bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Sixteen Established Pancreatic Cancer Susceptibility Loci in American Jews
Authors: Streicher Samantha A. , Klein Alison P. , Olson Sara H. , Amundadottir Laufey T. , DeWan Andrew T. , Zhao Hongyu , Risch Harvey A.
Published: July 2017

Background: The higher risk of pancreatic cancer in Ashkenazi Jews compared with non-Jews is only partially explained by the increased frequency of BRCA1 and BRCA2 mutations in Ashkenazi Jews.

Methods: We evaluated the impact of 16 established pancreatic cancer susceptibility loci in a case–control sample of American Jews, largely Ashkenazi, including 406 full-Jewish pancreatic cancer patients and 2,332 full-Jewish controls, genotyped as part of the Pancreatic Cancer Cohort and Case–Control Consortium I/II (PanScan I/II), Pancreatic Cancer Case-Control Consortium (PanC4), and Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) datasets. We compared risk in full-Jewish subjects with risk in part-Jewish; non-Jewish Southern European; and in the combined non-Jewish Eastern, Northern, Southern, and Western European (non-Jewish white European) subjects from the same datasets. Jewish ancestries were genetically identified using seeded Fast principal component analysis. Data were analyzed by unconditional logistic regression, and adjusted for age, sex, and principal components.

Results: One SNP on chromosome 13q22.1 (rs9543325; OR, 1.36; 95% confidence interval, 1.16–1.58; P = 10−4.1) was significant in full-Jews. Individual ORs and minor allele frequencies were similar between Jewish and non-Jewish white European subjects. The average ORs across the 16 pancreatic cancer susceptibility loci for full-Jewish, full- plus part-Jewish, non-Jewish Southern European, and non-Jewish white European subjects were 1.25, 1.30, 1.31, and 1.26, respectively.

Conclusions: The 16 pancreatic cancer susceptibility loci similarly impact Jewish and non-Jewish white European subjects, both individually and as summary odds.

Impact: These 16 pancreatic cancer susceptibility loci likely do not explain the higher risk seen in Ashkenazi Jews. Cancer Epidemiol Biomarkers Prev; 26(10); 1540–8. ©2017 AACR.
A Prospective Study of Chronic Inflammation in Benign Prostate Tissue and Risk of Prostate Cancer: Linked PCPT and SELECT Cohorts
Authors: Platz Elizabeth A. , Kulac Ibrahim , Barber John R. , Drake Charles G. , Joshu Corinne E. , Nelson William G. , Lucia M. Scott , Klein Eric A. , Lippman Scott M. , Parnes Howard L. , Thompson Ian M. , Goodman Phyllis J. , Tangen Catherine M. , De Marzo Angelo M.
Published: July 2017

Background: We leveraged two trials to test the hypothesis of an inflammation–prostate cancer link prospectively in men without indication for biopsy.

Methods: Prostate Cancer Prevention Trial (PCPT) participants who had an end-of-study biopsy performed per protocol that was negative for cancer and who subsequently enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were eligible. We selected all 100 cases and sampled 200 frequency-matched controls and used PCPT end-of-study biopsies as “baseline.” Five men with PSA > 4 ng/mL at end-of-study biopsy were excluded. Tissue was located for 92 cases and 193 controls. We visually assessed inflammation in benign tissue. We estimated ORs and 95% confidence intervals (CI) using logistic regression adjusting for age and race.

Results: Mean time between biopsy and diagnosis was 5.9 years. In men previously in the PCPT placebo arm, 78.1% of cases (N = 41) and 68.2% of controls (N = 85) had at least one baseline biopsy core (∼5 evaluated per man) with inflammation. The odds of prostate cancer (N = 41 cases) appeared to increase with increasing mean percentage of tissue area with inflammation, a trend that was statistically significant for Gleason sum <4+3 disease (N = 31 cases; vs. 0%, >0–<1.8% OR = 1.70, 1.8–<5.0% OR = 2.39, ≥5% OR = 3.31, Ptrend = 0.047). In men previously in the finasteride arm, prevalence of inflammation did not differ between cases (76.5%; N = 51) and controls (75.0%; N = 108).

Conclusions: Benign tissue inflammation was positively associated with prostate cancer.

Impact: This first prospective study of men without biopsy indication supports the hypothesis that inflammation influences prostate cancer development. Cancer Epidemiol Biomarkers Prev; 26(10); 1549–57. ©2017 AACR.
Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
Authors: Ritthipichai Krit , Haymaker Cara L. , Martinez Melisa , Aschenbrenner Andrew , Yi Xiaohui , Zhang Minying , Kale Charuta , Vence Luis M. , Roszik Jason , Hailemichael Yared , Overwijk Willem W. , Varadarajan Navin , Nurieva Roza , Radvanyi Laszlo G. , Hwu Patrick , Bernatchez Chantale
Published: July 2017

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40%–50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte associated) expression on transferred CD8+ TILs was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8+BTLA+TIL subset and define the contribution of the Grb2 motif of BTLA in T-cell costimulation.

Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8+ TILs and mouse CD8+ T cells. Functional assays were used including single-cell analysis, reverse-phase protein array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as patient-derived xenograft (PDX) model using immunodeficient NOD-scid IL2Rgammanull (NSG) tumor-bearing mice treated with autologous TILs.

