Publications by authors named "Salvatore Cucchiara"

203 Publications

Assessment of a new score for capsule endoscopy in pediatric Crohn's disease (CE-CD).

Endosc Int Open 2021 Oct 16;9(10):E1480-E1490. Epub 2021 Sep 16.

Children's Center for Digestive Health Care, Children's Healthcare of Atlanta, and Emory University, Atlanta, Georgia, United States.

Two scores have been implemented to standardize capsule endoscopic (CE) findings in patients with Crohn's disease (CD): Lewis score (LS) and Capsule Endoscopy Crohn's Disease Activity Index (CECDAI). Both have limitations and are not well validated in the pediatric population. The aim of our study was to assess a new score (capsule endoscopy - Crohn's disease index, CE-CD) in pediatric patients with CD and to compare it to preexisting scores. This was a double-center, retrospective study involving pediatric subjects with CD who underwent CE. Correlation analyses between CE-CD, endoscopy scores and noninvasive markers of disease activities were performed. The ability of different CE scores to predict clinical and endoscopic outcomes was evaluated with regression and survival analyses. A total of 312 subjects were analyzed. The CE-CD score showed a moderate (Pearson's r = 0.581,  < 0.001) and strong (r = 0.909,  < 0.001) association with LS and CECDAI, respectively. CE-CD was a statistically significant predictor of hospitalization (hazard ratio [HR]1.061), treatment escalation (HR 1.062), steroid therapy (HR 1.082), clinical (HR 1.064) and endoscopic (HR 1.060) relapse over the twenty-four months (  < 0.001). Subjects with mucosal inflammation according to CE-CD (CE-CD ≥ 9) had worse outcomes compared to patients without inflammation (CE-CD < 9) (Log rang test < 0.001). The CE-CD score is a simple, reliable, reproducible, and predictive score for evaluation of small bowel inflammation in pediatric patients with CD. Prospective validation is needed to confirm the applicability of this new index in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1522-8723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445685PMC
October 2021

Microbiome signatures of progression toward celiac disease onset in at-risk children in a longitudinal prospective cohort study.

Proc Natl Acad Sci U S A 2021 Jul;118(29)

Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA 02114;

Other than exposure to gluten and genetic compatibility, the gut microbiome has been suggested to be involved in celiac disease (CD) pathogenesis by mediating interactions between gluten/environmental factors and the host immune system. However, to establish disease progression markers, it is essential to assess alterations in the gut microbiota before disease onset. Here, a prospective metagenomic analysis of the gut microbiota of infants at risk of CD was done to track shifts in the microbiota before CD development. We performed cross-sectional and longitudinal analyses of gut microbiota, functional pathways, and metabolites, starting from 18 mo before CD onset, in 10 infants who developed CD and 10 matched nonaffected infants. Cross-sectional analysis at CD onset identified altered abundance of six microbial strains and several metabolites between cases and controls but no change in microbial species or pathway abundance. Conversely, results of longitudinal analysis revealed several microbial species/strains/pathways/metabolites occurring in increased abundance and detected before CD onset. These had previously been linked to autoimmune and inflammatory conditions (e.g., , sp., , tryptophan metabolism, and metabolites serine and threonine). Others occurred in decreased abundance before CD onset and are known to have anti-inflammatory effects (e.g., , , and ). Additionally, we uncovered previously unreported microbes/pathways/metabolites (e.g., , high mannose-type -glycan biosynthesis, and serine) that point to CD-specific biomarkers. Our study establishes a road map for prospective longitudinal study designs to better understand the role of gut microbiota in disease pathogenesis and therapeutic targets to reestablish tolerance and/or prevent autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2020322118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307711PMC
July 2021

Fecal High-Mobility Group Box 1 as a Marker of Early Stage of Necrotizing Enterocolitis in Preterm Neonates.

Front Pediatr 2021 10;9:672131. Epub 2021 Jun 10.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

An early diagnosis of necrotizing enterocolitis (NEC), a major gastrointestinal emergency in preterm newborns, is crucial to improve diagnostic approach and prognosis. We evaluated whether fecal high-mobility group box protein 1 (HMGB1) may early identify preterms at risk of developing NEC. A case-control study including neonates admitted at the Neonatal Intensive Care Unit (NICU) of the Sapienza University Hospital "Umberto I" in Rome, from July 2015 to December 2016. Stool samples obtained from cases (preterm newborns with NEC) and controls (newborns without NEC) were collected at the enrolment (T0) and within 7-14 days after the first sample collection (T1). HMGB1, extracted and measured with western blot, was reported as densitometry units (DUS). HMGB1 levels in 30 cases ( = 28-Bell stage 1, = 2 Bell stage 2) were higher [T0: 21,462 DUS (95% CI, 16,370-26,553 DUS)-T1: 17,533 DUS (95% CI, 13,052-22,014 DUS)] than in 30 preterm controls [T0: 9,446 DUS (95% CI, 6,147-12,746 DUS)-T1: 9,261 DUS (95% CI, 5,126-13,396 DUS), < 0.001). Preterm newborns showed significant higher levels of HMGB1 (15,690 DUS (95% CI, 11,929-19,451 DUS)] in comparison with 30 full-term neonates with birth weight >2,500 g [6,599 DUS (95% CI, 3,141-10,058 DUS), = 0.003]. Multivariate analysis showed that the risk of NEC was significantly ( = 0.012) related to the HMGB1 fecal levels at T0. We suggest fecal HMGB1 as a reliable marker of early NEC in preterm neonates. This study supports further investigation on the role of fecal HMGB1 assessment in managing preterm newborns at risk of NEC. Further studies are advocated to evaluate diagnostic accuracy of this marker in more severe forms of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2021.672131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222523PMC
June 2021

Emerging Roles of Gut Virome in Pediatric Diseases.

