Physiologic Effects of Isolated or Synthetic Dietary Fiber in Children: A Scoping Review.

Background: Fiber is an integral part of a healthy diet. Studies have shown that the fiber intake in children is below adequate amounts, leading to adverse health outcomes. Objectives: This study aimed to perform a scoping review to assess the available evidence for the impact of isolated and synthetic dietary fiber on children's health outcomes. Methods: A systematic literature search was conducted in Ovid Medline, Ovid Global Health, Embase, and Cochrane Library via Wiley to identify randomized controlled trials (RCTs) in healthy children aged 1-18 y at baseline who consumed added, isolated, or synthetic dietary fiber. The outcomes of interest were categorized based on the Food and Drug Administration's guidance for industry on nondigestible carbohydrates and the Vahouny Fiber Symposium criteria, which included reduced fasting blood, glucose, total and/or LDL cholesterol concentrations, attenuation of postprandial glycemia/insulinemia, increased fecal bulk/laxation, reduced transit time, weight loss/reduction in adiposity, reduced energy intake from food consumption, increased satiety, bone health/enhanced mineral absorption, and blood pressure. We also cataloged additional reported outcomes. Results: Of 3837 randomized controlled parallel or crossover trials screened at the abstract level, 160 were eligible for full-text review, and 32 included for data extraction. This scoping review presents analysis of data from 32 RCTs in children who were healthy, overweight/obese or had mild hypercholesterolemia. Inulin-type fructans (41%) and psyllium (22%) were the most frequently administered fiber types, with weight/adiposity, markers of lipid metabolism (41%), and bone-related markers (38%) being the most frequently reported health outcomes. Only a few RCTs have investigated the effects of laxation (9%), and none specifically studied the impact of fiber on reducing postprandial glycemia/insulinemia. Conclusions: This scoping review demonstrates sufficient evidence for conducting systematic reviews and meta-analyses for several outcomes. Evidence gaps remain on the impact of isolated fibers on outcomes such as laxation, colonic transit time, and postprandial glycemia/insulinemia in children.

Perspective: Appraisal of the Evidence Base to Update DRI Values-Lessons from the Past, Thoughts for the Future.

Updating evidence-based nutrient guidance is challenging. One set of recommendations for which a robust evidence base is essential is the DRIs. In the past 10 y, DRI values for 4 essential nutrients have been re-evaluated in 2 groups: vitamin D and calcium, and sodium and potassium. To support the work of the committees tasked with evaluating the available evidence, the federal agencies that sponsor the DRI reviews contracted with the Agency for Healthcare Research and Quality to perform systematic reviews on predefined questions for these nutrient groups. Our aims were to tabulate the studies included in these systematic reviews and then, within the context of prespecified outcomes, summarize the totality of the available evidence and identify areas for consideration to maximize the value of the end products for future DRI committees. For the outcomes of interest, the available studies did not tend to report age data consistent with the current DRI categories. For some life stage categories, particularly pregnancy and lactation, there is a dearth of data. A wide range of study interventions were used, making it challenging to combine data to accurately derive or re-evaluate DRI values. There is also an under-representation of data on race/ethnicity and overweight/obesity, which is of concern, given the shifting demographic in the US and Canadian populations. Moving forward, it may be advantageous to develop a process to prospectively target research funding for studies designed to generate data that will most closely support re-evaluation of DRI values.

Effectiveness of ezetimibe in human immunodeficiency virus patients treated for hyperlipidaemia: a systematic review and meta-analysis.

