quantify the burden of cardiometabolic risk factors in South American children (0-21 years) and identify knowledge gaps. METHODS: We systematically searched PubMed, Google Scholar, and the Latin American and Caribbean Health Sciences Literature via Virtual Health Library from 2000-2021 in any language. Two independent reviewers screened and extracted all data. RESULTS: 179 studies of 2,181 screened were included representing 10 countries (n = 2,975,261). 12.2% of South American children experienced obesity, 21.9% elevated waist circumference, 3.0% elevated fasting glucose, 18.1% high triglycerides, 29.6% low HDL cholesterol, and 8.6% high blood pressure. Cardiometabolic risk factor definitions varied widely. Chile exhibited the highest prevalence of obesity/overweight, low HDL, and impaired fasting glucose. Ecuador exhibited the highest prevalence of elevated blood pressure. Rural setting (vs. urban or mixed) and indigenous origin protected against most cardiometabolic risk factors. CONCLUSIONS: South American children experience high rates of obesity, overweight, and dyslipidemia. International consensus on cardiometabolic risk factor definitions for children will lead to improved diagnosis of cardiometabolic risk factors in this population, and future research should ensure inclusion of unreported countries and increased representation of indigenous populations.

Customized Postoperative Therapy Improves Bile Drainage in Biliary Atresia: A Single Center Preliminary Report.

BACKGROUND: Controversies in management of biliary atresia (BA) after hepatoportoenterostomy (HPE) lead to variable treatment protocols. We implemented standardized medical management after HPE, customizing the use of antibiotics and corticosteroids based on patient-specific factors. METHODS: In this retrospective analysis, 20 consecutive infants underwent HPE for BA and were compared to a historical cohort. Analysis of successful biliary drainage 3 months after HPE (defined as serum total bilirubin <2 mg/dL) was the primary endpoint; survival with native liver at 2 years was the secondary endpoint. RESULTS: Sixteen of 20 (80%) infants had successful bile drainage, compared to 8 of 20 (40%) infants in the historical cohort (P = 0.0225). Sixteen of 20 patients in the new protocol have reached 2 years of age or required liver transplantation. Among the sixteen, 11 (68.8%) are alive with native livers versus 10 of 20 (50%) in the historical cohort (P = 0.0970). CONCLUSION: This preliminary report suggests the potential benefit of tailored use of postoperative antibiotics and corticosteroids in improving biliary drainage after HPE. LEVEL OF EVIDENCE: III.

Fructose impairs fat oxidation: Implications for the mechanism of western diet-induced NAFLD.

Increased fructose intake from sugar-sweetened beverages and highly processed sweets is a well-recognized risk factor for the development of obesity and its complications. Fructose strongly supports lipogenesis on a normal chow diet by providing both, a substrate for lipid synthesis and activation of lipogenic transcription factors. However, the negative health consequences of dietary sugar are best observed with the concomitant intake of a HFD. Indeed, the most commonly used obesogenic research diets, such as "Western diet", contain both fructose and a high amount of fat. In spite of its common use, how the combined intake of fructose and fat synergistically supports development of metabolic complications is not fully elucidated. Here we present the preponderance of evidence that fructose consumption decreases oxidation of dietary fat in human and animal studies. We provide a detailed review of the mitochondrial ß-oxidation pathway. Fructose affects hepatic activation of fatty acyl-CoAs, decreases acylcarnitine production and impairs the carnitine shuttle. Mechanistically, fructose suppresses transcriptional activity of PPARα and its target CPT1α, the rate limiting enzyme of acylcarnitine production. These effects of fructose may be, in part, mediated by protein acetylation. Acetylation of PGC1α, a co-activator of PPARα and acetylation of CPT1α, in part, account for fructose-impaired acylcarnitine production. Interestingly, metabolic effects of fructose in the liver can be largely overcome by carnitine supplementation. In summary, fructose decreases oxidation of dietary fat in the liver, in part, by impairing acylcarnitine production, offering one explanation for the synergistic effects of these nutrients on the development of metabolic complications, such as NAFLD.