Int J Mol Sci 2021 Apr 16;22(8). Epub 2021 Apr 16.

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

In the last decade, the widespread application of shotgun metagenomics provided extensive characterization of the bacterial "dark matter" of the gut microbiome, propelling the development of dedicated, standardized bioinformatic pipelines and the systematic collection of metagenomic data into comprehensive databases. The advent of next-generation sequencing also unravels a previously underestimated viral population (virome) present in the human gut. Despite extensive efforts to characterize the human gut virome, to date, little is known about the childhood gut virome. However, alterations of the gut virome in children have been linked to pathological conditions such as inflammatory bowel disease, type 1 diabetes, malnutrition, diarrhea and celiac disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22084127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073368PMC
April 2021

Diagnostic Value of Persistently Low Positive TGA-IgA Titers in Symptomatic Children With Suspected Celiac Disease.

J Pediatr Gastroenterol Nutr 2021 05;72(5):712-717

Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department.

Objectives: While the algorithm to diagnose celiac disease (CD) in children with elevated anti-transglutaminase IgA (TGA-IgA) titers (>10 times upper limit of normal, ULN) is well defined, the management of children with low TGA-IgA values represents a clinical challenge. We aimed to identify the diagnostic value of persistently low positive TGA-IgA titers in predicting CD in children.

Methods: We retrospectively analyzed children with symptoms or signs of CD, not eligible for a no-biopsy approach. We included children with at least 2 TGA-IgA measurements, endomysial antibody (EMA) assessment and esophagogastroduodenoscopy with biopsies. TGA-IgA values were provided as multiples of ULN. Patients were classified in groups according to median TGA-IgA values: A (TGA-IgA>1 ≤ 5 × ULN; defined as "low-positive"), B (TGA-IgA > 5 < 10 × ULN; "moderate-positive"), and C (controls).

Results: Data of 281 children were analyzed. Of 162 children in group A, CD was diagnosed in 142 (87.7%), whereas normal duodenal mucosa was found in 20. In group B, all 62 children (100%) received a CD diagnosis. Group C included 57 controls. EMA were undetectable in 31 (15%) of mucosal atrophy cases. On the receiver-operating characteristic curve (area under the curve = 0.910), a mean value of 1.7 ULN showed a sensitivity of 81.4% and specificity of 81.8% to predict mucosal damage.

Conclusions: Repeated low or moderate TGA-IgA values (<5 ULN or <10 ULN) are good predictors of a CD diagnosis. Symptomatic children with persistently low positive TGA-IgA titers should undergo esophagogastroduodenoscopy regardless of their EMA status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000003047DOI Listing
May 2021

Gastrointestinal endoscopy in children and adults: How do they differ?

Dig Liver Dis 2021 Jun 7;53(6):697-705. Epub 2021 Mar 7.

Maternal and Child Health Department, Pediatric Gastroenterology and Liver Unit, Sapienza - University of Rome, Rome, Italy. Electronic address:

Gastrointestinal endoscopy has grown dramatically over the past century, and with subsequent improvements in technology and anaesthesia, it has become a safe and useful tool for evaluation of GI pathology in children. There are substantial differences between paediatric and adult endoscopy beyond size, including: age-related patho-physiology and the different spectrum of diseases in children. Literature on endoscopic procedures in children is sparse but significant. The present review aims at describing the current knowledges on paediatric endoscopy practice and highlights the main areas of differences between paediatric and adult practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2021.02.016DOI Listing
June 2021

Transition of inflammatory bowel disease patients from pediatric to adult care: an observational study on a joint-visits approach.

Ital J Pediatr 2021 Jan 28;47(1):18. Epub 2021 Jan 28.

Fondazione Policlinico Universitario A. Gemelli IRCCS, OU Internal Medicine and Gastroenterology, Largo A. Gemelli, 00168, Rome, Italy.

Background: Transition from pediatric to adult care of patients affected by Inflammatory Bowel Disease (IBD) is a critical step that needs specific care and multidisciplinary involvement. The aim of our study was to evaluate the outcome of the transition process of a cohort of IBD patients, exploring their readiness and the possible impact on quality of life.

Methods: This observational study followed transitioned IBD patients from pediatric to adult care. Transition was carried-out through combined visits, jointly performed by the pediatrician and the adult gastroenterologist. Clinical data were collected before and after transition. A subgroup of patients was submitted to an anonymous online questionnaire of 38 items based on the validated questionnaires TRAQ and SIBDQ within the first 6 months from the beginning of the transition process.

Results: Eighty-two patients with IBD were enrolled, with a mean age at transition of 20.2±2.7 years. Before transition, 40.2% of patients already had major surgery and 64.6% started biologics. At transition, 24% of patients were in moderate to severe active phase of their disease and 40% of them had already been treated with ≥ 2 biologics. The mean score of the TRAQ questionnaires collected is 3.4±1.5 and the mean score of SIBDQ is 53.9±9.8. A significant association was found between a TRAQ mean score > 3 and a SIBDQ > 50 (p=0.0129). Overall, 75% of patients had a positive opinion of the transition model adopted.