OBJECTIVE: Systematic review and meta-analysis of lipid outcomes for human immunodeficiency virus (HIV)-positive or HIV-infected patients treated with ezetimibe. METHODS: We conducted a literature search from 1946 to 2021 for trials studying the effectiveness of ezetimibe in hyperlipidaemic HIV patients. We included trials of all designs in which HIV patients on highly active antiretroviral therapy (HAART)/non-nucleoside reverse transcriptase inhibitor (NNRTI) therapy had hyperlipidaemia, were treated with ezetimibe, and reported lipid outcomes. RESULTS: Of thirteen eligible trials, five were randomized controlled trials (RCTs) and eight were single-arm trials. Two of the eligible RCTs were placebo-controlled; we performed a meta-analysis across those two trials for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG). LDL-C was significantly lower in the ezetimibe arm (net change: -23.56 mg/dL, 95% CI: -40.22, -6.90 mg/dL). We then performed meta-analysis of the single-arm trials examining lipid outcomes after ezetimibe treatment which, like in the RCTs, revealed significant reductions of LDL-C (-23.89 mg/dL, 95% CI -29.94 to -17.83 mg/dL). In addition, significant reductions were seen for total cholesterol (TC) (-26.17 mg/dL, 95% CI -32.81 to -19.54 mg/dL) and TG (-18.57 mg/dL, 95% CI -34.01 to -3.14 mg/dL) but HDL-C did not show a change. CONCLUSIONS: Evidence for LDL-C reduction is limited in RCTs; single-arm trial LDL-C reductions are consistent with the RCTs. In addition, significant reductions in TC and TG were also seen in the meta-analysis of the single arm trials. The single-arm trials' meta-analysis corroborates evidence from RCTs to suggest that ezetimibe can be an option for hyperlipidaemia among HIV patients with mildly elevated TC and LDL-C levels, especially in cases where statins are contra-indicated due to drug-drug interactions with concomitant anti-retroviral therapy.

Walnut intake, cognitive outcomes and risk factors: a systematic review and meta-analysis.

BACKGROUND: Walnuts contain nutrients that are associated with improved cognitive health. To our knowledge, no review has systematically examined the effects of walnuts on cognitive function and risk for cognitive decline. OBJECTIVE: To conduct a systematic review and meta-analysis evaluating the effects of walnut intake on cognition-related outcomes and risk-factors for cognitive decline in adults. METHODS: Medline®, Commonwealth Agricultural Bureau, and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) and observational studies published until April 2020 on walnut intake, cognition (e.g. cognitive function, stroke, and mood), and selected risk factors for cognitive decline (e.g. glucose homeostasis and inflammation). Risk-of-bias and strength-of-evidence assessments were conducted using standard validated tools. Random-effects meta-analyses were conducted when ≥3 studies reported quantitative data for each outcome. RESULTS: 32 RCT and 7 observational study publications were included. Meta-analysis of cognition-related outcomes could not be conducted due to heterogeneity of tests. None of the 5 cognition RCTs found significant effects of walnuts on overall cognition, although 3 studies found improvements on subdomains and/or subgroups. All 7 observational studies found significant associations and a dose-response relationship between walnut intake and cognition-related outcomes. Meta-analyses of 27 RCTs reporting glucose homeostasis and inflammation outcomes, selected risk factors for cognitive decline, did not show significant effects of walnut intake. CONCLUSIONS: Due to the non-uniformity of tests for cognition-related outcomes, definitive conclusions regarding the effect of walnut consumption on cognition could not be reached. Additionally, evidence does not show associations between walnut intake and glucose homeostasis or inflammation, cognitive decline risk-factors. High-quality studies with standardized measures are needed to clarify the role of walnuts in cognitive health.KEY MESSAGESThis is a systematic review and meta-analysis of 5 randomized clinical trials and 7 observational study articles of the impact of walnut intake on cognition decline and 27 randomized clinical trials of the effect of walnut intake on risk factors for cognitive decline including glucose homeostasis and inflammation.The non-uniformity of tests performed to measure cognitive function in the various studies did not allow for a meta-analysis of these studies. A definitive conclusion could therefore not be reached regarding the effect of walnut intake on cognitive decline.The evidence available does not show an association between walnut intake and glucose homeostasis or inflammation.

Effects of Intake of Apples, Pears, or Their Products on Cardiometabolic Risk Factors and Clinical Outcomes: A Systematic Review and Meta-Analysis.