The impact of Moringa oleifera leaf supplementation on human and animal nutrition, growth, and milk production: A systematic review.

Childhood undernutrition contributes to up to 45% of deaths in children under age 5. Moringa oleifera (moringa) leaves are nutrient dense and promote breastmilk production. We performed a systematic review assessing the impact of moringa leaf supplementation in humans and animals on the outcomes of iron, vitamin A status, the measures of growth, and/or breastmilk production. Our inclusion/exclusion criteria were as follows; inclusion: quantitative primary data assessing the effect of moringa leaf supplementation on humans or animals including any of the outcomes defined earlier with no exclusion for geography, age, or language. Exclusion: full text not available. Our search yielded 148 unique studies; among them, 33 were included (seven human studies and 26 animal studies). Quality assessment by Effective Public Health Practice Project guidelines was strong for one study and moderate for all other studies. In humans, moringa at higher (14-30 g/day) not lower (<10 g/day) doses improved hemoglobin (Hgb) in children with iron deficiency anemia, improved Hgb and vitamin A status in postmenopausal women, and increased BMI in HIV+ underweight adults. Moringa (0.5 g/day) also increased breastmilk volumes. In animals, moringa increased milk production in two of three studies, inconsistently affected growth, and had no effect on iron status. Evidence on moringa supplementation's utility is limited but promising. Larger, more rigorous trials are needed to characterize its impact.

Investigating the Impact of Moringa oleifera Supplemented to Kenyan Breastfeeding Mothers on Maternal and Infant Health: A Cluster Randomized Single-Blinded Controlled Pilot Trial Protocol.

Undernutrition contributes to up to 45% of deaths globally in children <5 years, with an optimal time for intervention before 24 months of age. Breastmilk microbiome helps establish the infant intestinal microbiome and impacts infant intestinal and nutritional health. Inadequacies in breastmilk composition such as low vitamin A contribute to infant nutrient deficiencies. Changes in milk fatty acid composition (reduced saturated and increased unsaturated fatty acids) may reduce susceptibility to enteric infection and increase protective intestinal bacteria. Moringa oleifera leaves (moringa) provide high nutrient concentrations (including protein, iron, vitamin A) and increase milk production; this may enhance breastmilk quantity and quality and improve infant health. Objective: To investigate the role of moringa supplementation to improve maternal and infant nutritional and intestinal health via changes in maternal milk quantity and quality. Methods: Fifty mother-infant pairs exclusively breastfeeding will be enrolled in a single-blinded randomized controlled trial in Kombewa County Hospital and Chulaimbo SubCounty Hospital, Kisumu, Kenya. Intervention: Dietary Supplementation of 20 g of Moringa oleifera leaf powder divided twice daily in corn porridge consumed daily for 3 months while control comparator will receive porridge daily for 3 months. Outcomes: Change in infant growth and maternal milk output (primary); maternal and infant vitamin A and iron status, changes in infant and maternal intestinal health (secondary). Participating Centers: Pamoja Community Based Organization, Kombewa Sub-County Hospital, and Chulaimbo Sub-County Hospital.

Stratification by obesity class, rather than age, can identify a higher percent of children at risk for non-alcoholic fatty liver disease and metabolic dysfunction.