Conclusions: A strong association has been found between TRAQ and SIBDQ questionnaires, showing how transition readiness has a direct impact on the quality of life of the young adult with IBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13052-021-00977-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844940PMC
January 2021

Fecal and mucosal microbiota profiling in pediatric inflammatory bowel diseases.

Eur J Gastroenterol Hepatol 2021 Jan 18. Epub 2021 Jan 18.

Scientific Institute Pediatric Hospital "Bambino Gesù" Department of Women's and Children's Health, Sapienza University of Rome Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Background: An altered gut microbiota profile has been widely documented in inflammatory bowel diseases (IBD). The intestinal microbial community has been more frequently investigated in the stools than at the level of the mucosa, while most of the studies have been performed in adults. We aimed to define the gut microbiota profile either by assessing fecal and colonic mucosa samples (inflamed or not) from pediatric IBD patients.

Patients And Methods: Fecal and colonic samples from pediatric IBD (Crohn's disease or ulcerative colitis) and controls were analyzed. The relative abundance of bacteria at phylum and genus/species levels and bacterial diversity were determined through 16S rRNA sequence-based of fecal and mucosal microbiota analysis.

Results: A total of 59 children with IBD (26 Crohn's disease, 33 ulcerative colitis) and 39 controls were analyzed. A clear separation between IBD and controls in the overall composition of fecal and mucosal microbiota was found, as well as a reduced bacterial richness in the fecal microbiota of IBD. At the phylum level, abundance of Proteobacteria and Actinobacteria occurred in fecal microbiota of IBD, while species with anti-inflammatory properties (i.e., Ruminococcus) were reduced. Fusobacterium prevailed in inflamed IBD areas in comparison to noninflamed and controls samples.

Conclusion: Significant alterations in gut microbiota profile were shown in our IBD pediatric patients, in whom an abundance of species with a proinflammatory mucosal activity was clearly detected. An analysis of gut microbiota could be incorporated in designing personalized IBD treatment scenarios in future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MEG.0000000000002050DOI Listing
January 2021

Paradoxical Psoriasis Induced by Anti-TNFα Treatment: Evaluation of Disease-Specific Clinical and Genetic Markers.

Int J Mol Sci 2020 Oct 23;21(21). Epub 2020 Oct 23.

Clinic of Dermatology Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy.

Paradoxical psoriasis (PP) may occur during treatment with anti-tumor necrosis factor-alpha (TNF-α) drugs in various chronic immune-mediated diseases, mainly inflammatory bowel diseases (IBD) and psoriasis. In this study, clinical and genetic characteristics of PP arising in IBD and psoriatic patients were investigated to identify disease-specific markers of the paradoxical effect. A total of 161 IBD and psoriatic patients treated with anti-TNF-α drugs were included in the study. Of these patients, 39 developed PP. All patients were characterized for the main clinical-pathologic characteristics and genotyped for six candidate single nucleotide polymorphisms (SNPs) selected for their possible role in PP susceptibility. In IBD patients, the onset of PP was associated with female sex, presence of comorbidities, and use of adalimumab. IBD patients with PP had a higher frequency of the rs1799964 rare allele ( = 0.006) compared with cases without the paradoxical effect, and a lower frequency of the human leucocyte antigen ()- rs10484554 rare allele ( = 0.03) compared with psoriatic patients with PP. Overall, these findings point to specific clinical and genetic characteristics of IBD patients with PP and provide data showing that genetic variability may be related to the paradoxical effect of anti-TNF-α drugs with possible implications into clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21217873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660646PMC
October 2020

Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives.

Biomolecules 2020 10 10;10(10). Epub 2020 Oct 10.

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom10101431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599789PMC
October 2020

Effect of LRE02- LR04 Combination on Antibiotic-Associated Diarrhea in a Pediatric Population: A National Survey.

J Clin Med 2020 Sep 24;9(10). Epub 2020 Sep 24.

Department of Biomedical Science and Human Oncology-Section of Neonatology and NICU, University "Aldo Moro" of Bari, 70124 Bari, Italy.

Probiotics are living microorganisms, which, upon oral ingestion, may prevent antibiotic-associated diarrhea (AAD) through the normalization of an unbalanced gastrointestinal flora. The objective of this study was to evaluate the benefits of a probiotic combination ( LRE02-DSM 23878 and LR04-DSM 16605) on the prevention of AAD in an outpatient pediatric setting. Questionnaires were delivered to pediatricians by each patient/parent during the visits after antibiotics and probiotics treatment to monitor physiological parameters. The primary outcome of both groups (probiotics and no probiotics treated) was the evaluation of the prevalence of AAD between the two groups. Evaluation of stool consistency using the Bristol Stool Scale (BSS) score was performed, as well as the evaluation of AAD duration, frequencies of daily evacuation, and the beginning of diarrhea and weight loss during AAD in both groups and related to antibiotic categories. Results indicated that probiotics, at the recommended dosage of 1.2 × 10 CFU (Colony Forming Unit) per day for 30 days, are associated with lower rates of AAD and a decreased number of days with diarrhea, independent of the type of antibiotic used. Moreover, the use of probiotics resulted in a normal stool consistency in a shorter time period, as evaluated by the BSS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9103080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650601PMC
September 2020

ESPGHAN 'biopsy-sparing' guidelines for celiac disease in children with low antitransglutaminase during COVID-19.

