Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort.

BACKGROUND AIMS: High levels of serum matrix metalloproteinase-7 (MMP-7) have been linked to biliary atresia (BA), with wide variation in concentration cutoffs. We investigated accuracy of serum MMP-7 as a diagnostic biomarker in a large North American cohort. APPROACH RESULTS: MMP-7 was measured in serum samples of 399 cholestatic infants in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p=0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved-fluorescence energy transfer (TR-FRET) assays. Discriminative performance of MMP-7 was compared with other clinical markers. On the single-plex assay, MMP-7 generated an area under receiver operating curve (AUROC) of 0.90 (confidence interval [CI] 0.87-0.94). At cutoff 52.8 ng/mL, it produced sensitivity=94.03%, specificity=77.78%, positive predictive value=64.46%, and negative predictive value=96.82% for BA. AUROC for gamma-glutamyl transferase (GGT)=0.81 (CI 0.77-0.86), stool color=0.68 (CI 0.63-0.73), and pathology=0.84 (CI 0.76-0.91). Logistic regression models of MMP-7 with other clinical variables individually or combined showed an increase for MMP-7+GGT AUROC to 0.91 (CI 0.88-0.95). Serum concentrations produced by TR-FRET differed from single-plex, with optimal cutoff of 18.2 ng/mL. Results were consistent within each assay technology and generated similar AUROCs. CONCLUSIONS: Serum MMP-7 has high discriminative properties to differentiate BA from other forms of neonatal cholestasis. MMP-7 cutoff values vary according to assay technology. Using MMP-7 in evaluation of cholestatic infants may simplify diagnostic algorithms and shorten time to hepatoportoenterostomy.

Single breath counting technique to assess pulmonary function: a systematic review and meta-analysis.

Pulmonary function is usually assessed by measuring Vital Capacity (VC) using equipment such as a spirometer or ventilometer, but these are not always available to the population, as they are relatively expensive tests, difficult to transport and require trained professionals. However, the single breath counting technique (SBCT) appears as a possible alternative to respiratory function tests, to help in the pathophysiological understanding of lung diseases. The objective is to verify the applicability of the SBCT as a parameter for evaluating VC. This is a systematic review registered in the International Prospective Register of Systematic Reviews (CRD42023383706) and used for PubMed®, Scientific Electronic Library Online, LILACS, EMBASE, and Web of Science databases of articles published until January 2023. Methodological quality regarding the risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and National Institutes of Health tools. Eleven of a total of 574 studies were included, of these, nine showed a correlation between VC and SBCT (weak in healthy, moderate in neuromuscular and strong in hospitalized patients). One study of hospitalized patients accurately identified a count value of 21 for a VC of 20 ml kg-1(Sensitivity = 94% and Specificity = 77%), and another estimated a count lower than 41 for a VC below 80% of predicted in patients with neuromuscular dystrophy (Sensitivity = 89% and Specificity = 62%), and another showed good intra and inter-examiner reproducibility in young, adult, and elderly populations. A meta-analysis of three studies showed a moderate correlation in subjects with neuromuscular diseases (r= 0.62, 95% CI = 0.52-0.71,p< 0.01). A high risk of bias was identified regarding the justification of the sample size and blinding of the evaluators. SBCT has been presented as an alternative to assess VC in the absence of specific equipment. There is a clear relationship between SBCT and VC, especially in neuromuscular and hospitalized individuals. New validation studies conducted with greater control of potential bias risks are necessary.

Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children.

BACKGROUND: Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH. METHODS: We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes. RESULTS: Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported. CONCLUSIONS: Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies.

Plasticity between type 2 innate lymphoid cell subsets and amphiregulin expression regulates epithelial repair in biliary atresia.