BACKGROUND: An increasing number of clinical practice guidelines recommend screening children with obesity for non-alcoholic fatty liver disease (NAFLD). However, there is limited evidence regarding what parameters should be used to initiate the screening. OBJECTIVE: The objective of this study was to determine whether obesity class rather than age group can identify a higher percent of children at risk of NAFLD as assessed by abnormal alanine aminotransferase (ALT). METHODS: This is a cross-sectional study in a regional referral clinic for evaluation of obesity. Children were stratified by age group or by obesity class, and data obtained at first visit were analysed. RESULTS: Of the 784 children, 482 were ≥10, 209 were 6 to 9 and 93 were 2 to 5 years of age. Abnormal ALT was observed in 32.1%, 46.9% and 61.0% of children with class I, II or III obesity, respectively (p < 0.001), while the risk of abnormal ALT did not differ in very young (2-5), young (6-9), or children older than 10 years. A multivariable analysis showed that class II and class III obesity were associated with 2.1-fold (1.27-3.72) and 4-fold (2.41-6.96) greater odds of abnormal ALT compared with class I obesity. African-American children had lower risk of abnormal ALT (0.27), whereas Hispanic children had higher risk (2.37). Obesity class was a better predictor of abnormal ALT than age, especially in girls. Furthermore, 66.7% of boys (p = 0.009) and 69% of girls (p < 0.001) with abnormal ALT exhibited additional signs of metabolic dysfunction. CONCLUSION: Obesity class is more strongly associated with abnormal ALT than age.

Identifying Targets for the Prevention of Childhood Undernutrition in a Resource-Limited Peri-Urban Ecuadorian Community.

BACKGROUND: In middle-income countries, malnutrition concentrates in marginalized populations with a lack of effective preventive strategies. OBJECTIVE: Identify risk factors for undernutrition in a peri-urban Ecuadorian community of children aged 12 to 59 months. METHODS: Data from a cross-sectional survey in 2011 of children 1 to 5 years were analyzed including demographic data, medical history and examination, food frequency questionnaire (FFQ), anthropometric measurements, and blood for complete blood count, C-reactive protein, vitamin A, iron, and zinc levels. Dietary Diversity Score (DDS) was calculated from FFQ. Bivariate and multivariate analysis assessed effects on primary outcome of undernutrition by DDS, vitamin deficiencies, and demographic and nutritional data. RESULTS: N = 67, 52.2% undernourished: 49.3% stunted, 25.4% underweight, and 3% wasted; 74.6% (n = 50) were anemic and 95.1% (n = 39) had low serum zinc. Dietary Diversity Score was universally low (mean 4.91 ± 1.36, max 12). Undernutrition was associated with lower vitamin A levels (20 306, IQR: 16605.25-23973.75 vs 23665, IQR: 19292-26474 ng/mL, P = .04); underweight was associated with less parental report of illness (43.8%, n = 7 vs 80% n = 40, P = .005) and higher white blood count (13.7, IQR: 11.95-15.8 vs 10.9, IQR: 7.8-14.23 × 109/L, P = .02). In multiple regression, risk of undernutrition decreased by 4% for every $10 monthly income increase (95 CI%: 0.5%-7.4%, P = .02, n = 23); risk of underweight decreased by 0.06 for every increased DDS point (adjusted odds ratio: 0.06; 95 CI%: 0.004-0.91, P = .04, n = 23). CONCLUSIONS: In this peri-urban limited-resource, mostly Indigenous Ecuadorian community, stunting exceeds national prevalence, lower monthly income is the strongest predictor of undernutrition, lower DDS can predict some forms of undernutrition, and vitamin deficiencies are associated with but not predictive of undernutrition.

Evolving Role for Pharmacotherapy in NAFLD/NASH.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-ß agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.

Effects of neonatal nutrition interventions on neonatal mortality and child health and development outcomes: A systematic review.