Eur J Gastroenterol Hepatol 2020 12;32(12):1523-1526

Maternal and Child Health Department, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Italy.

Objectives: Recent guidelines for celiac disease have allowed a biopsy-free approach in endomysial antibodies (EMAs) positive children with high antitransglutaminase (TGA-IgA) titer [>10 time upper limit of normal (ULN)]. Esophagogastroduodenoscopy is still necessary for diagnosis in children with lower title. Because elective pediatric endoscopy has been substantially shouted down during coronavirus disease (COVID-19) pandemic, many children remained undiagnosed - and therefore untreated - for a long time. We aimed to analyze the feasibility and accuracy of a biopsy-free approach in suspected celiac disease children with TGA-IgA values <10 ULN to facilitate the diagnostic process by avoiding endoscopy.

Methods: In this study cohort, we retrospectively analyzed all biopsy-confirmed diagnosis of celiac disease in our center (between 2014 and 2019). The positive predictive value (PPV) of TGA-IgA titers between 5 and 10 ULN and positive EMA in diagnosing celiac disease were determined. Mucosal atrophy and resolution of symptoms after gluten-free diet (GFD) were considered to confirm initial diagnosis.

Results: Of 430 celiac disease patients (F: 274; mean age 7.54 years) diagnosed by endoscopy, 84 (F: 46; mean age 8 years) with TGA-IgA between 5 and 10 ULN and positive EMA were identified. The PPV of TGA-IgA between 5 and 10 ULN and positive EMA was 0.93 (95% confidence interval 0.90-0.96). All these children had a symptom resolution and antibodies normalization after GFD.

Conclusion: During the COVID-19 outbreak, a temporarily reduction of the TGA-IgA threshold for biopsy-sparing approach seems feasible in EMA positive children with TGA-IgA between 5 and 10 ULN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MEG.0000000000001924DOI Listing
December 2020

Multi-omics analysis reveals the influence of genetic and environmental risk factors on developing gut microbiota in infants at risk of celiac disease.

Microbiome 2020 09 11;8(1):130. Epub 2020 Sep 11.

Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA.

Background: Celiac disease (CD) is an autoimmune digestive disorder that occurs in genetically susceptible individuals in response to ingesting gluten, a protein found in wheat, rye, and barley. Research shows that genetic predisposition and exposure to gluten are necessary but not sufficient to trigger the development of CD. This suggests that exposure to other environmental stimuli early in life, e.g., cesarean section delivery and exposure to antibiotics or formula feeding, may also play a key role in CD pathogenesis through yet unknown mechanisms. Here, we use multi-omics analysis to investigate how genetic and early environmental risk factors alter the development of the gut microbiota in infants at risk of CD.

Results: Toward this end, we selected 31 infants from a large-scale prospective birth cohort study of infants with a first-degree relative with CD. We then performed rigorous multivariate association, cross-sectional, and longitudinal analyses using metagenomic and metabolomic data collected at birth, 3 months and 6 months of age to explore the impact of genetic predisposition and environmental risk factors on the gut microbiota composition, function, and metabolome prior to the introduction of trigger (gluten). These analyses revealed several microbial species, functional pathways, and metabolites that are associated with each genetic and environmental risk factor or that are differentially abundant between environmentally exposed and non-exposed infants or between time points. Among our significant findings, we found that cesarean section delivery is associated with a decreased abundance of Bacteroides vulgatus and Bacteroides dorei and of folate biosynthesis pathway and with an increased abundance of hydroxyphenylacetic acid, alterations that are implicated in immune system dysfunction and inflammatory conditions. Additionally, longitudinal analysis revealed that, in infants not exposed to any environmental risk factor, the abundances of Bacteroides uniformis and of metabolite 3-3-hydroxyphenylproprionic acid increase over time, while those for lipoic acid and methane metabolism pathways decrease, patterns that are linked to beneficial immunomodulatory and anti-inflammatory effects.

Conclusions: Overall, our study provides unprecedented insights into major taxonomic and functional shifts in the developing gut microbiota of infants at risk of CD linking genetic and environmental risk factors to detrimental immunomodulatory and inflammatory effects. Video Abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40168-020-00906-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488762PMC
September 2020

Children and Fecal SARS-CoV-2 shedding: Just the tip of the Iceberg of Italian COVID-19 outbreak?

Dig Liver Dis 2020 11 7;52(11):1219-1221. Epub 2020 Jul 7.

Maternal and Child Health Department, Sapienza University of Rome, Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2020.06.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340015PMC
November 2020

Reply to: "Characterization of acute acro-ischemic lesions in non-hospitalized patients: A case series of 132 patients during the COVID-19 outbreak".

J Am Acad Dermatol 2020 09 1;83(3):e237-e239. Epub 2020 Jun 1.

Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza University of Rome, Rome, Italy. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.05.122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262530PMC
September 2020

Gluten-free diet impact on dynamics of pancreatic islet-specific autoimmunity detected at celiac disease diagnosis.

Pediatr Diabetes 2020 08 8;21(5):774-780. Epub 2020 Jun 8.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Objective: Almost 6% of celiac disease (CD) patients at diagnosis are positive for at least one of the main pancreatic islet autoantibodies that characterize type 1 diabetes (T1D). Few information, dated back to almost two decades ago, exist as to whether a gluten-free diet (GFD) could reduce the islet-specific autoimmunity detected in patients at CD diagnosis. Aim of the study was to evaluate the impact of GFD on 31 patients who presented islet-specific autoimmunity at CD diagnosis.

