Elevated serum mtDNA in COVID-19 patients is linked to SARS-CoV-2 envelope protein targeting mitochondrial VDAC1, inducing apoptosis and mtDNA release.

Mitochondria dysfunction is implicated in cell death, inflammation, and autoimmunity. During viral infections, some viruses employ different strategies to disrupt mitochondria-dependent apoptosis, while others, including SARS-CoV-2, induce host cell apoptosis to facilitate replication and immune system modulation. Given mitochondrial DNAs (mtDNA) role as a pro-inflammatory damage-associated molecular pattern in inflammatory diseases, we examined its levels in the serum of COVID-19 patients and found it to be high relative to levels in healthy donors. Furthermore, comparison of serum protein profiles between healthy individuals and SARS-CoV-2-infected patients revealed unique bands in the COVID-19 patients. Using mass spectroscopy, we identified over 15 proteins, whose levels in the serum of COVID-19 patients were 4- to 780-fold higher. As mtDNA release from the mitochondria is mediated by the oligomeric form of the mitochondrial-gatekeeper-the voltage-dependent anion-selective channel 1 (VDAC1)-we investigated whether SARS-CoV-2 protein alters VDAC1 expression. Among the three selected SARS-CoV-2 proteins, small envelope (E), nucleocapsid (N), and accessory 3b proteins, the E-protein induced VDAC1 overexpression, VDAC1 oligomerization, cell death, and mtDNA release. Additionally, this protein led to mitochondrial dysfunction, as evidenced by increased mitochondrial ROS production and cytosolic Ca2+ levels. These findings suggest that SARS-CoV-2 E-protein induces mitochondrial dysfunction, apoptosis, and mtDNA release via VDAC1 modulation. mtDNA that accumulates in the blood activates the cGAS-STING pathway, triggering inflammatory cytokine and chemokine expression that contribute to the cytokine storm and tissue damage seen in cases of severe COVID-19.

The Outbreak of Unexplained Acute Hepatitis in Children: The Role of Viral Infections in View of the COVID-19 Pandemic.

BACKGROUND AND AIMS: An increase in the number of cases of acute hepatitis of unknown origin (HUO) in children was observed in 2021. Adenovirus and adeno-associated virus 2 (AAV2) infections have been suggested as possible triggers. However, the potential etiology is still unclear. We aimed to characterize a cohort of children with HUO in Israel in view of the COVID-19 pandemic. METHOD: Demographics, clinical data, and laboratory results on the children compatible with the CDC criteria for HUO were collected by the established registry of the Ministry of Health. Available specimens were sent to the Central Virology Laboratory. RESULTS: A total of 39 children were included in the registry. A total of 20 were enrolled prospectively, in which human herpes virus 6 (HHV6) infection or reactivation was identified in 11/19, adenovirus was found in 4/19 of the cases, and AAV2 was detected in 2/16. Past COVID-19 exposure was recorded for 24/39 of the children. A total of 10 children underwent liver biopsy, and 8 were successfully treated with steroids and 2 underwent liver transplantation. CONCLUSIONS: The COVID-19 pandemic and the related containment measures combined with reactivation or active infection with other viruses could have been a trigger for the HUO outbreak. In our cohort, HHV6 was the most abundant finding.

Oral vancomycin is associated with improved inflammatory bowel disease clinical outcomes in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD): A matched analysis from the Paediatric PSC Consortium.

BACKGROUND: Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS: Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS: In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS: 113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION: Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis.

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 µg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 µmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 µmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

Preoperative clear fluid fasting and endoscopy-measured gastric fluid volume in children.