Background: The last two decades have seen a significant decrease in mortality for children <5 years of age in low and middle-income countries (LMICs); however, neonatal (age, 0-28 days) mortality has not decreased at the same rate. We assessed three neonatal nutritional interventions that have the potential of reducing morbidity and mortality during infancy in LMICs. Objectives: To determine the efficacy and effectiveness of synthetic vitamin A, dextrose oral gel, and probiotic supplementation during the neonatal period. Search Methods: We conducted electronic searches for relevant studies on the following databases: PubMed, CINAHL, LILACS, SCOPUS, and CENTRAL, Cochrane Central Register for Controlled Trials, up to November 27, 2019. Selection Criteria: We aimed to include randomized and quasi-experimental studies. The target population was neonates in LMICs. The interventions included synthetic vitamin A supplementation, oral dextrose gel supplementation, and probiotic supplementation during the neonatal period. We included studies from the community and hospital settings irrespective of the gestational age or birth weight of the neonate. Data Collection and Analysis: Two authors screened the titles and extracted the data from selected studies. The risk of bias (ROB) in the included studies was assessed according to the Cochrane Handbook of Systematic Reviews. The primary outcome was all-cause mortality. The secondary outcomes were neonatal sepsis, necrotizing enterocolitis (NEC), prevention and treatment of neonatal hypoglycaemia, adverse events, and neurodevelopmental outcomes. Data were meta-analyzed by random effect models to obtain relative risk (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean difference with 95% CI for continuous outcomes. The overall rating of evidence was determined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Main Results: Sixteen randomized studies (total participants 169,366) assessed the effect of vitamin A supplementation during the neonatal period. All studies were conducted in low- and middle-income (LMIC) countries. Thirteen studies were conducted in the community setting and three studies were conducted in the hospital setting, specifically in neonatal intensive care units. Studies were conducted in 10 different countries including India (four studies), Guinea-Bissau (three studies), Bangladesh (two studies), and one study each in China, Ghana, Indonesia, Nepal, Pakistan, Tanzania, and Zimbabwe. The overall ROB was low in most of the included studies for neonatal vitamin A supplementation. The pooled results from the community based randomized studies showed that there was no significant difference in all-cause mortality in the vitamin A (intervention) group compared to controls at 1 month (RR, 0.99; 95% CI, 0.90-1.08; six studies with 126,548 participants, statistical heterogeneity I 2 0%, funnel plot symmetrical, grade rating high), 6 months (RR, 0.98; 95% CI, 0.89-1.07; 12 studies with 154,940 participants, statistical heterogeneity I 2 43%, funnel plot symmetrical, GRADE quality high) and 12 months of age (RR, 1.04; 95% CI, 0.94-1.14; eight studies with 118,376 participants, statistical heterogeneity I 2 46%, funnel plot symmetrical, GRADE quality high). Neonatal vitamin A supplementation increased the incidence of bulging fontanelle by 53% compared to control (RR, 1.53; 95% CI, 1.12-2.09; six studies with 100,256 participants, statistical heterogeneity I 2 65%, funnel plot symmetrical, GRADE quality high). We did not identify any experimental study that addressed the use of dextrose gel for the prevention and/or treatment of neonatal hypoglycaemia in LMIC. Thirty-three studies assessed the effect of probiotic supplementation during the neonatal period (total participants 11,595; probiotics: 5854 and controls: 5741). All of the included studies were conducted in LMIC and were randomized. Most of the studies were done in the hospital setting and included participants who were preterm (born < 37 weeks gestation) and/or low birth weight (<2500 g birth weight). Studies were conducted in 13 different countries with 10 studies conducted in India, six studies in Turkey, three studies each in China and Iran, two each in Mexico and South Africa, and one each in Bangladesh, Brazil, Colombia, Indonesia, Nepal, Pakistan, and Thailand. Three studies were at high ROB due to lack of appropriate randomization sequence or allocation concealment. Combined data from 25 studies showed that probiotic supplementation reduced all-cause mortality by 20% compared to controls (RR, 0.80; 95% CI, 0.66-0.96; total number of participants 10,998, number needed to treat 100, statistical heterogeneity I 2 0%, funnel plot symmetrical, GRADE quality high). Twenty-nine studies reported the effect of probiotics on the incidence of NEC, and the combined results showed a relative reduction of 54% in the intervention group compared to controls (RR, 0.46; 95% CI, 0.35-0.59; total number of participants 5574, number needed to treat 17, statistical heterogeneity I 2 24%, funnel plot symmetrical, GRADE quality high). Twenty-one studies assessed the effect of probiotic supplementation during the neonatal period on neonatal sepsis, and the combined results showed a relative reduction of 22% in the intervention group compared to controls (RR, 0.78; 95% CI, 0.70-0.86; total number of participants 9105, number needed to treat 14, statistical heterogeneity I 2 23%, funnel plot symmetrical, GRADE quality high). Authors' Conclusions: Vitamin A supplementation during the neonatal period does not reduce all-cause neonatal or infant mortality in LMICs in the community setting. However, neonatal vitamin A supplementation increases the risk of Bulging Fontanelle. No experimental or quasi-experimental studies were available from LMICs to assess the effect of dextrose gel supplementation for the prevention or treatment of neonatal hypoglycaemia. Probiotic supplementation during the neonatal period seems to reduce all-cause mortality, NEC, and sepsis in babies born with low birth weight and/or preterm in the hospital setting. There was clinical heterogeneity in the use of probiotics, and we could not recommend any single strain of probiotics for wider use based on these results. There was a lack of studies on probiotic supplementation in the community setting. More research is needed to assess the effect of probiotics administered to neonates in-home/community setting in LMICs.