Methods: CD patient sera collected at diagnosis and throughout the GFD were analyzed for the main humoral autoantibodies so far identified in T1D, directed against one or more among insulin, glutamic-acid decarboxylase, tyrosine-phosphatase 2, and zinc cation-efflux transporter autoantigens.

Results: GFD (median duration 39 months) was associated to a decrease or disappearance of the islet-specific autoantibodies in 71% of CD patients. Almost 80% of the patients who became autoantibody-negative during the GFD were positive for only one of the islet-specific autoimmune markers at CD diagnosis, with none of them developing diabetes. Conversely, 80% of the CD patients positive at diagnosis for ≥2 islet-specific autoantibodies were still positive after more than two years of GFD, with 25% of them developing T1D.

Conclusions: Various factors appear to influence, individually or in combination, the effects of the GFD on pancreatic islet-specific autoimmune response detected at CD diagnosis. These factors include the number of diabetes autoantibodies found at CD diagnosis, the adherence to the GFD, its duration and an asymptomatic clinical presentation of CD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pedi.13054DOI Listing
August 2020

Intestinal Inflammation Alters the Expression of Hepatic Bile Acid Receptors Causing Liver Impairment.

J Pediatr Gastroenterol Nutr 2020 08;71(2):189-196

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Objectives: The gut-liver axis has been recently investigated in depth in relation to intestinal and hepatic diseases. Key actors are bile acid (BA) receptors, as farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR), and G-protein-coupled-receptor (GPCR; TGR5), that control a broad range of metabolic processes as well as inflammation and fibrosis. The present study aims to investigate the impact of intestinal inflammation on liver health with a focus on FXR, PXR, and TGR5 expression. The strategy to improve liver health by reducing gut inflammation is also considered. Modulation of BA receptors in the inflamed colonic tissues of inflammatory bowel disease (IBD) pediatric patients is analyzed.

Methods: A dextran sodium sulphate (DSS) colitis animal model was built. Co-cultures with Caco2 and HepG2 cell lines were set up. Modulation of BA receptors in biopsies of IBD pediatric patients was assessed by real-time PCR and immunohistochemistry.

Results: Histology showed inflammatory cell infiltration in the liver of DSS mice, where FXR and PXR were significantly decreased and oxidative stress was increased. Exposure of Caco2 to inflammatory stimuli resulted in the reduction of BA receptor expression in HepG2. Caco2 treatment with dipotassium glycyrrhizate (DPG) reduced these effects on liver cells. Inflamed colon of patients showed altered FXR, PXR, and TGR5 expression.

Conclusions: This study strongly suggests that gut inflammation affects hepatic cells by altering BA receptor levels as well as increasing the production of pro-inflammatory cytokines and oxidative stress. Hence, reducing gut inflammation is needed not only to improve the intestinal disease but also to protect the liver.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000002759DOI Listing
August 2020

Mucosal healing in Crohn's disease: new insights.

Expert Rev Gastroenterol Hepatol 2020 May 13;14(5):335-345. Epub 2020 May 13.

Department of Molecular Medicine, Sapienza University of Rome , Rome, Italy.

Introduction: Traditional management of patients with Crohn's disease includes symptoms and quality of life improvement. With the advent of biological agents, mucosal healing has become an achievable goal, documented through endoscopy. However, due to the transmural nature of inflammation, the prevention of bowel damage should be included in the aims of a targeted therapeutic strategy.

Areas Covered: Updated literature has been searched in PubMed from 2008 to 2020. This review focuses on the state of the art in the innovative therapeutic goals in Crohn's disease, also considering still controversial aspects and future research topics in the management of Crohn's disease.

Expert Opinion: Although a widely agreed view supports the notion that mucosal healing and bowel damage control may promote beneficial outcomes (i.e. reduction in hospitalization and surgical rates, avoidance of steroids), long-term robust data are still missing. On the other hand, the development of -omics techniques has expanded our knowledge of the pathogenetic mechanism underlying inflammatory bowel disease and opened up new horizons in precision or personalized medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17474124.2020.1759416DOI Listing
May 2020

Challenges in paediatric inflammatory bowel diseases in the COVID-19 time.

Dig Liver Dis 2020 05 8;52(5):593-594. Epub 2020 Apr 8.

Department of Human Pathology in Adulthood and Childhood "G. Barresi", Pediatric Gastroenterology and Cystic Fibrosis Unit, University of Messina, Via Consolare Valeria, Messina 98124, Italy. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2020.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141464PMC
May 2020

Fasting Neurotensin Levels in Pediatric Celiac Disease Compared with a Control Cohort.

Gastroenterol Res Pract 2020 22;2020:1670479. Epub 2020 Feb 22.

Pediatric Unit, AOU San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy.

Background And Aims: Neurotensin (NT) is a gut hormone secreted by specific endocrine cells scattered throughout the epithelial layer of the small intestine, which has been identified as an important mediator in several gastrointestinal functions and disease conditions. Its potential involvement in celiac disease (CD) has been investigated, but there are conflicting findings. The aim of this study was to evaluate serum NT levels in children with CD at diagnosis, compared to a control group, and to investigate whether NT correlated in CD patients with symptoms, antibody response, and intestinal mucosal damage. . Children (1-16 years old) undergoing gastrointestinal endoscopy for CD or for other clinical reasons were included in this study. Patients with CD diagnosed according to the 2012 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines without biopsy were also recruited. Fasting serum samples were analyzed for NT levels using ELISA. Logistic regression, Wilcoxon rank sum, and Spearman's rank tests were used for statistical analysis.

