Manuscript Review at the Journal of Pediatric Gastroenterology and Nutrition: The Impact of Reviewers on Editor Decisions.

OBJECTIVE: Given the importance of scholarly work in academic medicine, better understanding of the manuscript review process (MRP) is useful for authors, reviewers, and editorial boards. We aim to describe the MRP at the Journal of Pediatric Gastroenterology and Nutrition (JPGN), assess the correlation between editor decisions and reviewer recommendations, and provide transparency to this process. METHODS: All manuscripts submitted in 2018 to JPGN were included in this analysis. Data included reviewers' manuscript scores and recommendations, time spent on each review by reviewers, the editor's rating of the reviewers' reviews, the editor's first decision, and final outcome. Data were collated using the JPGN manuscript submission website, Editorial Manager. RESULTS: 1023 manuscripts were submitted to JPGN in 2018 and included in this analysis. Of these, 486 manuscripts had at least two peer reviewers. The recommendations of the two reviewers were in agreement 43% of the time. Intra-class correlation (ICC) between the two reviewers suggests moderate agreement (ICC = 0.40). When both reviewers agreed to Not Reject (289/486), the editor agreed in 93% of cases (269/289). When both reviewers agreed to Reject (55/486), the editor agreed 100% of the time (55/55). The reviewers disagreed in about one-third of submissions (142/486), and the editor recommended to Reject in two-thirds of these cases (95/142). Overall, inter-reviewer agreement strongly correlated with the editor's initial decision (P < 0.001). CONCLUSIONS: The editor most often agreed with reviewers' assessments when there was concordance between the two reviewers' recommendations. About a third of peer reviews result in discordant recommendations between the two reviewers.

Preformed and de novo DSA are associated with T-cell-mediated rejection in pediatric liver transplant recipients requiring clinically indicated liver biopsy.

Despite growing interest about the impact of donor-specific HLA antibodies (DSA) in LT limited data are available for pediatric recipients. Our aim was to perform a retrospective single-center chart review of children (0-16 years) having undergone LT between January 1, 2005 and December 31, 2017, to characterize DSA, to identify factors associated with the development of de novo DSA, and to analyze potential associations with the diagnosis of TCMR. Information on patient- and donor-characteristics and LB reports were analyzed retrospectively. Serum obtained before LT and at LB was analyzed for presence of recipient HLA antibody using Luminex® technology. MFI > 1000 was considered positive. In 63 pediatric LT recipients with a median follow-up of 72 months, the overall prevalence of de novo DSA was 60.3%. Most were directed against class II antigens (33/38, 86.8%). Preformed DSA were present in 30% of patients. Twenty-eight (28/63) patients (44.4%) presented at least one episode of TCMR, mostly (12/28, 43%) moderate (Banff 6-7). De novo DSA were significantly more frequent in patients with TCMR than in patients without (75% vs 48.6%, P = .03), and patients with preformed and de novo DSA had a significantly higher rate of TCMR than patients without any DSA (66.7% vs 20%, P = .02). Neither preformed DSA nor de novo DSA were associated with frequency or severity of TCMR. Recipients with lower weight at LT developed de novo DSA more frequently (P = .04). De novo DSA were highly prevalent in pediatric LT recipients. Although associated with the development of TCMR, they did not appear to impact the frequency or severity of TCMR or graft survival. Instead, de novo DSA may suggest a state of insufficient IS.

Validity Evidence for a Residency Admissions Standardized Assessment Letter for Pediatrics.

