bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition
Authors: Ren Jiangtao , Liu Xiaojun , Fang Chongyun , Jiang Shuguang , June Carl H. , Zhao Yangbing 
Published: November 2016

Abstract
Purpose: Using gene-disrupted allogeneic T cells as universal effector cells provides an alternative and potentially improves current chimeric antigen receptor (CAR) T-cell therapy against cancers and infectious diseases.
Experimental Design: The CRISPR/Cas9 system has recently emerged as a simple and efficient way for multiplex genome engineering. By combining lentiviral delivery of CAR and electro-transfer of Cas9 mRNA and gRNAs targeting endogenous TCR, β-2 microglobulin (B2M) and PD1 simultaneously, to generate gene-disrupted allogeneic CAR T cells deficient of TCR, HLA class I molecule and PD1.
Results: The CRISPR gene–edited CAR T cells showed potent antitumor activities, both in vitro and in animal models and were as potent as non-gene–edited CAR T cells. In addition, the TCR and HLA class I double deficient T cells had reduced alloreactivity and did not cause graft-versus-host disease. Finally, simultaneous triple genome editing by adding the disruption of PD1 led to enhanced in vivo antitumor activity of the gene-disrupted CAR T cells.
Conclusions: Gene-disrupted allogeneic CAR and TCR T cells could provide an alternative as a universal donor to autologous T cells, which carry difficulties and high production costs. Gene-disrupted CAR and TCR T cells with disabled checkpoint molecules may be potent effector cells against cancers and infectious diseases. Clin Cancer Res; 23(9); 2255–66. ©2016 AACR.
Cytokine-Induced Killer Cells Kill Chemo-surviving Melanoma Cancer Stem Cells
Authors: Gammaitoni Loretta , Giraudo Lidia , Macagno Marco , Leuci Valeria , Mesiano Giulia , Rotolo Ramona , Sassi Francesco , Sanlorenzo Martina , Zaccagna Alessandro , Pisacane Alberto , Senetta Rebecca , Cangemi Michela , Cattaneo Giulia , Martin Valentina , Coha Valentina , Gallo Susanna , Pignochino Ymera , Sapino Anna , Grignani Giovanni , Carnevale-Schianca Fabrizio , Aglietta Massimo , Sangiolo Dario 
Published: November 2016

AbstractPurpose: The MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSC) was explored, as CSCs are considered responsible for chemoresistance and relapses.Experimental Design: Putative mCSCs were visualized by engineering patient-derived melanoma cells (MC) with a lentiviral vector encoding eGFP under expression control by stemness gene promoter oct4. Their stemness potential was confirmed in vivo by limiting dilution assays. We explored the sensitivity of eGFP+ mCSCs to chemotherapy (CHT), BRAF inhibitor (BRAFi) or CIK cells, as single agents or in sequence, in vitro. First, we treated MCs in vitro with fotemustine or dabrafenib (BRAF-mutated cases); then, surviving MCs, enriched in mCSCs, were challenged with autologous CIK cells. CIK cell activity against chemoresistant mCSCs was confirmed in vivo in two distinct immunodeficient murine models.Results: We visualized eGFP+ mCSCs (14% ± 2.1%) in 11 MCs. The tumorigenic precursor rate in vivo was higher within eGFP+ MCs (1/42) compared with the eGFP− counterpart (1/4,870). In vitro mCSCs were relatively resistant to CHT and BRAFi, but killed by CIK cells (n = 11, 8/11 autologous), with specific lysis ranging from 95% [effector:tumor ratio (E:T), 40:1] to 20% (E:T 1:3). In vivo infusion of autologous CIK cells into mice bearing xenografts from three distinct melanomas demonstrated significant tumor responses involving CHT-spared eGFP+ mCSCs (P = 0.001). Sequential CHT–immunotherapy treatment retained antitumor activity (n = 12, P = 0.001) reducing mCSC rates (P = 0.01).Conclusions: These findings are the first demonstration that immunotherapy with CIK cells is active against autologous mCSCs surviving CHT or BRAFi. An experimental platform for mCSC study and rationale for CIK cells in melanoma clinical study is provided. Clin Cancer Res; 23(9); 2277–88. ©2016 AACR.
YKL‐40 Level and Hypertension Incidence: A Population‐Based Nested Case‐Control Study in China
Authors: Xu Tian , Zhong Chongke , Wang Aili , Guo Zhirong , Bu Xiaoqing , Zhou Yipeng , Tian Yunfan , HuangFu Xinfeng , Zhu Zhengbao , Zhang Yonghong 
Published: November 2016

