Serum bile acids as a prognostic biomarker in biliary atresia following Kasai portoenterostomy.

BACKGROUND AND AIMS: In biliary atresia, serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes in the latter group. APPROACH AND RESULTS: Participants with biliary atresia from the Childhood Liver Disease Research Network were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6-month post-KP clinic visit ( n  = 137). Bile acids were measured from the stored serum samples and used to divide participants into ≤40 µmol/L ( n  = 43) or >40 µmol/L ( n  = 94) groups. At 2 years of age, the ≤40 µmol/L compared with >40 µmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts. Furthermore, during 734 person-years of follow-up, those in the ≤40 µmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The ≤40 µmol/L group had a 10-year cumulative incidence of liver transplant/death of 8.5% (95% CI: 1.1%-26.1%), compared with 42.9% (95% CI: 28.6%-56.4%) for the >40 µmol/L group ( p  = 0.001). CONCLUSIONS: Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP.

Risk of variceal hemorrhage and pretransplant mortality in children with biliary atresia.

BACKGROUND AND AIMS: The natural history of gastroesophageal variceal hemorrhage (VH) in biliary atresia (BA) is not well characterized. We analyzed risk factors, incidence, and outcomes of VH in a longitudinal multicenter study. APPROACH AND RESULTS: Participants enrolled in either an incident (Prospective Database of Infants with Cholestasis [PROBE]) or prevalent (Biliary Atresia Study of Infants and Children [BASIC]) cohort of BA were included. Variceal hemorrhage (VH) was defined based on gastrointestinal bleeding in the presence of varices accompanied by endoscopic or nontransplant surgical intervention. Cumulative incidence of VH and transplant-free survival was compared based on features of portal hypertension (e.g., splenomegaly, thrombocytopenia) and clinical parameters at baseline in each cohort (PROBE: 1.5 to 4.5 months after hepatoportoenterostomy [HPE]; BASIC: at enrollment > 3 years of age). Analyses were conducted on 869 children with BA enrolled between June 2004 and December 2020 (521 in PROBE [262 (51%) with a functioning HPE] and 348 in BASIC). The overall incidence of first observed VH at 5 years was 9.4% (95% CI: 7.0-12.4) in PROBE and 8.0% (5.2-11.5) in BASIC. Features of portal hypertension, platelet count, total bilirubin, aspartate aminotransferase (AST), albumin, and AST-to-platelet ratio index at baseline were associated with an increased risk of subsequent VH in both cohorts. Transplant-free survival at 5 years was 45.1% (40.5-49.6) in PROBE and 79.2% (74.1-83.4) in BASIC. Two (2.5%) of 80 participants who had VH died, whereas 10 (12.5%) underwent transplant within 6 weeks of VH. CONCLUSIONS: The low risk of VH and associated mortality in children with BA needs to be considered in decisions related to screening for varices and primary prophylaxis of VH.

Neurodevelopmental Outcomes in Children With Inherited Liver Disease and Native Liver.

OBJECTIVE: To evaluate neurodevelopmental status among children with inherited cholestatic liver diseases with native liver and variables predictive of impairment. METHODS: Participants with Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and alpha 1 antitrypsin deficiency (A1AT) enrolled in a longitudinal, multicenter study and completed the Wechsler Preschool and Primary Scale of Intelligence-III or Intelligence Scale for Children-IV. Full Scale Intelligence Quotient (FSIQ) was analyzed continuously and categorically (>100, 85-99, 70-84, <70). Univariate linear regression was performed to study association between FSIQ and risk factors, stratified by disease. RESULTS: Two hundred and fifteen completed testing (ALGS n = 70, PFIC n = 43, A1AT n = 102); median age was 7.6 years (3.0-16.9). Mean FSIQ in ALGS was lower than A1AT (94 vs 101, P = 0.01). Frequency of FSIQ < 85 (>1 standard deviation [SD] below average) was highest in ALGS (29%) versus 18.6% in PFIC and 12.8% in A1AT, and was greater than expected in ALGS based on normal distribution (29% vs 15.9%, P = 0.003). ALGS scored significantly lower than test norms in almost all Wechsler composites; A1AT scored lower on Working Memory and Processing Speed; PFIC was not different from test norms. Total bilirubin, alkaline phosphatase, albumin, hemoglobin, and parental education were significantly associated with FSIQ. CONCLUSIONS: Patients with ALGS are at increased risk of lower FSIQ, whereas our data suggest A1AT and PFIC are not. A1AT and ALGS appear vulnerable to working memory and processing speed deficits suggestive of attention/executive function impairment. Malnutrition, liver disease severity, and sociodemographic factors appear related to FSIQ deficits, potentially identifying targets for early interventions.