Construct: This study aims to provide validity evidence for the standardized Assessment Letter for Pediatrics as a measure of competencies expected of a 1st-year pediatrics resident as part of a pediatric residency admissions process. BACKGROUND: The Narrative Letter of Recommendation is a frequently used tool in the residency admissions process even though it has poor interrater reliability, lacks pertinent content, and does not correlate with residency performance. A newer tool, the Standardized Letter, has shown validity evidence for content and interrater reliability in other specialties. We sought to develop and provide validity evidence for the standardized Assessment Letter for Pediatrics. APPROACH: All 2012 and 2013 applicants invited to interview at the University of Geneva Pediatrics Residency Program provided 2 standardized Assessment Letters. Content for the letter was based on CanMEDS roles and ratings of 6 desired competencies and an overall assessment. Validity evidence was gathered for internal structure (Cronbach's alpha and generalizability), response process (interrater reliability with intraclass correlation), relations to other variables (Pearson's correlation coefficient), and consequences (logistic regression to predict admission). RESULTS: One hundred fourteen faculty completed 142 standardized Assessment Letters for 71 applicants. Average overall assessment was 3.0 of 4 (SD = 0.59). Cronbach's alpha was 0.93. The G-coefficient was 0.59. The decision study projected that four Assessment Letters are needed to attain a G-coefficient of 0.73. Applicant variance (28.5%) indicated high applicant differentiation. The Assessment Letter intraclass coefficient was 0.51, 95% confidence interval (CI) [0.43, 0.59]. Assessment Letter scores were correlated with the structured interview (r = .28), 95% CI [0.05, 0.51]; global rating (r = .36), 95% CI [0.13, 0.58]; and admissions decision (r = .25), 95% CI [0.02, 0.46]. Assessment Letter scores did not predict the admissions decision (odds ratio = 1.67, p = .37) after controlling for the unique contribution of the structured interview and global rating scores. CONCLUSION: Validity evidence supports use of the Assessment Letter for Pediatrics; future studies should refine items to improve predictive validity and explore how to best integrate the Assessment Letter into the residency admissions process.

Improving the residency admissions process by integrating a professionalism assessment: a validity and feasibility study.

The purpose of this study was to provide validity and feasibility evidence in measuring professionalism using the Professionalism Mini-Evaluation Exercise (P-MEX) scores as part of a residency admissions process. In 2012 and 2013, three standardized-patient-based P-MEX encounters were administered to applicants invited for an interview at the University of Geneva Pediatrics Residency Program. Validity evidence was gathered for P-MEX content (item analysis); response process (qualitative feedback); internal structure (inter-rater reliability with intraclass correlation and Generalizability); relations to other variables (correlations); and consequences (logistic regression to predict admission). To improve reliability, Kane's formula was used to create an applicant composite score using P-MEX, structured letter of recommendation (SLR), and structured interview (SI) scores. Applicant rank lists using composite scores versus faculty global ratings were compared using the Wilcoxon signed-rank test. Seventy applicants were assessed. Moderate associations were found between pairwise correlations of P-MEX scores and SLR (r = 0.25, P = .036), SI (r = 0.34, P = .004), and global ratings (r = 0.48, P < .001). Generalizability of the P-MEX using three cases was moderate (G-coefficient = 0.45). P-MEX scores had the greatest correlation with acceptance (r = 0.56, P < .001), were the strongest predictor of acceptance (OR 4.37, P < .001), and increased pseudo R-squared by 0.20 points. Including P-MEX scores increased composite score reliability from 0.51 to 0.74. Rank lists of applicants using composite score versus global rating differed significantly (z = 5.41, P < .001). Validity evidence supports the use of P-MEX scores to improve the reliability of the residency admissions process by improving applicant composite score reliability.

Complications of indwelling central venous catheters in pediatric liver transplant recipients.

In pLT recipients, the advantages of ICVCs need to be weighed against the risk of complications. This single-center retrospective study aimed to review ICVC complications in our cohort of pLT recipients. We performed chart reviews of pLT patients having undergone transplant between 01/2000 and 03/2014 and who underwent ICVC placement either before or after LT. We identified 100 ICVC in 85 patients. Overall observation time was 90 470 catheter-days. There was no difference in catheter lifespan between those inserted pre- or post-transplant; 46% of ICVC presented a complication. Most frequent complications were MD and infection. The infection rate was 0.09 per 1000 catheter-days, and MD rate was 0.36 per 1000 catheter-days. Patients having received technical variant grafts were more at risk of complications. To the best of our knowledge, this is the first study examining ICVC complications in pLT recipients. We conclude that ICVC have a high rate of MD. Children receiving technical variants may be more at risk of complications. By removing ICVC in a select number of patients at six months post-insertion, we might avoid as much as 60% of complications.

Risk factors for early and late biliary complications in pediatric liver transplantation.

