Search

We study bias arising from rounding categorical variables following multivariate normal (MVN) imputation. This task has been well studied for binary variables, but not for more general categorical variables. Three methods that assign imputed values to categories based on fixed reference points are compared using 25 specific scenarios covering variables withk=3, …, 7 categories, and five distributional shapes, and for eachk=3, …, 7, we examine the distribution of bias arising over 100,000 distributions drawn from a symmetric Dirichlet distribution. We observed, on both empirical and theoretical grounds, that one method (projected-distance-based rounding) is superior to the other two methods, and that the risk of invalid inference with the best method may be too high at sample sizesn≥150 at 50% missingness,n≥250 at 30% missingness andn≥1500 at 10% missingness. Therefore, these methods are generally unsatisfactory for rounding categorical variables (with up to seven categories) following MVN imputation. [ABSTRACT FROM PUBLISHER]

Objectives: To evaluate gastric emptying in patients with chronic liver disease and portal hypertension. Methods: We measured gastric emptying of both the liquid and solid components of a meal in 10 consecutive patients with chronic liver disease and portal hypertension, hut free of ascites, and 14 age- and sex-matched healthy controls. In the patients with liver disease, relationships between emptying and liver function were examined. To measure gastric emptying, subjects consumed a test meal that consisted of scrambled eggs labeled with 99mTc-sulfur colloid and 4 oz of water labeled with 111In-diethylene triamine pentacetic acid (DTPA). Results: Patients with liver disease and portal hypertension demonstrated delayed emptying of both the liquid (t½A, min, mean ± SE, patients vs. Controls: 69.4 ± 19.4 vs. 31.4 ± 1.8, p < 0.01) and solid (post-lag phase solid emptying: 141 ± 32.9 vs. 69.8 ± 4.6, p < 0.006) components of the meal. We could not identify any correlation between gastric emptying and tests of liver function. Conclusions: Gastric emptying is delayed in patients with liver disease and portal hypertension; this abnormal gastric motor function may contribute to the pathophysiology of foregut complaints in this patient population. [ABSTRACT FROM AUTHOR]

Abstract Background The insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity. DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression. Results The principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC. Conclusions As greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required.

Introduction: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD)., Methods: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation., Results: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49-0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients., Discussion: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response., (Copyright © 2022 by The American College of Gastroenterology.)

The incidence and prevalence of inflammatory bowel disease (IBD) is increasing in the elderly population. Compared with patients with onset during younger years, patients with elderly-onset IBD have a distinct clinical presentation, disease phenotype, and natural history. Genetics contribute less to pathogenesis of disease, whereas aging-related biological changes, such as immunosenescence and dysbiosis, are associated with elderly-onset IBD. Frailty is an increasingly recognized predictor of adverse outcomes. As an increasingly wider array of biologic and small molecule therapeutic options becomes available, data regarding efficacy and safety of these agents in patients are paramount given the unique characteristics of this population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: We conducted a systematic review and meta-analysis to summarize emerging data on the safety and effectiveness of dual biologic therapy in combination or with tofacitinib in patients with refractory inflammatory bowel disease (IBD)., Methods: Through a systematic search of multiple electronic databases through November 9, 2020, we identified cohort studies or case series (>10 patients) reporting the safety and effectiveness of simultaneous use of biologic agents in combination or with tofacitinib in patients with IBD. Rates of adverse events, clinical remission, and endoscopic remission were synthesized using pooled data, and we identified factors associated with successful dual therapy., Results: We identified 30 studies reporting 288 trials of dual biologic or small molecule therapy in 279 patients (76% Crohn's disease; median duration of treatment 24 weeks (IQR 25 -IQR 75 1332)). The main indications for dual therapy included medically refractory IBD (81%) and concurrent extra-intestinal manifestations or rheumatologic disease (12%). The most common combinations of dual therapy included tumor necrosis factor-α antagonists & anti-integrins (48%), ustekinumab & anti-integrins (19%); 61% of patients had previously failed at least one of the two therapies used in combination. Over a median follow-up of 32 weeks (IQR 25 -IQR 75 24-52), pooled rates of adverse and serious adverse events were 31% (95% CI, 13%-54%) and 6.5% (95% CI, 2.1%-13.1%); pooled rates of clinical and endoscopic remission were 59% (95% CI, 42%-74%), and 34% (95% CI, 23%-46%), respectively. 12% (95% CI, 4%-24%) of patients required surgery. Rates of success were higher in patients on dual therapy due to EIM. Heterogeneity was not significant for endoscopic response (P = .88, I 2  = 0%), endoscopic remission (P = .44, I 2  = 0%), and malignancy (P = .87, I 2  = 0%). However, significant heterogeneity existed for other outcomes., Conclusions: Dual biologic or small molecule therapy may be a possible option in highly selected, refractory IBD patients at specialized centers. Higher quality combination of therapies with a significant improvement in the quality of data is required prior to more widespread use., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. Currently, liver transplantation may be the optimal treatment for HCC in cirrhotic patients. Patient selection is currently based on tumor size. We developed a program to offer liver transplantation to selected patients with HCC outside of traditional criteria., Methods: Retrospective review for patients transplanted with HCC between April 2008 and June 2017. Patients were grouped by tumor size according to Milan, University of California San Francisco (UCSF), and outside UCSF criteria. Patient demographics, laboratory values, and outcomes were compared. Patients radiographically outside Milan criteria were selected based on tumor control with locoregional therapy (LRT) and 9 months of stability from LRT. α-fetoprotein values were not exclusionary., Results: Two hundred twenty HCC patients were transplanted, 138 inside Milan, 23 inside UCSF, and 59 beyond UCSF criteria. Patient survival was equivalent at 1, 3, or 5 years despite pathologic tumor size. Waiting time to transplantation was not significantly different at an average of 344 days. In patients outside UCSF, tumor recurrence was equivalent to Milan and UCSF criteria recipients who waited >9 months from LRT. Although tumor recurrence was more likely in outside of UCSF patients (3% versus 9% versus 15%; P = 0.02), recurrence-free survival only trended toward significance among the groups (P = 0.053)., Conclusions: Selective patients outside of traditional size criteria can be effectively transplanted with equivalent survival to patients with smaller tumors, even when pathologic tumor burden is considered. Tumor stability over time can be used to help select patients for transplantation.