Results: Thirty children (18 females, 2.2-15.9 years old) were enrolled. Of 25 patients who underwent endoscopy, 9 were CD patients, 13 were controls, and 3 were excluded due to nonspecific inflammation at duodenal biopsy. CD was diagnosed in 5 patients without biopsy. NT median was higher in CD patients compared to controls (13.25 (IQR 9.4-17.5) pg/ml vs. 7.8 (IQR 7.6-10) pg/ml; = 0.02). No statistically significant association between NT and clinical, serological, or histological data of CD was observed in this CD cohort.

Conclusions: To our knowledge, this is the first study that evaluates NT in CD children from Italy. Results show that NT is higher in the serum of CD children at diagnosis compared to controls. However, larger-scale studies are required to validate these findings. Whether serum NT levels can be an adjunctive marker for pediatric CD remains currently elusive.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/1670479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056991PMC
February 2020

Assessment of public perceptions and concerns of celiac disease: A Twitter-based sentiment analysis study.

Dig Liver Dis 2020 04 29;52(4):464-466. Epub 2020 Feb 29.

Center of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, Institute of Reproductive and Regenerative Biology, Münster, Germany; University of Rome Tor Vergata, Chair of Endocrinology and Medical Sexology, Department of Systems Medicine, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2020.02.004DOI Listing
April 2020

The Challenge of Treatment in Potential Celiac Disease.

Gastroenterol Res Pract 2019 20;2019:8974751. Epub 2019 Oct 20.

Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy.

Potential celiac disease (PCD) is defined by the presence of positive serum antibodies, HLA-DQ2/DQ8 haplotypes, and a normal small intestinal mucosa (Marsh grade 0-1). This condition occurs in one-fifth of celiac disease (CD) patients and usually represents a clinical challenge. We reviewed genetic, histologic, and clinical features of this specific condition by performing a systematic search on MEDLINE, Embase, and Scholar database. Accordingly, we identified different genetic features in patients with PCD compared to the classical forms. Frequently, signs of inflammation (deposits of immunoglobulin A (IgA) and/or increased number of intraepithelial lymphocytes) can be clearly identify in the mucosa of PCD patients after an accurate histological assessment. Finally, the main challenge is represented by the treatment: the gluten-free diet should be considered only in the presence of gluten-dependent symptoms in both children and adults. : (i) potential celiac disease (PCD) occurs in one-fifth of all celiac diseases (CD), and (ii) despite the absence of classical lesions, clear signs of inflammation are often detectable. : (i) patients with PCD show different genetic features, and (ii) the presence of gluten-dependent symptoms is the main determinant to initiate the gluten-free diet, after a complete diagnostic work-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/8974751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854910PMC
October 2019

Celiac Disease and the Microbiome.

Nutrients 2019 Oct 8;11(10). Epub 2019 Oct 8.

European Biomedical Research Institute of Salerno, 84125 Salerno, Italy.

Growing evidence supports the hypothesis that changes in both the composition and function of the intestinal microbiome are associated with a number of chronic inflammatory diseases including celiac disease (CD). One of the major advances in the field of microbiome studies over the last few decades has been the development of culture-independent approaches to identify and quantify the components of the human microbiota. The study of nucleic acids DNA and RNA found in feces or other biological samples bypasses the need for tissue cultures and also allows the characterization of non-cultivable microbes. Current evidence on the composition of the intestinal microbiome and its role as a causative trigger for CD is highly heterogeneous and sometimes contradictory. This review is aimed at summarizing both pre-clinical (basic science data) and clinical (cross-sectional and prospective studies) evidence addressing the relationship between the intestinal microbiome and CD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11102403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835875PMC
October 2019

Hypoallergenicity of a thickened hydrolyzed formula in children with cow's milk allergy.

World J Clin Cases 2019 Aug;7(16):2256-2268

Department of Pediatrics, Sapienza University of Rome, Rome 00161, Italy.

Background: Allergy to cow's milk is the most frequent allergy occurring in infants and young children. The dietary management of these patients consists of the elimination of any cow's milk proteins from the diet, and for formula-fed infants, the substitution of the usual infant formula with an adapted formula that is generally based on extensively hydrolyzed cow's milk proteins. The American Academy of Pediatrics has established specific criteria to confirm the hypoallergenicity of a formula intended for these children.

Aim: To assess the hypoallergenicity of a new thickened extensively hydrolyzed casein-based formula (TeHCF) in children with cow's milk allergy (CMA).

Methods: Children diagnosed with CMA through a double-blind placebo-controlled food challenge (DBPCFC) were randomly administered increased doses of a placebo formula or the TeHCF [Allernova, new thickener including fibres (Novalac)] under double-blind conditions and medical surveillance on two separate days. Otherwise, both of these formulas and a cow's milk-based formula were randomly introduced to children who were highly suspected of having CMA on three separate days. Immediate and late reactions occurring after the introduction of any of these formulas were thoroughly recorded by the physician at the hospital and reported by parents to the physician after hospital discharge, respectively. If the children tolerated the TeHCF during the DBPCFC, they were exclusively fed this formula during a 3-mo period where potential allergic symptoms, anthropometric parameters, as secondary outcomes, and adverse events were registered. The Cow's Milk-related Symptoms Score (CoMiSS) was assessed and anthropometric parameters were compared to World Health Organization (WHO) reference data.