Results: CD8+BTLA− TILs could not control tumor growth in vivo as well as their BTLA+ counterpart and antigen-specific CD8+BTLA− T cells had impaired recall response to a vaccine. However, CD8+BTLA+ TILs displayed improved survival following the killing of a tumor target and heightened “serial killing” capacity. Using mutants of BTLA signaling motifs, we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation.

Conclusions: Our data portrays BTLA as a molecule with the singular ability to provide both costimulatory and coinhibitory signals to activated CD8+ T cells, resulting in extended survival, improved tumor control, and the development of a functional recall response. Clin Cancer Res; 23(20); 6151–64. ©2017 AACR.
Tumor Purity as an Underlying Key Factor in Glioma
Authors: Zhang Chuanbao , Cheng Wen , Ren Xiufang , Wang Zheng , Liu Xing , Li Guanzhang , Han Sheng , Jiang Tao , Wu Anhua
Published: July 2017

Purpose: Glioma tissues consist of not only glioma cells but also glioma-associated nontumor cells, such as stromal cells and immune cells. These nontumor cells dilute the purity of glioma cells and play important roles in glioma biology. Currently, the implications of variation in glioma purity are not sufficiently clarified.

Experimental Design: Here, tumor purity was inferred for 2,249 gliomas and 29 normal brain tissues from 5 cohorts. Based on the transcriptomic profiling method, we classified CGGA and TCGA-RNAseq cohorts as the RNAseq set for discovery. Cases from TCGA-microarray, REMBRANDT, and GSE16011 cohorts were grouped as a microarray set for validation. Tissues from the CGGA cohort were reviewed for histopathologic validation.

Results: We found that glioma purity was highly associated with major clinical and molecular features. Low purity cases were more likely to be diagnosed as malignant entities and independently correlated with reduced survival time. Integrating glioma purity into prognostic nomogram significantly improved the predictive validity. Moreover, most recognized prognostic indicators were no longer significantly effective under different purity conditions. These results highlighted the clinical importance of glioma purity. Further analyses found distinct genomic patterns associated with glioma purity. Low purity cases were distinguished by enhanced immune phenotypes. Macrophages, microglia, and neutrophils were mutually associated and enriched in low purity gliomas, whereas only macrophages and neutrophils served as robust indicators for poor prognosis.

Conclusions: Glioma purity and relevant nontumor cells within microenvironment confer important clinical, genomic, and biological implications, which should be fully valued for precise classification and clinical prediction. Clin Cancer Res; 23(20); 6279–91. ©2017 AACR.
TP53 Mutation and Its Prognostic Significance in Waldenstrom's Macroglobulinemia
Authors: Poulain Stéphanie , Roumier Christophe , Bertrand Elisabeth , Renneville Aline , Caillault-Venet Aurélie , Doye Emmanuelle , Geffroy Sandrine , Sebda Sheherazade , Nibourel Olivier , Nudel Morgane , Herbaux Charles , Renaud Loic , Tomowiak Cécile , Guidez Stéphanie , Tricot Sabine , Roche-Lestienne Catherine , Quesnel Bruno , Preudhomme Claude , Leleu Xavier
Published: July 2017

Purpose: TP53 is a tumor-suppressor gene that functions as a regulator influencing cellular responses to DNA damage, and TP53 alterations are associated with pejorative outcome in most B-lymphoid disorders. Little is known regarding TP53 alteration in Waldenstrom's macroglobulinemia (WM).

Experimental Design: Here, we have explored the incidence of TP53 alteration using Sanger sequencing and ultradeep-targeted sequencing in 125 WM and 10 immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS), along with the clinical features and the associated genomic landscape using single-nucleotide polymorphism array and mutational landscape in an integrative study.

Results: Overall, we have identified alteration of TP53 locus including mutation, deletion, and copy-neutral LOH in 11.2% of WM. TP53 mutation was acquired in 7.3% of patients with WM at diagnosis, being absent in IgM MGUS, and was highly correlated to deletion 17p. No correlation with CXCR4 mutations was observed. Patients with TP53 alteration had a greater number of genomic abnormalities. Importantly, WM with TP53 alteration had a significantly shorter overall survival, particularly in symptomatic WM, and independently of the international prognostic scoring system for Waldenstrom macroglobulinemia (IPSSWM) score. Specific treatment for WM with TP53 may have to be studied. Nutlin-3a–targeted p53 signaling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, PrimaMet, or CP31398 that bypass p53 pathway in WM, paving the path for future treatment-tailored options.

Conclusions: Our results highlight the clinical significance of detection of TP53 alteration in WM to determine the prognosis of WM and guide the treatment choice. Clin Cancer Res; 23(20); 6325–35. ©2017 AACR.
An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia
Authors: Shouval Roni , Ruggeri Annalisa , Labopin Myriam , Mohty Mohamad , Sanz Guillermo , Michel Gerard , Kuball Jürgen , Chevallier Patrice , Al-Seraihy Amal , Milpied Noel-Jean , de Heredia Cristina Diaz , Arcese William , Blaise Didier , Rocha Vanderson , Fein Joshua , Unger Ron , Baron Frederic , Bader Peter , Gluckman Eliane , Nagler Arnon
Published: July 2017

Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2 years following UCBT in AL patients.

Experimental Design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n = 2,362, 65%) and validation set (n = 778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score.

Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2 years OS and LFS, ranging from 70.21% [68.89–70.71, 95% confidence interval (CI)] and 64.76% (64.33–65.86, 95% CI) to 14.78% (10.91–17.41) and 18.11% (14.40–22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19–69.04, range) and 65.78 (65.20–66.28) for 2 years OS and LFS, respectively.

Conclusions: The UCBT score is a simple tool for risk stratification of AL patients undergoing UCBT. Widespread application of the score will require further independent validation. Clin Cancer Res; 23(21); 6478–86. ©2017 AACR.
Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype
Authors: Lowery Maeve A. , Jordan Emmet J. , Basturk Olca , Ptashkin Ryan N. , Zehir Ahmet , Berger Michael F. , Leach Tanisha , Herbst Brian , Askan Gokce , Maynard Hannah , Glassman Danielle , Covington Christina , Schultz Nikolaus , Abou-Alfa Ghassan K. , Harding James J. , Klimstra David S. , Hechtman Jaclyn F. , Hyman David M. , Allen Peter J. , Jarnagin William R. , Balachandran Vinod P. , Varghese Anna M. , Schattner Mark A. , Yu Kenneth H. , Saltz Leonard B. , Solit David B. , Iacobuzio-Donahue Christine A. , Leach Steven D. , O'Reilly Eileen M.
Published: July 2017

Purpose: Molecular profiling in cancer has identified potential actionable drug targets that have prompted attempts to discover clinically validated biomarkers to guide therapeutic decision-making and enrollment to clinical trials. We evaluated whether comprehensive genetic analysis of patients with pancreatic adenocarcinoma is feasible within a clinically relevant timeframe and whether such analyses provide predictive and/or prognostic information along with identification of potential targets for therapy.

Experimental Design: Archival or prospectively acquired FFPE samples and matched normal DNA from N = 336 patients with pancreatic cancer were analyzed using a hybridization capture–based, next-generation sequencing assay designed to perform targeted deep sequencing of all exons and selected introns of 410 key cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.

Results: The median time from protocol consent to reporting of the genomic results was 45 days with a median time from tissue delivery of 20 days. All genetic alterations identified were stratified based upon prior evidence that the mutation is a predictive biomarker of drug response using the MSKCC OncoKB classification. Three of 225 patients (1%) received a matched therapy based upon the sequencing results.

Conclusions: The practical application of molecular results to guide individual patient treatment is currently limited in patients with pancreatic adenocarcinoma. Future prospective molecular profiling efforts should seek to incorporate routine germline genetic analysis and the identification of DNA profiles that predict for clinical benefit from agents that target DNA damage repair and or immunotherapy. Clin Cancer Res; 23(20); 6094–100. ©2017 AACR.
Multiparametric Detection of Antibodies against Different EBV Antigens to Predict Risk for Nasopharyngeal Carcinoma in a High-Risk Population of China
Authors: Chen Hao , Chen Shulin , Lu Jie , Wang Xueping , Li Jianpei , Li Linfang , Fu Jihuan , Scheper Thomas , Meyer Wolfgang , Peng Yu-Hui , Liu Wanli
Published: July 2017

In this study, we aimed to use the combined detection of multiple antibodies against Epstein–Barr virus (EBV) antigens to develop a model for screening and diagnosis of nasopharyngeal carcinoma (NPC). Samples of 300 nasopharyngeal carcinoma patients and 494 controls, including 294 healthy subjects (HC), 99 non-nasopharyngeal carcinoma cancer patients (NNPC), and 101 patients with benign nasopharyngeal lesions (BNL), were incubated with the EUROLINE Anti-EBV Profile 2, and band intensities were used to establish a risk prediction model. The nasopharyngeal carcinoma risk probability analysis based on the panel of VCAgp125 IgA, EBNA-1 IgA, EA-D IgA, EBNA-1 IgG, EAD IgG, and VCAp19 IgG displayed the best performance. When using 26.1% as the cutoff point in ROC analysis, the AUC value and sensitivity/specificity were 0.951 and 90.7%/86.2%, respectively, in nasopharyngeal carcinoma and all controls. In nasopharyngeal carcinoma and controls without the non-nasopharyngeal carcinoma and BNL groups, the AUC value and sensitivity/specificity were 0.957 and 90.7%/88.1%, respectively. The diagnostic specificity and sensitivity of the EUROLINE Anti-EBV Profile 2 assay for both nasopharyngeal carcinoma and early-stage nasopharyngeal carcinoma were higher than that of mono-antibody detection by immune-enzymatic assay and real-time PCR (EBV DNA). In the VCA-IgA–negative group, 82.6% of nasopharyngeal carcinoma patients showed high probability for nasopharyngeal carcinoma, and the negative predictive value was 97.1%. In the VCA-IgA–positive group, 73.3% of healthy subjects showed low probability. The positive predictive value reached 98.2% in this group. The nasopharyngeal carcinoma risk probability value determined by the EUROLINE Anti-EBV Profile 2 might be a suitable tool for nasopharyngeal carcinoma screening. Cancer Prev Res; 10(9); 542–50. ©2017 AACR.
In Vivo Functional Selection Identifies Cardiotrophin-1 as a Cardiac Engraftment Factor for Mesenchymal Stromal Cells
Authors: Bortolotti Francesca , Ruozi Giulia , Falcione Antonella , Doimo Sara , Dal Ferro Matteo , Lesizza Pierluigi , Zentilin Lorena , Banks Lawrence , Zacchigna Serena , Giacca Mauro
Published: July 2017

Background:

Transplantation of cells into the infarcted heart has significant potential to improve myocardial recovery; however, low efficacy of cell engraftment still limits therapeutic benefit. Here, we describe a method for the unbiased, in vivo selection of cytokines that improve mesenchymal stromal cell engraftment into the heart both in normal conditions and after myocardial infarction.