BC are a common source of morbidity after pediatric LT. Knowledge about risk factors may help to reduce their incidence. Retrospective analysis of BC in 116 pediatric patients (123 LT) (single institution, 05/1990-12/2011, medium follow-up 7.9 yr). One-, five-, and 10-yr survival was 91.1%, no patient died of BC. Prevalence and risk factors for anastomotic and intrahepatic BC were examined. There were 29 BC in 123 LT (23.6%), with three main categories: 10 (8.1%) primary anastomotic strictures, eight (6.5%) anastomotic leaks, and three (2.4%) intrahepatic strictures. Significant risk factors for anastomotic leaks were total operation time (increase 1.26-fold) and early HAT (<30 days post-LT; increase 5.87-fold). Risk factor for primary anastomotic stricture was duct-to-duct choledochal anastomosis (increase 5.96-fold when compared to biliary-enteric anastomosis). Risk factors for intrahepatic strictures were donor age >48 yr (increase 1.09-fold) and MELD score >30 (increase 1.2-fold). To avoid morbidity from anastomotic BC in pediatric LT, the preferred biliary anastomosis appears to be biliary-enteric. Operation time should be kept to a minimum, and HAT must by all means be prevented. Children with a high MELD score or receiving livers from older donors are at increased risk for intrahepatic strictures.

High bone density in adolescents with obesity is related to fat mass and serum leptin concentrations.

OBJECTIVES: Obesity has been associated with increased bone mass, but the mechanisms involved are still poorly understood. We aimed to explore the relation between bone mineral density and factors known to influence bone formation in obese and lean adolescents. METHODS: We recruited 24 obese and 25 lean adolescents in a case-control study. Total body bone mineral density (TB-BMD) z scores and body composition were determined using dual-energy x-ray absorptiometry. We measured 25-hydroxyvitamin D (25-OH-D), glucose, insulin, and leptin concentrations. Physical activity (PA) level was quantified using accelerometer. RESULTS: TB-BMD z score was higher, whereas 25-OH-D and PA levels were lower in obese compared with lean subjects (TB-BMD z score 1.06 ±â€Š0.96 vs 0.26 ±â€Š0.91, P = 0.004; 25-OH-D 9.9 ±â€Š6.4 vs 18.5 ±â€Š7.4 ng mL, P < 0.001; PA level 308.3 ±â€Š22.1 vs 406.8 ±â€Š29.2 count min, P = 0.01). TB-BMD z score was not related to 25-OH-D or PA levels, but was positively correlated with leptin concentration and fat mass (P < 0.05). Vitamin D concentration was negatively correlated with fat mass (P < 0.001). CONCLUSIONS: Despite lower serum vitamin D and PA levels, BMD was higher in adolescents with obesity and associated with higher serum leptin concentrations. Furthermore, adolescents with obesity have lower vitamin D serum concentrations than lean controls, probably owing to its distribution in adipose tissue.

Parental functioning improves the developmental quotient of pediatric liver transplant recipients.

Psychomotor development in pediatric liver transplant (LT) recipients depends on several factors. Our aim was to evaluate the importance of parental involvement and family dynamics on psychomotor development by assessing (i) children and parents individually, (ii) the parent-child relationship, and (iii) the correlation between parental functioning and patient outcome, all before and after LT. Age-appropriate scales were used before and after LT. Twenty-one patients, 19 mothers, and 16 fathers were evaluated. Developmental quotient (DQ): No subjects scored in the "very good" range. The proportion of children with deficits increased from LT to two yr: 17.6% vs. 28.6%. Subjects 0-2 yr were more likely to have normal DQ at transplant (66.7% vs. 50% for older children). Abnormal DQ was more prevalent two yr post-LT in children older at LT (p = 0.02). The mother-child relationship was normal in 59% of families pre-LT and in 67% at two yr. The relationship was more favorable when the child received a transplant as an infant (p = 0.014 at 12 months post-LT). Normal DQ was associated with higher maternal global functioning score pre-LT (p = 0.03). Paternal performance scores were higher than maternal scores. Children transplanted after two yr of age suffer greater long-term deficits than those transplanted as infants.

Caroli disease, bilateral diffuse cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas: a ciliopathy caused by a homozygous NPHP3 mutation.