BACKGROUND AND AIMS: Although a dysregulated type 1 immune response is integral to the pathogenesis of biliary atresia, studies in both humans and mice have uncovered a type 2 response, primarily driven by type 2 innate lymphoid cells. In nonhepatic tissues, natural type 2 innate lymphoid cell (nILC2s) regulate epithelial proliferation and tissue repair, whereas inflammatory ILC2s (iIlC2s) drive tissue inflammation and injury. The aim of this study is to determine the mechanisms used by type 2 innate lymphoid cell (ILC2) subpopulations to regulate biliary epithelial response to an injury. APPROACH AND RESULTS: Using Spearman correlation analysis, nILC2 transcripts, but not those of iILC2s, are positively associated with cholangiocyte abundance in biliary atresia patients at the time of diagnosis. nILC2s are identified in the mouse liver through flow cytometry. They undergo expansion and increase amphiregulin production after IL-33 administration. This drives epithelial proliferation dependent on the IL-13/IL-4Rα/STAT6 pathway as determined by decreased nILC2s and reduced epithelial proliferation in knockout strains. The addition of IL-2 promotes inter-lineage plasticity towards a nILC2 phenotype. In experimental biliary atresia induced by rotavirus, this pathway promotes epithelial repair and tissue regeneration. The genetic loss or molecular inhibition of any part of this circuit switches nILC2s to inflammatory type 2 innate lymphoid cell-like, resulting in decreased amphiregulin production, decreased epithelial proliferation, and the full phenotype of experimental biliary atresia. CONCLUSIONS: These findings identify a key function of the IL-13/IL-4Rα/STAT6 pathway in ILC2 plasticity and an alternate circuit driven by IL-2 to promote nILC2 stability and amphiregulin expression. This pathway induces epithelial homeostasis and repair in experimental biliary atresia.

Recent Increase in Incidence of Severe Acute Hepatitis of Unknown Etiology in Children is Associated with Infection with Adenovirus and Other Nonhepatotropic Viruses.

OBJECTIVE: To evaluate whether the nature and severity of non-A-E severe acute hepatitis in children noted by the World Health Organization from late 2021 through early 2022 was indeed increased in 2021-2022 compared with prior years. STUDY DESIGN: We performed a single-center, retrospective study to track the etiology and outcomes of children with non-A-E severe acute hepatitis in 2021-2022 compared with the prior 3-year periods (2018-2019, 2019-2020, and 2020-2021). We queried electronic medical records of children ≤16 years of age with alanine or aspartate aminotransferase levels of >500 IU. Data were analyzed for the periods of October 1, 2021, to May 1, 2022, and compared with the same time periods in 2018-2021. RESULTS: Of 107 children meeting entry criteria, 82 cases occurred from October to May of 2018-2022. The average annual case number was 16.3 in 2018-2021 compared with a 2-fold increase (to 33) in 2021-2022 (P = .0054). Analyses of etiologies showed that this increase was associated with a higher number of children who tested positive for viruses (n = 16) when compared with the average of 3.7 for 2018-2021 (P = .018). Adenovirus (26.1%) and severe acute respiratory syndrome coronavirus-2 (10.3%) were the most frequently detected viruses in 2021-2022. Despite evidence of acute liver failure in 37.8% of children in the entire cohort and in 47% of those with viral infection, the overall survival rate was high at 91.4% and 88.9%, respectively. CONCLUSIONS: The number of children with severe acute hepatitis in our center increased from 2021 to May 2022, with a greater frequency of cases associated with adenovirus, yet transplant-free survival remains high.

Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease.

BACKGROUND AND AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis. APPROACH AND RESULTS: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS. CONCLUSIONS: Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.

Serum bile acids as a prognostic biomarker in biliary atresia following Kasai portoenterostomy.

BACKGROUND AND AIMS: In biliary atresia, serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes in the latter group. APPROACH AND RESULTS: Participants with biliary atresia from the Childhood Liver Disease Research Network were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6-month post-KP clinic visit ( n  = 137). Bile acids were measured from the stored serum samples and used to divide participants into ≤40 µmol/L ( n  = 43) or >40 µmol/L ( n  = 94) groups. At 2 years of age, the ≤40 µmol/L compared with >40 µmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts. Furthermore, during 734 person-years of follow-up, those in the ≤40 µmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The ≤40 µmol/L group had a 10-year cumulative incidence of liver transplant/death of 8.5% (95% CI: 1.1%-26.1%), compared with 42.9% (95% CI: 28.6%-56.4%) for the >40 µmol/L group ( p  = 0.001). CONCLUSIONS: Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP.

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.