Fluids affecting bladder urgency and lower urinary symptoms: results from a randomized controlled trial.

INTRODUCTION AND HYPOTHESIS: Caffeinated, alcoholic, artificially sweetened, carbonated, and acidic beverages are pervasive and consumed in large quantities. Reputedly, these beverages are "irritating to the bladder" and result in heightened void frequency, but prior studies lack control for intake volume. We tested the null hypothesis that women recruited from the community who demonstrate overactive bladder symptoms will show no difference by groups in void frequency when one group is instructed to replace listed beverages by substituting non-irritants (emphasis on water or milk) and the other group is instructed in healthy eating. METHODS: This was a parallel-group randomized controlled trial design with a three-period fixed sequence (baseline and 2 and 6 weeks post-baseline). We recruited 105 community women with overactive bladder symptoms. INCLUSION CRITERIA: >7 voids per day or 2 voids per night, daily intake of ≥16 oz. (473 ml) of beverages containing the ingredients listed above, and ≥ 32 oz. (946 ml) of total fluid intake. Stratified randomization was conducted. The primary outcome was average daily void frequency on a 3-day diary. RESULTS: Participants were 86% white, mean (SD) age was 46.6 (17.6) years, and baseline void frequency was 9.2 (2.9) voids per day. At 2 and 6 weeks, estimated average (SD) difference in void frequency between group 1 and group 2 was -0.46 (0.57) and -0.31 (0.57) voids per day (p > 0.05); the null hypothesis was not rejected. CONCLUSIONS: Women who reduce potentially irritating beverages while maintaining total fluid volume intake is not predictive of void frequency. Further research on type and volume of beverage intake is recommended.

Presentation and Outcomes of Infants With Idiopathic Cholestasis: A Multicenter Prospective Study.

OBJECTIVES: The aim of the study was to determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multicenter cohort of infants. METHODS: We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they were followed up to 30 months of age. RESULTS: Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at < 37 weeks' gestational age), and low birth weight (25/89; 28% born at <2500 g) were frequent, with no significant differences between outcomes. Clinical outcomes included death (n = 1), liver transplant (n = 1), biochemical resolution (total bilirubin [TB] ≤1 mg/dL and ALT < 35 U/L; n = 51), partial resolution (TB > 1 mg/dL and/or ALT > 35 U/L; n = 7), and exited healthy (resolved disease per study site report but without documented biochemical resolution; n = 34). Biochemical resolution occurred at median of 9 months of age. GGT was <100 U/L at baseline in 34 of 83 participants (41%). CONCLUSIONS: Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely because of recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis-this warrants further study.

Longitudinal Outcomes in Young Patients with Alpha-1-Antitrypsin Deficiency with Native Liver Reveal that Neonatal Cholestasis is a Poor Predictor of Future Portal Hypertension.

OBJECTIVES: To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. STUDY DESIGN: The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. RESULTS: We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. CONCLUSIONS: Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

Neurodevelopmental Outcomes in Preschool and School Aged Children With Biliary Atresia and Their Native Liver.