Results: Of the 30 children included in the study, the CMA diagnosis of 29 (mean age: 8.03 ± 7.43 mo) patients was confirmed by a DBPCFC. The children all tolerated the TeHCF during both the challenge and the subsequent 3-mo feeding period, which they all completed. During the latter period, the CoMiSS remained at a very low level, never exceeding its baseline value (1.4 ± 2.0), growth parameters were within WHO reference standards and no adverse event related to the TeHCF was reported. Over the first week of this period, the proportion of patients with digestive discomfort significantly decreased from 20.7% (6/29) to 3.4% (1/29), = 0.025. The proportion of satisfaction with the overall effect of the formula reported by the parents and investigator was high, as was the formula acceptability by the child.

Conclusion: The new TeHCF meets the hypoallergenicity criteria according to the American Academy of Pediatrics standards, confirming that the tested TeHCF is adapted to the dietary management of children with CMA. Moreover, growth was adequate in the included population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12998/wjcc.v7.i16.2256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718785PMC
August 2019

Infections and malignancies risks related to TNF-α-blocking agents in pediatric inflammatory bowel diseases.

Expert Rev Gastroenterol Hepatol 2019 Oct 6;13(10):957-961. Epub 2019 Sep 6.

Pediatric Gastroenterology Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy.

: Tumor necrosis factor-α (TNF-α)-blocking agents are drugs approved for the treatment of inflammatory bowel diseases (IBDs). Infliximab and adalimumab are approved for the treatment of IBD in the pediatric setting with the improvement of therapeutic management. Biological agents, also in the pediatric population, can be administered either alone or in combination with immunomodulators. Their use has raised safety concerns regarding the risk of infections and malignancies.: A broad review of the safety concerns for the use of anti-TNF-α drugs in children with IBD was performed, and information regarding the risk of infections and malignancies were updated, also in comparison with the safety of traditional drugs such as steroids and/or immunosuppressants.: Anti-TNF-α drugs have shown favorable safety profiles, and adalimumab treatment is associated with lower immunogenicity compared with infliximab. Heightened awareness and vigilant surveillance leading to prompt diagnosis and treatment are important for optimal management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17474124.2019.1663173DOI Listing
October 2019

Neuropsychiatric manifestations in celiac disease.

Epilepsy Behav 2019 10 31;99:106393. Epub 2019 Aug 31.

NESMOS Department, Faculty of Medicine and Psychology, Sapienza University, Sant'Andrea Hospital, Rome, Italy. Electronic address:

Celiac disease (CD) is a systemic, chronic immune-mediated disorder elicited by gluten and related prolamines in genetically susceptible subjects. Main manifestations of CD involve the digestive tract; however, a growing body of evidence supports the theory that symptoms may occur in every part of the body. It is known that some patients with CD can be asymptomatic, and additionally, the incidence of "nonclassical" CD with extraintestinal presentation is apparently increasing. We aimed to perform a thorough review of existing evidence for neurological manifestations of CD, providing an up-to-date description of prevalence and examining the pathogenetic mechanisms possibly involved. Neurological presentations are rare in children but as many as 36% of adult patients present with neurological findings. With severe malnutrition after progression of CD, different vitamin deficiencies may develop. Such problems can in turn overlap with previous neurological abnormalities including ataxia, epilepsy, neuropathy, dementia, and cognitive disorders. Here, the most prevalent clinical manifestations in adults and children have been discussed in further detail. Further research is needed to achieve a complete understanding of the nervous system involvement in CD, but clinicians should always remember that neurological and psychiatric symptoms might be part of the CD spectrum of manifestations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2019.06.036DOI Listing
October 2019

Functional analysis of gut microbiota and immunoinflammation in children with autism spectrum disorders.

Dig Liver Dis 2019 10 16;51(10):1366-1374. Epub 2019 Jul 16.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. Electronic address:

Background And Aims: Recent evidence implicates gut microbiota (GM) and immune alterations in autism spectrum disorders (ASD). We assess GM profile and peripheral levels of immunological, neuronal and bacterial molecules in ASD children and controls. Alarmin HMGB1 was explored as a non-invasive biomarker to monitor gastrointestinal (GI) symptoms.

Methods: Thirty ASD children and 14 controls entered into the study. GM metagenomic analysis was performed for 16 ASD patients and 7 controls. GM functional profile was assessed by GO term analysis. Blood levels of IL-1β, TNFα, TGFβ, IL-10, INFγ, IL-8, lipopolysaccharide, Neurotensin, Sortilin1 and GSSG/GSH ratio were analyzed in all subjects by ELISA. Fecal HMGB1 was analyzed by Western blot.

Results: We observed a significant decrease in bacterial diversity. Furthermore, 82 GO terms underrepresented in ASD. Four of them pointed at 3,3 phenylpropionate catabolism and were imputable to Escherichia coli (E. coli) group. Serum levels of TNFα, TGFβ, NT, and SORT-1 increased in ASD patients. Fecal levels of HMGB1 correlated with GI sign severity in ASD children.

Conclusions: We suggest that a decrease of E. coli might affect the propionate catabolism in ASD. We report occurrence of peripheral inflammation in ASD children. We propose fecal HMGB1 as a non-invasive biomarker to detect GI symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2019.06.006DOI Listing
October 2019

Dipotassium Glycyrrhizate Improves Intestinal Mucosal Healing by Modulating Extracellular Matrix Remodeling Genes and Restoring Epithelial Barrier Functions.