Apples and pears contain nutrients that have been linked to cardiovascular health. We conducted a systematic review and meta-analysis to summarize related research. Medline, Cochrane Central, and Commonwealth Agricultural Bureau databases were searched for publications on apple or pear intake and cardiovascular disease (CVD)/ cardiometabolic disease (CMD). Studies in adults (healthy or at risk for CVD) that quantified apple or pear intake were included. Random-effects models meta-analysis was used when ≥3 studies reported the same outcome. In total, 22 studies were eligible including 7 randomized controlled trial, 1 nonrandomized trial, and 14 prospective observational studies. In RCTs, apple intake significantly decreased BMI, but made no difference in body weight, serum lipids, blood glucose, or blood pressure. In observational studies, apple or pear intake significantly decreased risk of cerebrovascular disease, cardiovascular death, type 2 diabetes mellitus, and all-cause mortality. No association was reported for cerebral infarction or intracerebral hemorrhage. In conclusion, apple or pear intake significantly decreased BMI and risk for CVD outcomes.

Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families.

Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1-p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals.

Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy.

BACKGROUND: Canakinumab is a human anti-interleukin-1ß (IL-1ß) monoclonal antibody neutralizing IL-1ß-mediated pathways. We sought to characterize the molecular response to canakinumab and evaluate potential markers of response using samples from two pivotal trials in systemic juvenile idiopathic arthritis (SJIA). METHODS: Gene expression was measured in patients with febrile SJIA and in matched healthy controls by Affymetrix DNA microarrays. Transcriptional response was assessed by gene expression changes from baseline to day 3 using adapted JIA American College of Rheumatology (aACR) response criteria (50 aACR JIA). Changes in pro-inflammatory cytokines IL-6 and IL-18 were assessed up to day 197. RESULTS: Microarray analysis identified 984 probe sets differentially expressed (≥2-fold difference; P < 0.05) in patients versus controls. Over 50% of patients with ≥50 aACR JIA were recognizable by baseline expression values. Analysis of gene expression profiles from patients achieving ≥50 aACR JIA response at day 15 identified 102 probe sets differentially expressed upon treatment (≥2-fold difference; P < 0.05) on day 3 versus baseline, including IL-1ß, IL-1 receptors (IL1-R1 and IL1-R2), IL-1 receptor accessory protein (IL1-RAP), and IL-6. The strongest clinical response was observed in patients with higher baseline expression of dysregulated genes and a strong transcriptional response on day 3. IL-6 declined by day 3 (≥8-fold decline; P < 0.0001) and remained suppressed. IL-18 declined on day 57 (≥1.5-fold decline, P ≤ 0.002). CONCLUSIONS: Treatment with canakinumab in SJIA patients resulted in downregulation of innate immune response genes and reductions in IL-6 and clinical symptoms. Additional research is needed to investigate potential differences in the disease mechanisms in patients with heterogeneous gene transcription profiles. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.

Canakinumab reverses overexpression of inflammatory response genes in tumour necrosis factor receptor-associated periodic syndrome.

OBJECTIVE: To explore whether gene expression profiling can identify a molecular mechanism for the clinical benefit of canakinumab treatment in patents with tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Blood samples were collected from 20 patients with active TRAPS who received canakinumab 150 mg every 4 weeks for 4 months in an open-label proof-of-concept phase II study, and from 20 aged-matched healthy volunteers. Gene expression levels were evaluated in whole blood samples by microarray analysis for arrays passing quality control checks. RESULTS: Patients with TRAPS exhibited a gene expression signature in blood that differed from that in healthy volunteers. Upon treatment with canakinumab, many genes relevant to disease pathogenesis moved towards levels seen in the healthy volunteers. Canakinumab downregulated the TRAPS-causing gene (TNF super family receptor 1A (TNFRSF1A)), the drug-target gene (interleukin (IL)-1B) and other inflammation-related genes (eg, MAPK14). In addition, several inflammation-related pathways were evident among the differentially expressed genes. Canakinumab treatment reduced neutrophil counts, but the observed expression differences remained after correction for this. CONCLUSIONS: These gene expression data support a model in which canakinumab produces clinical benefit in TRAPS by increasing neutrophil apoptosis and reducing pro-inflammatory signals resulting from the inhibition of IL-1ß. Notably, treatment normalised the overexpression of TNFRSF1A, suggesting that canakinumab has a direct impact on the main pathogenic mechanism in TRAPS. TRIAL REGISTRATION NUMBER: NCT01242813.

