Clostridioides difficile Infection in Hospitalized Pediatric Patients: Comparisons of Epidemiology, Testing, and Treatment from 2013 to 2019.

OBJECTIVES: To compare the incidence, epidemiology, testing patterns, treatment, and outcomes of Clostridioides difficile infection (CDI) among hospitalized pediatric patients from 2013 to 2019. STUDY DESIGN: The Pediatric Health Information System database was queried for patient admissions (age 0-17 years) with International Classification of Diseases, 9th and 10th edition, codes for diagnoses of CDI with a billing code for a CDI-related antibiotic treatment. RESULTS: We identified 17 142 pediatric patients, representing 23 052 admissions, with CDI. The adjusted annual CDI incidence decreased over the study period from 7.09 cases per 10 000 patient-days (95% CI, 6.15-8.18) in 2013 to 4.89 cases per 10 000 patient-days (95% CI, 4.03-5.93) in 2019 (P < .001). C difficile-specific testing also decreased during the study period (P < .001). Chronic gastrointestinal conditions (36%) and malignancy (32%) were the most common comorbidities in CDI encounters. Oral metronidazole use decreased during the study period (P < .01) and oral vancomycin use increased (P < .001). CONCLUSIONS: Our study demonstrates a decrease in CDI incidence in hospitalized pediatric patients, a notable change from prior studies, although this may have been influenced by altered testing patterns. We found a high incidence of CDI in patients with cancer and gastrointestinal conditions: groups that warrant targeted evaluation of CDI prevention and treatment.

Fecal Microbiota Transplantation for Clostridioides difficile Infection in Immunocompromised Pediatric Patients.

OBJECTIVES: We sought to evaluate the safety and effectiveness of fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (CDI) in pediatric immunocompromised (IC) patients. METHODS: This is a multicenter retrospective cohort study of pediatric participants who underwent FMT between March 2013 and April 2020 with 12-week follow-up. Pediatric patients were included if they met the definition of IC and were treated with FMT for an indication of recurrent CDI. We excluded patients over 18 years of age, those with incomplete records, insufficient follow-up, or not meeting study definition of IC. We also excluded those treated for Clostridioides difficile recurrence without meeting the study definition and those with inflammatory bowel disease without another immunocompromising condition. RESULTS: Of 59 pediatric patients identified at 9 centers, there were 42 who met inclusion and no exclusion criteria. Included patients had a median age of 6.7 years. Etiology of IC included: solid organ transplantation (18, 43%), malignancy (12, 28%), primary immunodeficiency (10, 24%), or other chronic conditions (2, 5%). Success rate was 79% after first FMT and 86% after 1 or more FMT. There were no statistically significant differences in patient characteristics or procedural components when patients with a failed FMT were compared to those with a successful FMT. There were 15 total serious adverse events (SAEs) in 13 out of 42 (31%) patients that occurred during the follow-up period; 4 (9.5%) of which were likely treatment-related. There were no deaths or infections with multidrug resistant organisms during follow-up and all patients with a SAE fully recovered. CONCLUSIONS: The success rate of FMT for recurrent CDI in this pediatric IC cohort is high and mirrors data for IC adults and immunocompetent children. FMT-related SAEs do occur (9.5%) and highlight the need for careful consideration of risk and benefit.

IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.

Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.

Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study.

BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.

Efficacy of Fecal Microbiota Transplantation for Clostridium difficile Infection in Children.