Front Immunol 2019 26;10:939. Epub 2019 Apr 26.

Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, ENEA, Rome, Italy.

Gut mucosal healing (MH) is considered a key therapeutic target and prognostic parameter in the management of inflammatory bowel disease (IBD). The dipotassium glycyrrhizate (DPG), a salt of the glycoconjugated triterpene glycyrrhizin, has been shown to inhibit the High Mobility Group Box 1 (HMGB1) protein, an allarmin strongly implicated in the pathogenesis of most inflammatory and auto-immune disorders. Here we discuss new insights on how DPG acts on MH comparing the acute phase and the recovery phase from experimental colitis in mice. We found that DPG strongly accelerates MH by differently regulating pro-inflammatory (CXCL1, CXCL3, CXCL5, PTGS2, IL-1β, IL-6, CCL12, CCL7) and wound healing (COL3A1, MMP9, VTN, PLAUR, SERPINE, CSF3, FGF2, FGF7, PLAT, TIMP1) genes as observed only during the recovery phase of colitis. Relevant issue is the identification of extracellular matrix (ECM) remodeling genes, VTN, and PLAUR, as crucial genes to achieve MH during DPG treatment. Furthermore, a noticeable recovery of intestinal epithelial barrier structural organization, wound repair ability, and functionality is observed in two human colorectal adenocarcinoma cell lines exposed to DPG during inflammation. Thus, our study identifies DPG as a potent tool for controlling intestinal inflammation and improving MH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.00939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498413PMC
September 2020

Anaphylaxis after wheat ingestion in a patient with coeliac disease: two kinds of reactions and the same culprit food.

Eur J Gastroenterol Hepatol 2019 Jul;31(7):893-895

Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy.

In recent years, the role of atopic dermatitis epidermal skin barrier defects in inducing a transcutaneous allergic sensitization is highly debated, possibly explaining why some children with eczema are sensitized to foods they have never eaten. In our specific situation, the association between coeliac disease and wheat allergy might be particularly harmful owing to unavoidable strict food avoidance. We describe the case of a young boy affected by coeliac disease who, after an occasional unexpected ingestion of gluten, experienced a complete anaphylactic reaction characterized by urticarial, labial angioedema, wheezing, and hypotension. To better investigate the state of allergic sensitization to wheat in our patient, we then performed the component resolved diagnosis, which showed Tri a19 2 kU/l and Tri a14 0.3 kU/l. These results demonstrated the association of IgE-mediated allergy to wheat and coeliac disease. The natural course of specific IgE in allergic patients who are on a food-free diet needs further investigation, such as the possible influence that the increasing popularity of gluten-free diets may have on the epidemiology of wheat allergy in westernized societies. National and International registers of cases of anaphylaxis may improve the still limited knowledge in this field. The final message of our contribution is that the decision to eliminate a food should to take into account a patient's awareness of possible consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MEG.0000000000001421DOI Listing
July 2019

MRI reveals different Crohn's disease phenotypes in children and adults.

Eur Radiol 2019 Sep 7;29(9):5082-5092. Epub 2019 Feb 7.

Department of Pediatrics and Pediatric Neuropsychiatry, Sapienza University of Rome, Policlinico Umberto I Hospital, Viale del Policlinico, 155, 00161, Rome, Italy.

Objectives: To identify differences between two cohorts of adult and pediatric patients affected by Crohn's disease (CD), with regard to lesion location in the small intestine and colon-rectum, lesion activity, and prevalence of perianal disease (PD), using MRI as the main diagnostic tool.

Methods: We retrospectively reviewed 350 consecutive MRI examinations performed between 2013 and 2016 in outpatients or inpatients with histologically proven CD, monitored by the Gastroenterology and Pediatric Units of our Hospital. The magnetic resonance enterography (MRE) protocol for adult and pediatric CD patients routinely includes evaluation of nine different intestinal segments (from jejunum to rectum) and of the anal canal. Intestinal activity was also calculated using a validated score. Perianal disease (PD) was staged. Fisher's exact test was used and the odds ratio (OR) was calculated.

Results: Two hundred and nineteen out of 350 MRI studies (118 adults and 101 children) were included. The prevalence of PD was 34.6% in children and 16.1% in adults (OR = 2.8; p = 0.0017). Pediatric patients showed more frequent rectal involvement (29.7% vs 13.5%, OR = 2.7; p = 0.0045) and higher risk of PD in the presence of rectal disease (p = 0.043; OR = 4.5). In pediatric patients with severe colorectal disease, the prevalence of PD was twofold (86.7% vs 40%; p = 0.072). Using the clinical Montreal classification for lesion location, no significant differences emerged between the two patient populations.

Conclusions: MRI showed a significantly higher prevalence of rectal involvement and perianal disease in the pediatric population. These results may have a relevant clinical impact and deserve further investigation.

Key Points: • To our knowledge, this is the largest morphological comparative study available in the literature using MRI as the main diagnostic tool to compare adult patients and children with Crohn's disease. • Our study showed significant differences between adults and children: a higher prevalence of rectal and perianal fistulous disease (PD) in pediatric patients and an increased prevalence of PD in the presence of severe colon-rectum involvement. • The association of rectal and perianal disease implies a poorer clinical prognosis and a higher risk of disabling complications in pediatric patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00330-019-6006-5DOI Listing
September 2019
-->