Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen.

RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS: The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS: While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION: This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.

Association of Vitamin A and D Deficiencies with Infectious Outcomes in Children Undergoing Intensive Induction Therapy for Acute Lymphoblastic Leukemia.

OBJECTIVE: To evaluate the association between deficiency of vitamin A or D at diagnosis of pediatric acute lymphoblastic leukemia (ALL) and subsequent infectious complications during induction therapy. STUDY DESIGN: We conducted an institutional review board-approved, retrospective cohort study of children with newly diagnosed ALL from 2007 to 2017 at St. Jude Children's Research Hospital. We measured vitamin D, vitamin D binding protein, retinol binding protein as a surrogate for vitamin A, and immunoglobulin isotypes in serum obtained at ALL diagnosis, and we assessed the association between vitamin deficiencies or levels and infection-related complications during the 6-week induction phase using Cox regression models. RESULTS: Among 378 evaluable participants, vitamin A and D deficiencies were common (43% and 17%, respectively). Vitamin D deficiency was associated with higher risks of febrile neutropenia (adjusted hazard ratio [aHR], 1.7; P = .0072), clinically documented infection (aHR, 1.73; P = .025), and likely bacterial infection (aHR, 1.86; P = .008). Conversely, vitamin A deficiency was associated solely with a lower risk of sepsis (aHR, 0.19; P = .027). CONCLUSIONS: In this retrospective study, vitamin D deficiency was associated with an increased risk of common infection-related complications during induction therapy for ALL. Additional studies are warranted to evaluate whether vitamin D supplementation could mitigate this effect.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. METHODS: The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). RESULTS: Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut-off. CONCLUSIONS: Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

A multisociety Delphi consensus statement on new fatty liver disease nomenclature.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.

Assessing Disease Activity in Pediatric Crohn's Disease Using Ultrasound: The Pediatric Crohn Disease Intestinal Ultrasound Score.

OBJECTIVES: Currently, there is no consensus on how to score Crohn disease (CD) activity assessed by intestinal ultrasound (IUS) in children. This study aimed to design an easy-to-use IUS score for disease activity in pediatric CD. METHODS: Children undergoing ileo-colonoscopy for CD assessment underwent IUS the day before ileo-colonoscopy, assessed with simple endoscopic score for CD (SES-CD). IUS features were compared to the SES-CD on segmental level. Multiple regression analyses, separately for terminal ileum (TI) and colon, were done to assess predictors of disease activity and to develop a model. RESULTS: In 74 CD patients (median 15 years, 48% female), 67 TI and 364 colon segments were assessed. Based on receiver operating characteristics curves, bowel wall thickness (BWT) was categorized into low [1 point: 2-3 mm (TI) and 1.6-2 mm (colon)], medium [2 points: 3.0-3.7 mm (TI) and 2.0-2.7 mm (colon)], and high [3 points: >3.7 mm (TI) and >2.7 mm (colon)]. In TI, only BWT was retained in the model [high BWT: odds ratio (OR) 11.50, P < 0.001]. In colon, BWT (high BWT: OR 8.63, P < 0.001) and mesenteric fat (1 point: OR 3.02, P < 0.001) were independent predictors. A pediatric Crohn disease IUS score (PCD-US) cut-off of 1 resulted in a sensitivity of 82% (95% confidence interval, CI: 65%-93%) and 85% (95% CI: 80%-89%) and a cut-off of 3 in a specificity of 88% (72%-97%) and 92% (87%-96%) for TI and colon, respectively. Inter-observer agreement was moderate for TI and colon ( K : 0.42, K : 0.49, respectively). CONCLUSIONS: The PCD-US score is an easy-to-use and reliable score to detect or rule out CD activity on segmental level in children. External validation is needed before applying this score in clinical practice.

Using Vital Signs to Place Acutely Ill Patients Quickly and Easily into Clinically Helpful Pathophysiologic Categories: Derivation and Validation of Eight Pathophysiologic Categories in Two Distinct Patient Populations of Acutely Ill Patients.