OBJECTIVES: The aim of the study was to assess neurodevelopmental outcomes among children with biliary atresia (BA) surviving with their native liver at ages 3 to 12 years and evaluate variables that associate with neurodevelopment. METHODS: Participants (ages 3-12 years) in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with Weschler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III, ages 3-5 years) and Weschler Intelligence Scale for Children, 4th edition (WISC-IV, ages 6-12 years). Continuous scores were analyzed using Kolmogorov-Smironov tests compared with a normal distribution (mean = 100 ±â€Š15). Effect of covariates on Full-Scale Intelligence Quotient (FSIQ) was analyzed using linear regression. RESULTS: Ninety-three participants completed 164 WPPSI-III (mean age 3.9) and 51 WISC-IV (mean age 6.9) tests. WPPSI-III FSIQ (104 ±â€Š14, P < 0.02), Verbal IQ (106 ±â€Š14, P < 0.001), and General Language Composite (107 ±â€Š16, P < 0.001) distributions were shifted higher compared with test norms. WISC-IV FSIQ (105 ±â€Š12, P < 0.01), Perceptual Reasoning Index (107 ±â€Š12, P < 0.01), and Processing Speed Index (105 ±â€Š10, P < 0.02) also shifted upwards. In univariate and multivariable analysis, parent education (P < 0.01) was a significant predictor of FSIQ on WPPSI-III and positively associated with WISC-IV FSIQ. Male sex and higher total bilirubin and gamma glutamyl transferase (GGT) predicted lower WPPSI-III FSIQ. Portal hypertension was predictive of lower WISC-IV FSIQ. CONCLUSIONS: This cohort of children with BA and native liver did not demonstrate higher prevalence of neurodevelopmental delays. Markers of advanced liver disease (higher total bilirubin and GGT for age ≤5 years; portal hypertension for age ≥6) correlate with lower FSIQ and may identify a vulnerable subset of patients who would benefit from intervention.

Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial.

OBJECTIVE: To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants. STUDY DESIGN: A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age. RESULTS: Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life. CONCLUSIONS: Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00294684.

Clinical and Emergent Biomarkers and Their Relationship to the Prognosis of Ovarian Cancer.

OBJECTIVE: Ovarian cancer is the most lethal gynecological malignancy, but information relevant to prognosis and outcomes remain unknown. Here, we used statistical methods to focus specifically on interactions between candidate prognostic variables. METHODS AND RESULTS: Univariate, multivariate, and elastic net modeling of 42 variables were applied to a cohort of 542 ovarian cancer patients with 393 episodes of cancer recurrence/death. In univariate analyses, overexpression of TFF3, MDM2, and p53 were associated with improved recurrence-free survival. In multivariate analyses adjusted for age, histology, stage, grade, ascites, and residual disease, overexpression of PR appeared to provide a protective effect [hazard ratio for >50% of cells positive, 0.64 (95% confidence interval 0.44-0.94) compared to <1%], and TFF3 showed a nonlinear association. Importantly, we observed no interactions among variables. However, patients with tumors with moderate TFF3 expression were at a marginally increased risk of recurrence, and patients with tumors with high expression were at a similar to slightly lower risk, compared to those with tumors with no TFF3 expression. CONCLUSIONS: Although no interactions among variables were observed, this study provides important precedent for seeking interactions between clinical and tumor variables in future studies.

In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma.

OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo. METHODS: Massively parallel sequencing was performed on HGSOCs to identify mutations contributing to HR deficiency. HR pathway integrity was assessed using fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib (MK-4827) on treatment-naïve PDX tumor growth as monotherapy, in combination with carboplatin/paclitaxel, and as maintenance therapy were assessed by transabdominal ultrasound. Niraparib responses were correlated with changes in levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting. RESULTS: Five PDX models were evaluated in vivo. Tumor regressions were induced by single-agent niraparib in one of two PDX models with deleterious BRCA2 mutations and in a PDX with RAD51C promoter methylation. Diminished formation of RAD51 foci failed to predict response, but Artemis loss was associated with resistance. Niraparib generally failed to enhance responses to carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed progression in a BRCA2-deficient PDX. CONCLUSIONS: Mutations in HR genes are neither necessary nor sufficient to predict response to niraparib. Assessment of repair status through multiple complementary assays is needed to guide PARP inhibitor therapy, design future clinical trials and identify ovarian cancer patients most likely to benefit from PARP inhibition.

Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer.

