Malnutrition-related parasite dissemination from the skin in visceral leishmaniasis is driven by PGE2-mediated amplification of CCR7-related trafficking of infected inflammatory monocytes.

People are infected with Leishmania donovani when the parasite is deposited in the dermis during the blood meal of the sand fly vector. Most infected people develop a subclinical latent infection, but some develop progressive visceral leishmaniasis. Malnutrition is a risk factor for the development of active VL. We previously demonstrated increased parasite dissemination from the skin to visceral organs in a murine model of malnutrition. Here we investigated the mechanism of early parasite dissemination. After delivery of L. donovani to the skin, we found enhanced capture of parasites by inflammatory monocytes and neutrophils in the skin of malnourished mice. However, parasite dissemination in malnourished mice was driven primarily by infected inflammatory monocytes, which showed increased CCR7 expression, greater intrinsic migratory capacity, and increased trafficking from skin to spleen. PGE2 production, which was increased at the site of skin infection, increased monocyte CCR7 expression and promoted CCR7-related monocyte-mediated early parasite dissemination in malnourished mice. Parasite dissemination in monocytes was reduced by inhibition of PGE2, knockdown or silencing of CCR7 in monocytes, and depletion of inflammatory monocytes through administration of diphtheria toxin to CSFR1-DTR transgenic mice that have monocyte-specific DT receptor expression. CCR7-driven trafficking of infected inflammatory monocytes through the lymph node was accompanied by increased expression of its ligands CCL19 and CCL21. These results show that the CCR7/PGE2 axis is responsible for the increased trafficking of L. donovani-infected inflammatory monocytes from the skin to the spleen in the malnourished host. Undernutrition and production of PGE2 are potential targets to reduce the risk of people developing VL. Nutritional interventions that target improved immune function and reduced PGE2 synthesis should be studied in people at risk of developing VL.

Inflammatory stimuli alter bone marrow composition and compromise bone health in the malnourished host.

Inflammation has a role in the pathogenesis of childhood malnutrition. We investigated the effect of malnutrition and inflammatory challenge on bone marrow composition and bone health. We studied an established murine model of moderate acute malnutrition at baseline and after acute inflammatory challenge with bacterial lipopolysaccharide (LPS), a surrogate of Gram-negative bacterial sepsis, or Leishmania donovani, the cause of visceral leishmaniasis. Both of these infections cause significant morbidity and mortality in malnourished children. Of the 2 stimuli, LPS caused more pronounced bone marrow changes that were amplified in malnourished mice. LPS challenge led to increased inflammatory cytokine expression (Il1b, Il6, and Tnf), inflammasome activation, and inflammatory monocyte accumulation in the bone marrow of malnourished mice. Depletion of inflammatory monocytes in Csfr1-LysMcre-DT malnourished mice significantly reduced the inflammasome activation and IL1-ß production after LPS challenge. The inflammatory challenge also led to increased expansion of mesenchymal stem cells (MSCs), bone marrow adiposity, and expression of genes (Pparg, Adipoq, and Srbp1) associated with adipogenesis in malnourished mice. This suggests that inflammatory challenge promotes differentiation of BM MSCs toward the adipocyte lineage rather than toward bone-forming osteoblasts in the malnourished host. Concurrent with this reduced osteoblastic potential there was an increase in bone-resorbing osteoclasts, enhanced osteoclast activity, upregulation of inflammatory genes, and IL-1B involved in osteoclast differentiation and activation. The resulting weakened bone formation and increased bone resorption would contribute to the bone fragility associated with malnutrition. Lastly, we evaluated the effect of replacing lipid rich in omega-6 fatty acids (corn oil) with lipid-rich in omega-3 fatty acids (fish oil) in the nutrient-deficient diet. LPS-challenged malnourished mice that received dietary fish oil showed decreased expression of inflammatory cytokines and Rankl and reduced osteoclast differentiation and activation in the bone marrow. This work demonstrates that the negative effect of inflammatory challenge on bone marrow is amplified in the malnourished host. Increasing dietary intake of omega-3 fatty acids may be a means to reduce inflammation and improve bone health in malnourished children.

