Brucellosis in Pediatric Populations: An 11-Year Cohort Study.

BACKGROUND: Brucellosis is an endemic infection affecting the Mediterranean Basin, Arabian Peninsula, India, Mexico, and South America. Data on brucellosis infections in children are limited. OBJECTIVES: To review and characterize the clinical presentation of pediatric patients diagnosed with brucellosis in a tertiary medical center. METHODS: Retrospective data analysis was conducted on all pediatric patients from January 2010 to December 2020 admitted to the pediatric department with a diagnosis of brucellosis based on a positive serology test or growth of Brucella bacteria in blood culture. RESULTS: The study comprised 53 children aged 0-18 years. The mean age at presentation was 11.01 ± 4.91 years; 39 male (73.6%). Pre-infection exposure to unpasteurized milk or unvaccinated livestock was reported in 37 (69.8%). Fever was present in 64.6%, followed by arthralgia (49%), loss of appetite (42.3%), and weight loss (24.6%). Gastrointestinal symptoms were reported in 52.8% and included abdominal pain (34.6%), nausea (28.3%), vomiting (24.5%), and diarrhea (2.6%). Eight patients experienced pancytopenia (15.1%). The median length of intravenous antibiotic treatment was 7 days (range 3-14 days) and for oral antibiotic treatment 6 weeks (range 2-24 weeks). Most patients were initially treated with intravenous gentamycin (90.5%) and long-term oral antibiotics, most commonly doxycycline. Two (3.7%) required admission to the pediatric intensive care unit. No mortality was documented, and all cases of relapses were successfully treated. CONCLUSIONS: Pediatric brucellosis is an acute febrile disease often associated with rheumatologic complaints. Patients 8-18 years of age also presented with headache, weight loss, and night sweats.

Bronchiolitis Due to RSV and HMPV-Epidemiology, Clinical Course, and Prognosis: Experience of a Single Tertiary Center.

Acute bronchiolitis is a leading cause of hospitalization in infants. In this retrospective study, 645 patients with acute bronchiolitis diagnosed as respiratory syncytial virus (RSV; n = 538) or human metapneumovirus (HMPV; n = 107) were compared in terms of demographic, clinical, and laboratory findings. The HMPV patients presented later in the winter, were older (20 vs 7.55 months; P < .001)), had higher levels of C-reactive protein (4.55 vs 3.03 mg/dL; P = .007), and a higher prevalence of complications (43.9% vs 32.7%; P = .03). This study highlights the similarities and differences between these 2 common respiratory viral pathogens and shows that HMPV has a slightly more severe disease course than RSV. These findings can help guide approaches to these 2 common viruses that cause bronchiolitis.

Improving pediatric idiopathic intracranial hypertension care: a retrospective cohort study.

To describe the clinical course and prognosis of pediatric idiopathic intracranial hypertension (IIH) and examine the preferred management setting. IIH is characterized by increased intracranial pressure and is often associated with headaches and visual complaints. IIH is a preventable cause of vision loss in children. Hence, a rapid diagnosis followed by prompt treatment and follow-up is essential. However, standardization of the management of IIH in the pediatric population is not well established. Computerized medical charts of all 82 pediatric (< 18 years) patients diagnosed with IIH between 2007 and 2018 in the metropolitan area of Jerusalem were reviewed. Comparison was made between children followed in a multidisciplinary clinic in tertiary centers and those followed elsewhere. Detailed demographic and clinical data, as well as data regarding the follow-up setting and clinical course of the disease, were collected and analyzed. Recurrent IIH-related hospital returns were selected as a measurable marker for the uncontrolled disease. Recurrent IIH-related hospital return rate was significantly lower and occurred later among children followed by multidisciplinary teams compared to individual experts. Follow-up in multidisciplinary clinics improve the quality of life, and financial burden and may prevent permanent visual impairment in children with IIH.

Beneficial Effects of Milk-Derived Extracellular Vesicles on Liver Fibrosis Progression by Inhibiting Hepatic Stellate Cell Activation.

