bluuebunny/crossref_metadata_2025_split huggingface dataset:
An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma
Authors: Lee Lydia , Draper Benjamin , Chaplin Neil , Philip Brian , Chin Melody , Galas-Filipowicz Daria , Onuoha Shimobi , Thomas Simon , Baldan Vania , Bughda Reyisa , Maciocia Paul , Kokalaki Eva , Neves Margarida P. , Patel Dominic , Rodriguez-Justo Manuel , Francis James , Yong Kwee , Pule Martin 
Published: December 2017

Key PointsAPRIL is a compact, self-protein that binds 2 MM antigens (BCMA and TACI) with high affinity; we present an APRIL-based CAR. Dual-antigen targeting increases the availability of tumor-binding sites and reduces the risk of antigen-negative disease escape.
Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL
Authors: Wood Brent , Wu David , Crossley Beryl , Dai Yunfeng , Williamson David , Gawad Charles , Borowitz Michael J. , Devidas Meenakshi , Maloney Kelly W. , Larsen Eric , Winick Naomi , Raetz Elizabeth , Carroll William L. , Hunger Stephen P. , Loh Mignon L. , Robins Harlan , Kirsch Ilan 
Published: December 2017

Key Points
HTS identifies MRD at the conventional clinical cutoff in more patients than FC, and these patients have worse outcomes. A subset of B-ALL patients essentially cured using current chemotherapy is identified at end of induction by HTS.
The effects on calcaneofibular ligament function of differences in the angle of the calcaneofibular ligament with respect to the long axis of the fibula: a simulation study
Authors: Edama Mutsuaki , Kageyama Ikuo , Kikumoto Takanori , Nakamura Masatoshi , Ito Wataru , Nakamura Emi , Hirabayashi Ryo , Takabayashi Tomoya , Inai Takuma , Onishi Hideaki 
Published: December 2017

AbstractBackgroundIn the present study, CFLs harvested from cadavers were categorized according to the differences in the angle of the CFL with respect to the long axis of the fibula and their shape, and then three‐dimensional reconstructions of the CFLs were used to simulate and examine the differences in the angles of the CFLs with respect to the long axis of the fibula and how they affect CFL function.MethodsThe study sample included 81 ft from 43 Japanese cadavers. CFLs were categorized according to their angle with respect to the long axis of the fibula and the number of fiber bundles. Five categories were subsequently established: CFL20° (angle of the CFL with respect to the long axis of the fibula from 20° to 29°); CFL30° (range 30–39°); CFL40° (range 40–49°); CFL50° (range 50–59°); and CFL2 (CLFs with two crossing fiber bundles). Three‐dimensional reconstructions of a single specimen from each category were then created. These were used to simulate and calculate CFL strain during dorsiflexion (20°) and plantarflexion (30°) on the talocrural joint axis and inversion (20°) and eversion (20°) on the subtalar joint axis.ResultsIn terms of proportions for each category, CFL20° was observed in 14 ft (17.3%), with CFL30° in 22 ft (27.2%), CFL40° in 29 ft (35.8%), CFL50° in 15 ft (18.5%), and CFL2 in one foot (1.2%). Specimens in the CFL20° and CFL30° groups contracted with plantarflexion and stretched with dorsiflexion. In comparison, specimens in the CFL40°, CFL50°, and CFL2 groups stretched with plantarflexion and contracted with dorsiflexion. Specimens in the CFL20° and CFL2 groups stretched with inversion and contracted with eversion.ConclusionsCFL function changed according to the difference in the angles of the CFLs with respect to the long axis of the fibula.
The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis
Authors: Graham Catriona , Lewis Steff , Forbes John , Mead Gillian , Hackett Maree L. , Hankey Graeme J. , Gommans John , Nguyen Huy Thang , Lundström Erik , Isaksson Eva , Näsman Per , Rudberg Ann-Sofie , Dennis Martin 
Published: December 2017

Abstract
Background
Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients’ functional outcome.

Methods/Design
The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2–15 days after stroke onset. Patients are randomised centrally via each trials’ web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months.

Discussion
Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020.