Effects of cilostazol, a Phosphodiesterase-3 inhibitor, on kidney function and redox imbalance in acute kidney injury caused by Bothrops alternatus venom.

The mechanisms of pathogenesis of acute kidney injury (AKI) in snakebites is multifactorial and involves hemodynamic disturbances, with release of free radical causing cytotoxic effects. The phosphodiesterase-3 (PDE3) inhibitor, Cilostazol, has been reported to provide protection against renal oxidative stress. OBJECTIVE: We evaluated the protective effects of cilostazol against Bothrops alternatus snake venom (BaV)-induced nephrotoxicity. METHODS: Wistar rat kidneys (n = 6, 260-300 g) were isolated and perfused with Krebs-Henseleit solution containing 6 g/100 mL of bovine serum albumin. After 30 min, the kidneys were perfused with BaV to a final concentration of 1 and 3 µg/mL, and subsequently evaluated for perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), and percentage of electrolyte tubular sodium and chloride transport (%TNa+, %TCl-). Oxidative stress and renal histological analyses were performed. RESULTS: BaV caused a reduction in all the evaluated renal parameters (PP, RVR, GFR, UF, %TNa+, and %TCl-). Although only the effects on PP and UF were reversed with cilostazol treatment, the decrease in the malondialdehyde levels, without changes in glutathione levels, further reduced the venom-induced renal tissue changes. CONCLUSION: Our data suggest that PDE3 is involved in BaV-induced nephrotoxicity, as cilostazol administration significantly ameliorated these effects.

Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases-Examination of cholestatic liver disease in Alagille syndrome.

The conduct of long-term conventional randomized clinical trials in rare diseases is very difficult, making evidenced-based drug development problematic. As a result, real-world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2-year prospective follow-up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (-1.43 [0.28] -1.99, -0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (-65.2 [16.2] -98.3, -32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real-world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies.

The Liver Biopsy in Neonatal Cholestasis: Just a Cherry on Top?

Content available: Author Audio Recording.

Participação nas aulas de Educação Física em Pernambuco: uma análise de tendência temporal / Participation in Physical Education classes in Pernambuco: a temporal trend analysis

O objetivo do estudo foi analisar a tendência temporal e fatores associados à participação nas aulas de educação física de estudantes de Pernambuco. Estudo de tendência temporal composto por três levantamentos de abrangência estadual. Foram entrevistados 4.207 estudantes em 2006, 6.264 em 2011 e 6.002 em 2016, por meio do questionário "Global School-based Student Health Survey" (GSHS). O desfecho foi a participação nas aulas de Educação Física e as exposições foram as informações sociodemográficas. A análise bivariada foi realizada mediante teste Qui-quadrado e as análises multivariadas por regressão logística binária. Observou-se um aumento na prevalência de participação nas aulas de Educação Física (2006: 35%, 2011: 74% e 2016: 81,2%) destacando o aumento significativo no sexo masculino Δ% (2006-2016) = 123,5%. Ser do sexo masculino, estudar no período integral e ser filho de mães que estudaram, independente do tempo de estudo foi associado a maior participação nas aulas de educação física, assim como residir nas regiões do Agreste, Sertão e Sertão do São Francisco. Apesar do aumento na participação nas aulas de Educação Física em Pernambuco, a garantia deste componente curricular deve ser fortalecida, levando em consideração os grupos de risco para que aumente a participação nas aulas desses grupos

The aim of the study was to analyze the temporal trend and factors associated with participation in physical education classes in Pernambuco. The temporal trend study was composed of three surveys. A total of 4,207 students were interviewed in 2006, 6,264 in 2011 and 6,002 in 2016, using the "Global School-based Stu-dent Health Survey" (GSHS) questionnaire. The outcome was participation in Physical Education classes and the independent variables were sociodemographic information. The bivariate analysis was performed using the chi-square test and the multivariate analysis using binary logistic regression. There was an increase in the prevalence of participation in Physical Education classes (2006: 35%, 2011: 74% and 2016: 81.2%), highlighting the significant increase in males Δ% (2006-2016) = 123.5%. Male, studying full-time and being the son of mothers who studied was associated with greater participation in physical education classes, as well as living in the regions of Agreste, Sertão and Sertão do São Francisco. Despite the increase in par-ticipation in Physical Education classes in Pernambuco, the guarantee of this curricular component must be strengthened, considering risk groups in order to increase participation in classes for these groups

Maternal regulation of biliary disease in neonates via gut microbial metabolites.

Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We hypothesized that feeding butyrate to pregnant mice influences the newborn's susceptibility to biliary atresia, a severe cholangiopathy of neonates. Here, we show that butyrate administration to mothers renders newborn mice resistant to inflammation and injury of bile ducts and improves survival. The prevention of hepatic immune cell activation and survival trait is linked to fecal signatures of Bacteroidetes and Clostridia and increases glutamate/glutamine and hypoxanthine in stool metabolites of newborn mice. In human neonates with biliary atresia, the fecal microbiome signature of these bacteria is under-represented, with suppression of glutamate/glutamine and increased hypoxanthine pathways. The direct administration of butyrate or glutamine to newborn mice attenuates the disease phenotype, but only glutamine renders bile duct epithelial cells resistant to cytotoxicity by natural killer cells. Thus, maternal intake of butyrate influences the fecal microbial population and metabolites in newborn mice and the phenotypic expression of experimental biliary atresia, with glutamine promoting survival of bile duct epithelial cells.

Serum Proteomics Uncovers Biomarkers of Clinical Portal Hypertension in Children With Biliary Atresia.

Children with biliary atresia (BA) often develop portal hypertension (PHT) and its complications, which are associated with high morbidity and mortality. The goal of this study was to identify serum biomarkers of PHT by using large-scale proteomics. We applied the slow off-rate modified aptamer scan (SOMAscan) to measure 1,305 proteins in serum samples of children with BA with and without clinical evidence of PHT in validation and discovery cohorts enrolled in the Biliary Atresia Study of Infants and Children. Serum proteomics data was analyzed using logistic regression to identify protein(s) with an area under the receiver operating characteristic curve (AUROC) ≥ 0.90. Immunostaining was used to characterize the cellular localization of the new biomarker proteins in liver tissues. We identified nine proteins in the discovery cohort (n = 40 subjects) and five proteins in the validation cohort (n = 80 subjects) that individually or in combination predicted clinical PHT with AUROCs ≥ 0.90. Merging the two cohorts, we found that semaphorin 6B (SEMA6B) alone and three other protein combinations (SEMA6B+secreted frizzle protein 3 [SFRP3], SEMA6B+COMM domain containing 7 [COMMD7], and vascular cell adhesion molecule 1 [VCAM1]+BMX nonreceptor tyrosine kinase [BMX]) had AUROCs ≥ 0.90 in both cohorts, with high positive- and negative-predictive values. Immunostaining of the new protein biomarkers showed increased expression in hepatic endothelial cells, cholangiocytes, and immune cells within portal triads in BA livers with clinical PHT compared to healthy livers. Conclusion: Large-scale proteomics identified SEMA6B, SFRP3, COMMD7, BMX, and VCAM1 as biomarkers highly associated with clinical PHT in BA. The expression of the biomarkers in hepatic epithelial, endothelial, and immune cells support their potential role in the pathophysiology of PHT.

Universal school-based intervention targeting depressive symptoms in adolescents: A cluster randomized trial.

We investigated the effects of three different interventions on depressive symptoms in adolescents. As a secondary aim, we explored the mediating role of social isolation, anxiety, sleep quality, and cognitive function of the intervention effect on depressive symptoms. We conducted a cluster randomized controlled trial, in which schools were randomly assigned to 1. Doubling physical education (PE) classes (3:20 h of PE/week); 2. Workshop with the PE teachers; 3. Workshop with the PE teachers + Doubling PE classes; and 4. Control group (1:40 h of PE/week). In total, 1279 adolescents were included, 56.4% females. Doubling PE classes and the workshop with the PE teachers + Doubling PE classes groups did not affect depressive symptoms (-0.947, 95% CI -3.176 to 1.281; and, 0.726, 95% CI -1.558 to 3.009, respectively). The workshop with the PE teachers decreased adolescents' depressive symptoms (-2.495, 95% CI -4.668 to -0.323), social isolation (-4.759, 95% CI -9.025 to -0.493), and poor sleep quality (-0.560, 95% CI -1.108 to -0.012) compared with the control group. Social isolation mediated 32% of the workshop effect on depressive symptoms. The workshop with the PE teachers and the workshop with the PE teachers + Doubling PE classes groups lowered in 93% and in 54% the risk of the adolescents in developing high depressive symptomatology compared with the control group, respectively. A workshop updating PE teachers on pedagogical and health-related topics decreased depressive symptoms in adolescents. Moreover, improvements in the adolescents' social isolation mediated the effect of PE teachers' workshop intervention on the depressive symptoms in adolescents.