Background
Human cartilage glycoprotein‐39 (YKL‐40) has been suggested to be a new marker of inflammation, atherosclerosis, and endothelial dysfunction. However, whether a higher level of YKL‐40 is an independent risk factor for hypertension incidence is still unknown.

Methods and Results

In a nested case‐control study within a prospective cohort of 12 423 initially healthy Chinese adults, we measured baseline plasma concentrations of YKL‐40 among 700 new‐onset hypertension cases and 700 age‐ and sex‐matched controls. Multiple conditional logistic regression analyses were used to calculate the odds ratios (95% CIs) of hypertension associated with higher levels of YKL‐40 both in the total population and in the age‐ (>55 and ≤55 years) and sex‐matched subgroups. Among the total population, YKL‐40 levels were not associated with hypertension risk. In the subgroup older than 55 years, odds ratios (95% CIs) of hypertension for those in the two higher tertiles of YKL‐40 were 1.23 (0.77–1.97) and 1.59 (0.99–2.55) (
P
for linear trend=0.05). In the male subgroup, odds ratios (95% CIs) of hypertension for those in the two higher tertiles of YKL‐40 were 1.55 (0.88–2.72) and 2.09 (1.14–3.82) (
P
for linear trend=0.02). An interaction effect was observed between YKL‐40 and sex (
P
for interaction <0.01) but not between YKL‐40 and age (
P
for interaction=0.21). High YKL‐40 level significantly increased hypertension risk in men but decreased hypertension risk with a trend although not significant in women.

Conclusions
This study suggests that YKL‐40 is associated with hypertension incidence only among men. The study findings need to be further verified by prospective cohort studies or clinical trials.
Smellmap: Amsterdam—Olfactory Art and Smell
Visualization
Authors: McLean Kate 
Published: November 2016

Abstract
Creating a smellmap of a city is a subjective, collaborative exercise. During a series of smellwalks local participants foreground their sense of smell and name perceived aromas emanating from the urban smell-scape. Data and conversations arising from the walks are “analyzed,” and a representative smellscape of the city is visualized as a map. Scents—the nasal stimuli and a catalyst for discussion—accompany the map. As a map of what we do not know, indications of geolocated smell possibilities and ephemeral scents combine visualization with the olfactory to place the emphasis on human interaction with sensory data to create meaning and an understanding of place.
Stigma and need for care in individuals who hear voices
Authors: Vilhauer Ruvanee P 
Published: November 2016

Background: Voice hearing experiences, or auditory verbal hallucinations, occur in healthy individuals as well as in individuals who need clinical care, but news media depict voice hearing primarily as a symptom of mental illness, particularly schizophrenia. Aims: This article explores whether, and how, public perception of an exaggerated association between voice hearing and mental illness might influence individuals’ need for clinical care. Method: A narrative literature review was conducted, using relevant peer-reviewed research published in the English language. Results: Stigma may prevent disclosure of voice hearing experiences. Non-disclosure can prevent access to sources of normalizing information and lead to isolation, loss of social support and distress. Internalization of stigma and concomitantly decreased self-esteem could potentially affect features of voices such as perceived voice power, controllability, negativity and frequency, as well as distress. Increased distress may result in a decrease in functioning and increased need for clinical care. Conclusion: The literature reviewed suggests that stigma has the potential to increase need for care through many interrelated pathways. However, the ability to draw definitive conclusions was constrained by the designs of the studies reviewed. Further research is needed to confirm the findings of this review.
Recovery and its correlates among patients with bipolar disorder: A study from a tertiary care centre in North India
Authors: Grover Sandeep , Hazari Nandita , Aneja Jitender , Chakrabarti Subho , Sharma Sunil , Avasthi Ajit 
Published: November 2016