Pathologic Inflammation in Malnutrition Is Driven by Proinflammatory Intestinal Microbiota, Large Intestine Barrier Dysfunction, and Translocation of Bacterial Lipopolysaccharide.

Acute malnutrition, or wasting, is implicated in over half of all deaths in children under five and increases risk of infectious disease. Studies in humans and preclinical models have demonstrated that malnutrition is linked to an immature intestinal microbiota characterized by increased prevalence of Enterobacteriaceae. Observational studies in children with moderate acute malnutrition (MAM) have also observed heightened systemic inflammation and increased circulating bacterial lipopolysaccharides (LPS; endotoxin). However, the mechanisms that underpin the systemic inflammatory state and endotoxemia, and their pathophysiological consequences, remain uncertain. Understanding these pathophysiological mechanisms is necessary to design targeted treatments that will improve the unacceptable rate of failure or relapse that plague current approaches. Here we use a mouse model of MAM to investigate the mechanisms that promote inflammation in the malnourished host. We found that mice with MAM exhibited increased systemic inflammation at baseline, increased translocation of bacteria and bacterial LPS, and an exaggerated response to inflammatory stimuli. An exaggerated response to bacterial LPS was associated with increased acute weight loss. Remarkably, intestinal inflammation and barrier dysfunction was found in the cecum and colon. The cecum showed a dysbiotic microbiota with expansion of Gammaproteobacteria and some Firmicutes, and contraction of Bacteroidetes. These changes were paralleled by an increase in fecal LPS bioactivity. The inflammatory phenotype and weight loss was modulated by oral administration of non-absorbable antibiotics that altered the proportion of cecal Gammaproteobacteria. We propose that the heightened inflammation of acute malnutrition is the result of changes in the intestinal microbiota, intestinal barrier dysfunction in the cecum and colon, and increased systemic exposure to LPS.

Growth and Clinical Outcomes of Very Low-Birth-Weight Infants Receiving Acidified vs Nonacidified Liquid Human Milk Fortifiers.

BACKGROUND: Liquid human milk fortifiers are used commonly in neonatal intensive care. Use of an acidified HMF (A-HMF) is associated with transient metabolic acidosis, but whether growth outcomes differ between infants fed A-HMF vs nonacidified HMF (NA-HMF) remains unknown. METHODS: Retrospective cohort study of 255 infants born at <33 weeks' gestation and ≤1500 g who were receiving ≥75% fortified human milk on day of life 14, in a level III neonatal intensive care unit (NICU) from May 2015 to December 2018. Infants born before October 2017 (n = 165) received A-HMF, whereas infants born after October 2017 (n = 90) received NA-HMF. We used logistic regression to estimate odds of metabolic acidosis (serum bicarbonate <16 mEq/L in the first 21 days of life) in infants receiving A-HMF vs NA-HMF and linear mixed models to compare the mean size at discharge (weight, length, head z-scores) by HMF type. We adjusted models for confounders and accounted for the nonindependence of multiple births. RESULTS: Median gestational age was 28.7 weeks (range, 22.6-32.9) and birth weight 1.1 kg (range, 0.4-1.5). Infants receiving A-HMF had higher adjusted odds of metabolic acidosis than infants receiving NA-HMF (adjusted odds ratio, 2.7; 95% CI, 1.2-6.2). There were no differences between groups in size z-scores at discharge. CONCLUSIONS: In human-milkfed, very-low-birthweight infants, fortification with liquid A-HMF may contribute to metabolic acidosis in the first month of life, but this practice does not appear to impair growth through NICU discharge, compared with fortification with NA-HMF.

Association of Poor Postnatal Growth with Neurodevelopmental Impairment in Infancy and Childhood: Comparing the Fetus and the Healthy Preterm Infant References.