BACKGROUND: Early warning scores reliably identify patients at risk of imminent death, but do not provide insight into what may be wrong with the patient or what to do about it. OBJECTIVE: Our aim was to explore whether the Shock Index (SI), pulse pressure (PP), and ROX Index can place acutely ill medical patients in pathophysiologic categories that could indicate the interventions required. METHODS: A retrospective post-hoc analysis of previously obtained and reported clinical data for 45,784 acutely ill medical patients admitted to a major regional referral Canadian hospital between 2005 and 2010 and validated on 107,546 emergency admissions to four Dutch hospitals between 2017 and 2022. RESULTS: SI, PP, and ROX values divided patients into eight mutually exclusive physiologic categories. Mortality was highest in patient categories that included ROX Index value < 22, and a ROX Index value < 22 multiplied the risk of any other abnormality. Patients with a ROX Index value < 22, PP < 42 mm Hg, and SI > 0.7 had the highest mortality and accounted for 40% of deaths within 24 h of admission, whereas patients with a PP ≥ 42 mm Hg, SI ≤ 0.7, and ROX Index value ≥ 22 had the lowest risk of death. These results were the same in both the Canadian and Dutch patient cohorts. CONCLUSIONS: SI, PP, and ROX Index values can place acutely ill medical patients into eight mutually exclusive pathophysiologic categories with different mortality rates. Future studies will assess the interventions needed by these categories and their value in guiding treatment and disposition decisions.

THE ASSOCIATION BETWEEN SYSTOLIC BLOOD PRESSURE AND HEART RATE IN EMERGENCY DEPARTMENT PATIENTS: A MULTICENTER COHORT STUDY.

BACKGROUND: Guidelines and textbooks assert that tachycardia is an early and reliable sign of hypotension, and an increased heart rate (HR) is believed to be an early warning sign for the development of shock, although this response may change by aging, pain, and stress. OBJECTIVE: To assess the unadjusted and adjusted associations between systolic blood pressure (SBP) and HR in emergency department (ED) patients of different age categories (18-50 years; 50-80 years; > 80 years). METHODS: A multicenter cohort study using the Netherlands Emergency department Evaluation Database (NEED) including all ED patients ≥ 18 years from three hospitals in whom HR and SBP were registered at arrival to the ED. Findings were validated in a Danish cohort including ED patients. In addition, a separate cohort was used including ED patients with a suspected infection who were hospitalized from whom measurement of SBP and HR were available prior to, during, and after ED treatment. Associations between SBP and HR were visualized and quantified with scatterplots and regression coefficients (95% confidence interval [CI]). RESULTS: A total of 81,750 ED patients were included from the NEED, and a total of 2358 patients with a suspected infection. No associations were found between SBP and HR in any age category (18-50 years: -0.03 beats/min/10 mm Hg, 95% CI -0.13-0.07, 51-80 years: -0.43 beats/min/10 mm Hg, 95% CI -0.38 to -0.50, > 80 years: -0.61 beats/min/10 mm Hg, 95% CI -0.53 to -0.71), nor in different subgroups of ED patient. No increase in HR existed with a decreasing SBP during ED treatment in ED patients with a suspected infection. CONCLUSION: No association between SBP and HR existed in ED patients of any age category, nor in ED patients who were hospitalized with a suspected infection, even during and after ED treatment. Emergency physicians may be misled by traditional concepts about HR disturbances because tachycardia may be absent in hypotension.

Increased risk of aseptic loosening for posterior stabilized compared with posterior cruciate-retaining uncemented total knee replacements: a cohort study of 13,667 knees from the Dutch Arthroplasty Registry.

BACKGROUND AND PURPOSE: While registry studies have suggested a higher risk of revision for posterior-stabilized (PS) compared with posterior cruciate-retaining (CR) total knee replacements (TKR) using cement, it is unknown whether this is also the case for uncemented TKR. We aimed to compare the revision rates of PS and CR designs in patients receiving primary uncemented TKR. PATIENTS AND METHODS: Data from the Dutch arthroplasty register (LROI) was analyzed, comprising 12,226 uncemented primary CR TKRs and 750 uncemented PS TKRs registered between 2007 and 2022. Competing risk and multivariable Cox regression analyses were used to compare revision rates, risks of revision, and reasons for revision between groups. Sensitivity analyses were performed to analyze the risk, concerning the 5 most commonly used implants and performing hospitals for each group. RESULTS: Uncemented PS TKRs had higher 10-year revision rates for any reason and aseptic loosening (6.5%, 95% confidence interval [CI] 4.6-9.2 and 3.9%, CI 2.6-6.7) compared with uncemented CR TKRs (4.2%, CI 3.8-4.7 and 1.4%, CI 1.2-1.7). PS TKRs were 1.4 and 2.5 times more likely to be revised for any reason and aseptic loosening, respectively. These results remained consistent after adjustment for age, sex, BMI, previous surgeries, bearing mobility, and surface modification, with sensitivity analyses. CONCLUSION: We found that uncemented PS implants have a higher rate of revision than uncemented CR implants, mainly due to a higher risk of aseptic loosening.