BACKGROUND: In light of new recommendations to shorten clear fluid fasting time before anesthesia, our study aimed at exploring residual fluid volume in the stomach after different fasting times. We intended to perform direct endoscopic aspiration of stomach contents under vision, as part of routine gastroscopy assessment. Hereby we would be able to quantify true residual gastric fluid volume and acidity in children and measure their correlation with fasting times. METHODS: The study was performed as a single-center, prospective study in pediatric perioperative day care at a university-affiliated tertiary care center. Aspiration of gastric fluid contents was performed in anesthetized children aged 1-18 years undergoing an elective gastroscopy. Recorded data included patient fast time, last meal content, last clear fluid content, and aspirated gastric volume and pH, as well as patient characteristics. RESULTS: We included 253 gastroscopies, performed in 245 children. Mean fasting time for clear fluids was 6.9 h (range 1 h 40 min - 18 h 35 min) (SD 4.5). Mean age was 9.8 years (SD 5.1) and mean body weight was 33.2 kg (SD 18.7). Mean residual gastric volume was 12 mL (0-90) (SD 13.5) or 0.34 mL/kg (SD 0.37) and mean pH was 1.5 (SD 0.9). No significant correlation was observed between clear fluid fasting time and the child's residual gastric fluid volume per kg body weight (r = -.103, p = .1), nor between clear fluid fasting time and the pH of the residual gastric fluid (r = -.07, p = .3). In more than half of the patients the residual gastric volume was less than 10 mL, unrelated to fasting time. CONCLUSIONS: In children undergoing gastroscopy, we could not demonstrate any association between clear fluid fasting time and the child's residual gastric fluid volume per kg body weight. Since we did not see a clinically relevant association between clear fluids fasting time and gastric residual volume, this study may support the recommendation to shorten clear fluids fasting time.

A feasibility study using sodium alginate injection for penetrating abdominal trauma in a swine model.

Penetrating abdominal injury is a major cause of death in trauma. Sodium alginate hydrogel, a hemostatic agent, offers a platform for targeting both mechanical and biological injuries. The current study assessed the effect of Very Low Viscosity (high) G (VLVG) alginate following abdominal trauma in a swine model of penetrating abdominal injury. Seven anesthetized pigs were instrumented with invasive monitoring catheters and abdominal trauma was introduced by laparoscopic hepatectomy. Ten minutes after the induction of hypovolemic shock, three animals were intra-abdominally administered with VLVG alginate (study group) and four animals with saline (control group). During 8 h of continuous monitoring, various hemodynamic and biochemical variables were measured and liver biopsies for histological evaluation were taken. Hemodynamically, VLVG alginate-treated animals were more stable than controls, as reflected by their lower heart rate and higher blood pressure (p < 0.05 for both). They also had lower levels of liver enzymes and lactate, and less histopathological damage. We show that VLVG alginate might be a promising new agent for reducing penetrating intra-abdominal injury, with hemostatic and biocompatibility efficiency, and tissue preserving properties. Future effort of integrating it with a dispersal device may turn it into a valuable pre-hospital emergency tool to improve survival of trauma casualties.

Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 µg/kg, or odevixibat 120 µg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 µmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 µg/kg per day (n=23), or odevixibat 120 µg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 µg/kg per day group and 52% in the 120 µg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 µg/kg per day group and four in the 120 µg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.

Children included in randomised controlled trials of biologics in inflammatory bowel diseases do not represent the real-world patient mix.

BACKGROUND: Patients enrolled in randomised controlled trials (RCTs) may differ from the target population due to restricted eligibility criteria. AIM: To compare treatment response to biologics in routine practice for children with inflammatory bowel diseases (IBD) who would and would not have been eligible for enrolment in the regulatory RCT of the same drug. METHODS: We enrolled children with IBD who initiated adalimumab, infliximab, vedolizumab or ustekinumab. The eligibility criteria as defined in the RCT of the corresponding biologic were applied to each patient. The primary outcome was 12-month steroid-free remission (SFR) without switching biologics or undergoing surgery. RESULTS: We screened 289 children (198 [68%] with Crohn's disease [CD], 91 [32%] with ulcerative colitis [UC]) with 326 initiations of biologics. Only 62 of 164 (38%) children with moderate-to-severe disease would have been eligible for inclusion in the original RCTs. The SFR rate was higher in the eligible children (51%) than in the ineligible children (31%; OR 2.3 [95%CI 1.2-4.5]; p = 0.01). The main exclusion criterion was prohibited previous therapies (47%). Ineligible CD patients were older, more often had a family history of IBD and had higher levels of CRP than eligible children; in UC there were no differences between the groups. CONCLUSION: Most children with IBD who initiate biologics would not have been eligible to be included in the corresponding regulatory RCTs. The outcomes of ineligible patients were worse than for eligible patients. Results from RCTs should be interpreted with caution when applied to clinical practice.

Existing Prediction Models of Disease Course in Paediatric Crohn's Disease Are Poorly Replicated in a Prospective Inception Cohort.