Background and Aim: The goal of treatment in mental illness has evolved from a symptom-based approach to a personal recovery–based approach. The aim of this study was to evaluate the predictors of personal recovery among patients with bipolar disorder. Methodology: A total of 185 patients with bipolar disorder, currently in remission, were evaluated on Recovery Assessment Scale (RAS), Internalized Stigma of Mental Illness Scale (ISMIS), Brief Religious coping scale (RCOPE), Duke University Religiosity Index (DUREL), Religiousness Measures Scale, Hamilton depression rating scale (HDRS), Young Mania rating scale (YMRS) and Global Assessment of Functioning (GAF) scale. Results: The mean age of the sample was 40.5 (standard deviation (SD), 11.26) years. Majority of the participants were male, married, working, Hindu by religion and belonged to extended/joint families of urban background. In the regression analysis, RAS scores were predicted significantly by discrimination experience, stereotype endorsement and alienation domains of ISMIS, level of functioning as assessed by GAF, residual depressive symptoms as assessed by HDRS and occupational status. The level of variance explained for total RAS score and various RAS domains ranged from 36.2% to 46.9%. Conclusion: This study suggests that personal recovery among patients with bipolar disorder is affected by stigma, level of functioning, residual depressive symptoms and employment status of patients with bipolar disorder.
Whole body perfusion for hybrid aortic arch repair: evolution of selective regional perfusion with a modified extracorporeal circuit
Authors: Fernandes Philip , Walsh Graham , Walsh Stephanie , O’Neil Michael , Gelinas Jill , Chu Michael W. A. 
Published: November 2016

Background: Patients undergoing hybrid aortic arch reconstruction require careful protection of vital organs. We believe that whole body perfusion with tailored dual circuitry may help to achieve optimal patient outcomes. Methods: Our circuit has evolved from a secondary circuit utilizing a cardioplegia delivery device for lower body perfusion to a dual-oxygenator circuit. This allows individually controlled regional perfusion with ease of switching from secondary to primary circuit for total body flow. The re-design allows for separate flow and temperature regulation with two oxygenators in parallel. All patients underwent a single-stage operation for simultaneous treatment of arch and descending aortic pathology via a sternotomy, using a hybrid frozen elephant trunk technique. Results: We report six consecutive patients undergoing hybrid arch and frozen elephant trunk reconstruction using a dual-oxygenator circuit. Five patients underwent elective surgery and one was emergent. One patient had an acute dissection while three underwent concomitant procedures, including a Ross procedure and two valve-sparing root reconstructions. Three cases were redo sternotomies. The mean pump time was 358 ± 131 min, the aortic cross clamp time 243 ± 135 min, the cardioplegia volume of 33,208 ml ± 16,173, cerebral ischemia 0 min, lower body ischemia 76 ± 34 min and the average lower body perfusion time was 142 min. Two patients did not require any donor blood products. The median intensive care unit (ICU) and hospital lengths of stay (LOS) were two days and 10 days, respectively. The average peak serum lactate on CPB was 7.47 mmol/L and, at admission to the ICU, it was 3.37 mmol/L. Renal and respiratory failure developed in the salvage acute type A dissection patient. No other complications occurred in this series. Conclusions: Whole body perfusion as delivered through individually controlled dual-oxygenator circuitry allows maximum flexibility for hybrid aortic arch reconstruction. A modified circuit perfusion strategy may help to limit intra-operative metabolic derangements, providing improved clinical outcomes.
In vitro effects of an extracorporeal membrane oxygenation circuit on the sequestration of ϵ-aminocaproic acid
Authors: Wagner Deborah , Caraballo Miguel , Waldvogel John , Peterson Yuki , Sun Duxin 
Published: November 2016

