Decreasing Prescribing Errors in Antimicrobial Stewardship Program-Restricted Medications.

OBJECTIVES: Antimicrobial stewardship programs (ASPs) restrict prescribing practices to regulate antimicrobial use, increasing the risk of prescribing errors. This quality improvement project aimed to decrease the proportion of prescribing errors in ASP-restricted medications by standardizing workflow. METHODS: The study took place on all inpatient units at a tertiary care children's hospital between January 2020 and February 2022. Patients <22 years old with an order for an ASP-restricted medication course were included. An interprofessional team used the Model for Improvement to design interventions targeted at reducing ASP-restricted medication prescribing errors. Plan-Do-Study-Act cycles included standardizing communication and medication review, implementing protocols, and developing electronic health record safety nets. The primary outcome was the proportion of ASP-restricted medication orders with a prescribing error. The secondary outcome was time between prescribing errors. Outcomes were plotted on control charts and analyzed for special cause variation. Outcomes were monitored for a 3-month sustainability period. RESULTS: Nine-hundred ASP-restricted medication orders were included in the baseline period (January 2020-December 2020) and 1035 orders were included in the intervention period (January 2021-February 2022). The proportion of prescribing errors decreased from 10.9% to 4.6%, and special cause variation was observed in Feb 2021. Mean time between prescribing errors increased from 2.9 days to 8.5 days. These outcomes were sustained. CONCLUSIONS: Quality improvement methods can be used to achieve a sustained reduction in the proportion of ASP-restricted medication orders with a prescribing error throughout an entire children's hospital.

Presentation of Severe Acute Respiratory Syndrome-Coronavirus 2 Infection as Cholestatic Jaundice in Two Healthy Adolescents.

Liver abnormalities in severe acute respiratory syndrome-coronavirus 2 infection, including hepatitis and cholestasis, have been observed in adults and are associated with worse outcomes. We describe 2 adolescents with cholestasis and hepatitis with mild presentation of severe acute respiratory syndrome-coronavirus 2 lacking typical symptoms. Our intention is to raise index of suspicion for testing and protective equipment use.

Detection of graft fibrosis by vibration-controlled transient elastography in pediatric liver transplant recipients.

Pediatric liver transplant recipients are at risk of developing graft fibrosis which can affect patient survival. VCTE is a non-invasive tool that measures LSM and has been shown to correlate with hepatic fibrosis. The aim of this study was to therefore evaluate the ability of LSM to predict fibrosis in pediatric liver transplant recipients with different graft types. We performed a cross-sectional study evaluating LSM of 28 pediatric liver transplant recipients who underwent a total of 20 liver biopsies within 1 month of LSM. LSM was compared to liver histology as well as graft type: WL or PL. The median LSM of all post-transplant patients was 5.6 kPa (range = 2.7-18.3). There was a statistically significant correlation between LSM and METAVIR fibrosis score (P = .001) and LAF score (P < .001). There was no difference in LSM between graft type (P = .088). The AUROC curve for LSM predicting any significant fibrosis (F ≥ 2) was 0.863. A cutoff value of 7.25 had a sensitivity of 71%, specificity of 100%, NPV of 87%, and PPV of 100% for significant fibrosis. LSM by VCTE is feasible in pediatric liver transplant recipients regardless of graft type. We found a significant correlation between LSM and hepatic fibrosis and established a cutoff value that may help determine which patients warrant further evaluation for graft fibrosis.

Notch signaling and progenitor/ductular reaction in steatohepatitis.

BACKGROUND AND OBJECTIVE: Persistent hepatic progenitor cells (HPC) activation resulting in ductular reaction (DR) is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis. METHODS: Steatohepatitis was generated using methionine-choline deficient (MCD) diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre. RESULTS: MCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-ß1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent) Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-ß1 treatment in primary hepatic stellate cells (HSC) induced Jag1 expression. In MCD diet-fed mice, αSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-ß1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression. CONCLUSION: Our data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target.

Hepatic Inflammation May Influence Liver Stiffness Measurements by Transient Elastography in Children and Young Adults.