Trial registration
FOCUS: ISRCTN, ISRCTN83290762. Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012.
AFFINITY: Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Registered on 22 July 2011.
EFFECTS: ISRCTN, ISRCTN13020412. Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213. Registered on 2 February 2016. EudraCT, 2011-006130-16. Registered on 8 August 2014.
Using single‐cell multiple omics approaches to resolve tumor heterogeneity
Authors: Ortega Michael A. , Poirion Olivier , Zhu Xun , Huang Sijia , Wolfgruber Thomas K. , Sebra Robert , Garmire Lana X. 
Published: December 2017

AbstractIt has become increasingly clear that both normal and cancer tissues are composed of heterogeneous populations. Genetic variation can be attributed to the downstream effects of inherited mutations, environmental factors, or inaccurately resolved errors in transcription and replication. When lesions occur in regions that confer a proliferative advantage, it can support clonal expansion, subclonal variation, and neoplastic progression. In this manner, the complex heterogeneous microenvironment of a tumour promotes the likelihood of angiogenesis and metastasis. Recent advances in next‐generation sequencing and computational biology have utilized single‐cell applications to build deep profiles of individual cells that are otherwise masked in bulk profiling. In addition, the development of new techniques for combining single‐cell multi‐omic strategies is providing a more precise understanding of factors contributing to cellular identity, function, and growth. Continuing advancements in single‐cell technology and computational deconvolution of data will be critical for reconstructing patient specific intra‐tumour features and developing more personalized cancer treatments.
Reproductive Alterations in Chronically Exposed Female Mice to Environmentally Relevant Doses of a Mixture of Phthalates and Alkylphenols
Authors: Patiño-García Daniel , Cruz-Fernandes Leonor , Buñay Julio , Palomino Jaime , Moreno Ricardo D 
Published: December 2017

Abstract
Endocrine-disrupting chemicals (EDCs) are exogenous compounds that modify hormone biosynthesis, causing adverse effects to human health. Among them, phthalates and alkylphenols are important due to their wide use in plastics, detergents, personal care products, cosmetics, and food packaging. However, their conjoint effects over reproductive female health have not been addressed. The aim of this work was to test the effect of chronically exposed female mice to a mixture of three phthalates [bis (2-ethylhexyl), dibutyl, and benzyl butyl] and two alkylphenols (4-nonylphenol and 4-tert-octylphenol) from conception to adulthood at environmentally relevant doses. These EDCs were administered in two doses: one below the minimal risk dose to cause adverse effects on human development and reproduction [1 mg/kg body weight (BW)/d of the total mixture] and the other one based on the reference value close to occupational exposure in humans (10 mg/kg BW/d of the total mixture). Our results show that both doses had similar effects regarding the uterus and ovary relative weight, estrous cyclicity, serum levels of progesterone and 17β-estradiol, and expression of key elements in the steroidogenesis pathway (acute steroidogenic regulatory protein and CYP19A1). However, only the 1-mg/kg BW/d dose delayed the onset of puberty and the transition from preantral to antral follicles, whereas the 10-mg/kg BW/d dose decreased the number of antral follicles and gonadotropin receptor expression. In addition, we observed changes in several fertility parameters in exposed females and in their progeny (F2 generation). In conclusion, our results indicate that chronic exposure to a complex EDC mixture, at environmentally relevant doses, modifies reproductive parameters in female mice.
Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies
Authors: Koskinen Maarit K , Lempainen Johanna , Löyttyniemi Eliisa , Helminen Olli , Hekkala Anne , Härkönen Taina , Kiviniemi Minna , Simell Olli , Knip Mikael , Ilonen Jorma , Toppari Jorma , Veijola Riitta 
Published: December 2017

Abstract

Context
A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both.

Objective
To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR.

Design, Setting, Participants
A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR.

Main Outcome Measure
The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR.

Results
A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P &lt; 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P &lt; 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P &lt; 0.0001 and P = 0.0013, respectively).

Conclusions
The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.
Effects of Hypoglycemia on Circulating Stem and Progenitor Cells in Diabetic Patients
Authors: Fadini Gian Paolo , Boscari Federico , Cappellari Roberta , Galasso Silvia , Rigato Mauro , Bonora Benedetta Maria , D’Anna Marianna , Bruttomesso Daniela , Avogaro Angelo 
Published: December 2017

Abstract

Context
Iatrogenic hypoglycemia is the most common acute diabetic complication, and it significantly increases morbidity. In people with diabetes, reduction in the levels of circulating stem and progenitor cells predicts adverse outcomes.

Objective
To evaluate whether hypoglycemia in diabetes affects circulating stem cells and endothelial progenitor cells (EPCs).

Design
We performed an experimental hypoglycemia study (Study 1) and a case-control study (Study 2).

Setting
Tertiary referral inpatient clinic.

Patients and Other Participants
Type 1 diabetic patients (Study 1, n = 19); diabetic patients hospitalized for severe iatrogenic hypoglycemia, matched inpatient and outpatient controls (Study 2, n = 22/group).