Change in CT-measured acetabular bone density following total hip arthroplasty: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Assessing peri-acetabular bone quality is valuable for optimizing the outcomes of primary total hip arthroplasty (THA) as preservation of good quality bone stock likely affects implant stability. The aim of this study was to perform a meta-analysis of peri-acetabular bone mineral density (BMD) changes over time measured using quantitative computer tomography (CT) and, second, to investigate the influence of age, sex, and fixation on the change in BMD over time. METHODS: A systematic search of Embase, Scopus, Web of Science, and PubMed databases identified 19 studies that measured BMD using CT following THA. The regions of interest (ROI), reporting of BMD results, and scan protocols were extracted. A meta-analysis of BMD was performed on 12 studies that reported measurements immediately postoperatively and at follow-up. RESULTS: The meta-analysis determined that periacetabular BMD around both cemented and uncemented components decreases over time. The amount of BMD loss increased relative to proximity of the acetabular component. There was a greater decrease in cortical BMD over time in females and cancellous BMD for young patients of any sex. CONCLUSION: Peri-acetabular BMD decreases at different rates relative to its proximity to the acetabular component. Cancellous BMD decreases more in young patients and cortical bone decreases more in females. Standardized reporting parameters and suggested ROI to measure peri-acetabular BMD are proposed, to enable comparison between implant and patient variables in the future.

6-month migration sufficient for evaluation of total knee replacements: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: This updated meta-analysis evaluates the migration pattern of the tibial component of primary total knee replacements measured with radiostereometric analysis (RSA). We aimed to evaluate whether 6-month maximum total point motion (MTPM) values could be used instead of 1-year MTPM for RSA threshold testing and to present the pooled migration patterns for different implant designs that can be used as a benchmark. PATIENTS AND METHODS: The search included all published RSA studies on migration patterns of tibial components until 2023. Study groups were classified according to their prosthesis brand, fixation, and insert (PFI). Sub-analyses were performed to compare the mean tibial component migration patterns of different implant variables, stratified according to fixation. RESULTS: 96 studies (43 new studies), including 197 study groups and 4,706 knees, were included. Most migration occurred within the first 6 postoperative months (126 study groups: mean 0.58 mm, 95% confidence interval [CI] 0.50-0.65), followed by minimal migration between 6 and 12 months (197 study groups: mean 0.04 mm, CI 0.03-0.06), irrespective of the fixation method used. Distinct migration patterns were observed among the different fixation methods. No differences were found in migration patterns among cemented components in any of the sub-group analyses conducted. For uncemented implants, trabecular metal surfaced components seemed to migrate less than porous-coated or uncoated components Conclusion: Based on the small difference between MTPM values at 6 months and 1 year, MTPM at 6 months could be used instead of MTPM at 1 year for RSA threshold testing. The pooled migration patterns can be used as benchmark for evaluation of new implants by defining fixation-specific RSA thresholds when combined with implant survival.

Migration patterns of acetabular cups: a systematic review and meta-analysis of RSA studies.

BACKGROUND AND PURPOSE: We conducted a systematic review and meta-analysis of RSA studies to investigate the early and long-term migration patterns of acetabular cups and the influence of implant factors on cup migration over time. METHODS: We performed a systematic search of PubMed, Embase, and Scopus databases to identify all RSA studies of cup migration following primary total hip replacement (THR). Proximal migration at 3 and 6 months, 1, 2, 5, and 10 years were considered for analysis. Implant factors investigated included fixation type, head size, bearing surface, uncemented coating design, and the decade of RSA introduction. RESULTS: 47 studies reported the proximal migration of 83 cohorts (2,328 cups). Besides 1 threaded cup design, no implant factor investigated was found to significantly influence proximal migration. The mean pooled 2-year proximal migration of cemented cups (0.14 mm, 95% confidence interval [CI] 0.08-0.20) was not significantly different from uncemented cups (0.12 mm, CI 0.04-0.19). The mean pooled proximal migration at 6 months was 0.11 mm (CI 0.06-0.16) and there was no significant increase between 6 months and 2 years (0.015 mm, CI 0.000-0.030). 27 of 75 cohorts (36%) reported mean proximal migration greater than 0.2 mm at 2 years, which has previously been identified as a predictor of implants at risk of long-term loosening. CONCLUSION: Our meta-analysis demonstrated that the majority of cup migration occurs within the first 6 months. With one exception, no implant factors influenced the 2-year proximal migration of acetabular cups. 36% of studies with 2-year migration were considered at risk of long-term loosening. Further investigation and comparison against long-term survivorship data would validate 6-month and/or 1-year proximal migration measurements as an earlier predictor of long-term loosening than the current 2-year threshold.

