Publications by authors named "Nicola Santoro"

164 Publications

Early impairment of insulin sensitivity, β-cell responsiveness, and insulin clearance in youth with Stage 1 type 1 diabetes.

J Clin Endocrinol Metab 2021 May 17. Epub 2021 May 17.

Department of Woman and Child's Health, University of Padova, Padova, Italy.

Background: Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a pre-symptomatic phase characterized by multiple islet autoantibodies with normal glucose tolerance (Stage 1 T1D). The metabolic phenotypes of beta-cell function and insulin sensitivity and clearance were explored in normoglycemic youth with Stage 1 T1D and compared to healthy non-related peers during a 3-h oral glucose tolerance test (OGTT).

Methods: Twenty-eight lean youth, 14 with ≥2 islet autoantibodies (cases) and 14 healthy controls underwent a 3-h 9-point OGTT with measurement of glucose, C-peptide and insulin. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI= φtotal x SI). Fasting insulin clearance (CL0) was calculated as the ratio between the fasting insulin secretion rate (ISR) and plasma insulin levels (ISR0/I0), while post-load clearance (CL180) was estimated by the ratio of AUC of ISR over the plasma insulin AUC for the 3-h OGTT (ISRAUC/IAUC). Subjects with impaired fasting glucose, impaired glucose tolerance or any OGTT glucose concentration ≥200mg/dL were excluded.

Results: Cases (10.5y [8, 15]) exhibited reduced DI (p<0.001) due to a simultaneous reduction in both φtotal (p<0.001) and SI (p=0.008) compared to controls (11.5y [10.4, 14.9]). CL0 and CL180 were lower in cases than controls (p=0.005 and p=0.019).

Conclusion: Pre-symptomatic Stage 1 T1D in youth is associated with reduced insulin sensitivity and lower β-cell responsiveness, and the presence of blunted insulin clearance.
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http://dx.doi.org/10.1210/clinem/dgab344DOI Listing
May 2021

A Unique Case of Bilateral Thalamic High-Grade Glioma in a Pediatric Patient with LI-Fraumeni Syndrome: Case Presentation and Review of the Literature.

Neurol Int 2021 Apr 22;13(2):175-183. Epub 2021 Apr 22.

Department of Emergency and Organ Transplantation-Section of Pathology, University "Aldo Moro" of Bari, 70124 Bari, Italy.

Li-Fraumeni syndrome (LFS) is a rare high-penetrance and autosomal-dominant pathological condition caused by the germline mutation of the TP53 gene, predisposing to the development of tumors from pediatric age. We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) framework. A search was made in MEDLINE/Pubmed and MeSH Database using the terms "Li-Fraumeni" AND "pediatric high-grade glioma (HGG)", identifying six cases of HGGs in pediatric patients with LFS. We added a further case with peculiar features such as no familiar history of LFS, association of embryonal rhabdomyosarcoma and bithalamic HGG, whose immunohistochemical profile was accurately defined by Next Generation Sequencing. Knowledge synthesis and case analysis grounded the discussion about challenges in the management of this pathology in pediatric age.
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http://dx.doi.org/10.3390/neurolint13020017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167566PMC
April 2021

CD56, HLA-DR, and CD45 recognize a subtype of childhood AML harboring CBFA2T3-GLIS2 fusion transcript.

Cytometry A 2021 Apr 2. Epub 2021 Apr 2.

Pediatric Hemato Oncology, Maternal and Child Health Department, University of Padua, Padua, Italy.

The presence of CBFA2T3-GLIS2 fusion gene has been identified in childhood Acute Myeloid Leukemia (AML). In view of the genomic studies indicating a distinct gene expression profile, we evaluated the role of immunophenotyping in characterizing a rare subtype of AML-CBFA2T3-GLIS2 rearranged. Immunophenotypic data were obtained by studying a cohort of 20 pediatric CBFA2T3-GLIS2-AML and 77 AML patients not carrying the fusion transcript. Enrolled cases were included in the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) AML trials and immunophenotypes were compared using different statistical approaches. By multiple computational procedures, we identified two main core antigens responsible for the identification of the CBFA2T3-GLIS2-AML. CD56 showed the highest performance in single marker evaluation (AUC = 0.89) and granted the most accurate prediction when used in combination with HLA-DR (AUC = 0.97) displaying a 93% sensitivity and 99% specificity. We also observed a weak-to-negative CD45 expression, being exceptional in AML. We here provide evidence that the combination of HLA-DR negativity and intense bright CD56 expression detects a rare and aggressive pediatric AML genetic lesion improving the diagnosis performance.
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http://dx.doi.org/10.1002/cyto.a.24339DOI Listing
April 2021

Glutamate-Serine-Glycine Index: A Novel Potential Biomarker in Pediatric Non-Alcoholic Fatty Liver Disease.

Children (Basel) 2020 Dec 4;7(12). Epub 2020 Dec 4.

Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, 56126 Pisa, Italy.