Background: Race, ethnicity and socio-economic status impact clinical outcomes in inflammatory bowel disease (IBD) patients. However, their impact on disability has not been studied., Aim: To determine the association between race, ethnicity and socio-economic factors with disability in IBD, using the validated IBD disability index (IBD-DI)., Methods: Ambulatory IBD patients were enrolled at five academic centres participating in the New York Crohn's and Colitis Organization. We assessed the IBD-DI, and collected clinical and socio-economic data. Factors associated with moderate-to-severe disability (IBD-DI score > 35) on univariable analysis were tested in multivariable models with adjusted odds ratios (aOR) and 95% confidence intervals (CI) reported., Results: In this study, 323 patients (57.3% CD, 51.4% female) were enrolled; 17.7% were Hispanic, 17% were non-Hispanic black, 56.0% were non-Hispanic Caucasian and 9.3% belonged to non-Hispanic non-black minority races. However, 39.0% of patients were publicly insured and 38.4% of patients had low annual household income (<$50 000). 100 (31.0%) patients reported moderate-to-severe disability. On multivariable analysis, Hispanic ethnicity (aOR 2.7, 95% CI 1.3-5.6), non-Hispanic non-black minority race (aOR 3.5, 95% CI 1.3-8.9), public payer (aOR 2.1, 95% CI 1.1-4.0) and low annual household income (aOR 3.0, 95% CI 1.7-5.4) were associated with moderate-to-severe disability controlling for disease characteristics., Conclusions: IBD patients who are minorities, have public insurance, or low household income, are 2-3 times more likely to report moderate-to-severe disability independent of disease characteristics in the United States. Future studies are needed to study their complex relationship and to mitigate disability., (© 2019 John Wiley & Sons Ltd.)

Objective: Hearing loss rates in infants admitted to neonatal intensive care units (NICU) run at 2-15%, compared to 0.3% in full-term births. The etiology of this difference remains poorly understood. We examined whether the level of ambient sound and/or cumulative gentamicin (an aminoglycoside) exposure affect NICU hearing screening results, as either exposure can cause acquired, permanent hearing loss. We hypothesized that higher levels of ambient sound in the NICU, and/or gentamicin dosing, increase the risk of referral on the distortion product otoacoustic emission (DPOAE) assessments and/or automated auditory brainstem response (AABR) screens., Methods: This was a prospective pilot outcomes study of 82 infants (<37 weeks gestational age) admitted to the NICU at Oregon Health & Science University. An ER-200D sound pressure level dosimeter was used to collect daily sound exposure in the NICU for each neonate. Gentamicin dosing was also calculated for each infant, including the total daily dose based on body mass (mg/kg/day), as well as the total number of treatment days. DPOAE and AABR assessments were conducted prior to discharge to evaluate hearing status. Exclusion criteria included congenital infections associated with hearing loss, and congenital craniofacial or otologic abnormalities., Results: The mean level of ambient sound was 62.9 dBA (range 51.8-70.6 dBA), greatly exceeding American Academy of Pediatrics (AAP) recommendation of <45.0 dBA. More than 80% of subjects received gentamicin treatment. The referral rate for (i) AABRs, (frequency range: ∼1000-4000 Hz), was 5%; (ii) DPOAEs with a broad F2 frequency range (2063-10031 Hz) was 39%; (iii) DPOAEs with a low-frequency F2 range (<4172 Hz) was 29%, and (iv) DPOAEs with a high-frequency F2 range (>4172 Hz) was 44%. DPOAE referrals were significantly greater for infants receiving >2 days of gentamicin dosing compared to fewer doses (p = 0.004). The effect of sound exposure and gentamicin treatment on hearing could not be determined due to the low number of NICU infants without gentamicin exposure (for control comparisons)., Conclusion: All infants were exposed to higher levels of ambient sound that substantially exceed AAP guidelines. More referrals were generated by DPOAE assessments than with AABR screens, with significantly more DPOAE referrals with a high-frequency F2 range, consistent with sound- and/or gentamicin-induced cochlear dysfunction. Adding higher frequency DPOAE assessments to existing NICU hearing screening protocols could better identify infants at-risk for ototoxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The placenta richly expresses nonheme and heme Fe transport proteins. To address the impact of maternal and neonatal Fe status and hepcidin on the regulation of these proteins, mRNA expression and protein abundance of nonheme and heme Fe transport proteins were evaluated in placental tissue from 154 adolescents. Regression analyses found maternal Fe status was significantly associated with multiple placental nonheme and heme transporters, whereas neonatal Fe status was related to only 3 heme transporters. Across statistical analyses, maternal Fe status was consistently associated with the placental nonheme Fe importer transferrin receptor 1 (TfR1). Protein abundance of TfR1 was related to midgestation maternal serum ferritin (SF) (β = -0.32; P = 0.005) and serum TfR (β = 0.25; P = 0.024). Protein abundance of the heme importer, proton-coupled folate transporter, was related to neonatal SF (β = 0.30; P = 0.016) and serum TfR (β = -0.46; P < 0.0001). Neonatal SF was also related to mRNA expression of the heme exporter feline leukemia virus subgroup C receptor 1 (β = -0.30; P = 0.004). In summary, maternal Fe insufficiency during pregnancy predicts increased expression of the placental nonheme Fe transporter TfR1. Associations between placental heme Fe transporters and neonatal Fe status require further study.-Best, C. M., Pressman, E. K., Cao, C., Cooper, E., Guillet, R., Yost, O. L., Galati, J., Kent, T. R., O'Brien, K. O. Maternal iron status during pregnancy compared with neonatal iron status better predicts placental iron transporter expression in humans., (© FASEB.)

Aspergillus infection remains a significant and deadly complication after liver transplantation (LT). We sought to determine whether the antifungal prophylactic use of voriconazole reduces the incidence of invasive aspergillosis (IA) in high-risk LT recipients without prohibitively increasing cost. During the study era (April 2008 to April 2014), 339 deceased donor LTs were performed. Of those patients, 174 high-risk recipients were administered antifungal prophylaxis with voriconazole. The median biological Model for End-Stage Liver Disease score at the time of LT was 33 (range, 18-49) with 56% requiring continuous renal replacement therapy and 50% requiring ventilatory support immediately before transplantation. Diagnosis of IA was stratified as proven, probable, or possible according to previously published definitions. No IA was documented in patients receiving voriconazole prophylaxis. At 90 days after LT, the institutional cost of prophylaxis was $5324 or 5.6% of the predicted cost associated with post-LT aspergillosis. There was no documentation of resistant strains isolated from any recipient who received voriconazole. In conclusion, these data suggest that voriconazole prophylaxis is safe, clinically effective, and cost-effective in high-risk LT recipients., (© 2015 American Association for the Study of Liver Diseases.)

Background & Aims: Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response (<2-log10 decline in HCV RNA), to peginterferon/ribavirin., Methods: Patients in the control arms of boceprevir Phase 2/3 studies who did not achieve SVR were re-treated with BOC/PR for up to 44 weeks. Patients enrolling >2 weeks after end-of-treatment in the prior study received PR for 4 weeks before adding boceprevir., Results: Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000 IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with <1-log10 decline in HCV-RNA after lead-in and 76% of those with ⩾ 1-log10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events., Conclusions: Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Outcomes after operations for bicuspid aortic valve disease in pediatric patients were determined., Methods: Between 1977 and 2011, 146 consecutive patients underwent surgical repair of bicuspid aortic valve. Median age at operation was 207 days (range, 5 days to 16 years). Indication for surgery was stenosis in 113, insufficiency in 25, and both in 8. Valve debridement was done in 76 patients, and complex repairs in 70, including 61 who required addition of pericardial patches, consisting of the creation of a neocommissure in 55, cusp extension in 33, and a perforation repair in 6. The valve was made tricuspid in 38 patients (29 cusp extensions)., Results: Twenty-year survival was 88% (95% confidence interval, 73% to 95%). After a mean follow-up of 8 ± 7 years, 35 patients needed a reintervention. Freedom from reintervention at 18 years was 43% (95% confidence interval, 28% to 56%). At the latest follow-up, an additional 13 patients without reoperation had moderate or severe stenosis, and 17 had moderate regurgitation. Seventy-eight patients had an event-free long-term outcome (no reintervention, stenosis, or regurgitation). The only independent predictive factors of an event-free outcome were not having addition of patch material at repair (hazard ratio, 12; p = 0.05) and shorter bypass time (HR, 1.01; p = 0.023). The 10-year freedom from any significant event was 60% (95% confidence interval, 46% to 71%) for those without use of patch material, whereas nearly all those with a patch repair had an adverse event at that time., Conclusions: Outcomes after surgical repair of bicuspid aortic valves in the pediatric population are excellent, especially if the repair can be performed without the addition of patches. Primary repair should be offered because long-lasting results can be achieved if the disease can be relieved by simple procedures., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)