Assessing the Effectiveness of Cancer Screening Interventions Targeting Appalachian Populations: A Systematic Review.

PURPOSE: Appalachian residents have higher cancer prevalence and invasive cancer incidence in almost all cancer types relative to non-Appalachian residents. Public health interventions have been carried out to increase preventive cancer screening participation. However, no studies have evaluated the effectiveness of existing interventions targeting cancer screening uptake in this high-risk population. The main objective of this study is to assess the effectiveness of interventions aimed at increasing uptake and/or continuing participation in screened cancers (breast, cervical, colorectal, lung, and prostate) in Appalachia. METHODS: We conducted a systematic review of electronic databases and gray literature using a combination of MeSH and free-text search terms related to breast, cervical, colorectal, lung, and prostate cancer; mass screening; health promotion; and Appalachia. We identified 3,014 articles of which 15 articles were included. We assessed methodological quality using validated tools and analyzed findings using narrative synthesis. FINDINGS: Fifteen studies reported uptake and/or continued participation in screening interventions; these focused on cervical (n = 7), colorectal (n = 5), breast (n = 2), and lung (n = 1) cancers in Appalachia. Interventions included diverse components: mass media campaigns, community outreach events, community health workers, interpersonal counseling, and educational materials. We found that multi-strategy interventions had higher screening uptake relative to interventions employing 1 intervention strategy. Studies that targeted noncompliant populations and leveraged existing community-based organization partnerships had a substantial increase in screening participation versus others. CONCLUSIONS: There is an urgent need for further research and implementation of effective cancer prevention and screening interventions to reduce disparities in cancer morbidity and mortality in Appalachian populations.

Effect of Synthetic Vitamin A and Probiotics Supplementation for Prevention of Morbidity and Mortality during the Neonatal Period. A Systematic Review and Meta-Analysis of Studies from Low- and Middle-Income Countries.

Background: Suboptimal nutritional status of a newborn is a risk factor for short- and long-term morbidity and mortality. The objectives of this review were to assess the efficacy and effectiveness of neonatal synthetic vitamin A supplementation, dextrose gel and probiotic supplementation for prevention of morbidity and mortality during infancy in low and middle-income countries. Methods: We included randomized trials. Primary outcome was all-cause mortality. We conducted electronic searches on multiple databases. Data were meta-analyzed to obtain relative risk (RR) and 95% confidence interval (CI). Studies for vitamin A and Probiotics were analyzed separately. No studies were found for dextrose gel supplementation during neonatal period. The overall rating of evidence was determined by Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: Sixteen studies assessed the effect of vitamin A supplementation during the neonatal period. Based on pooled data from community-based studies only, there was no significant effect of vitamin A on all-cause mortality at age 1 month (RR 0.99, 95% CI 0.90, 1.08), 6 months (RR 0.98; 95% CI 0.89-1.08) and 12 months (RR 1.04, 95% CI 0.94, 1.14) but increased risk of bulging fontanelle (RR 1.53, 95% CI 1.12, 2.09). The overall quality of evidence was high for the above outcomes. Thirty-three studies assessed the effect of probiotic supplementation during the neonatal period and were mostly conducted in the hospital setting. Probiotics reduced the risk of all-cause mortality (RR 0.80, 95% CI 0.66, 0.96), necrotizing enterocolitis (RR 0.46, 95% CI 0.35, 0.59) and neonatal sepsis (RR 0.78, 95% CI 0.70, 0.86). The grade ratings for the above three outcomes were high. Conclusions: Vitamin A supplementation during the neonatal period does not reduce all-cause neonatal or infant mortality in low and middle-income countries in the community setting. Probiotic supplementation during the neonatal period seems to reduce all-cause mortality, NEC, and sepsis in babies born low birth weight and/or preterm in the hospital setting.