OBJECTIVES: To compare the classification of preterm postnatal poor growth using healthy preterm vs fetal growth references and to examine associations with neurodevelopmental impairment in infancy and childhood. STUDY DESIGN: We included 613 infants born at <33 weeks of gestation. Using the INTERGROWTH-21st (healthy-preterm growth) reference and the Fenton and Olsen (fetal growth) references, we classified poor growth as a decline in z-score from birth to term-equivalent >0.8 SD (weight), >1 SD (head), and >2 SD (length). We used generalized estimating equations to estimate aOR for neurodevelopmental impairment at 18 months and 7 years of corrected age, comparing infants with and without poor growth by each reference, accounting for multiple births and covariates. RESULTS: The prevalence of poor growth was higher with INTERGROWTH-21st than with fetal references for all measurements. Agreement was higher between the Fenton and Olsen (fetal) growth references (0.72-0.81) than between INTERGROWTH-21st and fetal references (0.41-0.59). Poor growth by fetal references (but not by INTERGROWTH-21st) was associated with low neurodevelopmental scores in infancy and childhood. Poor weight gain using the Fenton reference was associated with 18-month Mental Developmental Index <85 (aOR 1.6, 95%CI: 1.1, 2.4) whereas poor weight gain by the INTERGROWTH-21st reference was not (aOR 1.0, 95%CI: 0.6, 1.7). Poor linear growth by the Olsen reference, but not INTERGROWTH-21st, was associated with 7-year verbal intelligence quotient <70 (aOR 3.5, 95%CI: 1.1, 12.7). CONCLUSIONS: Poor neonatal growth categorized using fetal references showed stronger associations with long term neurodevelopment than poor growth categorized using the INTERGROWTH-21st standards.

Updates on Assessment and Monitoring of the Postnatal Growth of Preterm Infants.

Assessing and monitoring the physical growth of preterm infants is fundamental to NICU care. The goals of nutritional care are to approximate the growth and body composition of the healthy fetus and to support optimal brain development while minimizing future cardiometabolic risk. Both poor and excessive growth predict adverse long-term health outcomes. Growth curves are clinical tools used to assess the preterm infant's growth status. Several growth curves for preterm infants were developed in the past decade. To use them effectively, clinicians need to understand how each growth curve was developed; the underlying reference population; intended use; and strengths and limitations. Intrauterine growth curves are references that use size at birth to represent healthy fetal growth. These curves serve 2 purposes-to assign size classifications at birth and to monitor postnatal growth. The INTERGROWTH-21 st preterm postnatal growth standards were developed to compare the postnatal growth of preterm infants to that of healthy preterm infants rather than the fetus. Individualized weight growth curves account for the water weight loss that frequently occurs after birth. In addition, body mass index (BMI) curves are now available. In this review, we discuss the main characteristics of growth curves used for preterm infants as well as the use of percentiles, z scores, and their change over time to evaluate size and growth status. We also review the differences in body composition between preterm infants at term-equivalent age and term-born infants and the potential role of monitoring proportionality of growth using BMI curves.

Effect of low-cost interventions on the retention of knowledge and skills following Helping Babies Breathe training.

OBJECTIVE: To evaluate the impact of a post-Helping Babies Breathe bundle of interventions on the retention of provider-level knowledge and skills. METHOD: The present prospective pre-post study following a 1-day Helping Babies Breathe training of professional midwives, physicians, and nurses was conducted in Cajamarca Province, Peru between January 1 and July 31, 2017. The interventions to improve retention included structured worksite practice before every shift, weekly in-service simulated scenarios, and monthly supervised peer-to-peer abbreviated refresher trainings. Knowledge and skills were assessed before, immediately after, and 6 months after training using two validated multiple-choice knowledge test and objective structured clinical examinations (OSCEs; OSCE A and OSCE B). Data were analyzed for changes in knowledge and skills over time and to identify predictors of performance. RESULTS: There were 60 learners included. No significant differences were observed between assessments immediately after training and at 6-month follow-up for knowledge scores or time-to-effective-ventilation. Pass rates for OSCE B increased from 83% immediately after training to 95% at follow-up (P=0.007). The only factor associated with a reduced time to effective ventilation at 6-month follow-up was working in a hospital (P<0.001), accounting for years of training and experience. CONCLUSION: Helping Babies Breathe knowledge and skills can be retained and even improved with simple, inexpensive interventions, including supervised on-the-job and peer-to-peer training.