Interventions
Type 1 diabetic patients underwent two in-hospital sessions of glucose monitoring during a breakfast meal with or without induction of hypoglycemia in random order. In Study 2, patients hospitalized for hypoglycemia and matched controls were compared.

Main Outcome Measure
Circulating stem cells and EPCs were measured by flow cytometry based on the expression of CD34 and kinase insert domain receptor (KDR).

Results
In Study 1, the physiologic decline of CD34+KDR+ EPCs from 8 am to 2 pm was abolished by insulin-induced hypoglycemia in type 1 diabetic patients. In Study 2, diabetic patients hospitalized for severe iatrogenic hypoglycemia had significantly lower levels of CD34+ stem cells and CD34+KDR+ EPCs compared with diabetic inpatients or outpatient controls.

Conclusions
In diabetic patients, a single mild hypoglycemic episode can compromise the physiologic EPC fluctuation, whereas severe hypoglycemia is associated with a marked reduction in stem cells and EPCs. These data provide a possible link between hypoglycemia and adverse outcomes of diabetes.
A Simulation Study to Evaluate Improvements in Anesthesia Work Environment Contamination After Implementation of an Infection Prevention Bundle
Authors: Porteous Grete H. , Bean Helen A. , Woodward Crystal M. , Beecher Ryan P. , Bernstein Jennifer R. , Wilkerson Sarah , Porteous Ian , Hsiung Robert L. 
Published: December 2017

BACKGROUND:
Microbiological contamination of the anesthesia work environment (AWE) is a potential source of health care–associated infections. Medication syringes, stopcocks, and many other areas are routinely contaminated during anesthetic care, and adherence to hand hygiene recommendations is poor. Using a simulation model, we investigated whether AWE contamination could be reduced by implementing an intervention bundle focused on infection prevention.

METHODS:
Twenty-five anesthesia providers were enrolled in this nonrandomized simulation scenario crossover design study. Subjects were asked to complete 2 general anesthesia scenarios in a mock operating room: a baseline scenario and an intervention scenario in which the bundle was implemented. The bundle included: double gloving before intubation, confining all airway equipment to 1 area, and performing hand hygiene before touching the anesthesia cart. Before each scenario, a manikin’s oropharynx and face were marked with ultraviolet fluorescent tracers. After each scenario, the AWE was inspected with a ultraviolet light source to detect contaminant, and all sites were photographed. A blinded observer scored the images for the presence or absence of tracer at 20 sites. Videos of the scenarios were analyzed for duration and number of hand hygiene and glove removal events. Data were analyzed using a mixed effects model. Subjects completed a survey about their experience and the value of the scenarios.

RESULTS:
The intervention was associated with a decreased subject contamination score of 4.0 (95% confidence interval, 2.2–5.6; P < .001), a 27% reduction in score between baseline and intervention scenarios. Some sites were universally contaminated despite the intervention (eg, laryngoscope handles). The intervention had a statistically significant impact on reducing contamination on medication syringes and the anesthesia cart. There was no significant difference in time needed to complete baseline and intervention scenarios. The majority of subjects felt that the simulations had significant value and would affect their future clinical behavior.

CONCLUSIONS:
Our results support the concept of an infection prevention bundle in reducing AWE contamination. Anesthesia providers deliver care in a unique environment in which “clean” and “contaminated” tasks are performed rapidly and often in parallel. Linking hand hygiene to specific high-impact tasks such as administering medications, designating areas for contaminated equipment, and double gloving before airway management are simple steps that can be implemented rapidly and are compatible with timely patient care. Our study has improved awareness of infection prevention issues in our department, and has highlighted simple and achievable actions that have the potential to reduce health care–associated infections.
Anesthetic Management and Procedural Outcomes of Patients Undergoing Off-Pump Transapical Implantation of Artificial Chordae to Correct Mitral Regurgitation: Case Series of 76 Patients
Authors: Samalavicius Robertas Stasys , Norkiene Ieva , Drasutiene Agne , Lipnevicius Arturas , Janusauskas Vilius , Urbonas Karolis , Zakarkaite Diana , Aidietis Audrius , Rucinskas Kestutis 
Published: December 2017

BACKGROUND:
Transapical implantation of artificial chordae using the NeoChord system (NeoChord Inc, Minneapolis, MN) is an emerging beating-heart technique for correction of mitral regurgitation (MR) through a minimally invasive left minithoracotomy. The purpose of the study was to describe the anesthetic management and procedural success of patients undergoing this procedure.