Methods:

An arrayed library of 80 secreted factors, including most of the currently known interleukins and chemokines, were individually cloned into adeno-associated viral vectors. Pools from this library were then used for the batch transduction of bone marrow–derived mesenchymal stromal cells ex vivo, followed by intramyocardial cell administration in normal and infarcted mice. Three weeks after injection, vector genomes were recovered from the few persisting cells and identified by sequencing DNA barcodes uniquely labeling each of the tested cytokines.

Results:

The most effective molecule identified by this competitive engraftment screening was cardiotrophin-1, a member of the interleukin-6 family. Intracardiac injection of mesenchymal stromal cells transiently preconditioned with cardiotrophin-1 preserved cardiac function and reduced infarct size, parallel to the persistence of the transplanted cells in the healing hearts for at least 2 months after injection. Engraftment of cardiotrophin-1–treated mesenchymal stromal cells was consequent to signal transducer and activator of transcription 3–mediated activation of the focal adhesion kinase and its associated focal adhesion complex and the consequent acquisition of adhesive properties by the cells.

Conclusions:

These results support the feasibility of selecting molecules in vivo for their functional properties with adeno-associated viral vector libraries and identify cardiotrophin-1 as a powerful cytokine promoting cell engraftment and thus improving cell therapy of the infarcted myocardium.
Impact of Right Ventricular Performance in Patients Undergoing Extracorporeal Membrane Oxygenation Following Cardiac Surgery
Authors: Bartko Philipp E. , Wiedemann Dominik , Schrutka Lore , Binder Christina , Santos‐Gallego Carlos G. , Zuckermann Andreas , Steinlechner Barbara , Koinig Herbert , Heinz Gottfried , Niessner Alexander , Zimpfer Daniel , Laufer Günther , Lang Irene M. , Distelmaier Klaus , Goliasch Georg
Published: July 2017

Background

Extracorporeal membrane oxygenation following cardiac surgery safeguards end‐organ oxygenation but unfavorably alters cardiac hemodynamics. Along with the detrimental effects of cardiac surgery to the right heart, this might impact outcome, particularly in patients with preexisting right ventricular (
RV
) dysfunction. We sought to determine the prognostic impact of
RV
function and to improve established risk‐prediction models in this vulnerable patient cohort.

Methods and Results

Of 240 patients undergoing extracorporeal membrane oxygenation support following cardiac surgery, 111 had echocardiographic examinations at our institution before implantation of extracorporeal membrane oxygenation and were thus included. Median age was 67 years (interquartile range 60‐74), and 74 patients were male. During a median follow‐up of 27 months (interquartile range 16‐63), 75 patients died. Fifty‐one patients died within 30 days, 75 during long‐term follow‐up (median follow‐up 27 months, minimum 5 months, maximum 125 months). Metrics of
RV
function were the strongest predictors of outcome, even stronger than left ventricular function (
P
<0.001 for receiver operating characteristics comparisons). Specifically,
RV
free‐wall strain was a powerful predictor univariately and after adjustment for clinical variables, Simplified Acute Physiology Score‐3, tricuspid regurgitation, surgery type and duration with adjusted hazard ratios of 0.41 (95%
CI
0.24‐0.68;
P
=0.001) for 30‐day mortality and 0.48 (95%
CI
0.33‐0.71;
P
<0.001) for long‐term mortality for a 1‐
SD
(
SD
=−6%) change in
RV
free‐wall strain. Combined assessment of the additive Euro
SCORE
and
RV
free‐wall strain improved risk classification by a net reclassification improvement of 57% for 30‐day mortality (
P
=0.01) and 56% for long‐term mortality (
P
=0.02) compared with the additive Euro
SCORE
alone.

Conclusions

RV function is strongly linked to mortality, even after adjustment for baseline variables and clinical risk scores.
RV
performance improves established risk prediction models for short‐ and long‐term mortality.
Modeling Treatment Response for Lamin A/C Related Dilated Cardiomyopathy in Human Induced Pluripotent Stem Cells
Authors: Lee Yee‐Ki , Lau Yee‐Man , Cai Zhu‐Jun , Lai Wing‐Hon , Wong Lai‐Yung , Tse Hung‐Fat , Ng Kwong‐Man , Siu Chung‐Wah
Published: July 2017

Background

Precision medicine is an emerging approach to disease treatment and prevention that takes into account individual variability in the environment, lifestyle, and genetic makeup of patients. Patient‐specific human induced pluripotent stem cells hold promise to transform precision medicine into real‐life clinical practice. Lamin A/C (
LMNA
)‐related cardiomyopathy is the most common inherited cardiomyopathy in which a substantial proportion of mutations in the

LMNA

gene are of nonsense mutation.
PTC
124 induces translational read‐through over the premature stop codon and restores production of the full‐length proteins from the affected genes. In this study we generated human induced pluripotent stem cells‐derived cardiomyocytes from patients who harbored different

LMNA

mutations (nonsense and frameshift) to evaluate the potential therapeutic effects of
PTC
124 in

LMNA

‐related cardiomyopathy.