Childhood malnutrition within the indigenous Wayuú children of northern Colombia.

Malnutrition contributes to nearly half of all preventable deaths in children under the age of five. While the burden of disease is heaviest in Sub-Saharan Africa, South, and Southeast Asia, malnutrition in Latin America remains high, especially within indigenous communities. This study evaluates the prevalence of malnutrition and its relationship with access to healthcare resources within 172 indigenous Wayuú communities in La Guajira, Colombia. Healthcare workers administered a health questionnaire and collected anthropometric measurements on all children 6 months to 5 years of age within the Wayuú households. These data were utilised to calculate the prevalence of acute malnutrition, stunting, and underweight. Of all surveyed Wayuú children, 22.9% and 18.3% met criteria for moderate and severe malnutrition, 33.4% and 28.1% met criteria for moderate and severe stunting, and 28.1% and 16.6% were moderately and severely underweight. Across all categories, malnourished children were older, less likely to have had a medical professional present at birth, less likely to have received medical care after birth, and more likely to have been born in a non-medical, community setting. The prevalence of malnutrition is much higher than national levels in Colombia. This population requires urgent assistance to address their disproportionately high rates of malnutrition.

Intestinal pathogen clearance in children with severe acute malnutrition is unrelated to inpatient morbidity.

BACKGROUND & AIMS: Children with Severe Acute Malnutrition (SAM) often suffer from diarrhea, which is associated with increased mortality. The contribution of intestinal bacteria, parasites and viruses to morbidity such as diarrhea in SAM remains poorly understood. To evaluate their association with clinical outcomes, we detected stool pathogens in children with SAM at hospital admission and after clinical stabilization prior to discharge. METHODS: 15 intestinal pathogens, fecal calprotectin and C-reactive protein (CRP) were determined at admission and after clinical stabilization in children aged 8-59 months (n = 47) hospitalized in Malawi for complicated SAM. Differences in fecal pathogens, intestinal and systemic inflammation, and clinical outcomes between time points were evaluated using the Wilcoxon Signed-Rank test or Wilcoxon rank-sum test. RESULTS: On admission pathogens were present in nearly all children and after clinical stabilization many were cleared with only 55% of children still harboring a pathogen (89% vs. 55%, p = 0.001). Nosocomial infections were infrequent. The pathogens Giardia lamblia and Shigella spp. were most likely to persist. After clinical stabilization, fecal calprotectin was higher in children harboring a pathogen (median (IQR): 383 mg/kg (903-149 mg/kg) vs 140 mg/kg (300-71 mg/kg), p = 0.03). CRP did not correlate with fecal calprotectin levels nor was it associated with pathogen detection. Presence of stool pathogens was not associated with clinical outcomes such as diarrhea. CONCLUSIONS: Fecal pathogens were very common and cleared in most children with complicated SAM treated with antibiotics. The presence of stool pathogens after stabilization was associated with increased intestinal inflammation but not with clinical outcomes. (http://www.isrctn.com/ISRCTN13916953).

Starved Guts: Morphologic and Functional Intestinal Changes in Malnutrition.