Liver fibrosis is the consequence of various chronic liver diseases, resulting in accumulation of extracellular matrix, following the activation and proliferation of hepatic stellate cells (HSCs). Based on the milk-derived extracellular vesicles' (MDEs') characteristics and biological proprieties, we investigate whether MDEs may regulate fibrotic progression by inhibiting HSCs' activation via the MDEs' miRNA content. In order to study this question, we examined the effect of human and cow MDEs on HSCs isolated from murine livers, on activation, proliferation and their proteins' expression. We have shown that MDEs are able to enter into HSCs in vitro and into the livers in vivo. MDEs inhibited HSCs' proliferation following stimulation with PDGF. Moreover, in vivo treatment with MDEs resulted in an increase of in miRNA-148 and Let7a expression in HSCs. In contrast, treatment with MDEs reduced the expression of miR-21 in HSCs. In addition, MDEs regulate HSC activation, as was shown by downregulation of collagen I expression and alpha smooth muscle actin, and upregulation of PPARγ. MDEs carrying beneficial miRNAs can be a nontoxic natural target for treatment of liver cirrhosis.

Extracellular vesicles in human milk.

PURPOSE OF REVIEW: Milk-derived extracellular vesicles (MDEVs) are nanovesicles that carry microRNA (miRNA) DNA, RNA, proteins and lipids. MDEVs have a potential of therapeutic targets, based on their properties and cargo profile. The present review summarizes recent studies on MDEVs, their cargo and potential role in mammalian development. RECENT FINDINGS: The detailed characterization of their miRNA cargo leads to the conclusion of their potential importance in the regulation of gene expression, immune function, development and infant growth.While their miRNAs are important regulatory elements and their profile expression was characterized in various mammalian milk sources, little is known about their effect on infant health and development. MiRNA activity in breast milk is likely influenced by the overall ecosystem of the early environment, including maternal characteristics, behaviors, and health. SUMMARY: MDEVs may have an important role in early child development and infant future health. Understanding benefits of MDEVs characteristics have potential role on gut maturation, immune system development and the prevention of metabolic disorders.

Oxytocin Regulates the Expression of Selected Colostrum-derived microRNAs.

OBJECTIVE: The highly expressed microRNAs (miRNAs) in milk are known as beneficial miRNAs, such as mir148a-3p, which is related to immune system development and disease prevention. There is a need to study their expression and secretion regulatory mechanism in breast milk. We hypothesize that oxytocin can be involved in the regulation of expression and secretion of milk-derived miRNAs. METHODS: Initially, oxytocin's effect on miRNA expression in human mammary cells was analyzed. Secondly, the expression of selected miRNAs in mothers' colostrum treated or not with oxytocin before, during, or after labor was compared. MiRNA expression was analyzed by quantitative real-time PCR. RESULTS: The expression of miR-148a was significantly upregulated, and miR-320 downregulated in oxytocin-treated mammary cells as well as their secreted extracellular vesicles to the media, compared with untreated cells. MiR-148a was found to be upregulated, and miR-320 was downregulated in the human colostrum of exogenous oxytocin-treated mothers. Moreover, miR-320 was highly expressed compared with miR-148a in the colostrum of mothers that did not receive exogenous oxytocin. In contrast, in the milk of mothers who received exogenous oxytocin, the expression of miRNA-148-3p was highly expressed compared with miR-320. CONCLUSIONS: This study shows that oxytocin modulates the expression of main milk-derived miRNAs. Our findings provide a novel insight into oxytocin's role in milk composition by regulating miRNA expression. Our results implicate that oxytocin increases miRNA expression in mammary epithelial cells and human milk, affecting human milk composition and may contribute to further infant health.

Evaluation of gastrointestinal symptoms in pediatric patients post hematopoietic stem cell transplantation: Ileo-colonoscopy versus sigmoidoscopy. A single-center experience and review of literature.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a curative therapy used to treat high-risk hematological malignant disorders and other life-threatening nonmalignant diseases. Gastrointestinal (GI) symptoms post-HSCT might be due to GI graft-versus-host disease (GVHD) or GI infections or both. GI endoscopy with biopsies is safe and beneficial in guiding the management of GI symptoms in children after HSCT, justifying the therapeutic management and contributing to improved outcomes. METHODS: A retrospective cohort study including 16 children with malignant and nonmalignant diseases that underwent allogeneic HSCT who had 24 ileo-colonoscopies performed for GI symptoms. To facilitate an evidence-based approach to the endoscopic evaluation of GI symptoms in pediatric patients post HSCT, we examined whether a full ileo-colonoscopy, which includes right colon and terminal ileum (TI), as opposed to a limited sigmoidoscopy, was more accurate in the evaluation of GI symptoms in pediatric patients post HSCT. RESULTS: Specific findings on the right colon/TI were found in nine out of 24 ileo-colonoscopies (38%, CI = 19%-59%). The macroscopic findings on ileo-colonoscopy were compared with the histopathologic findings. When macroscopic findings were present, there were matching histopathologic findings in 100% of cases. However, even in the absence of any macroscopic findings on ileo-colonoscopy, there were histopathological findings in 29% of the cases (p-value = .016). CONCLUSIONS: This cohort favors ileo-colonoscopy over sigmoidoscopy, with systematic biopsy sampling, in evaluating GI symptoms in pediatric patients post HSCT.