Methods and Results

We generated human induced pluripotent stem cells lines from 3 patients who carried distinctive mutations (R225X, Q354X, and T518fs) in the

LMNA

gene. The cardiomyocytes derived from these human induced pluripotent stem cells lines reproduced the pathophysiological hallmarks of

LMNA

‐related cardiomyopathy. Interestingly,
PTC
124 treatment increased the production of full‐length LMNA proteins in only the R225X mutant, not in other mutations. Functional evaluation experiments on the R225X mutant further demonstrated that
PTC
124 treatment not only reduced nuclear blebbing and electrical stress‐induced apoptosis but also improved the excitation‐contraction coupling of the affected cardiomyocytes.

Conclusions

Using cardiomyocytes derived from human induced pluripotent stem cells carrying different

LMNA

mutations, we demonstrated that the effect of
PTC
124 is codon selective. A premature stop codon
UGA
appeared to be most responsive to
PTC
124 treatment.
Readmission After Aneurysmal Subarachnoid Hemorrhage
Authors: Dasenbrock Hormuzdiyar H. , Angriman Frederico , Smith Timothy R. , Gormley William B. , Frerichs Kai U. , Aziz-Sultan M. Ali , Du Rose
Published: July 2017

Background and Purpose—

The goal of this nationwide study is to evaluate the suitability of readmission as a quality indicator in the aneurysmal subarachnoid hemorrhage (SAH) population.

Methods—

Patients with aneurysmal SAH were extracted from the Nationwide Readmission Database (2013). Multivariable Cox proportional hazard regression was used to evaluate predictors of a 30-day readmission, and multivariable linear regression was used to analyze the association of hospital readmission rates with hospital mortality rates. Predictors screened included patient demographics, comorbidities, severity of SAH, complications from the SAH hospitalization, and hospital characteristics.

Results—

The 30-day readmission rate was 10.2% (n=346) among the 3387 patients evaluated, and the most common reasons for readmission were neurological, hydrocephalus, infectious, and venous thromboembolic complications. Greater number of comorbidities, increased severity of SAH, and discharge disposition other than to home were independent predictors of readmission (
P
≤0.03). Although hydrocephalus during the SAH hospitalization was associated with readmission for the same diagnosis, other readmissions were not associated with having sustained the same complication during the SAH hospitalization. Hospital mortality rate was inversely associated with hospital SAH volume (
P
=0.03) but not significantly associated with hospital readmission rate; hospital SAH volume was also not associated with SAH readmissions.

Conclusions—

In this national analysis, readmission was primarily attributable to new medical complications in patients with greater comorbidities and severity of SAH rather than exacerbation of complications from the SAH hospitalization. Additionally, hospital readmission rates did not correlate with other established quality metrics. Therefore, readmission may be a suboptimal quality indicator in the SAH population.
Vascular Tissue-Type Plasminogen Activator Promotes Intracranial Aneurysm Formation
Authors: Labeyrie Paul-Emile , Goulay Romain , Martinez de Lizarrondo Sara , Hébert Marie , Gauberti Maxime , Maubert Eric , Delaunay Barbara , Gory Benjamin , Signorelli Francesco , Turjman Francis , Touzé Emmanuel , Courthéoux Patrick , Vivien Denis , Orset Cyrille
Published: July 2017

Background and Purpose—

Although the mechanisms that contribute to intracranial aneurysm (IA) formation and rupture are not totally elucidated, inflammation and matrix remodeling are incriminated. Because tPA (tissue-type plasminogen activator) controls both inflammatory and matrix remodeling processes, we hypothesized that tPA could be involved in the pathophysiology of IA.

Methods—

Immunofluorescence analyses of tPA and its main substrate within the aneurysmal wall of murine and human samples were performed. We then compared the formation and rupture of IAs in wild-type, tPA-deficient and type 1 plasminogen activator inhibitor–deficient mice subjected to a model of elastase-induced IA. The specific contribution of vascular versus global tPA was investigated by performing hepatic hydrodynamic transfection of a cDNA encoding for tPA in tPA-deficient mice. The formation and rupture of IAs were monitored by magnetic resonance imaging tracking for 28 days.

Results—

Immunofluorescence revealed increased expression of tPA within the aneurysmal wall. The number of aneurysms and their symptomatic ruptures were significantly lower in tPA-deficient than in wild-type mice. Conversely, they were higher in plasminogen activator inhibitor–deficient mice. The wild-type phenotype could be restored in tPA-deficient mice by selectively increasing circulating levels of tPA via hepatic hydrodynamic transfection of a cDNA encoding for tPA.

Conclusions—

Altogether, this preclinical study demonstrates that the tPA present in the blood stream is a key player of the formation of IAs. Thus, tPA should be considered as a possible new target for the prevention of IAs formation and rupture.
Benchmarking Telestroke Proficiency
Authors: Jagolino-Cole Amanda L. , Bozorgui Shima , Ankrom Christy M. , Bambhroliya Arvind B. , Cossey Tiffany D. , Trevino Alyssa D. , Savitz Sean I. , Wu Tzu-Ching , Vahidy Farhaan S.
Published: July 2017

Background and Purpose—

Formal telestroke training for neurovascular fellows (NVFs) is necessary because of growing use of telestroke technologies in the management of acute ischemic stroke; yet, educational approaches and training benchmarks are not formalized. Time between telestroke consultant page and tissue-type plasminogen activator administration (page-to-needle time, PTNT) can provide an objective measure of proficiency. We compared PTNT between NVFs and neurovascular attendings (NVAs) and evaluated changes in PTNT with experience.