Publisher Correction: Stability, affinity, and chromatic variants of the glutamate sensor iGluSnFR.

In the version of this paper originally published, important figure labels in Fig. 3d were not visible. An image layer present in the authors' original figure that included two small dashed outlines and text labels indicating ROI 1 and ROI 2, as well as a scale bar and the name of the cell label, was erroneously altered during image processing. The figure has been corrected in the HTML and PDF versions of the paper.

Author Correction: Stability, affinity, and chromatic variants of the glutamate sensor iGluSnFR.

The version of this paper originally published cited a preprint version of ref. 12 instead of the published version (Proc. Natl. Acad. Sci. USA 115, 5594-5599; 2018), which was available before this Nature Methods paper went to press. The reference information has been updated in the PDF and HTML versions of the article.

The co-existence of multiple oak leaf flushes contributes to the large within-tree variation in chemistry, insect attack and pathogen infection.

Many plant species produce multiple leaf flushes during the growing season, which might have major consequences for within-plant variation in chemistry and species interactions. Yet, we lack a theoretical or empirical framework for how differences among leaf flushes might shape variation in damage by insects and diseases. We assessed the impact of leaf flush identity on leaf chemistry, insect attack and pathogen infection on the pedunculate oak Quercus robur by sampling leaves from each leaf flush in 20 populations across seven European countries during an entire growing season. The first leaf flush had higher levels of primary compounds, and lower levels of secondary compounds, than the second flush, whereas plant chemistry was highly variable in the third flush. Insect attack decreased from the first to the third flush, whereas infection by oak powdery mildew was lowest on leaves from the first flush. The relationship between plant chemistry, insect attack and pathogen infection varied strongly among leaf flushes and seasons. Our findings demonstrate the importance of considering differences among leaf flushes for our understanding of within-tree variation in chemistry, insect attack and disease levels, something particularly relevant given the expected increase in the number of leaf flushes with climate change.

Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis.

BACKGROUND AND AIMS: Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. APPROACH AND RESULTS: We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. CONCLUSIONS: We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.

Recurrence of Primary Sclerosing Cholangitis After Liver Transplant in Children: An International Observational Study.

BACKGROUND AND AIMS: Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. APPROACH AND RESULTS: We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). CONCLUSIONS: The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.

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.

Can 2 Different Fecal Calprotectin Assays be Used Interchangeably in IBD Treatment?

BACKGROUND: Fecal calprotectin (FC) is a biomarker for inflammation in inflammatory bowel disease (IBD). Interpretation of results can be complicated because of the use of different assays to determine FC. GOALS: To assess the agreement between 2 different assays for determining FC in patients with IBD. METHODS: Samples from adults and children with IBD were tested with 2 assays: (1) EliA 2 Calprotectin and (2) EK-Cal. Samples were uniformly tested on the same day. Interassay variability was displayed in a Bland-Altman plot. The difference in categorization of the FC result (1: 0 to 250 mg/kg, 2: 250 to 500 mg/kg, 3: >500 mg/kg) was assessed with the linear weighted κ for adults and children separately. RESULTS: A total of 171 patients [mean age: 33 (range: 7 to 81); 92 (54%) female; 117 (68%) Crohn's disease; 53 (31%) ulcerative colitis] were included. Median (interquartile ranges) FC levels were 281 mg/kg (70 to 971) (EK-Cal) and 159 mg/kg (31 to 778) (EliA 2), and the mean delta FC was 89 mg/kg. In the adult population, there was substantial agreement between the 2 assays (κ: 0.72; SE: 0.06; 95% confidence interval, 0.60-0.83) and for pediatric patients, the agreement was almost perfect (κ: 0.83; SE: 0.06; 95% confidence interval: 0.70-0.95). Five of 171 patients (all aged ≥17 y and all with colonic disease) had a difference of 2 categories (1 vs. 3) between assays. Interassay variability was the highest in category 3. CONCLUSIONS: The agreement between the EliA 2 and EK-Cal assay in this cohort of IBD patients is substantial to almost perfect. Interassay variability is higher in the highest FC category.