Cow and Human Milk-Derived Exosomes Ameliorate Colitis in DSS Murine Model.

The aim of this study was to investigate the therapeutic effect of cow and human milk derived exosomes (MDEs) on colitis. We used gavage administration of fluorescent labeled MDEs to track their localization patterns in vivo and studied their therapeutic effect on colitis in a dextran sulfate sodium (DSS)-induced colitis model. MDEs attenuated the severity of colitis induced by DSS and statistically reduced the histopathological scoring grade and shortening of the colon. Likewise, treatment with MDEs reduced the expression of interleukin 6 and tumor necrosis factor-α. Moreover, miRNAs highly expressed in milk, such as miRNA-320, 375, and Let-7, were found to be more abundant in the colon of MDE-treated mice compared with untreated mice; contrastingly, the expression of their target genes, mainly DNA methyltransferase 1 (DNMT1) and DNMT3 were downregulated. Furthermore, the level of TGF-ß was upregulated in the colon of MDE-treated mice. We demonstrated that MDEs have a therapeutic and anti-inflammatory effect on colitis, involving several complementary pathways in its mechanism of action. The therapeutic effects of MDEs might have implications for the possible addition of MDEs as a nutrient in enteral nutrition formulas for patients with inflammatory bowel disease.

Low complication rate in immunocompromised children with varicella-zoster virus infections in a single centre.

AIM: Recent studies focusing on morbidity and mortality rates of immunocompromised children with varicella-zoster virus (VZV) infections are scarce. We aimed to summarise our experience. METHODS: The study was a retrospective analysis of the medical records of children, who were admitted to Hadassah-Hebrew University Medical Centre, Jerusalem, Israel, during the period of 2008-2016. Data regarding baseline characteristics, treatment and outcome were extracted from patient's medical files. RESULTS: We enrolled 74 patients (43% males) with a mean age of 8 (1-19) years. Most patients (72%) had no reported complications. Clinical outcome was favourable with 73 (99%) patients who had completely recovered and none died. Multivariable analysis identified the presence of fever (P = .005 and 0.02; hazard ratio (HR) 7.72 and 17.61, for total and herpes zoster groups, respectively) and prolonged interval period from clinical presentation to treatment onset (P = .021 and 0.025; HR 1.68 and 2.26, respectively), as associated with higher rates of complications. CONCLUSION: Our results found low complication rate of VZV-associated infections in immunocompromised children admitted to a single centre. This should encourage conducting further large multicentre studies evaluating management of low-risk patients with oral acyclovir treatment.

Milk-derived exosomes (MDEs) have a different biological effect on normal fetal colon epithelial cells compared to colon tumor cells in a miRNA-dependent manner.

BACKGROUND: Breastfeeding is the ideal source of infant nutrition. Human milk consists not only of nutrients but also biologically active components. Among these latter compounds, exosomes contain proteins, lipids, mRNAs and miRNAs. METHODS: To elucidate the biological effects of milk-derived exosomes (MDEs) on normal colonic epithelial cells compared to colonic tumor cells, we incubated cells with MDEs. MDEs were able to enter into normal and tumor cells and change their miRNA expression profiles. Proliferation, cell morphology and protein expression were analyzed in these cells. RESULTS: Human milk-derived exosomes induced proliferation- and epithelial mesenchymal transformation-related changes, such as collagen type I and twist expression, in normal but not in tumor cells. PTEN, a target of miRNA-148a, was downregulated in normal but not in tumor cells following incubation with MDEs. Moreover, miRNA-148a-3p knockdown cells were used to demonstrate the importance of miRNA in the effect of exosomes on cell proliferation and protein expression. MDEs inhibited proliferation and DNMT1 expression in cells with knockdown of miRNA-148a. CONCLUSIONS: In conclusion, the positive effect of exosomes on normal cells without affecting tumor cells may presents an aspect of their safety when considering it use as a nutritional supplement to infant formula.