BACKGROUND: Several groups have proposed models to predict disease outcomes in paediatric Crohn's disease [CD], notably the RISK, GROWTH, and the Porto group, but none were externally validated. We aimed to explore these predictive models and individual predictors summarised by the PIBD-ahead project in a prospective inception cohort of paediatric CD. METHODS: We included children who were diagnosed with CD at two medical centres and followed them at 3 and 12 months thereafter as well as at the last follow-up. Outcomes included steroid-free remission [SFR], surgery, and stricturing/fistulising disease. RESULTS: In all 155 children were included (median follow-up of 31 [16-48] months, 107 [71%] had moderate-to-severe disease). Stricturing and penetrating disease at diagnosis were noted in 34 [22%] and two [1.3%] children, respectively, and these were excluded from the relevant analyses. At 1 year, 10 [8.3%] developed new stricturing disease, two [1.7%] developed penetrating disease, seven [5%] required intestinal surgery, and 15 [10%] required perianal surgery. The sensitivity/specificity/positive predictive value [PPV]/negative predictive value [NPV] of the GROWTH criteria for predicting SFR at 12 months [occurring in 70% of children] were 20%/85%/76%/31% and for surgery at 2 years were 96%/20%/16%/96%, respectively. Strictures were predicted by the RISK model with sensitivity/specificity/PPV/NPV of 33%/73%/18%/86%, respectively. The sensitivity/specificity/PPV/NPV of the Porto criteria to predict surgery were 86%/10%/4%/94%, respectively. None of the Pediatric Inflammatory Bowel Disease-ahead [PIBD-ahead] predictors were associated with surgery or stricturing disease. CONCLUSIONS: None of the three main predictive models in paediatric CD achieved sufficient accuracy, far from that reported in the original cohorts. This highlights the necessity of external validation in any prediction model prior to its implementation in clinical practice.

Pediatric Gastrointestinal Endoscopy: Diagnostic Yield and Appropriateness of Referral Based on Clinical Presentation: A Pilot Study.

Objectives: There is a lack of evidence-based consensus for the utility of gastrointestinal endoscopy (GIE) in an array of frequently occurring symptoms in children. We aimed to assess the diagnostic yield of endoscopy in an effort to aid clinical decision making. Methods: Retrospective analysis included patients ≤18 years who underwent GIE during one calendar year at Shaare Zedek Medical Center. We excluded children referred for predefined obvious indications for GIE, planned follow-up procedures, and therapeutic endoscopy. Clinician-assigned indication for endoscopy as well as endoscopic and histologic findings were recorded. Diagnostic yield of GIE was determined according to referral indication. Results: There were 794 endoscopies performed of which 329 were included in the analysis (mean age 9.3 ± 5.0 years, 51% female). No significant complications of GIE were recorded. Six major referral indications were identified among which abdominal pain was the most frequent 88/329 (26%) of whom 32/88 (36%) had a significant diagnostic finding. Among the other major indications, diagnostic findings were found in 36/85 (43%) children with primary indication of chronic diarrhea, 14/33 (42%) failure to thrive, 15/32 (46%) short stature, 30/56 (54%) iron deficiency, and 20/48 (42%) weight loss. Conclusions: Pediatric GIE is a safe procedure with diverse clinical indications. The diagnostic yield of endoscopy is variable, depending on the referral indication. These data can assist formulating judicious referral practices.

Anosmia and dysgeusia amongst COVID-19 patients are associated with low levels of serum glucagon-like peptide 1.

PURPOSE: Anosmia and dysgeusia (AD) are common amongst COVID-19 patients. These symptoms are not frequently associated with rhinorrhea or nasal congestion and the underlying mechanism is unclear. Previous reports suggested that glucagon-like peptide-1 (GLP-1) signalling plays a role in the modulation of olfaction and ageusia. We aimed to assess the correlation between GLP-1 and COVID-19-associated AD. METHODS: Blood samples obtained from COVID-19 patients with and without AD were tested for serum GLP-1 levels using enzyme-linked immunosorbent assay (ELISA). A second control group comprised of COVID-19-negative volunteers. RESULTS: Forty-nine subjects were included in the study. Nineteen were positive for COVID-19. Of the 19 patients, 10 had AD and 9 declined such complaints. Age and basic metabolic rate were similar amongst all study groups. Serum GLP-1 levels were significantly lower amongst patients with AD compared with patients without AD and COVID-19-negative individuals (1820 pg/mL vs 3536 pg/mL vs 3014 pg/mL, respectively, P < .02). CONCLUSION: COVID-19 patients who reported AD had lower serum levels of GLP-1 compared with those lacking AD symptoms and COVID-19-negative individuals. These results suggest that GLP-1 may be involved in the pathogenesis of AD. However, further larger scale studies should corroborate our findings.