[Incidence of hip and knee prosthetic infections in a specialized center of Mexico City]. / Incidencia de infecciones protésicas primarias de cadera y rodilla en un centro de la Ciudad de México.

BACKGROUND: Hip and knee prosthetic replacements have proven to be the most appropriate treatment in the joints that do not benefit from medical or arthroscopic interventions; however, infections are the most feared complication. It is recommended that the incidence of infection should not exceed 2%. MATERIAL AND METHODS: This was an observational, prospective, longitudinal and observational study conducted in patients fitted with a prosthetic joint from August 2011 to July 2012. Patients were followed up pre and post-surgery for one year to identify a prosthetic infection, diagnosed using international parameters. We calculated the incidence of prosthetic infection, as well as the incidence density. RESULTS: A total of 339 patients (179 hip and 160 knee) were included. Variations in the time of pre-operative antibiotics' administration were observed. Six prosthetic infections were identified with an incidence rate of 1.79/339 arthroplasties, 2.2/179 hip procedures, and 1.25/160 knee arthroplasties. An incidence density of 0.02/year for hip arthroplasties and 0.11/year for knee procedures was identified. There were 4 infections of hip and 2 of knee. Five infections were acute and one chronic. The isolated microorganisms were E. faecalis, S. epidermidis (2), S. mitis, S. aureus and P. stomatis. CONCLUSIONS: The incidence of prosthetic joint infection in the first year of follow-up at our centre is within the recommended parameters. Surgical techniques and organizational practices influence the results.

Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial fibrillation.

BACKGROUND: Chronic anticoagulation with vitamin K antagonists (VKAs) prevents ischaemic stroke and systemic embolism in people with non-valvular atrial fibrillation (AF) but dose adjustment, coagulation monitoring and bleeding limits its use. Direct thrombin inhibitors (DTIs) are under investigation as potential alternatives. OBJECTIVES: To assess (1) the comparative efficacy of long-term anticoagulation using DTIs versus VKAs on vascular deaths and ischaemic events in people with non-valvular AF, and (2) the comparative safety of chronic anticoagulation using DTIs versus VKAs on (a) fatal and non-fatal major bleeding events including haemorrhagic strokes, (b) adverse events other than bleeding and ischaemic events that lead to treatment discontinuation and (c) all-cause mortality in people with non-valvular AF. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, May 2013), MEDLINE (1950 to July 2013), EMBASE (1980 to October 2013), LILACS (1982 to October 2013) and trials registers (September 2013). We also searched the websites of clinical trials and pharmaceutical companies and handsearched the reference lists of articles and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing DTIs versus VKAs for prevention of stroke and systemic embolism in people with non-valvular AF. DATA COLLECTION AND ANALYSIS: All three review authors independently performed data extraction and assessment of risk of bias. Primary analyses compared all DTIs combined versus warfarin. We performed post hoc analyses excluding ximelagatran because this drug was withdrawn from the market owing to safety concerns. MAIN RESULTS: We included eight studies involving a total of 27,557 participants with non-valvular AF and one or more risk factors for stroke; 26,601 of them were assigned to standard doses groups and included in the primary analysis. The DTIs: dabigatran 110 mg twice daily and 150 mg twice daily (three studies, 12,355 participants), AZD0837 300 mg once per day (two studies, 233 participants) and ximelagatran 36 mg twice per day (three studies, 3726 participants) were compared with the VKA warfarin (10,287 participants). Overall risk of bias and statistical heterogeneity of the studies included were low.The odds of vascular death and ischaemic events were not significantly different between all DTIs and warfarin (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.85 to 1.05). Sensitivity analysis by dose of dabigatran on reduction in ischaemic events and vascular mortality indicated that dabigatran 150 mg twice daily was superior to warfarin although the effect estimate was of borderline statistical significance (OR 0.86, 95% CI 0.75 to 0.99). Sensitivity analyses by other factors did not alter the results. Fatal and non-fatal major bleeding events, including haemorrhagic strokes, were less frequent with the DTIs (OR 0.87, 95% CI 0.78 to 0.97). Adverse events that led to discontinuation of treatment were significantly more frequent with the DTIs (OR 2.18, 95% CI 1.82 to 2.61). All-cause mortality was similar between DTIs and warfarin (OR 0.91, 95% CI 0.83 to 1.01). AUTHORS' CONCLUSIONS: DTIs were as efficacious as VKAs for the composite outcome of vascular death and ischaemic events and only the dose of dabigatran 150 mg twice daily was found to be superior to warfarin. DTIs were associated with fewer major haemorrhagic events, including haemorrhagic strokes. Adverse events that led to discontinuation of treatment occurred more frequently with the DTIs. We detected no difference in death from all causes.