Objective: To assess the in vitro effects of drug sequestration in extracorporeal membrane oxygenation (ECMO) on ϵ-aminocaproic acid (EACA) concentrations. Methods and Design: This in vitro study will determine changes in EACA concentration over time in ECMO circuits. A pediatric dose of 2,500 mg was administered to whole expired blood in the simulated pediatric ECMO circuit. Blood samples were collected at 0, 30, 60, 360 and 1440-minute intervals after initial administration equilibration from three different sites of the circuit: pre-oxygenator (PRE), post-oxygenator (POST) and PVC tubing (PVC) to determine the predominant site of drug loss. The circuit was maintained for two consecutive days with a re-dose at 24 hours to establish a comparison between unsaturated (New) and saturated (Old) oxygenator membranes. Comparisons between sample sites, sample times and New versus Old membranes were statistically analyzed by a linear mixed-effects model with significance defined as a p-value <0.05. Results: There were no significant differences in EACA concentration with respect to sample site, with PRE and POST samples demonstrating respective mean differences of 0.30 mg/ml and 0.34 mg/ml as compared to PVC, resulting in non-significant p-values of 0.373 [95% CI (-0.37, 0.98)] and 0.324 [95% CI (-0.34, 1.01)], respectively. The comparison of New vs. Old ECMO circuits resulted in non-significant changes from baseline, with a mean difference of 0.50 mg/ml, 95% CI (-0.65, 1.65), p=0.315. Conclusion: The findings of this study did not show any significant changes in drug concentration that can be attributed to sequestration within the ECMO circuit. Mean concentrations between ECMO circuit sample sites did not differ significantly. Comparison between New and Old circuits also did not differ significantly in the change from baseline concentration over time. Sequestration within ECMO circuits appears not to be a considerable factor for EACA administration.
Somatosensory temporal discrimination remains intact in tension-type headache whereas it is disrupted in migraine attacks
Authors: Vuralli Doga , Boran H Evren , Cengiz Bulent , Coskun Ozlem , Bolay Hayrunnisa 
Published: November 2016

Background and objective Somatosensory temporal discrimination was recently reported as prolonged during migraine attacks, which is consistent with disrupted sensorial perception in migraine. However, knowledge about central sensory processing in tension-type headache is still lacking. This prospective, controlled study aimed to investigate somatosensory temporal discrimination thresholds in tension-type headache. Methods The study included 10 tension-type headache patients, 10 migraine patients and 10 healthy volunteers without headache. Somatosensory temporal discrimination thresholds were evaluated during the headache attacks of tension-type headache and migraine patients. Results Somatosensory temporal discrimination thresholds of tension-type headache patients (39.0 ± 5.5 ms for the right hand and 40.6 ± 4.6 ms for the left hand) were significantly lower than those of episodic migraine patients (137.1 ± 35.8 ms for the right hand and 118.4 ± 34.3 ms for the left hand, p < 0.0001 and p < 0.0001 respectively), and comparable to those of healthy volunteers (38.6 ± 5.3 ms for the right hand and 38.3 ± 7.2 ms for the left hand, p = 0.79 and p = 0.45 respectively). Conclusion Central sensory processing, as tested by somatosensory temporal discrimination, was remarkably disrupted during the headache attacks in migraineurs, whereas it remained intact in the tension-type headache patients.
Measuring the Impact of a Marketing Simulation Game
Authors: Wellington William J. , Hutchinson David B. , Faria Anthony J. 
Published: November 2016

Background. The evidence from past research suggests that business simulation games (BSGs) do offer a meaningful educational experience. One characteristic lacking across past research studies is the trait of indecisiveness. Aim. This study sought to explore whether business students would self-report a change in their perceptions of their indecisiveness after participating in a business simulation games (BSG). In addition, whether higher performance simulation decision makers would self-report being less indecisive (i.e. able to make decisions in a timely manner) than lower performance simulation decision makers. Method. Using a pre-test and post-test design with a comparison to an untreated control group, the change in 386 business students’ perceptions of their indecisiveness was assessed using a self-reporting questionnaire. Results. The findings showed a statistically significant reduction in the level of perceived indecisiveness as a result of the simulation experience. The higher performance students reported being less indecisive than lower performance students while both higher performance and lower performance students reported a reduction in perceived indecisiveness. The level of self-reported perceived indecisiveness amongst a control group of 137 business students indicated no significant change. Conclusion. If the combination of practice and positive reinforcement increases the comfort level (reduce feelings of risk and threat) of decision makers then perceived indecisiveness should decrease as a result of simulation participation, which may generalize across situations demanding decisions.
Safety of endovascular treatment in acute stroke patients taking oral anticoagulants
Authors: Uphaus Timo , Singer Oliver C , Berkefeld Joachim , Nolte Christian H , Bohner Georg , Niederkorn Kurt , Deutschmann Hannes , Haring Hans-Peter , Trenkler Johannes , Neumann-Haefelin Tobias , Hofmann Erich , Stoll Anett , Bormann Albrecht , Bussmeyer Matthias , Mpotsaris Aanastasios , Reich Arno , Wiesmann Martin , Petzold Gabor C , Urbach Horst , Jander Sebastian , Turowski Bernd , Weimar Christian , Schlamann Marc , Liebeskind David S , Gröschel Sonja , Boor Stephan , Gröschel Klaus 
Published: November 2016