Preliminary evidence suggests that the glutamate-serine-glycine (GSG) index, which combines three amino acids involved in glutathione synthesis, may be used as a potential biomarker of non-alcoholic fatty liver disease (NAFLD). We investigated whether the GSG index is associated with NAFLD in youth, independent of other risk factors. Intrahepatic fat content (HFF%) and abdominal fat distribution were measured by magnetic resonance imaging (MRI) in a multiethnic cohort of obese adolescents, including Caucasians, African Americans, and Hispanics. NAFLD was defined as HFF% ≥ 5.5%. Plasma amino acids were measured by mass spectrometry. The GSG index was calculated as glutamate/(serine + glycine). The GSG index was higher in NAFLD patients ( = 0.03) and positively correlated with HFF% (r = 0.26, = 0.02), alanine aminotransferase (r = 0.39, = 0.0006), and aspartate aminotransferase (r = 0.26, = 0.03). Adolescents with a high GSG index had a twofold higher prevalence of NAFLD than those with a low GSG index, despite similar adiposity, abdominal fat distribution, and liver insulin resistance. NAFLD prevalence remained significantly different between groups after adjustment for age, sex, race/ethnicity, and body mass index (OR 3.07, 95% confidence interval 1.09-8.61, = 0.03). This study demonstrates the ability of the GSG index to detect NAFLD in at-risk pediatric populations with different genetically determined susceptibilities to intrahepatic fat accumulation, independent of traditional risk factors.
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http://dx.doi.org/10.3390/children7120270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761842PMC
December 2020

Ocular oncology service during the COVID-19 outbreak in Florence (Italy): Practical considerations for the management of patients.

Eur J Ophthalmol 2021 Mar 25;31(2):NP4-NP7. Epub 2020 Nov 25.

Ocular Oncology Unit, Neuromuscular and Sense Organs Department, Careggi University Hospital, Florence, Italy.

The Coronavirus disease 2019 (COVID-19) outbreak has imposed the adoption of strategies to limit the risk of contagion for cancer patients without compromising their healthcare. As well as cancers of other sites, the treatment of certain ocular and periocular malignancies is considered non-deferrable and should proceed despite the pandemic. Delays in treatment of these patients may result in negative outcomes. Herein, we provide some practical considerations deriving from our experience at the Ocular Oncology Unit of Careggi University Hospital (Florence, Italy).
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http://dx.doi.org/10.1177/1120672120976031DOI Listing
March 2021

Ettore's song: The hero who had the courage to fight Achilles.

J Health Psychol 2021 01 26;26(1):5-11. Epub 2020 Oct 26.

University Hospital of Bari, Italy.

End-of-life accompaniment requires even greater care of the patient and their family by the multi-disciplinary team, which requires a clear, wellorganized interdisciplinary and interprofessional approach. Musictherapy (MT) is often use as a complementary approach to improve a person's quality of life by helping to relieve symptoms, addressing psychological needs, offering support and comfort, facilitating communication, and meeting spiritual needs.Through songwriting, Ettore, a teenager was able to make choices and act on his own will. Songwriting represented a channel for effective and powerful communication and expression. The song became the means by which the relationship with the team was maintained and deepened; it became something tangible, a product with its own consistency, a further bond that unites Ettore to his family to this day.
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http://dx.doi.org/10.1177/1359105320968144DOI Listing
January 2021

Eyelid skin metastasis as first sign of breast cancer recurrence.

Breast J 2020 12 9;26(12):2416-2417. Epub 2020 Oct 9.

Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.

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http://dx.doi.org/10.1111/tbj.14077DOI Listing
December 2020

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

J Hepatol 2021 Jan 31;74(1):20-30. Epub 2020 Aug 31.

MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.

Background & Aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis.

Methods: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models.

Results: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], p = 4.8×10) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], p = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (p = 0.002) and lower serum triglycerides (p = 1.5×10). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.

Conclusions: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.

Lay Summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.
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http://dx.doi.org/10.1016/j.jhep.2020.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755037PMC
January 2021

Vaccination coverage among paediatric onco-haematological patients: an Italian cross-sectional study.

Hum Vaccin Immunother 2021 Mar 26;17(3):818-823. Epub 2020 Aug 26.

Department of Biomedical Science and Human Oncology, Aldo Moro University of Bari, Bari, Italy.

Children with onco-hematological diseases are at increased risk of infection. However, this risk can in part be controlled or reduced using currently available vaccines. Despite available evidence, in patients diagnosed with a hematological or oncological disease the vaccination schedule is often inappropriately discontinued. In this study we evaluated whether the diagnosis of an oncological or hematological disease is a determinant of noncompliance with recommended vaccinations.The study was carried out between March and April 2019. The population was composed of a convenience sample of 228 children cared for in the Pediatric Oncology Department and Pediatric Hematology Department of the Policlinico Giovanni XXIII Pediatric Hospital (Bari, Italy) from 2005 to 2015. Information on the immunization status of the patients was obtained from the Apulia regional immunization database (GIAVA). A post-diagnosis adherence score was calculated.The vaccination coverage was 87.7% for the DTaP-IPV-Hep B-Hib vaccine (3 doses), 68.7% for the pneumococcal vaccine (3 doses), 75.8% for the MMR vaccine (2 doses) and 75.1% for the varicella vaccine (2 doses). The average age at vaccination was older than that recommended by the National Vaccination Plan. A diagnosis of oncological disease and an older age at enrollment were risk factors for missing vaccinations. These results showed that the overall vaccination status of pediatric onco-hematological patients is suboptimal. Improving provider communication and establishing the hospital as the primary environment for vaccine administration may lead to better vaccination compliance in this group.
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http://dx.doi.org/10.1080/21645515.2020.1797367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993150PMC
March 2021

A Reduced Incretin Effect Mediated by the rs7903146 Variant in the Gene Is an Early Marker of β-Cell Dysfunction in Obese Youth.