UNLABELLED: We report the rare association of Caroli disease (intrahepatic bile duct ectasia associated with congenital hepatic fibrosis), bilateral cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas in a female child. She presented with end-stage renal disease at the age of 1 month, followed by a rapidly progressing hepatic fibrosis and dilatation of the intrahepatic bile ducts, leading to secondary biliary cirrhosis and portal hypertension. Combined liver-kidney transplantation was performed at the age of 4 years, with excellent outcome. DNA analysis showed a NPHP3 (coding nephrocystin-3) homozygote mutation, confirming that this malformation complex is a ciliopathy. CONCLUSION: This rare association required an exceptional therapeutic approach: combined simultaneous orthotopic liver and kidney transplantation in a situs inversus recipient. The long-term follow-up was excellent with a very good evolution of the renal and hepatic grafts and normalization of growth and weight. This malformation complex has an autosomal recessive inheritance with a 25% recurrence risk in each pregnancy.

Increased pancreatic fat fraction is present in obese adolescents with metabolic syndrome.

OBJECTIVES: Little is known about pancreatic fat accumulation and its possible associations with metabolic syndrome (MetS) and glucose metabolism. The aim of the present study was to quantify pancreatic fat fraction (PFF) in lean and obese adolescents and explore its relation to metabolic parameters. METHODS: We recruited 25 lean and 24 obese adolescents. PFF and visceral adipose tissue (VAT) were determined using magnetic resonance imaging. We measured blood pressure, fasting glucose, insulin, liver enzymes, leptin, and lipid levels. Obese subjects underwent an oral glucose tolerance test. RESULTS: PFF was significantly higher in obese than in lean subjects (4.8±1.2 vs 3.6±0.9; P<0.001) and was associated with VAT, γ-glutamyltransferase, triglycerides, high-density lipoprotein cholesterol, leptin concentrations, and MetS (P<0.05 for all). None of the obese subjects had glucose intolerance, but when adjusted for VAT, the following 3 parameters correlated negatively with PFF: fasting and 30- minute and 120-minute insulin levels. We divided subjects into 3 groups: group I, lean without MetS; group II, obese without MetS; and group III, obese with MetS, and observed that PFF increased gradually among groups (I: 3.56%±0.88%; II: 4.70%±1.06%; III: 5.34%±1.49%; P<0.001). CONCLUSIONS: Obese adolescents accumulate fat in the pancreas. PFF correlates with the presence of MetS. Even in the absence of glucose intolerance, pancreatic fat deposition is associated with impaired insulin response to glucose overload. This suggests that ß-cell dysfunction may already be present in nondiabetic obese adolescents, mirroring what has been shown in adults, and that pancreatic fat accumulation may participate in obesity-associated pancreatic endocrine dysfunction.

Molecular and biochemical characterisation of a novel mutation in POLG associated with Alpers syndrome.

BACKGROUND: DNA polymerase γ (POLG) is the only known mitochondrial DNA (mtDNA) polymerase. It mediates mtDNA replication and base excision repair. Mutations in the POLG gene lead to reduction of functional mtDNA (mtDNA depletion and/or deletions) and are therefore predicted to result in defective oxidative phosphorylation (OXPHOS). Many mutations map to the polymerase and exonuclease domains of the enzyme and produce a broad clinical spectrum. The most frequent mutation p.A467T is localised in the linker region between these domains. In compound heterozygote patients the p.A467T mutation has been described to be associated amongst others with fatal childhood encephalopathy. These patients have a poorer survival rate compared to homozygotes. METHODS: mtDNA content in various tissues (fibroblasts, muscle and liver) was quantified using quantitative PCR (qPCR). OXPHOS activities in the same tissues were assessed using spectrophotometric methods and catalytic stain of BN-PAGE. RESULTS: We characterise a novel splice site mutation in POLG found in trans with the p.A467T mutation in a 3.5 years old boy with valproic acid induced acute liver failure (Alpers-Huttenlocher syndrome). These mutations result in a tissue specific depletion of the mtDNA which correlates with the OXPHOS-activities. CONCLUSIONS: mtDNA depletion can be expressed in a high tissue-specific manner and confirms the need to analyse primary tissue. Furthermore, POLG analysis optimises clinical management in the early stages of disease and reinforces the need for its evaluation before starting valproic acid treatment.

Partially hydrolysed 100% whey-based infant formula and the prevention of atopic dermatitis: comparative pharmacoeconomic analyses.