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is commonly used to treat Clostridium difficile infection (CDI). CDI is an increasing cause of diarrheal illness in pediatric patients, but the effects of FMT have not been well studied in children. We performed a multi-center retrospective cohort study of pediatric and young adult patients to evaluate the efficacy, safety, and factors associated with a successful FMT for the treatment of CDI. METHODS: We performed a retrospective study of 372 patients, 11 months to 23 years old, who underwent FMT at 18 pediatric centers, from February 1, 2004, to February 28, 2017; 2-month outcome data were available from 335 patients. Successful FMT was defined as no recurrence of CDI in the 2 months following FMT. We performed stepwise logistic regression to identify factors associated with successful FMT. RESULTS: Of 335 patients who underwent FMT and were followed for 2 months or more, 271 (81%) had a successful outcome following a single FMT and 86.6% had a successful outcome following a first or repeated FMT. Patients who received FMT with fresh donor stool (odds ratio [OR], 2.66; 95% CI, 1.39-5.08), underwent FMT via colonoscopy (OR, 2.41; 95% CI, 1.26-4.61), did not have a feeding tube (OR, 2.08; 95% CI, 1.05-4.11), or had 1 less episode of CDI before FMT (OR, 1.20; 95% CI, 1.04-1.39) had increased odds for successful FMT. Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations. CONCLUSIONS: Based on the findings from a large multi-center retrospective cohort, FMT is effective and safe for the treatment of CDI in children and young adults. Further studies are required to optimize the timing and method of FMT for pediatric patients-factors associated with success differ from those of adult patients.

Decreased Fecal Bacterial Diversity and Altered Microbiome in Children Colonized With Clostridium difficile.

OBJECTIVES: The gut microbiome is believed to play a role in the susceptibility to and treatment of Clostridium difficile infections (CDIs). It is, however, unknown whether the gut microbiome is also affected by asymptomatic C difficile colonization. Our study aimed to evaluate the fecal microbiome of children based on C difficile colonization, and CDI risk factors, including antibiotic use and comorbid inflammatory bowel disease (IBD). METHODS: Subjects with IBD and non-IBD controls were prospectively enrolled from pediatric clinics for a biobanking project (n = 113). A fecal sample was collected from each subject for research purposes only and was evaluated for asymptomatic toxigenic C difficile colonization. Fecal microbiome composition was determined by 16S rRNA sequencing. RESULTS: We found reduced bacterial diversity and altered microbiome composition in subjects with C difficile colonization, concurrent antibiotic use, and/or concomitant IBD (all P < 0.05). Accounting for antibiotic use and IBD status, children colonized with C difficile had significant enrichment in taxa from the genera Ruminococcus, Eggerthella, and Clostridium. Children without C difficile had increased relative abundances of Faecalibacterium and Rikenellaceae. Imputed metagenomic functions of those colonized were enriched for genes in oxidative phosphorylation and beta-lactam resistance, whereas in the subjects without C difficile, several functions in translation and metabolism were over-represented. CONCLUSIONS: In children, C difficile colonization, or factors that predispose to colonization such as antibiotic use and IBD status were associated with decreased gut bacterial diversity and altered microbiome composition. Averting such microbiome alterations may be a method to prevent or treat CDI.

Utilizing Information Technology to Improve Influenza Vaccination in Pediatric Patients With Inflammatory Bowel Disease.

Pediatric patients with inflammatory bowel disease are undervaccinated against influenza. Gastroenterology nurses are ideally situated to assist in improving vaccination in this population. The objective of this quality improvement project was to evaluate the implementation of information technology prompts within the electronic medical record to improve influenza vaccination during specialty clinic visits. The proportion of patients with yearly influenza vaccination was evaluated at baseline, Year 1, and Year 2 following implementation. At baseline, only 10% of a random sample had documented influenza vaccination. Vaccination documentation improved to 39% (96/246) by Year 1 and to 61% (175/287) by Year 2 (p < .001). Vaccine counseling improved from 27% to 77% by Year 2 for unvaccinated patients (p < .001). Among patients seen by gastroenterology nurses, the proportion of patients with either documented vaccination or counseling was 94% by Year 2 compared with 70% if seen only by a physician (p < .001). Documentation of influenza vaccination improved with the use of customized prompts. Patients seen by a gastroenterology nurse had higher vaccination documentation and vaccine counseling than those who were seen by a physician alone.

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study.

BACKGROUND: Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. METHODS: We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. FINDINGS: Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. INTERPRETATION: Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. FUNDING: Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.

Biologics Delay Progression of Crohn's Disease, but Not Early Surgery, in Children.