Methods—

We identified suspected acute ischemic stroke patients in our telestroke registry from July 2013 to December 2015 who received tissue-type plasminogen activator. Using multivariable quantile regression, we estimated the difference and 95% confidence interval in median PTNT between NVFs and NVAs. We also report the coefficient of change in PTNT over increasing number of telestroke consults.

Results—

NVFs evaluated 53.7% of 618 tissue-type plasminogen activator cases over telestroke. NVAs had significantly shorter PTNT compared with NVFs, with a difference in median PTNT of −9 minutes (95% confidence interval, −12.3 to −5.7). This difference persisted when adjusted for relative tissue-type plasminogen activator contraindications. For each additional telestroke consult, PTNT decreased by 0.07 minutes for NVFs or NVAs (
P
=0.02 and <0.01, respectively).

Conclusions—

PTNT improves by ≈1 minute for every 14 consults for both NVFs and NVAs. Our findings support the importance of integrating telestroke training into supervised neurovascular fellowships to increase proficiency prior to independent practice and suggest that PTNT can be a benchmark for tracking proficiency.
Dolichoectasia and Small Vessel Disease in Young Patients With Transient Ischemic Attack and Stroke
Authors: Thijs Vincent , Grittner Ulrike , Fazekas Franz , McCabe Dominick J.H. , Giese Anne-Katrin , Kessler Christof , Martus Peter , Norrving Bo , Ringelstein Erich Bernd , Schmidt Reinhold , Tanislav Christian , Putaala Jukka , Tatlisumak Turgut , von Sarnowski Bettina , Rolfs Arndt , Enzinger Christian
Published: July 2017

Background and Purpose—

We evaluated whether basilar dolichoectasia is associated with markers of cerebral small vessel disease in younger transient ischemic attack and ischemic stroke patients.

Methods—

We used data from the SIFAP1 study (Stroke in Young Fabry Patients), a large prospective, hospital-based, screening study for Fabry disease in young (<55 years) transient ischemic attack/stroke patients in whom detailed clinical data and brain MRI were obtained, and stroke subtyping with TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment) was performed.

Results—

Dolichoectasia was found in 508 of 3850 (13.2%) of patients. Dolichoectasia was associated with older age (odds ratio per decade, 1.26; 95% confidence interval, 1.09–1.44), male sex (odds ratio, 1.96; 95% confidence interval, 1.59–2.42), and hypertension (odds ratio, 1.39; 95% confidence interval, 1.13–1.70). Dolichoectasia was more common in patients with small infarctions (33.9% versus 29.8% for acute lesions,
P
=0.065; 29.1% versus 16.5% for old lesions,
P
<0.001), infarct location in the brain stem (12.4% versus 6.9%,
P
<0.001), and in white matter (27.8% versus 21.1%,
P
=0.001). Microbleeds (16.3% versus 4.7%,
P
=0.001), higher grades of white matter hyperintensities (
P
<0.001), and small vessel disease subtype (18.1% versus 12.4%, overall
P
for differences in TOAST (
P
=0.018) were more often present in patients with dolichoectasia.

Conclusions—

Dolichoectasia is associated with imaging markers of small vessel disease and brain stem localization of acute and old infarcts in younger patients with transient ischemic attack and ischemic stroke.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00414583.
Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials
Authors: Brownstein Daniel J , Salagre Estela , Köhler Cristiano , Stubbs Brendon , Vian João , Pereira Ciria , Chavarria Victor , Karmakar Chandan , Turner Alyna , Quevedo João , Carvalho André F , Berk Michael , Fernandes Brisa S
Published: July 2017

Objective:

It is unclear whether blockade of the angiotensin system has effects on mental health. Our objective was to determine the impact of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor (AT1R) blockers on mental health domain of quality of life.

Study design:

Meta-analysis of published literature.

Data sources:

PubMed and clinicaltrials.gov databases. The last search was conducted in January 2017.

Study selection:

Randomized controlled trials comparing any angiotensin converting enzyme inhibitor or AT1R blocker versus placebo or non-angiotensin converting enzyme inhibitor or non-AT1R blocker were selected. Study participants were adults without any major physical symptoms. We adhered to meta-analysis reporting methods as per PRISMA and the Cochrane Collaboration.

Data synthesis:

Eleven studies were included in the analysis. When compared with placebo or other antihypertensive medications, AT1R blockers and angiotensin converting enzyme inhibitors were associated with improved overall quality of life (standard mean difference = 0.11, 95% confidence interval = [0.08, 0.14], p < 0.0001), positive wellbeing (standard mean difference = 0.11, 95% confidence interval = [0.05, 0.17], p < 0.0001), mental (standard mean difference = 0.15, 95% confidence interval = [0.06, 0.25], p < 0.0001), and anxiety (standard mean difference = 0.08, 95% confidence interval = [0.01, 0.16], p < 0.0001) domains of QoL. No significant difference was found for the depression domain (standard mean difference = 0.05, 95% confidence interval = [0.02, 0.12], p = 0.15).