Diabetes Care 2020 10 11;43(10):2553-2563. Epub 2020 Aug 11.

Pediatrics Endocrinology and Diabetes Section, Department of Pediatrics, Yale School of Medicine, New Haven, CT

Objective: The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 () gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, β-cell function relative to insulin sensitivity, the gastrointestinal-induced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance.

Research Design And Methods: Thirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33, 43] kg/m) were genotyped for the rs7903146 variant of and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SR - AUC-SR) / AUC-SR, where AUC-SR = area under the curve of C-peptide secretion rate. Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype.

Results: The presence of T risk allele for was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [-7.2, 14] vs. 37.8% [12.5, 52.4], < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose ( = 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group ( = 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp.

Conclusions: A reduced incretin effect and its association with the variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.
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http://dx.doi.org/10.2337/dc20-0445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510033PMC
October 2020

Hepatic fat is a stronger correlate of key clinical and molecular abnormalities than visceral and abdominal subcutaneous fat in youth.

BMJ Open Diabetes Res Care 2020 07;8(1)

Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.

Introduction: Body fat distribution is strongly associated with cardiometabolic disease (CMD), but the relative importance of hepatic fat as an underlying driver remains unclear. Here, we applied a systems biology approach to compare the clinical and molecular subnetworks that correlate with hepatic fat, visceral fat, and abdominal subcutaneous fat distribution.

Research Design And Methods: This was a cross-sectional sub-study of 283 children/adolescents (7-19 years) from the Yale Pediatric NAFLD Cohort. Untargeted, high-resolution metabolomics (HRM) was performed on plasma and combined with existing clinical variables including hepatic and abdominal fat measured by MRI. Integrative network analysis was coupled with pathway enrichment analysis and multivariable linear regression (MLR) to examine which metabolites and clinical variables associated with each fat depot.

Results: The data divided into four communities of correlated variables (|r|>0.15, p<0.05) after integrative network analysis. In the largest community, hepatic fat was associated with eight clinical biomarkers, including measures of insulin resistance and dyslipidemia, and 878 metabolite features that were enriched predominantly in amino acid (AA) and lipid pathways in pathway enrichment analysis (p<0.05). Key metabolites associated with hepatic fat included branched-chain AAs (valine and isoleucine/leucine), aromatic AAs (tyrosine and tryptophan), serine, glycine, alanine, and pyruvate, as well as several acylcarnitines and glycerophospholipids (all q<0.05 in MLR adjusted for covariates). The other communities detected in integrative network analysis consisted of abdominal visceral, superficial subcutaneous, and deep subcutaneous fats, but no clinical variables, fewer metabolite features (280, 312, and 74, respectively), and limited findings in pathway analysis.

Conclusions: These data-driven findings show a stronger association of hepatic fat with key CMD risk factors compared with abdominal fats. The molecular network identified using HRM that associated with hepatic fat provides insight into potential mechanisms underlying the hepatic fat-insulin resistance interface in youth.
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http://dx.doi.org/10.1136/bmjdrc-2019-001126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380953PMC
July 2020

Childhood obesity and the associated rise in cardiometabolic complications.

Nat Metab 2020 03 16;2(3):223-232. Epub 2020 Mar 16.

Department of Pediatrics, Ruth Rappaport Children's Hospital, Rambam Medical Center, Technion School of Medicine, Haifa, Israel.

Childhood obesity is one of the most serious global public-health challenges of the twenty-first century. Over the past four decades, the number of children and adolescents with obesity has risen more than tenfold. Worldwide, an increasing number of youth are facing greater exposure to obesity throughout their lives, and this increase will contribute to the early development of type 2 diabetes, fatty liver and cardiovascular complications. Herein, we provide a brief overview of trends in the global shifts in, and environmental and genetic determinants of, childhood obesity. We then discuss recent progress in the elucidation of the central role of insulin resistance, the key element linking obesity and cardiovascular-risk-factor clustering, and the potential mechanisms through which ectopic lipid accumulation leads to insulin resistance and its associated cardiometabolic complications in obese adolescents. In the absence of effective prevention and intervention programs, childhood obesity will have severe public-health consequences for decades to come.
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http://dx.doi.org/10.1038/s42255-020-0183-zDOI Listing
March 2020

A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth.

J Nutr 2020 09;150(9):2314-2321

Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.

Background: Recent literature suggests that the Western diet's imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth.

Objectives: We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response.

Methods: In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used.

Results: Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time.

Conclusions: These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.
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http://dx.doi.org/10.1093/jn/nxaa183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467848PMC
September 2020

Effect of Gut Microbiota and PNPLA3 rs738409 Variant on Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Youth.

J Clin Endocrinol Metab 2020 10;105(10)

Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.

Context: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, affecting approximately 3 in 10 obese children worldwide.

Objective: We aimed to investigate the potential relationship between gut microbiota and NAFLD in obese youth, while considering the role of PNPLA3 rs738409, a strong genetic contributor to NAFLD.

Design: In this cross-sectional study, participants completed an abdominal magnetic resonance imaging to measure hepatic fat fraction (HFF), oral glucose tolerance test, and PNPLA3 rs738409 genotyping. Fecal samples were collected to analyze the V4 region of the 16S rRNA gene for intestinal bacteria characterization.