Clinical trials have demonstrated that the risk of developing atopic dermatitis is reduced when using hydrolysed formulas to feed infants with a documented risk of atopy (i.e. an affected parent and/or sibling)when breastfeeding is not practised. However, little is known about the cost-effectiveness of using hydrolysed formulas. Consequently, economic analyses in 5 European countries (Denmark, France, Germany, Spain and Switzerland) have evaluated the costs and cost-effectiveness of a specific brand of 100% whey-based partially hydrolysed infant formula, NAN-HA® (PHF-W) compared with a cow's milk standard formula (SF) in the prevention of atopic dermatitis in at-risk children. This review synthesises the findings of these studies. Cost-effectiveness analyses (CEA) used a decision-analytic model to determine treatment pathways, resource utilisation and costs associated with the management of atopic dermatitis in healthy at-risk newborns who were not exclusively breastfed. The model had a 12-month horizon and applied reimbursement rates of 60-100% depending on the country. Outcomes were considered from the perspective of the public healthcare system (e.g. the Ministry of Health; MOH), family and society. The final outcome was the incremental cost-effectiveness ratio per avoided case of atopic dermatitis (ICER) for PHF-W versus SF. A cost-minimisation analysis was also performed to compare PHF-W with extensively hydrolysed formulas (EHF). The base-case CEA produced ICERs per avoided case for PHF-W versus SF of EUR 982-1,343 (MOH perspective), EUR -2,202 to -624 (family perspective) indicating savings, and EUR -1,220 to 719 from the societal perspective. The main costs related to formula (MOH and society) and time loss (family). In the cost-minimisation analysis, PHF-W yielded savings of between EUR 4.3 and 120 million compared with EHF-whey when the latter was used in prevention. In conclusion, PHF-W was cost-effective versus SF in the prevention of atopic dermatitis and cost saving compared with EHF when used in prevention.

Immune reconstitution inflammatory syndrome and solid organ transplant recipients: are children protected?

The IRIS was initially described in HIV-positive patients as a sudden clinical deterioration after the introduction of highly active retroviral therapy. It is believed that IRIS is caused by a restored and exaggerated inflammatory immune response to different infectious or non-infectious triggers. This abnormal response is the consequence of an imbalance between pro-inflammatory and anti-inflammatory states. Recently, IRIS has also been reported in adult SOT recipients, causing local and systemic manifestations, and compromising long-term graft function and patient survival. However, IRIS has to date not been reported in pediatric SOT recipients. Here we review what is known and speculated about the pathogenesis of IRIS and propose that children may be relatively protected from IRIS.

E-Learning Training to Improve Pediatric Parenteral Nutrition Practice: A Pilot Study in Two University Hospitals.

BACKGROUND: Education and training may improve the prescription of pediatric parenteral nutrition. The aim was to evaluate the impact of an e-learning method on parenteral nutrition prescription skills among pediatric residents in 2 pediatric hospitals. METHODS: A randomized double-blind control study was conducted over a 9-month period among pediatric residents in HOSP1, Geneva, Switzerland, where physicians prescribe parenteral nutrition directly, and in HOSP2, Montreal, Canada, where physicians prescribe only occasionally because clinical pharmacists are devoted to this activity. The intervention consisted of an e-learning session about key issues of parenteral nutrition. Physician parenteral nutrition knowledge was evaluated with a standardized questionnaire based on clinical cases before and after the e-learning in the intervention groups; in the control groups, only the 2 tests were conducted. In HOSP1, participants also underwent iterative tests every 2 months to measure the retention of knowledge. RESULTS: Sixty-five physicians participated. Initial knowledge scores were higher in HOSP1 (pretest scores 180 ± 29 vs 133 ± 24, p < 0.001). Overall, there was no significant difference in the impact of the e-learning intervention between the control and e-learning groups (p > 0.05). A significant knowledge improvement was observed in HOSP2 in the e-learning group (p = 0.033). Iterative tests in HOSP1 showed persistence of knowledge without significant differences between the groups. E-learning satisfaction among the participants was outstanding (100%). CONCLUSION: E-learning seems to be an effective method for teaching parenteral nutrition among pediatric residents and fellows at the beginning of the training. High satisfaction with this teaching method was observed in this study.