BACKGROUND & AIMS: Up to 30% of patients with Crohn's disease (CD) require surgery within the first 5 years from diagnosis. We investigated the recent risk of bowel surgery in an inception cohort of pediatric patients with CD and whether early use of biologics (tumor necrosis factor antagonists) alters later disease course. METHODS: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group registry on 1442 children (age, ≤16 y) diagnosed with CD from January 2002 through December 2014. Data were collected at diagnosis, 30 days following diagnosis, and then quarterly and during hospitalizations for up to 12 years. Our primary aim was to determine the 10-year risk for surgery in children with CD. Our secondary aim was to determine whether early use of biologics (<3 mo of diagnosis) affected risk of disease progression. RESULTS: The 10-year risk of first bowel surgery was 26%. The 5-year risk of bowel surgery did not change from 2002 through 2014, and remained between 13% and 14%. Most surgeries occurred within 3 years from diagnosis. The only predictor of surgery was disease behavior at diagnosis. CD with inflammatory behavior had the lowest risk of surgery compared to stricturing disease, penetrating disease, or both. We associated slowing of disease progression to stricturing or penetrating disease (but not surgery) with early use of biologics, but this effect only became evident after 5 years of disease. Our results indicate that biologics slow disease progression over time (hazard ratio, 0.85; 95% CI, 0.76-0.95). CONCLUSIONS: In an analysis of data from a registry of pediatric patients with CD, we found that among those with significant and progressing disease at or shortly after presentation, early surgery is difficult to prevent, even with early use of biologics. Early use of biologics (<3 mo of diagnosis) can delay later disease progression to stricturing and/or penetrating disease, but this affect could become evident only years after initial management decisions are made.

The Effect of Early-Life Environmental Exposures on Disease Phenotype and Clinical Course of Crohn's Disease in Children.

OBJECTIVES: Environmental factors play an important role in the pathogenesis of Crohn's Disease (CD). In particular, by virtue of the instability of the microbiome and development of immunologic tolerance, early life factors may exert the strongest influence on disease risk and phenotype. METHODS: We used data from 1119 CD subjects recruited from RISK inception cohort to examine the impact of early life environment on disease progression. Our primary exposures of interest were breastfeeding in infancy and exposure to maternal, active, or passive smoke. Our primary outcomes were development of complicated (stricturing or penetrating) disease, and need for CD-related hospitalization, and surgery. Multivariable logistic regression models were used to define independent associations, adjusting for relevant covariates. RESULTS: Our study cohort included 1119 patients with CD among whom 15% had stricturing (B2) or penetrating disease (B3) by 3 years. 331 patients (35%) and 95 patients (10.6%) required CD-related hospitalizations and surgery respectively. 74.5% were breastfed in infancy and 31% were exposed to smoking among whom 7% were exposed to maternal smoke. On multivariable analysis, a history of breastfeeding was inversely associated with complicated (B2/B3 disease) 0.65, CI 95% 0.44-96; P = 0.03) in pediatric CD. Maternal smoking during pregnancy was associated with increased risk of hospitalization during the 3-year follow-up period (OR 1.75, CI 95% 1.05-2.89; P = 0.03). CONCLUSIONS: Early life environmental factors influence the eventual phenotypes and disease course in CD.

Fecal microbiota transplantation in children: a brief review.

There has been a growing interest in fecal microbiota transplantation (FMT) over recent years, in part due to the increasing prevalence of Clostridium difficile infection (CDI) and expanding association of intestinal dysbiosis with a wide range of human diseases. Many adult studies have shown that FMT is an effective treatment for recurrent CDI and may possibly have applications in other illnesses such as inflammatory bowel disease (IBD); however, there is a paucity of data available in children who may differ from adults for many reasons including having a dynamic developing microbiome compared to adults who have a relatively stable microbiome. Here, we review published studies looking at FMT in children, for CDI and IBD, and discuss special considerations needed when conducting FMT in children.

Concomitant Use of Immunomodulators Affects the Durability of Infliximab Therapy in Children With Crohn's Disease.