Gene-expression analysis of adult-onset Still's disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity.

BACKGROUND: Adult-onset Still's disease (AOSD), a rare autoinflammatory disorder, resembles systemic juvenile idiopathic arthritis (SJIA). The superimposable systemic clinical features of AOSD and SJIA suggest both clinical phenotypes represent the same disease continuum with different ages of onset. To further characterize the similarity between AOSD and SJIA at the molecular level, 2 previously identified response gene sets in SJIA were used to investigate how genes that respond to interleukin (IL)-1ß inhibition with canakinumab in SJIA patients behave in AOSD patients with active disease prior to IL-1ß targeting therapy, relative to healthy subjects. FINDINGS: All genes downregulated in SJIA patients following canakinumab treatment were upregulated in most patients with active AOSD prior to canakinumab treatment, relative to healthy subjects. A few patients with milder AOSD had expectedly gene-expression patterns that resembled those in healthy subjects. Comparison of the gene-expression patterns with neutrophil counts showed a correlation between elevated neutrophil numbers and upregulation of canakinumab-responsive genes. Correspondingly, most genes upregulated following canakinumab treatment in patients with SJIA patients were downregulated in the majority of AOSD patients. CONCLUSIONS: These results further support the concept of a Still's disease continuum that includes both a pediatric/juvenile onset (SJIA) and adult onset (AOSD) form.

Biomarkers in systemic juvenile idiopathic arthritis: a comparison with biomarkers in cryopyrin-associated periodic syndromes.

PURPOSE OF REVIEW: This review summarizes biomarkers in systemic juvenile idiopathic arthritis (sJIA). Broadly, the markers are classified under protein, cellular, gene expression and genetic markers. We also compare the biomarkers in sJIA to biomarkers in cryopyrin-associated periodic syndrome (CAPS). RECENT FINDINGS: Recent publications showing the similarity of clinical response of sJIA and CAPS to anti-interleukin 1 therapies prompted a comparison at the biomarker level. SUMMARY: sJIA traditionally is classified under the umbrella of juvenile idiopathic arthritis. At the clinical phenotypic level, sJIA has several features that are more similar to those seen in CAPS. In this review, we summarize biomarkers in sJIA and CAPS and draw upon the various similarities and differences between the two families of diseases. The main differences between sJIA and CAPS biomarkers are genetic markers, with CAPS being a family of monogenic diseases with mutations in NLRP3. There have been a small number of publications describing cellular biomarkers in sJIA with no such studies described for CAPS. Many of the protein marker's characteristics of sJIA are also seen to characterize CAPS. The gene expression data in both sJIA and CAPS show a strong upregulation of innate immunity pathways. In addition, we describe a strong similarity between sJIA and CAPS at the gene expression level in which several genes that form a part of the erythropoiesis signature are upregulated in both sJIA and CAPS.

Gene expression profiling of immunomagnetically separated cells directly from stabilized whole blood for multicenter clinical trials.