Conclusions:

Use of angiotensin blockers and inhibitors for the treatment of hypertension in otherwise healthy adults is associated with improved mental health domains of quality of life. Mental health quality of life was a secondary outcome in the included studies. Research specifically designed to analyse the usefulness of drugs that block the angiotensin system is necessary to properly evaluate this novel psychiatric target.
Who Says You Can’t Be a Saint? Female Saints as Heroes on the Italian Catholic Stage
Authors: Cavallaro Daniela
Published: July 2017

This essay considers how one modern order of Catholic priests and nuns, the Salesians, presented the lives of female saints as heroic role models through theater to young women in Italy in the post-World War II years. My discussion touches on the Salesian use of theater in education; the most important Salesian woman author, Caterina Pesci; the heroic journey of the saints that Pesci chose as role models; the effect that the theatrical representation of these saints was meant to make on performers and audience, and the historical reasons for the importance of saints as heroic role models in postwar Italy.
Where are we now? Twenty-five years of research, policy and practice on young carers
Authors: Aldridge Jo
Published: July 2017

It is more than 25 years since the critical dialogue on young carers was played out in the pages of this journal (see Morris and Keith, 1995; Aldridge and Becker, 1996). Since that time, research evidence has given us a clearer picture of the extent of young caring in the UK and its consequences for children and families, including two new national studies that focus on the prevalence and impact of young caring in England. The introduction of the Care Act, 2014 and the Children and Families Act, 2014 also places new duties on professionals to identify and support young carers and their families. However, this increased focus, not only in policy and practice but also in terms of public awareness, has created a number of dilemmas and challenges for health and social care professionals, whose duty it is to identify and support young carers. These challenges, to a large extent, both mirror and advance issues raised in the original dialogue on young carers in the mid-1990s. They centre on the drive to generate data on the numbers of young carers to support policy directives and service delivery and, some have argued – in the current climate of serious fiscal retrenchment and cuts to youth services – on promoting the needs of one group of vulnerable children and young people over other groups of children in need. This article considers some of these challenges and dilemmas.
Immigrant Women’s Experiences of Acculturative Stress
Authors: Greenwood Ronni Michelle , Adshead Maura , Jay Sarah
Published: July 2017

We examined the relation of two acculturation stressors, exclusion from ordinary privileges and overt discrimination, to two indicators of psychological well-being (i.e., psychiatric symptoms and satisfaction with life) among a diverse sample of immigrant women living in Ireland ( N = 174). We grouped our sample into “visible” immigrant women of color and “nonvisible” White immigrant women. As expected, visible immigrant women reported more experiences of overt discrimination and fewer experiences of ordinary privileges than did nonvisible immigrant women. The associations of belonging to a visible immigrant group with both psychiatric symptoms and satisfaction with life were each mediated through ordinary privileges and overt discrimination. The magnitude of the two indirect effects was equal for psychiatric symptoms, but for satisfaction with life, the indirect effect through ordinary privileges was stronger. After accounting for ordinary privileges and overt discrimination, the average score for satisfaction with life was higher for visible immigrant women than for nonvisible immigrant women. These findings suggest that visible immigrant women experience exclusion from ordinary privileges to a greater extent than nonvisible immigrant women and that this type of exclusion is at least as detrimental to psychological health as more overt forms of discrimination. Our findings demonstrate the importance of attending to discrimination of both visible and nonvisible immigrants and highlight the importance of ordinary privileges to immigrants’ well-being in their countries of destination. We discuss implications for future research and social policy.
“In Case of Emergency, Break-Open Glass”: The IMF’s “New” Institutional View, Financial Instability, and Financing Development Processes
Authors: Rafferty Devin Thomas
Published: July 2017

After the North Atlantic Financial Crisis, the International Monetary Fund (IMF) shifted towards a greater acceptance of capital controls (what it calls capital flow management measures) for regulating international capital flows with the publication of its “New” Institutional View. This begs the question of what such a change means for developing economies; specifically, whether the new framework addresses the needs they have for producing financial stability. That is the topic examined in this paper.
Oval housing for the St. Jude Medical bileaflet mechanical heart valve
Authors: Mohammadi Hadi , Fradet Guy
Published: July 2017

The St. Jude Medical bileaflet mechanical heart valve was approved by the Food and Drug Administration in late 1970s. The basic idea for the design of the valve is simply two semicircular flat plates pivoting on hinges. The overall performance of St. Jude Medical valves such as blood flow being central, the leaflets opening completely, and the pressure drop across the valve being trivial is satisfactory. St. Jude Medical valves provide an improved hemodynamics compared to the other mechanical heart valve models; however, their non-physiological hemodynamics which may lead to red blood cells lysis and thrombogenicity still remains a major issue. In this study, we hypothesize that applying ovality to the housing might improve their hemodynamics significantly which is based on the fact that the native annulus is oval by nature. A quick but precise numerical model based on the finite strip method was developed by which the regurgitation flow volume and velocity of the proposed design were assessed in the closing phase. The results are satisfactory and an improved hemodynamics is observed. The proposed design can be considered for further numerical and experimental studies and shows promise and merits further development.
Paleomagnetic constraints on the ages of the Holocene Malpaís de Zacapu lava flow eruptions, Michoacán (México): Implications for archeology and volcanic hazards
Authors: Mahgoub Ahmed Nasser , Reyes-Guzmán Nanci , Böhnel Harald , Siebe Claus , Pereira Gregory , Dorison Antoine
Published: July 2017