Characterization and natural history of congenital intrahepatic portosystemic shunts.

Congenital intrahepatic portosystemic shunts are rare vascular malformations in which abnormal communications are created between the portal veins and the hepatic veins or the inferior vena cava system. Diagnosis is made by prenatal or postpartum ultrasound. Published data regarding presentation, symptoms, and prognosis is scarce. This study aimed to better understand the natural history and the course of the intrahepatic portosystemic shunts. Data were collected from children in two medical centers who were diagnosed with congenital intrahepatic portosystemic shunts on either prenatal or postnatal sonographic screening. The subjects' medical information was collected including demographics, medical background, and sonographic and clinical outcome. Blood test results including ammonia levels and liver function tests were documented, as well as the sonographic dimensions of the shunt vessels and the spleen size. The data were analyzed using various statistical methods. Twenty-three children with portosystemic shunts were found and reviewed. Eight children were excluded from the study since records and follow-up were insufficient. Fifteen patients were included in the study (six females). All had intrahepatic shunt diagnosed either by prenatal screening or postnatal abdominal ultrasound and had more than one ultrasound and repeated blood tests. Shunt closure was observed in all children within a mean of 114.31 ± 115.05 days (median 84). There was no correlation between liver enzymes, ammonia, and ultrasound vascular and splenic diameters to time to closure. None of the children had any hepatic or other sequelae.Conclusions: Our study suggests that congenital intrahepatic portosystemic shunt is a benign, self-limiting condition in which no correlation between the size of the shunt and the blood ammonia level to the outcome of the shunt was found. This is the first study that correlated radiological measures to the outcome. These results suggest that the treating physician should reassure families and conduct minimal follow-up and interventions in children with such conditions. Further, larger and prospective studies should be done to corroborate these conclusions. What is Known: • Characteristics and natural history of intrahepatic portosystemic shunts are less defined. • The natural course of the intrahepatic malformations varies, but spontaneous, self-resolution of small shunts, usually occures within 1 to 2 years. What is New: • In this study, congenital intrahepatic portosystemic shunt was shown to be benign, self-limiting condition in which all shunts closed within 3 months. • No correlation between the size of the shunt and the blood ammonia level to the outcome of the shunt was found.

ChIP-seq of plasma cell-free nucleosomes identifies gene expression programs of the cells of origin.

Cell-free DNA (cfDNA) in human plasma provides access to molecular information about the pathological processes in the organs or tumors from which it originates. These DNA fragments are derived from fragmented chromatin in dying cells and retain some of the cell-of-origin histone modifications. In this study, we applied chromatin immunoprecipitation of cell-free nucleosomes carrying active chromatin modifications followed by sequencing (cfChIP-seq) to 268 human samples. In healthy donors, we identified bone marrow megakaryocytes, but not erythroblasts, as major contributors to the cfDNA pool. In patients with a range of liver diseases, we showed that we can identify pathology-related changes in hepatocyte transcriptional programs. In patients with metastatic colorectal carcinoma, we detected clinically relevant and patient-specific information, including transcriptionally active human epidermal growth factor receptor 2 (HER2) amplifications. Altogether, cfChIP-seq, using low sequencing depth, provides systemic and genome-wide information and can inform diagnosis and facilitate interrogation of physiological and pathological processes using blood samples.

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

BACKGROUND AND AIMS: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. APPROACH AND RESULTS: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. CONCLUSIONS: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

Clinical Criteria Can Identify Children With Osteopenia in Newly Diagnosed Crohn Disease.

OBJECTIVES: Chronic inflammation of Crohn disease (CD) is associated with reduced bone mineral density (BMD). As bone mass is almost exclusively accrued during childhood, early recognition of osteopenia is especially important in pediatric CD. We aimed to identify variables associated with osteopenia to guide dual-energy X-ray absorptiometry (DXA) scan screening to those who most need it. METHODS: This was a retrospective inception cohort study of children newly diagnosed with CD, and routinely referred to DXA scans. Demographic and explicit clinical data were recorded along with whole-body less head BMD, adjusted for age, sex, and height by z-scores. RESULTS: Of the 116 included children (mean age 13 ±â€Š3.1 years, 67 [58%] boys, mean body mass index [BMI] 16.7 ±â€Š2.6), 63 (54%) had normal BMD (z-score > -1) or borderline osteopenia (-1 ≥ z-score > -2) and 53 (46%) had osteopenia (z-score ≤ -2). Osteopenia was associated with lower BMI z-score (-0.8 ±â€Š1.2 vs -1.8 ±â€Š1.1, P < 0.001) and higher PCDAI (33.7 ±â€Š15.2 vs 25.7 ±â€Š16.5; P = 0.009) than those with BMD z-score >-2. In total, 59% of children with BMI z-score <-0.5 had moderate-severe osteopenia and only 18% of those with higher z-scores. Multivariate logistic regression identified BMI z-score as the sole risk factor (OR 1.28 [95% CI 1.08-1.52], P = 0.005). BMI z-score ≥-0.5 excludes osteopenia with a sensitivity 87%, specificity 49%, NPV 82%, and PPV 59%. CONCLUSIONS: Osteopenia was found in nearly half of children with newly onset CD. BMI z-score <-0.5 should prompt referral to DXA screening.