The immune system constitutes one of the host factors modifying outcomes in ovarian cancer. Regulatory T cells (Tregs) are believed to be a major factor in preventing the immune response from destroying ovarian cancers. Understanding mechanisms that regulate Tregs in the tumor microenvironment could lead to the identification of novel targets aimed at reducing their influence. In this study, we used immunofluorescence-based microscopy to enumerate Tregs, total CD4 T cells, and CD8(+) cytotoxic T cells in fresh frozen tumors from over 400 patients with ovarian cancer (>80 % high-grade serous). We sought to determine whether Tregs were associated with survival and genetic variation in 79 genes known to influence Treg induction, trafficking, or function. We used Cox regression, accounting for known prognostic factors, to estimate hazard ratios (HRs) associated with T cell counts and ratios. We found that the ratios of CD8 T cells and total CD4 T cells to Tregs were associated with improved overall survival (CD8/Treg HR 0.84, p = 0.0089; CD4/Treg HR 0.88, p = 0.046) and with genetic variation in IL-10 (p = 0.0073 and 0.01, respectively). In multivariate analyses, the associations between the ratios and overall survival remained similar (IL-10 and clinical covariate-adjusted CD8/Treg HR 0.85, p = 0.031; CD4/Treg HR 0.87, p = 0.093), suggesting that this association was not driven by variation in IL-10. Thus, integration of novel tumor phenotyping measures with extensive clinical and genetic information suggests that the ratio of T cells to Tregs may be prognostic of outcome in ovarian cancer, regardless of inherited genotype in genes related to Tregs.

Exposure to environmental chemicals and heavy metals, and risk of pancreatic cancer.

PURPOSE: Exposure to various chemicals and heavy metals has been associated with risk of different cancers; however, data on whether such exposures may increase the risk of pancreatic cancer (PC) are very limited and inconclusive. We examined PC risk with self-reported exposures to chemicals and heavy metals. METHODS: The design was a clinic-based, case-control study of data collected from 2000 to 2014 at Mayo Clinic in Rochester, Minnesota, USA. Cases were rapidly ascertained patients diagnosed with pancreatic ductal adenocarcinoma (n = 2,092). Controls were cancer-free patients in primary care clinics (n = 2,353), frequency-matched to cases on age, race, sex, and state/region of residence. Cases and controls completed identical risk factor questionnaires, which included yes/no questions about regular exposure to pesticides, asbestos, benzene, chlorinated hydrocarbons, chromium, and nickel. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) comparing those who affirmed exposure to each of the chemicals/heavy metals to those who reported no regular exposure, adjusting for potential confounders. RESULTS: Self-reported regular exposure to pesticides was associated with increased odds of PC (OR 1.21, 95% CI 1.02-1.44). Regular exposure to asbestos (OR 1.54, 95% CI 1.23-1.92), benzene (OR 1.70, 95% CI 1.23-2.35), and chlorinated hydrocarbons (OR 1.63, 95% CI 1.32-2.02) also was associated with higher odds of PC. Chromium and nickel exposures were not significantly associated with PC. CONCLUSIONS: These findings add to the limited data suggesting that exposure to pesticides, asbestos, benzene, and chlorinated hydrocarbons may increase PC risk. They further support the importance of implementing strategies that reduce exposure to these substances.

Assessment of published models and prognostic variables in epithelial ovarian cancer at Mayo Clinic.

OBJECTIVES: Epithelial ovarian cancer (EOC) is an aggressive disease in which first line therapy consists of a surgical staging/debulking procedure and platinum based chemotherapy. There is significant interest in clinically applicable, easy to use prognostic tools to estimate risk of recurrence and overall survival. In this study we used a large prospectively collected cohort of women with EOC to validate currently published models and assess prognostic variables. METHODS: Women with invasive ovarian, peritoneal, or fallopian tube cancer diagnosed between 2000 and 2011 and prospectively enrolled into the Mayo Clinic Ovarian Cancer registry were identified. Demographics and known prognostic markers as well as epidemiologic exposure variables were abstracted from the medical record and collected via questionnaire. Six previously published models of overall and recurrence-free survival were assessed for external validity. In addition, predictors of outcome were assessed in our dataset. RESULTS: Previously published models validated with a range of c-statistics (0.587-0.827), though application of models containing variables which are not part of routine practice were somewhat limited by missing data; utilization of all applicable models and comparison of results are suggested. Examination of prognostic variables identified only the presence of ascites and ASA score to be independent predictors of prognosis in our dataset, albeit with marginal gain in prognostic information, after accounting for stage and debulking. CONCLUSIONS: Existing prognostic models for newly diagnosed EOC showed acceptable calibration in our cohort for clinical application. However, modeling of prospective variables in our dataset reiterates that stage and debulking remains the most important predictors of prognosis in this setting.