BACKGROUND & AIMS: It is important to determine the effects of immunomodulators on the ability of children to remain on infliximab therapy for Crohn's disease (durability of therapy), given the potential benefits and risks of concomitant therapy-especially with thiopurines in male patients. We investigated how immunomodulatory treatment affects the durability of infliximab therapy. METHODS: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, from January 2002 through August 2014, on 502 children with Crohn's disease who participated in a prospective multicenter study. Data were collected from patients who received at least a 3-dose induction regimen of infliximab, and their concomitant use of immunomodulators: no thiopurine or methotrexate treatment, treatment for 6 months or less during infliximab therapy, or treatment for more than 6 months during infliximab therapy. RESULTS: The probabilities (± standard error) that children remained on infliximab therapy for 1 year, 3 years, and 5 years after the treatment began were 0.84 ± 0.02, 0.69 ± 0.03, and 0.60 ± 0.03, respectively. Age, sex, and disease extent or location did not affect the durability of infliximab therapy. Greater length of concomitant use of immunomodulators was associated with increased time of infliximab therapy. The probability that patients with more than 6 months of immunomodulator use remained on infliximab therapy for 5 years was 0.70 ± 0.04, compared with 0.48 ± 0.08 for patients who did not receive immunomodulators and 0.55 ± 0.06 for patients who received immunomodulators for 6 months or less (P < .001). In boys who received immunomodulators for 6 months or more after starting infliximab, the overall durability of infliximab therapy was greater among patients receiving methotrexate than thiopurine (P < .01); the probabilities that they remained on infliximab therapy for 5 years were 0.97 ± 0.03 vs 0.58 ± 0.08, respectively. CONCLUSIONS: In children with Crohn's disease, concomitant treatment with an immunomodulator for more than 6 months after starting infliximab therapy increases the chances that patients will remain on infliximab. In boys, methotrexate appears to increase the durability of infliximab therapy compared with thiopurine.

Increased effectiveness of early therapy with anti-tumor necrosis factor-α vs an immunomodulator in children with Crohn's disease.

BACKGROUND & AIMS: Standard therapy for children newly diagnosed with Crohn's disease (CD) includes early administration of immunomodulators after initial treatment with corticosteroids. We compared the effectiveness of early (≤3 mo after diagnosis) treatment with an anti-tumor necrosis factor (TNF)α with that of an immunomodulator in attaining clinical remission and facilitating growth of pediatric patients. METHODS: We analyzed data from the RISK study, an observational research program that enrolled patients younger than age 17 diagnosed with inflammatory (nonpenetrating, nonstricturing) CD from 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early immunomodulator, or no early immunotherapy. We evaluated relationships among therapies, corticosteroid and surgery-free remission (pediatric CD activity index scores, ≤10), and growth at 1 year for 204 children. Treatment after 3 months was a covariate. RESULTS: Early treatment with anti-TNFα was superior to early treatment with an immunomodulator (85.3% vs 60.3% in remission; relative risk, 1.41; 95% confidence interval [CI], 1.14-1.75; P = .0017), whereas early immunomodulator therapy was no different than no early immunotherapy (60.3% vs 54.4% in remission; relative risk, 1.11; 95% CI, 0.83-1.48; P = .49) in achieving remission at 1 year. Accounting for therapy after 3 months, early treatment with anti-TNFα remained superior to early treatment with an immunomodulator (relative risk, 1.51; 95% CI, 1.20-1.89; P = .0004), whereas early immunomodulator therapy was no different than no early immunotherapy (relative risk, 1.00; 95% CI, 0.75-1.34; P = .99). The mean height z-score increased compared with baseline only in the early anti-TNFα group. CONCLUSIONS: In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.

Clinical Presentation and Five-Year Therapeutic Management of Very Early-Onset Inflammatory Bowel Disease in a Large North American Cohort.