Four monogenetic Holocene lava flows located within the Michoacán-Guanajuato Volcanic Field, Mexico, were sampled for paleomagnetic dating. These flows (namely, El Infiernillo, Malpaís Las Víboras, El Capaxtiro, and Malpaís Prieto) are within the heartland of the pre-Hispanic Tarascan civilization and were inhabited repeatedly since at least 100 BC, but no relation with the volcanic evolution has been proposed so far. The stratigraphically oldest lava flow, El Infiernillo, has a radiocarbon age of 3200 ± 30 yr BP (cal. 1525–1420 BC), and it was used to validate the method. Using full-vector paleomagnetic data from three sites as input for paleomagnetic dating applying the global paleosecular variation model SHA.DIF.14k, an age range of 1500–1370 BC was obtained. Two age ranges of 1340–1230 and 1030–940 BC were obtained for Malpaís Las Víboras. A younger age range of 200–80 BC was obtained for the Capaxtiro lava flow and, finally, the Malpaís Prieto lava flow erupted within the range of AD 830–960. The human occupation history of these flows started around 100 BC during the late Pre-Classic, probably shortly after the Capaxtiro eruption. Archeological records indicate an abandonment of the entire area around AD 900 (late to terminal Classic), which coincides with the paleomagnetic age of the Malpaís Prieto eruption. Interestingly, this area was heavily repopulated again only few hundred years later around AD 1250 and belongs to the core region in which the Tarascan civilization has its roots. The eruption recurrence interval of roughly 1000 years indicates that a new monogenetic eruption should be expected to occur again in the future and that this area deserves to be studied in greater detail with particular emphasis on the impact of past eruptions. This could help to better evaluate volcanic hazards and design preparedness strategies to minimize the impact of a future eruption.
Axonal spheroids in ovine neuroaxonal dystrophy are immunopositive to kinesin and dynein
Authors: Finnie John W. , Manavis Jim
Published: July 2017

Neuroaxonal dystrophy (NAD) is a neurologic disorder of sheep characterized by accumulation of numerous axonal swellings (spheroids) in specific regions of the brainstem and spinal cord. Disruption of axonal transport, which is driven in anterograde and retrograde directions by the molecular motors, kinesin and dynein, respectively, is believed to contribute to spheroid development. Accordingly, we examined spheroids in ovine NAD cases immunohistochemically for kinesin and dynein and found both motor proteins, with dynein more strongly expressed than kinesin. Further investigations of the kinesin and dynein content of axonal spheroids in NAD, and other neurodegenerative disorders of domestic animals, could assist in better understanding the pathogenesis of these diseases.
Immunologic detection of Giardia duodenalis in a specific pathogen–free captive olive baboon (Papio cynocephalus anubis) colony
Authors: Saleh Meriam N. , Thomas Jennifer E. , Heptinstall Jack R. , Herbein Joel F. , Wolf Roman F. , Reichard Mason V. , Zajac Anne M.
Published: July 2017

Several commercial Giardia immunoassays were evaluated in baboons for sensitivity and specificity as well as ease of use in a large specific pathogen–free (SPF) colony. An additional objective was to identify the assemblage(s) of Giardia duodenalis present in this baboon colony. A direct immunofluorescent antibody test (IFAT) was used as the reference test. Tests evaluated were a patient-side rapid test for dogs and cats, a human rapid test, and a well-plate ELISA designed for use with humans. Test sensitivities and specificities were compared using the McNemar paired t-test and were further evaluated for agreement using an unweighted Cohen kappa statistic. When compared to the IFAT reference, both human tests were more sensitive than the veterinary test. Based on PCR and sequencing of the G. duodenalis small-subunit ribosomal RNA and glutamate dehydrogenase loci, assemblage AI was present in this baboon colony. We found that 10 of the 110 (9%) baboons in this SPF colony were infected with a zoonotic strain of G. duodenalis.
Acute disseminated mycobacteriosis in captive Atlantic guitarfish (Rhinobatos lentiginosus)
Authors: Tuxbury Kathryn A. , Young Samuel A. , Bradway Daniel S. , Marola Jamie L. , Salfinger Max , Garner Michael M.
Published: July 2017

An adult female captive-born Atlantic guitarfish ( Rhinobatos lentiginosus) was found acutely moribund on exhibit and died soon after presentation. Abnormalities on autopsy were focal cutaneous erythema on the tail, a small liver, many variably sized friable ovarian follicles, and coelomic effusion. Histologic examination revealed systemic bacterial embolization, and yolk coelomitis with minimal associated inflammation and some mineralization. Bacterial culture of blood and coelomic effusion grew a rapidly growing Mycobacterium species that was further identified as Mycobacterium chelonae by PCR amplification and sequencing of the RNA polymerase subunit beta ( rpoB) gene of isolated genomic DNA. Concurrent reproductive disease may have caused immunosuppression, thus predisposing to the mycobacterial infection. At another institution, an adult male wild-caught Atlantic guitarfish was found dead on exhibit with no premonitory signs. Abnormalities on autopsy were a thin body condition, small liver, and coelomic effusion. Histologic examination revealed acute mycobacterial septicemia. M. chelonae was also identified in this fish by PCR amplification and sequencing. Mycobacteriosis has rarely been reported in captive elasmobranchs. Guitarfish may have greater susceptibility to mycobacteriosis than other elasmobranchs, and acute and chronic manifestations of the disease may exist in this species.