Prenatal exposure to selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors and risk for persistent pulmonary hypertension of the newborn: a systematic review, meta-analysis, and network meta-analysis.

BACKGROUND: There is a marked increase in the use of selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors in the last decade. Many newborns are likely to be exposed during pregnancy and labor. OBJECTIVE: We aimed to evaluate the association between exposure to selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors during pregnancy and the risk for persistent pulmonary hypertension of the newborn. We sought to compare the risk for persistent pulmonary hypertension of the newborn between specific selective serotonin reuptake inhibitor agents. STUDY DESIGN: MEDLINE, Embase, and Cochrane were searched up to July 2017. No language restrictions were applied. Search key words included: "SSRI," "SNRI," "pregnancy," "risk," "new-born," and "pulmonary hypertension." Retrospective cohort studies and case-control studies reporting the risk for persistent pulmonary hypertension of the newborn in the offspring of women exposed to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors during pregnancy, were extracted. Two independent researchers identified relevant data. Random effects meta-analysis was used to pool results. Odds ratios were calculated with subsequent 95% confidence intervals. Network meta-analysis was conducted, incorporating direct and indirect comparisons among different selective serotonin reuptake inhibitors. The primary outcome was risk for persistent pulmonary hypertension of the newborn after exposure to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors during pregnancy. RESULTS: A total of 11 studies were identified. A total of 156,978 women and their offspring were exposed to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors during pregnancy. Persistent pulmonary hypertension of the newborn was detected among 452 exposed offspring, representing an incidence rate of 2.9 cases per 1000 live births and a number needed to harm of 1000. The risk for persistent pulmonary hypertension of the newborn was significantly increased in the analysis of exposure to selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor in any trimester (odds ratio, 1.82; 95% confidence interval, 1.31-2.54; I2 = 72%), as well as in analysis restricted to exposure week >20 (odds ratio, 2.08; 95% confidence interval, 1.44-3.01; I2 = 76%). In network meta-analysis, sertraline was ranked most likely to have the lowest risk for persistent pulmonary hypertension of the newborn among the different selective serotonin reuptake inhibitors (P = .83). CONCLUSION: Exposure to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors during pregnancy is associated with an increased risk for persistent pulmonary hypertension of the newborn. According to our findings, sertraline ranked as most likely to have the lowest risk for persistent pulmonary hypertension of the newborn compared to other selective serotonin reuptake inhibitors, suggesting it may have the best safety profile for use in pregnancy in this regard. Further studies are needed to fully establish these results.

Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies.

Acetaminophen is the analgesic and antipyretic most commonly used during pregnancy. Evidence of neurodisruptive properties is accumulating. Therefore, we sought to evaluate the risk for attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) in the offspring of women exposed to acetaminophen during pregnancy. We searched MEDLINE, Embase, and Cochrane databases for relevant studies up to January 2017. Data were independently extracted and assessed by 2 researchers. Seven eligible retrospective cohorts included 132,738 mother-child pairs, with follow-up periods ranging from 3 to 11 years. The pooled risk ratio for ADHD was 1.34 (95% confidence interval (CI): 1.21, 1.47; I2 = 72%); for ASD, the risk ratio was 1.19 (95% CI: 1.14, 1.25; I2 = 14%), and for hyperactivity symptoms, it was 1.24 (95% CI: 1.04, 1.43; I2 = 93%). In meta-regression analysis, the association between exposure and ADHD increased with the child's age upon follow-up (ß = 0.03, 95% CI: 0.00, 0.07) and with the mean duration of exposure (ß = 0.00, 95% CI: 0.00, 0.01). The available data is of observational nature only. Studies differed widely in exposure and outcome assessment. Acetaminophen use during pregnancy is associated with an increased risk for ADHD, ASD, and hyperactivity symptoms. These findings are concerning; however, results should be interpreted with caution given that the available evidence consists of observational studies and is susceptible to several potential sources of bias.