OBJECTIVE: To evaluate the presentation, therapeutic management, and long-term outcome of children with very early-onset (VEO) (≤ 5 years of age) inflammatory bowel disease (IBD). STUDY DESIGN: Data were obtained from an inception cohort of 1928 children with IBD enrolled in a prospective observational registry at multiple centers in North America. RESULTS: One hundred twelve children were ≤ 5 years of age with no child enrolled at <1 year of age. Of those, 42.9% had Crohn's disease (CD), 46.4% ulcerative colitis (UC), and 10.7% had IBD-unclassified. Among the children with CD, children 1-5 years of age had more isolated colonic disease (39.6%) compared with 6- to 10-year-olds (25.3%, P = .04), and 11- to 16-year-olds (22.3%, P < .01). The change from a presenting colon-only phenotype to ileocolonic began at 6-10 years. Children 1-5 years of age with CD had milder disease activity (45.8%) at diagnosis compared with the oldest group (28%, P = .01). Five years postdiagnosis, there was no difference in disease activity among the 3 groups. However, compared with the oldest group, a greater proportion of 1- to 5-year-olds with CD were receiving corticosteroids (P < .01) and methotrexate (P < .01), and a greater proportion of 1- to 5-year-olds with UC were receiving mesalamine (P < .0001) and thiopurine immunomodulators (P < .0002). CONCLUSIONS: Children with VEO-CD are more likely to have mild disease at diagnosis and present with a colonic phenotype with change to an ileocolonic phenotype noted at 6-10 years of age. Five years after diagnosis, children with VEO-CD and VEO-UC are more likely to have been administered corticosteroids and immunomodulators despite similar disease activity in all age groups. This may suggest development of a more aggressive disease phenotype over time.

Liver enzyme elevations within 3 months of diagnosis of inflammatory bowel disease and likelihood of liver disease.

BACKGROUND: Inflammatory bowel disease-associated liver diseases (IBD-LDs) include autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and an overlap syndrome. Prospective unbiased multicenter data regarding the frequency of IBD-LD in patients with pediatric inflammatory bowel disease (IBD) are lacking. We examined early alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT) elevations in children diagnosed as having IBD and assessed the likelihood of IBD-LD. METHODS: Data collected from the prospective observational Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry enrolling children of age <16 years within 30 days of diagnosis. AIH, PSC, and overlap syndrome were diagnosed using local institutional criteria. RESULTS: A total of 1569 subjects had liver enzymes available. Of the total, 757 had both ALT and GGT, 800 had ALT only (no GGT), and 12 had GGT only (no ALT). Overall, 29 of 1569 patients (1.8%) had IBD-LD. IBD-LD was diagnosed in 1 of 661 (0.15%) of patients with both ALT and GGT ≤ 50 IU/L compared with 21 of 42 (50%) of patients with both ALT and GGT > 50 (odds ratio 660, P < 0.0001). Of the 29 patients with IBD-LD, 21 had PSC, 2 had AIH, and 6 had overlap syndrome. IBD-LD was more common in patients with ulcerative colitis and IBD-unclassified (indeterminate colitis) than in those with Crohn disease (4% vs 0.8%, respectively, P < 0.001). CONCLUSIONS: Elevation of both ALT and GGT within 90 days after the diagnosis of IBD is associated with a markedly increased likelihood of IBD-LD. Both ALT and GGT levels should be measured in all of the pediatric patients newly diagnosed as having IBD.

Two single group, prospective, baseline-controlled feeding studies in infants and children with chronic diarrhea fed a hypoallergenic free amino acid-based formula.

