Citations

ObjectiveTo assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Vasculitis (RAVE) trial and identify novel potential risk factors.MethodsVTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA‐associated vasculitis (AAV).ResultsVTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0–2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247–134.842]; P = 0.006), positive proteinase 3 (PR3)–ANCA (HR 7.731 [95% CI 1.021–58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448–10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491–69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566–185.805]; P = 0.005), PR3‐ANCA (HR 9.12 [95% CI 1.158–71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453–10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607–75.075]; P < 0.001) remained.ConclusionPatients diagnosed as having AAV with pulmonary hemorrhage, positive PR3‐ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.

Abstract Human fibrin hydrogels are a popular choice for use as a biomaterial within tissue engineered constructs because they are biocompatible, nonxenogenic, autologous use compatible, and biodegradable. We have recently demonstrated the ability to culture induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium on fibrin hydrogels. However, iPSCs themselves have relatively few substrate options (e.g., laminin) for expansion in adherent cell culture for use in cell therapy. To address this, we investigated the potential of culturing iPSCs on fibrin hydrogels for three-dimensional applications and further examined the use of fibrinogen, the soluble precursor protein, as a coating substrate for traditional adherent cell culture. iPSCs successfully adhered to and proliferated on fibrin hydrogels. The two-dimensional culture with fibrinogen allows for immediate adaption of culture models to a nonxenogeneic model. Similarly, multiple commercially available iPSC lines adhered to and proliferated on fibrinogen coated surfaces. iPSCs cultured on fibrinogen expressed similar levels of the pluripotent stem cell markers SSea4 (98.7% ± 1.8%), Oct3/4 (97.3% ± 3.8%), TRA1-60 (92.2% ± 5.3%), and NANOG (96.0% ± 3.9%) compared with iPSCs on Geltrex. Using a trilineage differentiation assay, we found no difference in the ability of iPSCs grown on fibrinogen or Geltrex to differentiate to endoderm, mesoderm, or ectoderm. Finally, we demonstrated the ability to differentiate iPSCs to endothelial cells using only fibrinogen coated plates. On the basis of these data, we conclude that human fibrinogen provides a readily available and inexpensive alternative to laminin-based products for the growth, expansion, and differentiation of iPSCs for use in research and clinical cell therapy applications. Stem Cells Translational Medicine 2019;8:512–521

Abstract Background: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer–metabolite associations using two-sample Mendelian randomization (MR). Methods: The case–control portion of the study was conducted in nine UK centers with men ages 50–69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Results: Thirty-five metabolites were strongly associated with prostate cancer (P &lt; 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. Conclusions: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. Impact: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

Abstract BACKGROUND A decrease in diastolic blood pressure (DBP) with exercise is considered normal, but the significance of an increase in DBP has not been validated. Our aim was to determine the relationship of DBP increasing on a stress test regarding comorbidities and mortality. METHODS Our database was reviewed from 1993 to 2010 using the first stress test of a patient. Non-Minnesota residence, baseline cardiovascular (CV) disease, rest DBP &lt;60 or &gt;100 mm Hg, and age &lt;30 or ≥80 were exclusion criteria. DBP response was classified: normal if peak DBP–rest DBP &lt; 0, borderline 0–9, and abnormal ≥10 mm Hg. Mortality was determined from Mayo Clinic records and Minnesota Death Index. Logistic regression was used to determine the relationship of DBP response to the presence of comorbidities. Cox regression was used to determine total and CV mortality risk by DBP response. All analyses were adjusted for age, sex, and resting DBP. RESULTS Twenty thousand seven hundred sixty patients were included (51 ± 11 years, female n = 7,314). Rest/peak averaged DBP 82 ± 8/69 ± 15 mm Hg in normal vs. 79 ± 9/82 ± 9 mm Hg in borderline vs. 76 ± 9/92 ± 11 mm Hg in abnormal DBP response. There were 1,582 deaths (8%) with 557 (3%) CV deaths over 12 ± 5 years of follow-up. In patients with borderline and abnormal DBP response, odds ratios for obesity, hypertension, diabetes, and current smoking were significant, while hazard ratios for total and CV death were not significant compared with patients with normal DBP response. CONCLUSIONS DBP response to exercise is significantly associated with important comorbidities at the time of the stress test but does not add to the prognostic yield of stress test.

Background Heart rate ( HR ) recovery has been investigated in specific patient cohorts, but there is less information about the role of HR recovery in general populations. We investigated whether HR recovery has long‐term prognostic significance in primary prevention. Methods and Results Exercise tests performed between 1993 and 2010 on patients aged 30 to 79 years without cardiovascular disease were included. Mortality was determined from Mayo Clinic records and Minnesota Death Index. Total, cardiovascular , and non‐cardiovascular mortality was reported according to HR recovery <13 bpm using Cox regression. 19 551 patients were included, 6756 women (35%), age 51±10 years. There were 1271 deaths over follow‐up of 12±5 years. HR recovery declined after age 60, and was also lower according to diabetes mellitus, hypertension, obesity, current smoking, and poor cardiorespiratory fitness but not sex or β‐blockers. Adjusting for these factors, abnormal HR recovery was a significant predictor of total (hazard ratio [95% confidence interval]=1.56 [1.384–1.77]), cardiovascular (1.95 [1.57–2.42]), and non‐cardiovascular death (1.41 [1.22–1.64]). Hazard ratios for cardiovascular death according to abnormal HR recovery were significant in all age groups (30–59, 60–69, 70–79), in both sexes, in patients with and without hypertension, obesity, and diabetes mellitus, but not in patients taking β‐blockers, current smokers, and patients with normal cardiorespiratory fitness. Conclusions HR recovery is a powerful prognostic factor predicting total, cardiovascular, and non‐cardiovascular death in a primary prevention cohort. It performs consistently well according to sex, age, obesity, hypertension, and diabetes mellitus but shows diminished utility in patients taking β‐blockers, current smokers, and patients with normal cardiorespiratory fitness.

Background Bile leak after liver transplantation (LT) is commonly treated with endoscopic retrograde cholangiopancreatography (ERCP); however, there are limited data regarding the optimal treatment strategy. Objective We aimed to examine the role of ERCP in LT recipients with bile leaks at two large institutions. Methods We reviewed all ERCPs performed in LT recipients with bile leak and duct-to-duct biliary anastomosis at two high-volume transplant centers. Results Eighty patients were included. Forty-seven (59%) patients underwent ERCP with plastic stent placement (with or without sphincterotomy) and 33 patients (41%) underwent sphincterotomy alone. Complete resolution was obtained in 94% of the stent group vs. 58% of the sphincterotomy group ( p < 0.01). There was no difference in three-month survival among both groups. Percutaneous transhepatic therapy and surgery were required in 4% and 6% in the stent group vs. 12% and 42% in the sphincterotomy group, respectively ( p = 0.22 and p < 0.001). The only predictive factor of bile leak resolution was stent placement. Conclusion ERCP with plastic stent placement is highly successful and more effective than sphincterotomy alone for post-LT bile leak treatment. These results indicate that ERCP and plastic stent placement should be considered the standard of care for the treatment of bile leaks in LT.

We described physical activity measures and hourly patterns in patients with chronic obstructive pulmonary disease (COPD) after stratification for generic and COPD-specific characteristics and, based on multiple physical activity measures, we identified clusters of patients. In total, 1001 patients with COPD (65% men; age, 67 years; forced expiratory volume in the first second [FEV 1 ], 49% predicted) were studied cross-sectionally. Demographics, anthropometrics, lung function and clinical data were assessed. Daily physical activity measures and hourly patterns were analysed based on data from a multisensor armband. Principal component analysis (PCA) and cluster analysis were applied to physical activity measures to identify clusters. Age, body mass index (BMI), dyspnoea grade and ADO index (including age, dyspnoea and airflow obstruction) were associated with physical activity measures and hourly patterns. Five clusters were identified based on three PCA components, which accounted for 60% of variance of the data. Importantly, couch potatoes (i.e. the most inactive cluster) were characterised by higher BMI, lower FEV 1 , worse dyspnoea and higher ADO index compared to other clusters ( p < 0.05 for all). Daily physical activity measures and hourly patterns are heterogeneous in COPD. Clusters of patients were identified solely based on physical activity data. These findings may be useful to develop interventions aiming to promote physical activity in COPD.