Efficacy and duration of immunity after yellow fever vaccination: systematic review on the need for a booster every 10 years.

Abstract. Current regulations stipulate a yellow fever (YF) booster every 10 years. We conducted a systematic review of the protective efficacy and duration of immunity of YF vaccine in residents of disease-endemic areas and in travelers to assess the need for a booster in these two settings and in selected populations (human immunodeficiency virus-infected persons, infants, children, pregnant women, and severely malnourished persons). Thirty-six studies and 22 reports were included. We identified 12 studies of immunogenicity, 8 of duration of immunity, 8 of vaccine response in infants and children, 7 of human-immunodeficiency virus-infected persons, 2 of pregnant women, and 1 of severely malnourished children. Based on currently available data, a single dose of YF vaccine is highly immunogenic and confers sustained life-long protective immunity against YF. Therefore, a booster dose of YF vaccine is not needed. Special considerations for selected populations are detailed.

Parasite antigen in serum predicts the presence of viable brain parasites in patients with apparently calcified cysticercosis only.

BACKGROUND: Computed tomography (CT) remains the standard neuroimaging screening exam for neurocysticercosis, and residual brain calcifications are the commonest finding. Magnetic resonance imaging (MRI) is more sensitive than CT but is rarely available in endemic regions. Enzyme-linked immunoelectrotransfer blot (EITB) assay uses antibody detection for diagnosis confirmation; by contrast, enzyme-linked immunosorbent assay (ELISA) antigen detection (Ag-ELISA) detects circulating parasite antigen. This study evaluated whether these assays predict undetected viable cysts in patients with only calcified lesions on brain CT. METHODS: Serum samples from 39 patients with calcified neurocysticercosis and no viable parasites on CT were processed by Ag-ELISA and EITB. MRI was performed for each patient within 2 months of serologic testing. Conservatively high ELISA and EITB cutoffs were used to predict the finding of viable brain cysts on MRI. RESULTS: Using receiver operating characteristic-optimized cutoffs, 7 patients were Ag-ELISA positive, and 8 had strong antibody reactions on EITB. MRI showed viable brain cysts in 7 (18.0%) patients. Patients with positive Ag-ELISA were more likely to have viable cysts than Ag-ELISA negatives (6/7 vs 1/32; odds ratio, 186 [95% confidence interval, 1-34 470.0], P < .001; sensitivity 85.7%, specificity 96.9%, positive likelihood ratio of 27 to detect viable cysts). Similar but weaker associations were also found between a strong antibody reaction on EITB and undetected viable brain cysts. CONCLUSIONS: Antigen detection, and in a lesser degree strong antibody reactions, can predict viable neurocysticercosis. Serological diagnostic methods could identify viable lesions missed by CT in patients with apparently only calcified cysticercosis and could be considered for diagnosis workup and further therapy.