Inter-individual variability in children's physical growth and body composition: Findings of longitudinal ELOS-Pré study.

BACKGROUND: Children's physical growth (PG) and body composition (BC) can be influenced by birth weight and type of delivery. AIM: To longitudinally analyze the dynamics of PG and BC of children from 5 to 9 years; to investigate the inter-individual differences according to age, sex, BW, and type of delivery across the following years of the study. SUBJECTS AND METHODS: A total of 1236 children (597 boys) were evaluated at 5-years of age and followed annually until 9-years. PG and BC measurements were evaluated. Multilevel modeling was used. RESULTS: Annual increments were observed (p < .001). Girls presented lower height and fat-free-mass but higher %BF (p < .001). Distinct trajectories between the sexes were observed for height (p < .001). Low-birth-weight children presented lower height, body mass, and fat-free-mass (p < .001), but the interaction between velocity of growth and BC was significant only in height (p < .05). Children born by had lower height, body mass, and %BF, and gained less body mass per year than those born by vaginal delivery (p < .05). Significant inter-individual differences were observed at 5-years of age and in their trajectories, except for fat-free-mass (p < .01). CONCLUSION: There are differences in the dynamics of PG and BC, low-birth-weight and type of delivery influence the dynamics of PG during this interval of ages.

Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia.

BACKGROUND AND AIMS: Biliary atresia is a severe inflammatory and fibrosing cholangiopathy of neonates of unknown etiology. The onset of cholestasis at birth implies a prenatal onset of liver dysfunction. Our aim was to investigate the mechanisms linked to abnormal cholangiocyte development. APPROACH AND RESULTS: We generated biliary organoids from liver biopsies of infants with biliary atresia and normal and diseased controls. Organoids emerged from biliary atresia livers and controls and grew as lumen-containing spheres with an epithelial lining of cytokeratin-19pos albuminneg SOX17neg cholangiocyte-like cells. Spheres had similar gross morphology in all three groups and expressed cholangiocyte-enriched genes. In biliary atresia, cholangiocyte-like cells lacked a basal positioning of the nucleus, expressed fewer developmental and functional markers, and displayed misorientation of cilia. They aberrantly expressed F-actin, ß-catenin, and Ezrin, had low signals for the tight junction protein zonula occludens-1 (ZO-1), and displayed increased permeability as evidenced by a higher Rhodamine-123 (R123) signal inside organoids after verapamil treatment. Biliary atresia organoids had decreased expression of genes related to EGF signaling and FGF2 signaling. When treated with EGF+FGF2, biliary atresia organoids expressed differentiation (cytokeratin 7 and hepatocyte nuclear factor 1 homeobox B) and functional (somatostatin receptor 2, cystic fibrosis transmembrane conductance regulator [CFTR], aquaporin 1) markers, restored polarity with improved localization of F-actin, ß-catenin and ZO-1, increased CFTR function, and decreased uptake of R123. CONCLUSIONS: Organoids from biliary atresia are viable and have evidence of halted epithelial development. The induction of developmental markers, improved cell-cell junction, and decreased epithelial permeability by EGF and FGF2 identifies potential strategies to promote epithelial maturation and function.

The Role of Adiposity in the Association Between Physical Activity and Blood Pressure in Children.