Malnutrition contributes significantly to death and illness worldwide and especially to the deaths of children younger than 5 years. The relation between intestinal changes in malnutrition and morbidity and mortality has not been well characterized; however, recent research indicates that the functional and morphologic changes of the intestine secondary to malnutrition itself contribute significantly to these negative clinical outcomes and may be potent targets of intervention. The aim of this review was to summarize current knowledge of experimental and clinically observed changes in the intestine from malnutrition preclinical models and human studies. Limited clinical studies have shown villous blunting, intestinal inflammation, and changes in the intestinal microbiome of malnourished children. In addition to these findings, experimental data using various animal models of malnutrition have found evidence of increased intestinal permeability, upregulated intestinal inflammation, and loss of goblet cells. More mechanistic studies are urgently needed to improve our understanding of malnutrition-related intestinal dysfunction and to identify potential novel targets for intervention.

Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study.

BACKGROUND: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear. OBJECTIVE: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM. DESIGN: Intestinal pathogens (n = 15), cytokines (n = 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6-59 mo (n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling. RESULTS: Fatal subjects (n = 14; 18%) were younger (mean ± SD age: 17 ± 11 compared with 25 ± 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443-535 mg/kg feces) compared with 698 mg/kg feces (1438-244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112-22 ng/mL) compared with 2036 ng/mL (5800-149 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831-131 ng/mL) compared with 3174 ng/mL (5819-357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation. CONCLUSIONS: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of inflammatory changes in SAM, which may lead to improved therapies. This trial was registered at www.controlled-trials.com as ISRCTN13916953.

Congenital acinar dysplasia: report of a case and review of literature.

Objective Describe a case of congenital acinar dysplasia and review the literature. Study Design Retrospective chart review and literature search. Results Congenital acinar dysplasia is a rare malformation of growth arrest of the lower respiratory tract resulting in critical respiratory insufficiency at birth. It is a form of pulmonary hypoplasia that is characterized by diffuse maldevelopment and derangement of the acinar and alveolar architecture of the lungs, resulting in the complete absence of gas exchanging units. The growth-arrested lung tissue resembles the pseudoglandular phase of 16 weeks' gestation. The etiology is unknown. It is diagnosed by exclusion of all other causes of pulmonary hypoplasia and a summation of clinical, imaging, and histopathologic findings. Conclusion There is no cure and clinical treatment is supportive until death of the infant. We present a case of congenital acinar dysplasia in a male infant who lived 20 days with intensive support.

Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis.

In patients with HIV-1 infection who are starting combination antiretroviral therapy (ART), the incidence of immune reconstitution inflammatory syndrome (IRIS) is not well defined. We did a meta-analysis to establish the incidence and lethality of the syndrome in patients with a range of previously diagnosed opportunistic infections, and examined the relation between occurrence and the degree of immunodeficiency. Systematic review identified 54 cohort studies of 13 103 patients starting ART, of whom 1699 developed IRIS. We calculated pooled cumulative incidences with 95% credibility intervals (CrI) by Bayesian methods and did a random-effects metaregression to analyse the relation between CD4 cell count and incidence of IRIS. In patients with previously diagnosed AIDS-defining illnesses, IRIS developed in 37.7% (95% CrI 26.6-49.4) of those with cytomegalovirus retinitis, 19.5% (6.7-44.8) of those with cryptococcal meningitis, 15.7% (9.7-24.5) of those with tuberculosis, 16.7% (2.3-50.7) of those with progressive multifocal leukoencephalopathy, and 6.4% (1.2-24.7) of those with Kaposi's sarcoma, and 12.2% (6.8-19.6) of those with herpes zoster. 16.1% (11.1-22.9) of unselected patients starting ART developed any type of IRIS. 4.5% (2.1-8.6) of patients with any type of IRIS died, 3.2% (0.7-9.2) of those with tuberculosis-associated IRIS died, and 20.8% (5.0-52.7) of those with cryptococcal meningitis died. Metaregression analyses showed that the risk of IRIS is associated with CD4 cell count at the start of ART, with a high risk in patients with fewer than 50 cells per microL. Occurrence of IRIS might therefore be reduced by initiation of ART before immunodeficiency becomes advanced.