Setting: Yale Pediatric Obesity Clinic.

Participants: Obese youth (body mass index >95th percentile) with NAFLD (HFF ≥5.5%; n = 44) and without NAFLD (HFF <5.5%; n = 29).

Main Outcome Measure: Shannon-Wiener diversity index values and proportional bacterial abundance by NAFLD status and PNPLA3 genotype.

Results: Subjects with NAFLD had decreased bacterial alpha-diversity compared with those without NAFLD (P = 0.013). Subjects with NAFLD showed a higher Firmicutes to Bacteroidetes (F/B) ratio (P = 0.019) and lower abundance of Bacteroidetes (P = 0.010), Prevotella (P = 0.019), Gemmiger (P = 0.003), and Oscillospira (P = 0.036). F/B ratio, Bacteroidetes, Gemmiger, and Oscillospira were associated with HFF when controlling for group variations. We also observed an additive effect on HFF by PNPLA3 rs738409 and Gemmiger, and PNPLA3 rs738409 and Oscillospira.

Conclusions: Obese youth with NAFLD have a different gut microbiota composition than those without NAFLD. These differences were still statistically significant when controlling for factors associated with NAFLD, including PNPLA3 rs738409.
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http://dx.doi.org/10.1210/clinem/dgaa382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458486PMC
October 2020

Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: A cross-sectional and longitudinal study from the Yale Pediatric NAFLD cohort.

Diabetes Obes Metab 2020 09 31;22(9):1628-1638. Epub 2020 May 31.

Department of Pediatrics, Pediatrics Endocrinology and Diabetes Section, Yale School of Medicine, New Haven, Connecticut, USA.

Aim: To evaluate whether intrahepatic fat accumulation contributes to impaired insulin clearance and hepatic insulin resistance across different ethnic groups.

Methods: The intrahepatic fat content (HFF%) was quantified by magnetic resonance imaging in a multi-ethnic cohort of 632 obese youths aged 7-18 years at baseline and after a 2-year follow-up. Insulin secretion rate (ISR), endogenous insulin clearance (EIC) and hepatic insulin resistance index (HIRI) were estimated by modelling glucose, insulin and C-peptide data during 3-hour, 9-point oral glucose tolerance tests.

Results: African American youths exhibited the lowest HFF% and a prevalence of non-alcoholic fatty liver disease (NAFLD) less than half of that shown by Caucasians and Hispanics. Furthermore, African Americans had lower EIC and glucose-stimulated ISR, despite similar HIRI and plasma insulin levels, compared with Caucasians and Hispanics. EIC and HIRI were markedly reduced in individuals with NAFLD and declined across group-specific HFF% tertiles in all ethnic groups. Consistently, the HFF% correlated with EIC and HIRI, irrespective of the ethnic background, after adjustment for age, sex, ethnicity, adiposity, waist-hip ratio, pubertal status and plasma glucose levels. An increased HFF% at follow-up was associated with decreased EIC and increased HIRI across all groups.

Conclusions: Intrahepatic lipid accumulation is associated with reduced insulin clearance and hepatic insulin sensitivity in obese youths, irrespective of their ethnic background.
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http://dx.doi.org/10.1111/dom.14076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174801PMC
September 2020

Cardiometabolic risk factor clustering in patients with deficient branched-chain amino acid catabolism: A case-control study.

J Inherit Metab Dis 2020 09 6;43(5):981-993. Epub 2020 Apr 6.

Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Classical organic acidemias (OAs) result from defective mitochondrial catabolism of branched-chain amino acids (BCAAs). Abnormal mitochondrial function relates to oxidative stress, ectopic lipids and insulin resistance (IR). We investigated whether genetically impaired function of mitochondrial BCAA catabolism associates with cardiometabolic risk factors, altered liver and muscle energy metabolism, and IR. In this case-control study, 31 children and young adults with propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA) were compared with 30 healthy young humans using comprehensive metabolic phenotyping including in vivo P/ H magnetic resonance spectroscopy of liver and skeletal muscle. Among all OAs, patients with PA exhibited abdominal adiposity, IR, fasting hyperglycaemia and hypertriglyceridemia as well as increased liver fat accumulation, despite dietary energy intake within recommendations for age and sex. In contrast, patients with MMA more frequently featured higher energy intake than recommended and had a different phenotype including hepatomegaly and mildly lower skeletal muscle ATP content. In skeletal muscle of patients with PA, slightly lower inorganic phosphate levels were found. However, hepatic ATP and inorganic phosphate concentrations were not different between all OA patients and controls. In patients with IVA, no abnormalities were detected. Impaired BCAA catabolism in PA, but not in MMA or IVA, was associated with a previously unrecognised, metabolic syndrome-like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage. These findings suggest the need for early cardiometabolic risk factor screening in PA.
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http://dx.doi.org/10.1002/jimd.12231DOI Listing
September 2020

Designing a Streaming Algorithm for Outlier Detection in Data Mining-An Incrementa Approach.

Sensors (Basel) 2020 Feb 26;20(5). Epub 2020 Feb 26.

School of Computer Science, Carleton University, Ottawa, ON K1S 5B6, Canada.