BACKGROUND: Infants and children with chronic diarrhea (CD) often require specialized foods or parenteral nutrition (PN) to achieve adequate nutrient intakes to support growth and development. We assessed the efficacy of an amino acid-based formula (AAF) in supporting growth and improving symptoms in infants and children with CD from multiple etiologies. METHODS: Two studies were conducted: CD study in children (CD-C) and CD study in infants (CD-I). Each was a single group, baseline-controlled study in which each subject served as his/her own control. At enrollment, all subjects had CD lasting > 2 weeks and had ≥ 4 stools/day. Subjects were fed an AAF for 80 days starting at SD5, and were assessed at SD 28 and 84. RESULTS CD-C: 18 of 19 subjects completed the study. At enrollment, the mean age was 5.6 ± 0.7 years, the most common diagnosis was short bowel syndrome (SBS) (n = 13), and 5 subjects with SBS were on PN. Subjects achieved significant increases in weight-for-age z-scores (p = 0.026). Over 50% of subjects achieved improvements in clinical outcomes targeted most frequently by their physicians. Of the five subjects on PN at enrollment, four had substantial weight gain and four had their PN requirements decreased. CD-I: 22 of 27 subjects completed the study. At enrollment, the mean age was 3.3 ± 0.3 months, the most common diagnosis was food allergy (n = 20), and no subjects were on PN. Subjects achieved significant increases in weight-for-age z-scores (p = 0.0023), significant decreases in the number of stools/day (p = 0.0012), and improvements in stool consistency (p = 0.0024). Over 80% of subjects achieved improvements in the clinical outcomes targeted most frequently by their physicians. CONCLUSIONS: Infants and children with CD fed an AAF for three months displayed significant improvements in weight-for-age z-scores and clinical symptoms. Children dependent on PN also grew well and four of five decreased their dependence on PN. TRIAL REGISTRATION: Both trials were registered on ClinTrials.gov (CD-C, NCT01812629; CD-I, NCT01820494).

Commitment to inclusion: The importance of collaboration in gender equity work.

Despite decades of faculty professional development programs created to prepare women for leadership, gender inequities persist in salary, promotion, and leadership roles. Indeed, men still earn more than women, are more likely than women to hold the rank of professor, and hold the vast majority of positions of power in academic medicine. Institutions demonstrate commitment to their faculty's growth by investing resources, including creating faculty development programs. These programs are essential to help prepare women to lead and navigate the highly matrixed, complex systems of academic medicine. However, data still show that women persistently lag behind men in their career advancement and salary. Clearly, training women to adapt to existing structures and norms alone is not sufficient. To effectively generate organizational change, leaders with power and resources must commit to gender equity. This article describes several efforts by the Office of Faculty in the Johns Hopkins University School of Medicine to broaden inclusivity in collaborative work for gender equity. The authors are women and men leaders in the Office of Faculty, which is within the Johns Hopkins University School of Medicine dean's office and includes Women in Science and Medicine. Here, we discuss potential methods to advance gender equity using inclusivity based on our institutional experience and on the findings of other studies. Ongoing data collection to evaluate programmatic outcomes in the Johns Hopkins University School of Medicine will be reported in the future.

Inspiring and Preparing Our Future Leaders: Evaluating the Impact of the Early Career Women's Leadership Program.

Purpose: The number of women in high-level leadership in academic medicine remains disproportionately low. Early career programs may help increase women's representation in leadership. We evaluated the Early Career Women's Leadership Program (ECWLP). We hypothesized that participants would rate themselves as having increased confidence in their leadership potential, improved leadership skills, and greater alignment between their goals for well-being and leading after the program. We also explored the participants' aspirations and confidence around pursuing high-level leadership before and after the program. Methods: We surveyed women physicians and scientists before and after they participated in the 2023 ECWLP, consisting of 11 seminars over six months. We analyzed pre- and post-program data using Wilcoxon signed-rank tests. We analyzed answers to open-ended questions with a content analysis approach. Results: 47/51 (92%) participants responded, and 74% answered pre- and post-program questionnaires. Several metrics increased after the program, including women's confidence in their ability to lead (p<0.001), negotiate (p<0.001), articulate their career vision (p<0.001), reframe obstacles (p<0.001), challenge their assumptions (p<0.001), and align their personal and professional values (p=0.002). Perceptions of conflict between aspiring to lead and having family responsibilities (p=0.003) and achieving physical well-being (p=0.002) decreased. Perceived barriers to advancement included not being part of influential networks, a lack of transparency in leadership, and a competitive and individualistic culture. In the qualitative analysis, women described balancing internal factors such as self-doubt with external factors like competing professional demands when considering leadership. Many believed that becoming a leader would be detrimental to their well-being. Beneficial ECWLP components included support for self-reflection, tactical planning to pursue leadership, and creating a safe environment. Conclusion: The ECWLP improved women's confidence and strategic plans to pursue leadership in a way that supported their work-life integration. Early career leadership programs may encourage and prepare women for high-level leadership.