METHODS:
All patients (n = 76) who underwent mitral valve repair with the NeoChord system in our institution from December 2011 to December 2016 were included in this observational prospective study. Balanced anesthesia with a combination of fentanyl, propofol, and sevoflurane was used in all patients. Each patient’s core temperature was maintained at >36°C whenever possible. Two- and 3-dimensional transesophageal echocardiography was used in all patients to navigate the device to the posterior mitral valve leaflet (68 of 76 patients), anterior mitral valve leaflet (3 of 76 patients), or both leaflets (5 of 76 patients). After effective leaflet capture, the artificial chordae were deployed. Position and function of the artificial chordae were assessed by evaluating the degree of MR when the neochordae were tensed. After surgery, all patients were transferred to the intensive care unit.

RESULTS:
The mean age of the patients was 60 ± 13 years (range, 33–87 years), and the male/female ratio was 52/24. Most patients had severe MR (grade 4+ in 25 [33%] patients, grade 3+ in 51 [67%] patients). The average preoperative EuroSCORE II was 1.23% ± 1.16% (range, 0.46%–4.23%). The median duration of the procedure was 120 minutes (interquartile range [IQR] 115–145 minutes). After the procedure, 42 (56%) patients had trivial MR, 27 (36%) had grade 1+ MR, 4 (5%) had grade 2+ MR, and 2 (3%) had >2+ MR. One patient underwent conversion to conventional mitral valve repair due to perforation of the posterior mitral valve leaflet. The whole procedure was well tolerated by the patients, with hemodynamics remaining stable in the majority of the cases. Only 20 (26%) patients needed low-dose inotropic support perioperatively. All patients had an uneventful postoperative course. The median time to extubation was 4 hours (IQR, 2.6–6), and the length of intensive care unit stay was 22 hours (IQR, 21–24). Five (6.6%) patients required allogeneic blood products.

CONCLUSIONS:
Anesthesia for transapical NeoChord implantation can be safely performed under beating-heart conditions, with low perioperative morbidity and rare blood transfusions. Transesophageal echocardiography is crucial for the guidance, safety, and effectiveness of the procedure.
Deconstructing the Outsider Puzzle: The Legitimation Journey of Novelty
Authors: Cattani Gino , Ferriani Simone , Lanza Andrea 
Published: December 2017

The proposition that outsiders often are crucial carriers of novelty into an established institutional field has received wide empirical support. But an equally compelling proposition points to the following puzzle: the very same conditions that enhance outsiders’ ability to make novel contributions also hinder their ability to carry them out. We seek to address this puzzle by examining the contextual circumstances that affect the legitimation of novelty originating from a noncertified outsider that challenged the status quo in an established institutional field. Our research case material is John Harrison’s introduction of a new mechanical method for measuring longitude at sea—the marine chronometer—which challenged the dominant astronomical approach. We find that whether an outsider’s new offer gains or is denied legitimacy is influenced by (1) the outsider’s agency to further a new offer, (2) the existence of multiple audiences with different dispositions toward this offer, and (3) the occurrence of an exogenous jolt that helps create a more receptive social space. We organize these insights into a multilevel conceptual framework that builds on previous work but attributes a more decisive role to the interplay between endogenous and exogenous variables in shaping a field’s shifting receptiveness to novelty. The framework exposes the interdependencies between the micro-, meso-, and macro-level processes that jointly affect an outsider’s efforts to introduce novelty into an existing field. The e-companion is available at https://doi.org/10.1287/orsc.2017.1161 .
Motor imagery training with augmented cues of motor learning on cognitive functions in patients with Parkinsonism
Authors: Mahmoud Lama Saad El-Din , Abu Shady Nawal Abd EL-Raouf , Hafez Ehab Shaker 
Published: December 2017

Background/Aims: Patients with Parkinsonism demonstrate impairments in cognitive functions, such as deficit in attention, planning, and working memory. The objective was to investigate the effect of motor imagery training with augmented cues of motor learning on cognitive functions in patients with Parkinsonism. Methods: A total of 30 patients from both sexes participated in this study. All of the patients had been diagnosed as idiopathic Parkinson patients experiencing cognitive dysfunction. The patients were randomly divided into two equal groups: the study group (n=15) received motor imagery training with augmented cues of motor learning and the specifically designed intervention. The control group (n=15) received conventional treatment (cognitive remediation therapy). The treatment took place three times a week for 6 weeks (18 sessions). The patients were diagnosed with a computer-based cognitive assessment device (RehaCom). Findings: The result of this study showed that there was a significant difference between the study and control groups (p=0.0001), which indicated that the study group showed a greater improvement than the control group. Conclusions: Combined effect of motor imagery training with augmented cues of motor learning improved cognitive functions in patients with Parkinsonism.