MARS variant associated with both recessive interstitial lung and liver disease and dominant Charcot-Marie-Tooth disease.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNA with cognate amino acids during protein translation. Non-canonical functions are increasingly recognized, and include transcription and translation control and extracellular signaling. Monoallelic mutations in genes encoding several ARSs have been identified in axonal Charcot-Marie-Tooth (CMT2) disease, whereas biallelic mutations in ARS loci have been associated with multi-tissue syndromes, variably involving the central nervous system, lung, and liver. We report a male infant of non-consanguineous origin, presenting with successive onset of transfusion-dependent anemia, hypothyroidism, cholestasis, interstitial lung disease, and developmental delay. Whole-exome sequencing (WES) revealed compound heterozygosity for two variants (p.Tyr307Cys and p.Arg618Cys) in MARS, encoding methionyl-tRNA synthetase. Biallelic MARS mutations are associated with interstitial lung and liver disease (ILLD). Interestingly, the p.Arg618Cys variant, inherited from an unaffected father, was previously reported in a family with autosomal dominant late-onset CMT2. Yeast complementation assays confirmed pathogenicity of p.Arg618Cys, yet suggested retained function of p.Tyr307Cys. Our findings underscore the phenotypic variability associated with ARS mutations, and suggest genetic or environmental modifying factors in the onset of monoallelic MARS-associated CMT2.

Mechanism of Hyponatremia in Community-Acquired Pneumonia: Does B-type Natriuretic Peptide Play a Causative Role?

OBJECTIVE: Hyponatremia is a well-known sequela of community-acquired pneumonia (CAP). B-type natriuretic peptide (BNP) has a natriuretic effect and was found to be elevated in patients with CAP. We investigated whether BNP has a role in the pathophysiology of hyponatremia in pediatric CAP. METHODS: Serum and urine electrolytes and osmolality, as well as NT-pro-BNP (N-BNP), were obtained in 49 hospitalized pediatric patients with CAP (29 with hyponatremia, 20 with normal sodium levels. RESULTS: Urine sodium levels were lower in the hyponatremic group compared with the normonatremic group (24.3 meq/L vs 66.7 meq/L, P = 0.006). No difference in N-BNP levels was found between groups (median, 103.8 vs 100.1; P = 0.06; interquartile range, 63.7-263.3 pg/mL vs 47.4-146.4 pg/mL). N-BNP was not associated with serum or urinary sodium levels. CONCLUSIONS: These results indicate that BNP is unlikely to play a causative role in the mechanism of hyponatremia in CAP.

Lactose Breath Test in Children: Relationship Between Symptoms During the Test and Test Results.

BACKGROUND: Lactose malabsorption affects 70% of the world population. The hydrogen breath test (HBT) is used clinically to test for this condition. The aim of our study was to describe the relationship between symptoms experienced before and during the HBT and test results. METHODS: We included children who underwent the HBT in the pediatric gastroenterology unit at Dana-Dwek Children's Hospital during a 6-month period. Previous symptoms and those experienced before and after the HBT were assessed using a questionnaire and a validated pain scale. RESULTS: Ninety-five children were included in the study, and 66.3% had a positive HBT. Diarrhea and flatulence during the test were significantly more frequent in the group with a positive HBT compared to those with a negative test (31.7% vs. 9.4%, P = 0.016 and 69.8% vs. 40.6%, P = 0.006, respectively). The frequency of abdominal pain and bloating was similar. CONCLUSIONS: Diarrhea and flatulence during the HBT are the most specific symptoms of lactose intolerance. Abdominal pain should not be automatically attributed to lactose intolerance even in the presence of lactose malabsorption. Coupling the HBT with a real-time questionnaire facilitates interpretation of results and subsequent recommendations.

Treatment Response in Pediatric Patients With Pseudotumor Cerebri Syndrome.