Early Feeding in Acute Pancreatitis in Children: A Randomized Controlled Trial.

BACKGROUND: Studies have increasingly challenged the traditional management of acute pancreatitis (AP) with bowel rest. However, these studies used a low-fat diet or transgastric feeding and only included adults. Aiming to generate higher-quality prospective pediatric data, we compared the traditional approach of fasting and intravenous fluids and early enteral feeding with standard diet or formula. METHODS: Randomized controlled trial of children (2-18 years) with mild-moderate AP. Patients were randomly assigned 1:1 to initial fasting and intravenous fluids or an immediate, unrestricted diet. Pain scores, blood measures, and cross-sectional imaging were recorded throughout admission and follow-up. The primary outcome was time to discharge, and secondary outcomes were clinical and biochemical resolution and local and systemic complication rates. RESULTS: Of 33 patients (17 [52%] boys, mean age of 11.5 [±4.8] years), 18 (55%) were randomly assigned to early feeding and 15 (45%) were randomly assigned to initial fasting. We recorded the median (interquartile range [IQR]) time to discharge (2.6 [IQR 2.0 to 4.0] vs 2.9 [IQR 1.8 to 5.6]; P = .95), reduction in serum lipase levels by day 2 (58% [IQR 2% to 85%] vs 48% [IQR 3% to 71%]; P = .65), and readmission rates (1 of 18 [6%] vs 2 of 15 [13%]; P = .22) between the early feeding and fasting cohorts, respectively. Immediate or delayed complication rates did not differ. Patients randomly assigned to early feeding had weight gain of 1.3 kg (IQR 0.29 to 3.6) at follow-up, compared with weight loss of 0.8 kg (IQR -2.1 to 0.7) in fasted patients (P = .028). CONCLUSIONS: This is the first randomized controlled trial in pediatric AP. There was no difference between early commencement of a standard oral diet and initial fast in any of the major outcome measures.

Vedolizumab Therapy in Children With Primary Sclerosing Cholangitis: Data From the Pediatric Primary Sclerosing Cholangitis Consortium.

OBJECTIVES: Most patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). The liver and colon express MAdCAM-1, a target of lymphocyte homing integrins. Vedolizumab (VDZ) is an α4ß7 integrin antibody used to treat IBD. We investigated liver outcomes in children with PSC-IBD treated with VDZ. METHODS: Patients were identified within the Pediatric PSC Consortium, a multicenter research registry. Retrospective demographic, phenotypic, biochemical, radiological, histopathologic and IBD data for up to 1 year of VDZ therapy were collected. Liver biochemical and IBD responses were defined as: a 75% or greater reduction in initial γ-glutamyltransferase (GGT), or a GGT that fell to <50 IU/L and improved Mayo endoscopy grade or IBD activity scores after 9 to 12 months. RESULTS: Thirty-seven patients were identified from 19 centers. VDZ was initiated at median age of 16 years [IQR 15-18], 69% were male, 65% had large duct involvement, 19% had (Metavir F3/F4) fibrosis and 59% had ulcerative colitis. Of 32 patients with abnormal GGT at baseline, 22% had a liver biochemical response after 9 to 12 months. For IBD, 32% achieved remission, 30% had a clinical response, and 38% had no response. Final GGT after 9 to 12 months was 51 [IQR 28-71] in IBD patients in remission versus 127 [IQR 63-226] in those with active IBD, (P = 0.066). CONCLUSIONS: Liver biochemistry worsened over time in IBD unresponsive to VDZ but remained unchanged in IBD patients in remission. VDZ did not improve liver biochemistry in pediatric PSC-IBD. Progressive liver disease may be more common in patients with medically refractory IBD.