OBJECTIVES: Transient elastography (TE) measures liver stiffness to assess fibrosis. Studies in adults have shown that inflammation increases stiffness, leading to an overestimation of fibrosis. We investigated the contribution of inflammation to liver stiffness measurements (LSMs) in children/young adults. METHODS: This was a cohort analysis of children/young adults who underwent TE within 1 year of liver biopsy. Alanine aminotransferase (ALT) was obtained within 30 days of the biopsy and LSM. Fibrosis was assessed by METAVIR stage and inflammation by ALT and Ishak score. Data were stratified into METAVIR F0-F2 versus F3-F4. Change between ALT and LSM over time was also assessed. RESULTS: A total of 154 patients (50% male patients) ages 3 weeks to 24 years (18% <3 years) were studied. Diagnoses included autoimmune (N = 38, 25%), viral (N = 25, 16%), cholestasis (N = 17, 11%), fatty liver (N = 9, 6%), biliary atresia (N = 8, 5%), metabolic (N = 5, 3%), allograft rejection (N = 4, 3%), and other (N = 48, 31%). Thirty-four percent of patients had F3-F4. In patients with F0-F2, the proportion of those with LSM >8.6 kPa increased with increasing ALT (P = 0.002). In patients with F3-F4, there was no association between ALT and LSM (P = 0.17). A correlation between change in ALT and LSM was observed in patients with no/minimal fibrosis and inflammatory liver diseases (r = 0.33). CONCLUSIONS: In children with no/minimal hepatic fibrosis and inflammatory liver disease, high ALT values are associated with LSM in the range typical of advanced fibrosis. However, with more advanced fibrosis, inflammation does not appear to contribute to LSM. Caution must be taken when interpreting LSM for assessing fibrosis severity in the setting of inflammation.

Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice.

BACKGROUND & AIMS: Repair from biliary damages requires the biliary specification of hepatic progenitor cells and the remodeling of ductular reactive structures into branching biliary tubules. We hypothesized that the morphogenetic role of Notch signaling is maintained during the repair process and have addressed this hypothesis using pharmacologic and genetic models of defective Notch signaling. METHODS: Treatment with DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) or ANIT (alpha-naphthyl-isothiocyanate) was used to induce biliary damage in wild type mice and in mice with a liver specific defect in the Notch-2 receptor (Notch-2-cKO) or in RPB-Jk. Hepatic progenitor cells, ductular reaction, and mature ductules were quantified using K19 and SOX-9. RESULTS: In DDC treated wild type mice, pharmacologic Notch inhibition with dibenzazepine decreased the number of both ductular reaction and hepatic progenitor cells. Notch-2-cKO mice treated with DDC or ANIT accumulated hepatic progenitor cells that failed to progress into mature ducts. In RBP-Jk-cKO mice, mature ducts and hepatic progenitor cells were both significantly reduced with respect to similarly treated wild type mice. The mouse progenitor cell line BMOL cultured on matrigel, formed a tubular network allowing the study of tubule formation in vitro; γ-secretase inhibitor treatment and siRNAs silencing of Notch-1, Notch-2 or Jagged-1 significantly reduced both the length and number of tubular branches. CONCLUSIONS: These data demonstrate that Notch signaling plays an essential role in biliary repair. Lack of Notch-2 prevents biliary tubule formation, both in vivo and in vitro. Lack of RBP-Jk inhibits the generation of biliary-committed precursors and tubule formation.

Celiac disease in a child with ulcerative colitis: a possible genetic association.

Celiac disease and inflammatory bowel disease including ulcerative colitis (UC) and Crohn's disease are both immune-mediated enteropathies. It is rare for both celiac disease and inflammatory bowel disease to occur together in an individual patient. This association has been reported in adults, however, very rarely in children. Here, we report an unusual case of an 8-year-old child with a history of anemia and failure to thrive who presented with bloody diarrhea. His evaluation showed anemia, elevated inflammatory markers, and positive celiac antibodies. Endoscopic evaluation revealed partial duodenal villous atrophy and pancolitis. He was diagnosed with celiac disease and UC and responded well to a gluten-free diet and steroid/mesalamine therapy. The patient's genetic testing revealed markers showing susceptibility for both celiac disease and UC. It is important to be aware of this association as both conditions can present with similar clinical features, however, require different therapeutic approaches.

Acute necrotizing pancreatitis in children.

OBJECTIVE: To describe the etiologic factors, course, and outcome of acute necrotizing pancreatitis in children. STUDY DESIGN: We performed a retrospective study of children with necrotizing pancreatitis diagnosed during the last 21 years at Yale-New Haven Children's Hospital. Computed tomography (CT) criteria were used to diagnose necrotizing pancreatitis and to assess severity index. Charts were reviewed to collect demographics, etiology, details of hospital stay, complications, and outcome. RESULTS: Seven children (mean age, 11.6 years; range, 4-17.8 years) had necrotizing pancreatitis. Etiologic factors were medications, diabetes, and gallstones. All had prolonged hospitalization (9-40 days; mean, 20 days) and 5 patients required admission to the pediatric intensive care unit. During the hospital stay, patients developed complications involving the respiratory, hematologic, renal, metabolic, and circulatory systems. All patients had aggressive supportive medical therapy, and none required surgery. There were no deaths attributable to pancreatitis. Late complications after hospital discharge occurred in 5 patients and included pseudocysts, transient hyperglycemia, diabetes, and pancreatic exocrine insufficiency. The CT severity index correlated with the risk of complications. CONCLUSIONS: A cute necrotizing pancreatitis has a variable etiology in children. CT scan is useful in the diagnosis and assessment of severity. Necrotizing pancreatitis in children is associated with severe acute and late complications and requires intensive medical therapy.