To design an algorithm for detecting outliers over streaming data has become an important task in many common applications, arising in areas such as fraud detections, network analysis, environment monitoring and so forth. Due to the fact that real-time data may arrive in the form of streams rather than batches, properties such as concept drift, temporal context, transiency, and uncertainty need to be considered. In addition, data processing needs to be incremental with limited memory resource, and scalable. These facts create big challenges for existing outlier detection algorithms in terms of their accuracies when they are implemented in an incremental fashion, especially in the streaming environment. To address these problems, we first propose C_KDE_WR, which uses and to process the streaming data online, and reports its results demonstrating high throughput on handling real-time streaming data, implemented in a CUDA framework on Graphics Processing Unit (GPU). We also present another algorithm, C_LOF, based on a very popular and effective outlier detection algorithm called Local Outlier Factor (LOF) which unfortunately works only on batched data. Using a novel incremental approach that compensates the drawback of high complexity in LOF, we show how to implement it in a streaming context and to obtain results in a timely manner. Like C_KDE_WR, C_LOF also employs sliding-window and to help making decision based on the data in the current window. It also addresses all those challenges of streaming data as addressed in C_KDE_WR. In addition, we report the comparative evaluation on the accuracy of C_KDE_WR with the state-of-the-art SOD_GPU using Precision, Recall and F-score metrics. Furthermore, a t-test is also performed to demonstrate the significance of the improvement. We further report the testing results of C_LOF on different parameter settings and drew ROC and PR curve with their area under the curve (AUC) and Average Precision (AP) values calculated respectively. Experimental results show that C_LOF can overcome the problem, which often exists in outlier detection on streaming data. We provide complexity analysis and report experiment results on the accuracy of both C_KDE_WR and C_LOF algorithms in order to evaluate their effectiveness as well as their efficiencies.
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http://dx.doi.org/10.3390/s20051261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085525PMC
February 2020

Metabolic and Genetic Determinants of Glucose Shape After Oral Challenge in Obese Youths: A Longitudinal Study.

J Clin Endocrinol Metab 2020 02;105(2)

Department of Pediatrics, Pediatrics Endocrinology and Diabetes Section, Yale School of Medicine, New Haven, Connecticut.

Context: The time-to-glucose-peak following the oral glucose tolerance test (OGTT) is a highly reproducible marker for diabetes risk. In obese youths, we lack evidence for the mechanisms underlying the effects of the TCF7L2 rs7903146 variant on glucose peak.

Methods: We analyzed the metabolic phenotype and the genotype for the TCF7L2 rs7903146 in 630 obese youths with normal (NGT) and impaired (IGT) glucose tolerance. Participants underwent a 3-hour, 9-point OGTT to estimate, using the oral minimal model, the disposition index (DI), the static (φstatic) and dynamic (φdynamic) components β-cell responsiveness and insulin sensitivity (SI). In a subgroup (n = 241) longitudinally followed for 2 years, we estimated the effect of time-to-glucose-peak on glucose tolerance change.

Results: Participants were grouped into early (<30 minutes) and late (≥30 minutes) glucose peakers. A delayed glucose peak was featured by a decline in φstatic (P < .001) in the absence of a difference in φdynamic. The prevalence of T-risk allele for TCF7L2 rs7903146 variant significantly increased in the late peak group. A lower DI was correlated with higher glucose concentration at 1 and 2 hours, whereas SI was inversely associated with 1-hour glucose. Glucose peak <30 minutes was protective toward worsening of glucose tolerance overtime (odds ratio 0.35 [0.15-0.82]; P = .015), with no subjects progressing to NGT or persisting IGT, in contrast to the 40% of progressor in those with late glucose peak.

Conclusion: The prevalence of T-risk allele for the TCF7L2 rs7903146 prevailed in the late time-to-glucose peak group, which in turn is associated with impaired β-cell responsiveness to glucose (φ), thereby predisposing to prediabetes and diabetes in obese youths.
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http://dx.doi.org/10.1210/clinem/dgz207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977541PMC
February 2020

Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics.

Hepatol Commun 2019 Oct 13;3(10):1311-1321. Epub 2019 Aug 13.

Nutrition and Health Sciences, Laney Graduate School Emory University Atlanta GA.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning applied to high-resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untargeted metabolomics by liquid chromatography-mass spectrometry was performed on plasma samples from a combined cross-sectional sample of children and adolescents ages 2-25 years old with NAFLD (n = 222) and without NAFLD (n = 337), confirmed by liver biopsy or magnetic resonance imaging. Anthropometrics, blood lipids, liver enzymes, and glucose and insulin metabolism were also assessed. A machine learning approach was applied to the metabolomics and clinical phenotype data sets, which were split into training and test sets, and included dimension reduction, feature selection, and classification model development. The selected metabolite features were the amino acids serine, leucine/isoleucine, and tryptophan; three putatively annotated compounds (dihydrothymine and two phospholipids); and two unknowns. The selected clinical phenotype variables were waist circumference, whole-body insulin sensitivity index (WBISI) based on the oral glucose tolerance test, and blood triglycerides. The highest performing classification model was random forest, which had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 73%, and specificity of 97% for detecting NAFLD cases. A second classification model was developed using the homeostasis model assessment of insulin resistance substituted for the WBISI. Similarly, the highest performing classification model was random forest, which had an AUROC of 0.92, sensitivity of 73%, and specificity of 94%. The identified screening panel consisting of both metabolomics and clinical features has promising potential for screening for NAFLD in youth. Further development of this panel and independent validation testing in other cohorts are warranted.
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http://dx.doi.org/10.1002/hep4.1417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771165PMC
October 2019

Maternal Haplotypes in Promoter and Gene in Tuning Childhood Acute Lymphoblastic Leukemia Onset-Latency: Genetic/Epigenetic Mother/Child Dyad Study (GEMCDS).