BACKGROUND: Pseudotumor cerebri syndrome (PTCS) is a disorder defined by increased intracranial pressure in the absence of an intracranial space-occupying lesion. This retrospective study aimed to examine the outcomes in children with PTCS. METHODS: Data was collected retrospectively from the charts of consecutive pediatric patients treated for PTCS at our hospital between 2000 and 2007 (60 patients; 36 females, 24 males). RESULTS: Forty-six patients (76.6%) responded well to acetazolamide therapy, with full resolution of symptoms, including papilledema (average treatment duration 1 year; range: 1 month-5 years). Of the 14 patients with no response to treatment, 9 (23.4%) required surgical intervention. Nonresponders tended to be younger at presentation (8.7 vs 11.5 years, P = 0.04). Twelve patients (26%) experienced relapse after acetazolamide was discontinued. The group that experienced relapse was significantly younger than the nonrelapsers (8.9 vs 12.1 years, P < 0.05). CONCLUSIONS: Younger age at presentation with PTCS was found to be a risk factor for treatment failure or relapse.

Characterization and biological function of milk-derived miRNAs.

SCOPE: Breastfeeding is associated with reduced risk of infection, immune-mediated disorders, obesity, and even cancer. Recently it was found that breast milk contains a variety of microRNAs (miRNAs) in the skim and fat layer that can be transferred to infants, and appear to play important roles in those biological functions. METHODS AND RESULTS: This study applied next generation sequencing and quantitative real-time PCR analysis to determine the miRNA expression profile of the skim and fat fraction of human, goat, and bovine milk as well as infant formulas. Human and mammalian milk were found to contain known advantageous miRNAs in exosomes and also in the fat layer. These miRNAs are highly conserved in human, bovine and goat milk. However, they were not detected in several infant formulas. Further, miRNAs present in milk were able to enter normal and tumor cells and affect their biological functions. Following incubation of milk derived human miRNA with normal and cancer cells, the expression of miRNA-148a was upregulated and the expression of the DNA methyltransferase1 target gene of miRNA-148a was down regulated. CONCLUSION: These results reinforce previous findings on the importance of miRNA in breast milk. Future studies should concentrate on the addition of miRNA to infant formulas.

Meal time behavior difficulties but not nutritional deficiencies correlate with sensory processing in children with autism spectrum disorder.

BACKGROUND: Food aversion and nutritional difficulties are common in children with autism spectrum disorder. AIM: To compare meal time behavior of children with autism to their typically developing siblings and to typical controls and to examine if sensory profiles can predict meal time behavior or nutritional deficiencies in the autism group.

Role of vasopressin and terlipressin in refractory shock compared to conventional therapy in the neonatal and pediatric population: a systematic review, meta-analysis, and trial sequential analysis.

BACKGROUND: Vasopressin (AVP) and terlipressin (TP) have been used as last-line therapy in refractory shock in children. However, the efficacy and safety profiles of AVP and TP have not been determined in pediatric refractory shock of different origins. We aimed to assess the efficacy and safety of the addition of AVP/TP therapy in pediatric refractory shock of all causes compared to conventional therapy with fluid resuscitation and vasopressor and inotropic therapy. METHODS: We conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) comparing AVP and TP to conventional therapy. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched up to February 2016. The systematic review included all reports of AVP/TP use in the pediatric population. Reports of clinical trials were pooled using random-effects models and TSA. Main outcomes were mortality and tissue ischemia. RESULTS: Three randomized controlled trials and five "before-and-after clinical" trials (without comparator) met the inclusion criteria. Among 224 neonates and children (aged 0 to 18 years) with refractory shock, 152 received therapy with AVP or TP. Pooled analyses showed no association between AVP/TP treatment and mortality (relative risk (RR),1.19; 95% confidence interval (CI), 0.71-2.00), length of stay in the pediatric intensive care unit (PICU) (mean difference (MD), -3.58 days; 95% CI, -9.05 to 1.83), and tissue ischemia (RR, 1.48; 95% CI, 0.47-4.62). In TSA, no significant effect on mortality and risk for developing tissue ischemia was observed with AVP/TP therapy. CONCLUSION: Our results emphasize the lack of observed benefit for AVP/TP in terms of mortality and length of stay in the PICU, and suggest an increased risk for ischemic events. Our TSA suggests that further large studies are necessary to demonstrate and establish benefits of AVP/TP in children. PROSPERO registry: CRD42016035872.

Cellular and Molecular Mediators of Intestinal Fibrosis.

Intestinal fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent fibrosis once it has started. The processes that regulate fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of intestinal fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments.