Citations

PurposeDynamic manganese‐enhanced MRI (MEMRI) allows assessment of tissue viability by tracing manganese uptake. We aimed to develop a rapid T1 mapping method for dynamic MEMRI to facilitate assessments of murine kidney viability.MethodsA multi‐slice saturation recovery fast spin echo (MSRFSE) was developed, validated, and subsequently applied in dynamic MEMRI at 16.4T on ischemic mouse kidneys after 4 weeks of unilateral renal artery stenosis (RAS). Baseline T1 values and post‐contrast R1 (1/T1) changes were measured in cortex (CO), outer (OSOM), inner (ISOM) strips of outer medulla, and inner medulla (IM).ResultsValidation studies showed strong agreement between MSRFSE and an established saturation recovery Look‐Locker method. Baseline T1 (s) increased in the stenotic kidney CO (2.10 [1.95–2.56] vs. 1.88 [1.81–2.00], P = 0.0317) and OSOM (2.17 [2.05–2.33] vs. 1.96 [1.87–2.00], P = 0.0075) but remained unchanged in ISOM and IM. This method allowed a temporal resolution of 1.43 min in dynamic MEMRI. Mn2+ uptake and retention decreased in stenotic kidneys, particularly in the OSOM (ΔR1: 0.48 [0.38–0.56] vs. 0.64 [0.61–0.69] s−1, P < 0.0001).ConclusionDynamic MEMRI by MSRFSE detected decreased cellular viability and discerned the regional responses to RAS. This technique may provide a valuable tool for noninvasive evaluation of renal viability. Magn Reson Med 80:190–199, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Background: End-of-life (EOL) care intensity is known to vary by secular and geographic patterns. US physicians receive less aggressive EOL care than the general population, presumably the result of preferences shaped by work-place experience with EOL care. Objective: We investigated occupation as a source of variation in EOL care intensity. Methods: Across 4 states, we identified 660 599, nonhealth maintenance organization Medicare beneficiaries aged ≥66 years who died between 2004 and 2011. Linking death certificates, we identified beneficiaries with prespecified occupations: nurses, farmers, clergy, mortuary workers, homemakers, first-responders, veterinary workers, teachers, accountants, and the general population. End-of-life care intensity over the last 6 months of life was assessed using 5 validated measures: (1) Medicare expenditures, rates of (2) hospice, (3) surgery, (4) intensive care, and (5) in-hospital death. Results: Occupation was a source of large variation in EOL care intensity across all measures, before and after adjustment for sex, education, age-adjusted Charlson Comorbidity Index, race/ethnicity, and hospital referral region. For example, absolute and relative adjusted differences in expenditures were US$9991 and 42% of population mean expenditure ( P < .001 for both). Compared to the general population on the 5 EOL care intensity measures, teachers (5 of 5), homemakers (4 of 5), farmers (4 of 5), and clergy (3 of 5) demonstrated significantly less aggressive care. Mortuary workers had lower EOL care intensity (4 of 5) but small numbers limited statistical significance. Conclusion: Occupations with likely exposure to child development, death/bereavement, and naturalistic influences demonstrated lower EOL care intensity. These findings may inform patients and clinicians navigating choices around individual EOL care preferences.

Background Current American Heart Association/American College of Cardiology guidelines recommend the GRACE (Global Registry of Acute Coronary Events) and TIMI (Thrombolysis in Myocardial Infarction) scores to assess myocardial infarction ( MI ) prognosis. Changes in the epidemiological characteristics of MI and the availability of new biomarkers warrant an assessment of the performance of these scores in contemporary practice. We assessed the following: (1) the performance of GRACE and TIMI to predict 1‐year mortality in a cohort of patients stratified by ST ‐segment elevation MI (STEMI) and non‐STEMI ( NSTEMI ) and (2) the incremental discriminatory power of soluble suppression of tumorigenicity‐2, a myocardial fibrosis biomarker. Methods and Results Olmsted County, Minnesota, residents with incident MI (N=1401) were recruited prospectively from November 1, 2002 to December 31, 2012 (mean age, 67 years; 61% men; 79% with NSTEMI ). Baseline data were used to calculate risk scores; soluble suppression of tumorigenicity‐2 was measured in stored plasma samples obtained at index MI . C ‐statistics adapted to survival data were used to assess the discriminatory power of the risk scores and the improvement gained by adding other markers. During the first year of follow‐up, 190 patients (14%) died. The discriminatory performance to predict death was reasonable for GRACE and poor for TIMI , and was generally worse in those with NSTEMI versus those with STEMI. In people with NSTEMI , sequential addition of comorbidities and soluble suppression of tumorigenicity‐2 substantially improved the c ‐statistic over GRACE (from 0.78 to 0.80 to 0.84) and TIMI (from 0.61 to 0.73 to 0.81), respectively (all P ≤0.05). Conclusions Guideline‐recommended scores for risk assessment after MI underperform in contemporary community patients, particularly those with NSTEMI, which now represents most infarcts. Incorporating comorbidities and soluble suppression of tumorigenicity‐2 substantially improves risk prediction, thereby delineating opportunities to improve clinical care.

Abstract Existing general clinical natural language processing (NLP) systems such as MetaMap and Clinical Text Analysis and Knowledge Extraction System have been successfully applied to information extraction from clinical text. However, end users often have to customize existing systems for their individual tasks, which can require substantial NLP skills. Here we present CLAMP (Clinical Language Annotation, Modeling, and Processing), a newly developed clinical NLP toolkit that provides not only state-of-the-art NLP components, but also a user-friendly graphic user interface that can help users quickly build customized NLP pipelines for their individual applications. Our evaluation shows that the CLAMP default pipeline achieved good performance on named entity recognition and concept encoding. We also demonstrate the efficiency of the CLAMP graphic user interface in building customized, high-performance NLP pipelines with 2 use cases, extracting smoking status and lab test values. CLAMP is publicly available for research use, and we believe it is a unique asset for the clinical NLP community.

PurposeTo develop and validate a method for measuring murine single‐kidney glomerular filtration rate (GFR) using dynamic contrast‐enhanced MRI (DCE‐MRI).MethodsThis prospective study was approved by the Institutional Animal Care and Use Committee. A fast longitudinal relaxation time (T1) measurement method was implemented to capture gadolinium dynamics (1 s/scan), and a modified two‐compartment model was developed to quantify GFR as well as renal perfusion using 16.4T MRI in mice 2 weeks after unilateral renal artery stenosis (RAS, n = 6) or sham (n = 8) surgeries. This approach was validated by comparing model‐derived GFR and perfusion to those obtained by fluorescein isothiocyanante (FITC)‐inulin clearance and arterial spin labeling (ASL), respectively, using the Pearson's and Spearman's rank correlations and Bland‐Altman analysis.ResultsThe compartmental model provided a good fitting to measured gadolinium dynamics in both normal and RAS kidneys. The proposed DCE‐MRI method offered assessment of single‐kidney GFR and perfusion, comparable to the FITC‐inulin clearance (Pearson's correlation coefficient r = 0.95 and Spearman's correlation coefficient ρ = 0.94, P < 0.0001, and mean difference −7.0 ± 11.0 μL/min) and ASL (r = 0.92 and ρ = 0.84, P < 0.0001, and mean difference 4.4 ± 66.1 mL/100 g/min) methods.ConclusionThe proposed DCE‐MRI method may be useful for reliable noninvasive measurements of single‐kidney GFR and perfusion in mice. Magn Reson Med 79:2935–2943, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

SummaryObjectiveThymic neuroendocrine tumour (TH‐NET) accounts for almost 20% of multiple endocrine neoplasia type 1 (MEN1)‐associated mortality. Identifying risk factors for the development of these rare tumours and prognostic factors for clinical outcomes will be helpful in clinical practice.Design and PatientsWe performed a retrospective analysis of patients treated for TH‐NET associated with MEN1 in a single institution and meta‐analysis of literature reports. We used a fixed effect model to pool results across studies to evaluate the prevalence, clinical features and prognosis.ResultsTH‐NET was detected in 9 (7.4%) of 121 patients with MEN1 seen in our institution, and 5 (55.6%) were women. Seven additional studies were identified through a systematic review of the literature. The pool estimate of TH‐NET prevalence was 3.7% (n = 99) in MEN1 (n = 2710), sex ratio was 79:20 (male vs female), and the median age at diagnosis was 43.0 years (range, 16.0‐72.0 years). Forty‐three patients died with a median survival time of 8.4 years. Older age at diagnosis (HR = 1.4, 95% CI = 1.0‐1.8, P = .03), maximum tumour diameter (HR = 1.5, 95% CI = 1.0‐2.3, P = .04) and presence of metastasis (HR = 1.6, 95% CI = 1.0‐2.5, P = .04) were associated with worse outcome. A male predominance (91.9% vs 59.5%, P < .001) and history of smoking (59.0% vs 23.5%, P = .015) were more common in American/European series compared to Asian reports.ConclusionTH‐NET is a rare but fatal component of MEN1. Earlier detection of TH‐NET in patients with MEN1 may be recommended which should theoretically result in better outcomes. Different genetic backgrounds (race) appear to result in clinical difference.

Abstract IFN regulatory factor 4 (IRF4) is a key transcription factor that promotes effector CD8+ T cell differentiation and expansion. The roles of IRF4 in regulating the CD8+ T cell response to cytokines have not been explored. In this article, we show that IL-2 and IL-15 signaling and STAT5 activation regulate IRF4 expression in CD8+ T cells. Gene-expression profile analysis has also revealed that IRF4 is required for expression of the receptors of IL-2 family cytokines CD122 and CD127. We found that IRF4 binds directly to CD122 and CD127 gene loci, indicating that it may directly promote CD122 and CD127 gene transcription. As a consequence, IRF4-deficient CD8+ T cells show diminished sensitivity to IL-2, IL-15, and IL-7 treatment in vitro. Furthermore, we found that IRF4-deficient CD8+ T cells had lower expression of CD122 and CD127 in vivo during influenza virus infection. These data suggest that IRF4 regulates the sensitivity of CD8+ T cells to IL-2 family cytokines, which correlates with the diminished effector and memory CD8+ T cell responses in IRF4-deficient CD8+ T cells.

Abstract Glioma stem cells (GSC) and epithelial–mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here, we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo. We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and patient-derived glioma tumorspheres. In contrast with previous reports of S100A4 as a reporter of EMT, we discovered that S100A4 is an upstream regulator of the master EMT regulators SNAIL2 and ZEB along with other mesenchymal transition regulators in glioblastoma. Overall, our results establish S100A4 as a central node in a molecular network that controls stemness and EMT in glioblastoma, suggesting S100A4 as a candidate therapeutic target. Cancer Res; 77(19); 5360–73. ©2017 AACR.

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.