Purpose: To analyze whether body adiposity mediates and/or moderates the association between time in moderate-to-vigorous physical activities (MVPA) and blood pressure in children. Methods: This was a cross-sectional study of 577 children aged 5 to 7 years old. MVPA was measured by accelerometry. Body mass index (BMI), waist circumference (WC), and the sum of tricipital and subscapular skinfolds (skinfolds) assessed children's body adiposity. Systolic (SBP) and diastolic blood pressure (DBP) were used as the dependent variables. Results: In the primary analysis adjusting for BMI or skinfolds measures, additional time in MVPA was associated with higher SBP. On the other hand, further analyses showed that children in the largest BMI tertile (ßSBP:0.18; 95%CI: 0.12-0.24; ßDBP:0.11; 95%CI: 0.05-0.17), waist circumference (ßSBP:0.16; CI: 0.09-0.22; ßDBP:0.08; CI:0.02-0.14), or sum of skinfolds (ßSBP:0.18; CI: 0.11-0.24; ßDBP:0.09; CI: 0.03-0.16) presented a positive relationship between MVPA and blood pressure whereas no positive association was observed for children in the first and second adiposity tertiles. Adiposity also mediated the association between MVPA and blood pressure. A decrease of 0.03 mmHg in the systolic blood pressure was observed by decreasing the sum of skinfolds for each additional minute per day in MVPA. A decrease in diastolic blood pressure of 0.02 mmHg was observed for each additional minute per day in MVPA, which was related to a negative association between time in MVPA and waist circumference and sum of skinfolds. Conclusion: Not accounting for the potential moderation and mediation role of adiposity may lead to misinterpretations in the MVPA and blood pressure relationship.

Depressive symptoms in older adults: the role of physical activity and social support

Abstract Objective To evaluate the role of social support in the association between physical activity (PA) in its various domains and depressive symptoms in older adults. Methods This was a cross-sectional study involving 399 older adults seen at basic health units in the municipality of Recife, state of Pernambuco, northeastern Brazil. Linear regression was implemented using the forward method to assess the association between PA and its domains and depressive symptoms, as well as to test the possible moderating component of social support in this association. Results Of the total sample, 17.6% reported not practicing PA; 6.7% presented depressive symptoms, with a mean score of 1.59 points. A total of 18.6% of the older adults assessed reported not having social support. Older adults who did not practice total, transportation or domestic PA showed increased scores of depressive symptoms when compared to older adults who practiced PA in these domains. Older adults with social support also had fewer depressive symptoms. Practicing domestic, leisure and total PA, and/or having social support, decreased depressive symptoms in older adults. Having social support or practicing PA decreased depressive symptoms in older adults in a similar way. Conclusions Older adults with social support and who practiced PA, especially domestic and total PA, presented the lowest scores of depressive symptoms. The data showed the importance of providing elements to strengthen social support and PA practice in older adults living in poor communities as a strategy to prevent and reduce depressive symptoms.

Violence and psychosocial stress: A 10-year time trend analysis.

AIM: The aim of this study was to analyze the temporal trend of psychosocial stress and its association between exposure to violence in adolescents. METHODS: This is a cross-sectional study of temporal trends based on three school-based and statewide surveys with regular intervals of five years. The target population consisted of high school students from public schools. A total of 4,207 adolescents were evaluated in 2006, 6,264 in 2011, and 6,002 in 2016. The psychosocial stress indicator was the dependent study variable and was analyzed according to questions: a) Feeling of loneliness; b) Feeling of sadness; c) Difficulty sleeping due to worry; d) Number of close friends; e) Suicide ideation. Exposure variables were exposure to physical violence, involvement in fights and bullying. Logistic and linear regressions were used to verify the temporal trend of psychosocial stress, and to analyze the association between exposure of violence and psychosocial stress. RESULTS: Regardless of gender, the psychosocial stress score increasing trend between 2006 and 2016. The girls showed a variation in the feeling of loneliness from 18.7% to 22.8%, and suicide ideation increased from 10.4% to 14.2% between 2006 and 2016. All types of violence were associated with greater psychosocial stress for both boys and girls. CONCLUSION: Adolescents had a higher prevalence of feelings of loneliness, difficulty sleeping due to worry and suicide ideation during the period from 2006 to 2016, regardless of gender. Exposure to violence is associated with psychosocial stress in both genders, however, the strongest associations occurred in girls.