Genes (Basel) 2019 08 22;10(9). Epub 2019 Aug 22.

Department of Biomedical & Specialty Surgical Sciences, and Centre Haemostasis & Thrombosis, University of Ferrara, 44121 Ferrara, Italy.

Childhood acute lymphoblastic leukemia (ALL) peaks around age 2-4, and in utero genetic epigenetic mother-fetus crosstalk might tune ALL onset during childhood life. Folate genes variably interact with vitamin status on ALL risk and prognosis. We investigated and gene variants in 235 ALL children and their mothers to disclose their role in determining ALL onset age and survival. Pyrosequence of 19bp ins/del (rs70991108; W/D), C677T (rs1801133; C>T), and A1298C (rs1801131; A>C) was assessed in children and in 72% of mothers for dyad-analysis comparison. DD-children had delayed ALL onset compared to WW-children (7.5 ± 4.8 vs. 5.2 ± 3.7 years; = 0.002) as well as 1298 CC-children compared to AA-children (8.03 ± 4.8 vs. 5.78 ± 4.1 years; = 0.006), and according to the strong linkage disequilibrium between 677 T-allele and 1298C-allele, TT-children showed early mean age of onset though not significant. Offspring of 677 TT-mothers had earlier ALL onset compared to offspring of 677 CC-mothers (5.4 ± 3.3 vs. 7 ± 5.3 years; = 0.017). / polymorphism combination influenced onset age by comparing DD/CC vs. WW/TT children (8.1 ± 5.7 vs. 4.7 ± 2.1 years; = 0.017). Moreover, mother-child genotype combination gave 5.5-years delayed onset age in favor of DD-offspring of 677 CC-mothers vs. WW-offspring of 677 TT-mothers, and it was further confirmed including any D-carrier children and any 677 T-carrier mothers ( = 0.00052). Correction for multiple comparisons maintained statistical significance for ins/del and A1298C polymorphisms. Unexpectedly, among the very-early onset group (<2.89 years; 25th), DD-genotype inversely clustered in children and mothers (4.8% vs. 23.8% respectively), and accordingly ALL offspring of homozygous DD-mothers had increased risk to have early-onset (adjusted OR (odds ratio) = 3.08; 1.1-8.6; = 0.03). The opposite effect promoter variant has in tuning ALL onset-time depending on who is the carrier (i.e., mother or child) might suggest a parent-origin-effect of the D-allele or a two-faced epigenetic role driven by unbalanced folate isoform availability during the in-utero leukemogenesis responsible for the wide postnatal childhood ALL latency.
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http://dx.doi.org/10.3390/genes10090634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770441PMC
August 2019

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Nature 2019 06 22;570(7759):71-76. Epub 2019 May 22.

Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10) and candidate genes from knockout mice (P = 5.2 × 10). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
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http://dx.doi.org/10.1038/s41586-019-1231-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699738PMC
June 2019

Isavuconazole Treatment of Cerebral and Pulmonary Aspergillosis in a Pediatric Patient With Acute Lymphoblastic Leukemia: Case Report and Review of Literature.

J Pediatr Hematol Oncol 2020 08;42(6):e469-e471

Department of Pediatrics, Division of Pediatric Hematology-Oncology.

Invasive aspergillosis in hematologic pediatric patients is an opportunistic infection that is difficult to treat, with a high mortality rate when localized in the central nervous system. We are describing a 3-year-old girl who was affected by acute lymphoblastic leukemia who developed cerebral and pulmonary aspergillosis during induction chemotherapy. The patient failed first-line voriconazole treatment because of being a CYP2C19 ultrarapid metabolizer and received effective isavuconazole therapy with no notable side effects.
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http://dx.doi.org/10.1097/MPH.0000000000001508DOI Listing
August 2020

Cardiovascular dysfunction and vitamin D status in childhood acute lymphoblastic leukemia survivors.

World J Pediatr 2019 Oct 4;15(5):465-470. Epub 2019 May 4.

Department of Pediatric Oncology and Hematology, University Hospital of Policlinico, Piazza G. Cesare 11, 70124, Bari, Italy.

Background: Vitamin D (25-OHD) has a role in bone health after treatment for cancer. 25-OHD deficiency has been associated with risk factors for cardiovascular disease, but no data focusing on this topic in childhood cancer survivors have been published. We investigated the 25-OHD status in children treated for acute lymphoblastic leukemia (ALL), and evaluated its influence on vascular function.

Methods: 25-OHD levels were evaluated in 52 ALL survivors and 40 matched healthy controls. Patients were grouped according to 25-OHD level (< 20 ng/m or ≥ 20 ng/ml). Auxological parameters, biochemical and hemostatic markers of endothelial function (AD, HMW-AD, ET-1, vWFAg, TAT, D-dimers, Fbg, and hs-CRP), ultrasound markers of vascular endothelial function (flow-mediated dilatation, FMD, common carotid intima-media thickness, C-IMT, and antero-posterior diameter of infra-renal abdominal aorta, APAO) were evaluated in the patients.