Detection of endometrial cancer via molecular analysis of DNA collected with vaginal tampons.

OBJECTIVE: We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collection techniques with sensitive molecular testing. METHODS: Prior to hysterectomy for EC or benign indications, women collected vaginal pool samples with intravaginal tampons and underwent endometrial brushing. Specimens underwent pyrosequencing for DNA methylation of genes reported to be hypermethylated in gynecologic cancers and recently identified markers discovered by profiling over 200 ECs. Methylation was evaluated individually across CpGs and averaged across genes. Differences between EC and benign endometrium (BE) were assessed using two-sample t-tests and area under the curve (AUC). RESULTS: Thirty-eight ECs and 28 BEs were included. We evaluated 97 CpGs within 12 genes, including previously reported markers (RASSF1, HSP2A, HOXA9, CDH13, HAAO, and GTF2A1) and those identified in discovery work (ASCL2, HTR1B, NPY, HS3ST2, MME, ADCYAP1, and additional CDH13 CpG sites). Mean methylation was higher in tampon specimens from EC v. BE for 9 of 12 genes (ADCYAP1, ASCL2, CDH13, HS3ST2, HTR1B, MME, HAAO, HOXA9, and RASSF1) (all p<0.05). Among these genes, relative hypermethylation was observed in EC v. BE across CpGs. Endometrial brush and tampon results were similar. Within tampon specimens, AUC was highest for HTR1B (0.82), RASSF1 (0.75), and HOXA9 (0.74). This is the first report of HOXA9 hypermethylation in EC. CONCLUSION: DNA hypermethylation in EC tissues can also be identified in vaginal pool DNA collected via intravaginal tampon. Identification of additional EC biomarkers and refined collection methods are needed to develop an early detection tool for EC.

Racial, Ethnic, and Sex-based Disparities among High-risk Individuals Undergoing Pancreatic Cancer Surveillance.

Since its inception two years ago, the international, multicenter Pancreatic Cancer Early Detection (PRECEDE) Consortium has enrolled high-risk individuals (HRI) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Herein we aim to evaluate enrollment disparities in PRECEDE. Data on HRIs enrolled between May 2020 and March 2022 were collected, with HRIs defined as participants enrolled in PRECEDE meeting guideline-based criteria for PDAC surveillance. Of 1,273 HRIs enrolled, 1,113 were eligible for inclusion, with 47.2% meeting familial pancreatic cancer criteria without a known pathogenic variant (PV) and the remainder having a pathogenic variant in a PDAC-risk gene (CDKN2A, STK11, PRSS1, BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). Study participants were predominantly from the United States (82.7%), the most common age range at enrollment was 60-69 years (37.4%), and a non-PDAC cancer was present in 32.4%. There were racial/ethnic- and sex-based disparities among enrolled subjects, as the majority of participants were female (65.9%) and self-reported white (87.7%), with only 2.9% having Hispanic ethnicity. While more than 97% of participants consented to utilize imaging data and biosamples for research, there was no difference in rate of consent based on race/ethnicity, sex, or age, thereby demonstrating uniform participation in research activities among all subgroups after enrollment. Ensuring that diversity of HRIs in PDAC surveillance programs mirrors the communities served by participating centers is important. Substantial racial/ethnic- and sex-based disparities persist among recently enrolled HRIs undergoing PDAC surveillance, and therefore reducing these disparities will be a major focus of the PRECEDE Consortium moving forward. PREVENTION RELEVANCE: Pancreatic cancer surveillance is critical to decreasing pancreatic cancer mortality; therefore, it is important that pancreatic cancer surveillance studies enroll diverse patients. We demonstrate that substantial racial/ethnic- and sex-based disparities exist amongst enrollment in the international PRECEDE consortium, highlighting the dire need for future efforts to reduce these disparities. See related Spotlight, p. 305.

Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children.

BACKGROUND: Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH. METHODS: We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes. RESULTS: Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported. CONCLUSIONS: Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies.

Self-Perceived Improvement in Bladder Health After Viewing a Novel Tutorial on Knack Use: A Randomized Controlled Trial Pilot Study.

Purpose: To test a novel bladder health tutorial on use of the Knack for overcoming bladder control challenges. The Knack-tutorial is a self-administered vignette-based instructional program on preempting bladder challenges in daily life (urgency, stress-leakage, or urge-leakage) through anticipatory, well-timed pelvic floor muscle contraction at the moment of challenge. Materials and Methods: This is a randomized controlled trial pilot test of 108 women with stress or mixed urinary incontinence. The Knack-tutorial group saw a 15-minute slide show with 10 vignettes portraying use of the Knack in daily life. The slide show format used inserted narrated videos, dubbed and animation enhanced pictures and cartoons, and automatic slide advancement. A control group saw a similarly constructed slide show on incorporating good diet/exercise habits. Outcomes were self-perceived improvement (yes/no, and as 0%-100%) 1 month after viewing the tutorial. Results: We enrolled 123 women, randomizing 64 to Knack-tutorial group and 59 to diet/exercise tutorial group. Eleven and one participant, respectively, did not return. Three did not fill out the self-perceived improvement report. Significant improvement was reported by 71% in the Knack-tutorial group compared to 25% in the diet/exercise group (p < 0.001). Self-perceived improvement was 21%-22% higher (Model I Est: 21.01, SE: 4.25, p < 0.001) in the Knack-tutorial group. Conclusions: An electronic tutorial viewed independent of a health care provider with vignettes showing Knack application to manage the everyday bladder challenges women face shows benefit of a magnitude that warrants more widespread use and rigorous testing. A professional remake of the intervention is now available (www.myconfidentbladder.com).

Modeling Outcomes in Children With Biliary Atresia With Native Liver After 2 Years of Age.

Approximately 50% of infants with biliary atresia (BA) undergoing Kasai portoenterostomy show survival with native liver (SNL) at age 2 years. Predictors of disease progression after age 2 years are unknown, despite estimates of 20%-30% undergoing liver transplant (LT) between age 2 and 18 years. We sought to address this knowledge gap by developing prognostic models in participants of the multicenter prospective National Institutes of Health-supported Childhood Liver Disease Research Network. We extracted 14 clinical and biochemical variables at age 2 years to develop two models for future outcomes: 1) LT or death (LTD) and 2) first sentinel event (SE), either new onset ascites, hepatopulmonary syndrome (HPS), or gastrointestinal (GI) bleed. A total of 240 participants, enrolled between 2004 and 2017, were followed until a median age of 5.1 years (range, 2.0-13.3 years). Of these participants, 38 underwent LT (n = 37) or death (n = 1); cumulative incidence, 23.7% (95% confidence interval [CI], 16.2%-32.0%). Twenty-seven experienced either new-onset ascites (n = 13), HPS (n = 1), or GI bleed (n = 14). One participant had ascites and GI bleed concurrently; cumulative incidence, 21.5% (95% CI, 14.2%-29.8%) by age 10 years. The Cox proportional hazard model predicted risk of LTD, using total bilirubin, albumin, platelet count, and history of either ascites or cholangitis (BA LTD model), with a C-index of 0.88 (range, 0.86-0.89). A cause-specific hazard competing risk model predicted SE using platelet count and gamma glutamyltransferase levels (BA SE model) with a C-index of 0.81 (range, 0.80-0.84). Internal model validity was assessed using Harrell's C-index with cross-validation. Conclusion: Stratification using these models identified risk of poor outcomes in patients with BA SNL after age 2 years. The models may identify those who would benefit from enhanced clinical surveillance and prioritization in clinical trials.