BACKGROUND: Clinically useful biomarkers for patient stratification and monitoring of disease progression and drug response are in big demand in drug development and for addressing potential safety concerns. Many diseases influence the frequency and phenotype of cells found in the peripheral blood and the transcriptome of blood cells. Changes in cell type composition influence whole blood gene expression analysis results and thus the discovery of true transcript level changes remains a challenge. We propose a robust and reproducible procedure, which includes whole transcriptome gene expression profiling of major subsets of immune cell cells directly sorted from whole blood. METHODS: Target cells were enriched using magnetic microbeads and an autoMACS® Pro Separator (Miltenyi Biotec). Flow cytometric analysis for purity was performed before and after magnetic cell sorting. Total RNA was hybridized on HGU133 Plus 2.0 expression microarrays (Affymetrix, USA). CEL files signal intensity values were condensed using RMA and a custom CDF file (EntrezGene-based). RESULTS: Positive selection by use of MACS® Technology coupled to transcriptomics was assessed for eight different peripheral blood cell types, CD14+ monocytes, CD3+, CD4+, or CD8+ T cells, CD15+ granulocytes, CD19+ B cells, CD56+ NK cells, and CD45+ pan leukocytes. RNA quality from enriched cells was above a RIN of eight. GeneChip analysis confirmed cell type specific transcriptome profiles. Storing whole blood collected in an EDTA Vacutainer® tube at 4°C followed by MACS does not activate sorted cells. Gene expression analysis supports cell enrichment measurements by MACS. CONCLUSIONS: The proposed workflow generates reproducible cell-type specific transcriptome data which can be translated to clinical settings and used to identify clinically relevant gene expression biomarkers from whole blood samples. This procedure enables the integration of transcriptomics of relevant immune cell subsets sorted directly from whole blood in clinical trial protocols.

RAMP: a bioinformatics framework for researching imaging agents through molecular pathways.

Signaling pathways are the fundamental grammar of cellular communication, yet few frameworks are available to analyze molecular imaging probes in the context of signaling pathways. Such a framework would aid in the design and selection of imaging probes for measuring specific signaling pathways and, vice versa, help illuminate which pathways are being assayed by a given probe. RAMP (Researching imaging Agents through Molecular Pathways) is a bioinformatics framework for connecting signaling pathways and imaging probes using a controlled vocabulary of the imaging targets. RAMP contains signaling pathway data from MetaCore, the Kyoto Encyclopedia of Genes and Genomes, and the Gene Ontology project; imaging probe data from the Molecular Imaging and Contrast Agent Database (MICAD); and tissue protein expression data from The Human Protein Atlas. The RAMP search tool is available at . Examples are presented to demonstrate the utility of RAMP for pathway-based searches of molecular imaging probes.

Uncovering mechanisms of transcriptional regulations by systematic mining of cis regulatory elements with gene expression profiles.

BACKGROUND: Contrary to the traditional biology approach, where the expression patterns of a handful of genes are studied at a time, microarray experiments enable biologists to study the expression patterns of many genes simultaneously from gene expression profile data and decipher the underlying hidden biological mechanism from the observed gene expression changes. While the statistical significance of the gene expression data can be deduced by various methods, the biological interpretation of the data presents a challenge. RESULTS: A method, called CisTransMine, is proposed to help infer the underlying biological mechanisms for the observed gene expression changes in microarray experiments. Specifically, this method will predict potential cis-regulatory elements in promoter regions which could regulate gene expression changes. This approach builds on the MotifADE method published in 2004 and extends it with two modifications: up-regulated genes and down-regulated genes are tested separately and in addition, tests have been implemented to identify combinations of transcription factors that work synergistically. The method has been applied to a genome wide expression dataset intended to study myogenesis in a mouse C2C12 cell differentiation model. The results shown here both confirm the prior biological knowledge and facilitate the discovery of new biological insights. CONCLUSION: The results validate that the CisTransMine approach is a robust method to uncover the hidden transcriptional regulatory mechanisms that can facilitate the discovery of mechanisms of transcriptional regulation.

Dynamic resolution of functionally related gene sets in response to acute heat stress.

BACKGROUND: Using a gene clustering strategy we determined intracellular pathway relationships within skeletal myotubes in response to an acute heat stress stimuli. Following heat shock, the transcriptome was analyzed by microarray in a temporal fashion to characterize the dynamic relationship of signaling pathways. RESULTS: Bioinformatics analyses exposed coordination of functionally-related gene sets, depicting mechanism-based responses to heat shock. Protein turnover-related pathways were significantly affected including protein folding, pre-mRNA processing, mRNA splicing, proteolysis and proteasome-related pathways. Many responses were transient, tending to normalize within 24 hours. CONCLUSION: In summary, we show that the transcriptional response to acute cell stress is largely transient and proteosome-centric.