Results: Cases showed higher prevalence of 25-OHD deficiency than controls (p = 0.002). In univariate analysis via mean comparisons, 25-OHD deficient (< 20 ng/ml) patients showed higher C-IMT values compared to the 25-OHD non-deficient (≥ 20 ng/ml) group (P = 0.023). Significant differences were also found for ET-1 (P = 0.035) and AD-HMW (P = 0.015). In the multiple regression models controlling for some confounders, 25-OHD still was associated with C-IMT (P = 0.0163), ET-1 (P = 0.0077), and AD-HMW (P = 0.0008).

Conclusions: Childhood ALL survivors show higher prevalence of 25-OHD deficiency as compared to controls. The 25-OHD levels appear to be linked to indicators of endothelial and vascular dysfunction. Careful monitoring of 25-OHD balance may help to prevent cardiovascular diseases in childhood ALL survivors, characterized by high cardiovascular risk.
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http://dx.doi.org/10.1007/s12519-019-00258-yDOI Listing
October 2019

Altered In Vivo Lipid Fluxes and Cell Dynamics in Subcutaneous Adipose Tissues Are Associated With the Unfavorable Pattern of Fat Distribution in Obese Adolescent Girls.

Diabetes 2019 06 1;68(6):1168-1177. Epub 2019 Apr 1.

Division of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT

Patterns of abdominal fat distribution (for example, a high vs. low visceral adipose tissue [VAT]/[VAT + subcutaneous adipose tissue (SAT)] ratio), independent of obesity, during adolescence carry a high risk for insulin resistance and type 2 diabetes. Longitudinal follow-up of a cohort of obese adolescents has recently revealed that a high ratio (high VAT/[VAT + SAT]) is a major determinant of fatty liver and metabolic impairment over time, with these effects being more pronounced in girls than in boys. To unravel the underlying metabolic alterations associated with the unfavorable VAT/(VAT + SAT) phenotype, we used the HO labeling method to measure the turnover of adipose lipids and cells in the subcutaneous abdominal and gluteal/femoral adipose tissue (SAT) of weight-stable obese adolescent girls with a similar level of obesity but discordant VAT/(VAT + SAT) ratios. Girls with the unfavorable (high VAT/[VAT + SAT]) phenotype exhibited higher in vivo rates of triglyceride (TG) turnover (representing both lipolysis and synthesis at steady state), without significant differences in de novo lipogenesis in both abdominal and gluteal depots, compared with obese girls with the favorable phenotype. Moreover, mature adipocytes had higher turnover, with no difference in stromal vascular cell proliferation in both depots in the metabolically unfavorable phenotype. The higher TG turnover rates were significantly correlated with higher intrahepatic fat stores. These findings are contrary to the hypothesis that impaired capacity to deposit TGs or proliferation of new mature adipocytes are potential mechanisms for ectopic fat distribution in this setting. In summary, these results suggest that increased turnover of TGs (lipolysis) and of mature adipocytes in both abdominal and gluteal SAT may contribute to metabolic impairment and the development of fatty liver, even at this very early stage of disease.
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http://dx.doi.org/10.2337/db18-1162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610014PMC
June 2019

Late mortality and causes of death among 5-year survivors of childhood cancer diagnosed in the period 1960-1999 and registered in the Italian Off-Therapy Registry.

Eur J Cancer 2019 03 14;110:86-97. Epub 2019 Feb 14.

Department of Hematology and Oncology, University Hospital AOU Meyer, Florence, Italy.

Introduction: Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry.

Materials And Methods: CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs).

Results: Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86-88) and at 45 years was 81% (95% CI: 77-84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7-12), corresponding to an AER of 48 (95% CI: 45-51). Mortality decreased by 60% for survivors treated most recently (1990-1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death.

Conclusions: This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs.
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http://dx.doi.org/10.1016/j.ejca.2018.12.021DOI Listing
March 2019

One-hour post-load plasma glucose predicts progression to prediabetes in a multi-ethnic cohort of obese youths.

Diabetes Obes Metab 2019 05 28;21(5):1191-1198. Epub 2019 Feb 28.

Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.

Aims: One-hour post-load hyperglycaemia has been proposed as an independent predictor of type 2 diabetes in adults. We examined whether 1-hour plasma glucose (1hPG) during an oral glucose tolerance test (OGTT) can predict changes in the glucose tolerance status of a multi-ethnic cohort of youths with normal glucose tolerance (NGT).

Materials And Methods: A total of 202 obese youths with NGT (33.7% Caucasian, 31.1% Hispanic, 32.2% African American) underwent a 3-hour OGTT at baseline and after a 2-year follow-up period. Whole-body insulin sensitivity, insulin secretion, β-cell function and insulin clearance were estimated by modeling plasma glucose, insulin and C-peptide levels.

Results: Obese youths with 1hPG ≥7.4 mmol/L (or 133 mg/dL; n = 83) exhibited higher body mass index (BMI), plasma triglycerides and fasting and post-load glucose concentrations than individuals with 1hPG <7.4 mmol/L. Also, 1hPG ≥7.4 mmol/L was associated with a lower disposition index (DI) (P < 0.0001) and with alterations in whole-body insulin sensitivity, β-cell function and insulin clearance. Adolescents with 1hPG ≥7.4 mmol/L were approximately three times more likely to develop prediabetes (ie, impaired glucose tolerance and/or impaired fasting glucose) over time (OR, 2.92 [1.22-6.98]; P = 0.02), independent of age, sex, race/ethnicity, BMI, insulin sensitivity, DI and plasma glucose concentrations. No differences emerged in the risk of prediabetes related to 1-hour hyperglycaemia among different ethnic groups.