Background The endovascular treatment of acute cerebral ischemia has been proven beneficial without major safety concerns. To date, the role of endovascular treatment in patients treated with oral anticoagulants, which may be associated with periprocedural intracranial bleeding, remains uncertain. Aims The objective of the current analysis is to evaluate the safety of endovascular treatment in patients treated with oral anticoagulants. Methods The ENDOSTROKE-Registry is a commercially independent, prospective observational study in 12 stroke centers in Germany and Austria collecting pre-specified variables about endovascular stroke therapy. Results Data from 815 patients (median age 70 (interquartile range (IQR) 20), 57% male) undergoing endovascular treatment with known anticoagulation status were analyzed. A total of 85 (median age 76 (IQR 8), 52% male) patients (10.4%) took vitamin-K-antagonists prior to endovascular treatment. Anticoagulation status as measured with international normalized ratio was above 2.0 in 31 patients. Intracranial hemorrhage occurred in 11.8% of patients taking vitamin-K-antagonists compared to no-vitamin-K-antagonists (12.2%, p = 0.909). After adjustment for confounding factors which were unbalanced at univariate level such as NIHSS and age, anticoagulation status was not found to significantly influence clinical outcome (modified Rankin Scale 3–6) and occurrence of intracranial hemorrhage in a multivariate logistic regression analysis. Conclusion Prior use of vitamin-K-antagonists was not associated with a higher rate of periprocedural intracranial hemorrhage after endovascular treatment or worse outcome. Endovascular treatment should be considered as an important treatment option in patients taking vitamin-K-antagonists.
Development and Application of a Clinical Microsystem Simulation Methodology for Human Factors-Based Research of Alarm Fatigue
Authors: Kobayashi Leo , Gosbee John W. , Merck Derek L. 
Published: November 2016

Objectives: (1) To develop a clinical microsystem simulation methodology for alarm fatigue research with a human factors engineering (HFE) assessment framework and (2) to explore its application to the comparative examination of different approaches to patient monitoring and provider notification. Background: Problems with the design, implementation, and real-world use of patient monitoring systems result in alarm fatigue. A multidisciplinary team is developing an open-source tool kit to promote bedside informatics research and mitigate alarm fatigue. Method: Simulation, HFE, and computer science experts created a novel simulation methodology to study alarm fatigue. Featuring multiple interconnected simulated patient scenarios with scripted timeline, “distractor” patient care tasks, and triggered true and false alarms, the methodology incorporated objective metrics to assess provider and system performance. Developed materials were implemented during institutional review board–approved study sessions that assessed and compared an experimental multiparametric alerting system with a standard monitor telemetry system for subject response, use characteristics, and end-user feedback. Results: A four-patient simulation setup featuring objective metrics for participant task-related performance and response to alarms was developed along with accompanying structured HFE assessment (questionnaire and interview) for monitor systems use testing. Two pilot and four study sessions with individual nurse subjects elicited true alarm and false alarm responses (including diversion from assigned tasks) as well as nonresponses to true alarms. In-simulation observation and subject questionnaires were used to test the experimental system’s approach to suppressing false alarms and alerting providers. Conclusions: A novel investigative methodology applied simulation and HFE techniques to replicate and study alarm fatigue in controlled settings for systems assessment and experimental research purposes.