Conclusions: A plasma glucose concentration ≥ 7.4 mmol/L at 1 hour during an OGTT is associated with a worse clinical and metabolic phenotype and may be an independent predictor of progression to prediabetes in obese youths with NGT.
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http://dx.doi.org/10.1111/dom.13640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459710PMC
May 2019

Human Fibrinogen Concentrate and Fresh Frozen Plasma in the Management of Severe Acquired Hypofibrinogenemia in Children With Acute Lymphoblastic Leukemia: Results of a Retrospective Survey.

J Pediatr Hematol Oncol 2019 05;41(4):275-279

Division of Paediatric Haematology Oncology-Azienda Ospedaliera Universitaria Policlinico Consorziale di Bari, Bari.

Objective Of The Study: In this study we aimed to retrospectively evaluate how centers, belonging to the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP), manage severe acquired hypofibrinogenemia in children with acute lymphoblastic leukemia, particularly evaluating the therapeutic role of human fibrinogen concentrate (HFC) and fresh frozen plasma (FFP).

Methods: We conducted a survey among AIEOP centers; thereafter, we collected and analyzed data with regard to the treatment of episodes of severe acquired hypofibrinogenemia occurring during the induction and reinduction phases of the AIEOP-BFM ALL 2009 protocol.

Results: In total, 15 of the 37 AIEOP centers invited to join the survey agreed to collect the data, with 10 and 5 centers declaring to react to severe acquired hypofibrinogenemia (<70 mg/dL) by administering HFC or FFP, respectively. Of the 150 episodes of severe hypofibrinogenemia occurring in 101 patients, 47.3% were treated with HFC and 52.7% with FFP, with a normalization of fibrinogen levels achieved in greater proportion and in a shorter amount of time in the HFC group as compared with the FFP group. None of the patients presented with bleeding or thrombosis during the observation period.

Conclusions: Even with the limitations of the retrospective nature of this study, HFC seems to be a safe and effective alternative to FFP for replacement therapy in case of severe hypofibrinogenemia in children with acute lymphoblastic leukemia.
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http://dx.doi.org/10.1097/MPH.0000000000001390DOI Listing
May 2019

Relation of the degree of obesity in childhood to adipose tissue insulin resistance.

Acta Diabetol 2019 Feb 12;56(2):219-226. Epub 2019 Jan 12.

Department of Pediatrics, Ruth Rappaport Children's Hospital, Rambam Medical Center, Haifa, Israel.

Aims: In this study, we investigated whether adipose tissue insulin resistance (IR) is affected by the degree of obesity during the fasting and post-prandial state, independent of glucose tolerance among obese children and adolescents. We also tested whether systemic subclinical inflammation is associated with adipose tissue IR.

Methods: Subjects were recruited to the Yale Pathophysiology of Type 2 Diabetes in Youth Study (NCT01967849). An oral glucose-tolerance test was performed to establish glucose-tolerance status and blood samples were drawn for measurement of free fatty acids (FFAs), to calculate the area under the curve (AUC) of FFA. Adipose tissue insulin resistance was calculated as the product of insulin and FFA concentrations.

Results: In total, 671 children and adolescents (58.6% females) were included with a mean age of 13.3(2.7) years and BMI Z score of 2.45(0.31). The degree of obesity emerged as an independent predictor of both fasting and post-prandial adipose IR, p < 0.0001. Higher degree of obesity was associated with greater AUC FFA (lower suppression) compared to lower degree of obesity, p = 0.01. Furthermore, higher levels of IL-6 were positively associated with post-prandial adipose tissue IR, p = 0.02.

Conclusions: The degree of obesity in childhood and adolescence is strongly associated with adipose tissue IR independent of glucose tolerance. This is reflected not only in calculated indices of adipose IR but also in lower suppression of FFAs during the OGTT regardless of glucose tolerance or fasting adipose tissue IR. Furthermore, markers of subclinical inflammation such as IL-6 are associated with adipose tissue IR, independent of other factors.
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http://dx.doi.org/10.1007/s00592-018-01285-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373259PMC
February 2019

Primary Orbital Synovial Sarcoma Mimicking a Periocular Cyst.

Am J Dermatopathol 2019 Sep;41(9):655-660

Unit of Ocular Oncology, Department of Surgery and Translational Medicine, Careggi University Hospital, Florence, Italy.

Synovial sarcoma (SS) is a high-grade soft-tissue sarcoma occurring predominantly in older children and young adults. Only approximately 7% occur in the head and neck region, with SS representing less than 0.1% of all head and neck cancers. Orbital location is exceedingly rare with only 8 cases reported so far in the literature. It is noted for its propensity for late local recurrences and metastases. Histologically, SS is monophasic, biphasic, or poorly differentiated and harbors a specific chromosomal translocation t(X;18)(p11.2;q11.2) in >95% of cases. In this article, we describe a case of monophasic SS primarily arising in the left supero-nasal orbital region in a 24-year-old woman, clinically mistaken for a periocular cyst. The case is peculiar for its highly unusual location and for its clinical deceptively benign appearance.
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http://dx.doi.org/10.1097/DAD.0000000000001351DOI Listing
September 2019