bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors predicting cessation of status epilepticus in clinical practice: Data from a prospective observational registry (SENSE)
Authors: Kellinghaus Christoph , Rossetti Andrea O. , Trinka Eugen , Lang Nicolas , May Theodor W. , Unterberger Iris , Rüegg Stephan , Sutter Raoul , Strzelczyk Adam , Tilz Christian , Uzelac Zeljko , Rosenow Felix
Published: January 2019

Objective

To investigate the initial termination rate of status epilepticus (SE) in a large observational study and explore associated variables.

Methods

Data of adults treated for SE were collected prospectively in centers in Germany, Austria, and Switzerland, during 4.5 years. Incident episodes of 1,049 patients were analyzed using uni‐ and multivariate statistics to determine factors predicting cessation of SE within 1 hour (for generalized convulsive SE [GCSE]) and 12 hours (for non‐GCSE) of initiating treatment.

Results

Median age at SE onset was 70 years; most frequent etiologies were remote (32%) and acute (31%). GCSE was documented in 43%. Median latency between SE onset and first treatment was 30 minutes in GCSE and 150 minutes in non‐GCSE. The first intravenous compound was a benzodiazepine in 86% in GCSE and 73% in non‐GCSE. Bolus doses of the first treatment step were lower than recommended by current guidelines in 76% of GCSE patients and 78% of non‐GCSE patients. In 319 GCSE patients (70%), SE was ongoing 1 hour after initiating treatment and in 342 non‐GCSE patients (58%) 12 hours after initiating treatment. Multivariate Cox regression demonstrated that use of benzodiazepines as first treatment step and a higher cumulative dose of anticonvulsants within the first period of treatment were associated with shorter time to cessation of SE for both groups.

Interpretation

In clinical practice, treatment guidelines were not followed in a substantial proportion of patients. This underdosing correlated with lack of cessation of SE. Our data suggest that sufficiently dosed benzodiazepines should be used as a first treatment step.ANN NEUROL 2019;85:421–432.
Motor behavior unmasks residual cognition in disorders of consciousness
Authors: Pincherle Alessandro , Jöhr Jane , Chatelle Camille , Pignat Jean‐Michel , Du Pasquier Renaud , Ryvlin Philippe , Oddo Mauro , Diserens Karin
Published: January 2019

Disorders of consciousness (DOC) are a common consequence of severe brain injuries, and clinical evaluation is critical to provide a correct diagnosis and prognosis. The revised Motor Behavior Tool (MBT‐r) is a clinical complementary tool aiming to identify subtle motor behaviors that might reflect residual cognition in DOC. In this prospective study including 30 DOC patients in the early stage after brain injury, we show that the revised MBT‐r has an excellent inter‐rater agreement and has the ability to identify a subgroup of patients, underestimated by the Coma Recovery Scale‐Revised, showing residual cognition and a subsequent recovery of consciousness. ANN NEUROL 2019;85:443–447.
Participation in Dissection Affects Student Performance on Gross Anatomy Practical and Written Examinations: Results of a Four‐Year Comparative Study
Authors: Thompson Andrew R. , Marshall Aaron M.
Published: January 2019

The role of human dissection in modern medical curricula has been a topic of intense debate. In part, this is because dissection can be time‐consuming and curricular hours are being monitored more carefully. This has led some to question the efficacy and importance of dissection as a teaching method. While this topic has received considerable attention in the literature, the question of how dissection impacts learning has been difficult to evaluate in a real‐world, high‐stakes setting since participation in dissection is often one of many variables. In this study, this challenge was overcome due to a change in the curriculum of a Special Master Program (SMP) that permitted a comparison between two years of students that learned anatomy using prosection only and two years of students that participated in dissection laboratories. Since each class of SMP students took courses in the medical school, and the medical school anatomy curriculum was constant, medical student performance served as a control throughout the study period. Results demonstrate that SMP students who learned through prosection had lower performance on anatomy practical and written examinations compared to medical students. When the SMP program changed and students started participating in dissection, there were measurable improvements in both practical and written examinations. These findings provide evidence of dissection’s role in learning and applying anatomy knowledge both within and outside the gross anatomy laboratory.
How to Make Educational Lemonade Out of a Didactic Lemon: The Benefits of Listening to Your Students
Authors: Hortsch Michael
Published: January 2019

When educators develop and introduce new learning approaches or resources, they usually have specific didactic goals in mind that they want to achieve. However, these goals may not always match the needs of their students, who often confound such plans by finding new and different uses for the educational tools that are offered to them. Originating from the author’s work as the histology component director at the University of Michigan, the experience described here provides an example of a learning resource being reappropriated by the learning community. In order to encourage dental students to study histological micrographs after faculty‐guided laboratory sessions were eliminated, the author prepared and offered them a series of PowerPoint files with histology images and some corresponding questions. However, instead of increasing their motivation to use the online virtual microscopy resources, students adapted this new tool for reviewing the material and for self‐evaluation whether they were prepared for upcoming examinations. Although the product did not succeed as originally devised, it turned into a very popular review resource for the author’s students. Students’ feedback and critical input, as well as their active participation in producing additional, similar learning tools were the deciding factors for this successful change of purpose and the further development and refinement of this new learning resource.
Naming the Dead: What information do Physical Therapy and Physician Assistant Anatomy Faculty Share With Students?
Authors: Cope Janet M. , Precht Mackenzie C. , Hannah Mary C. , Bennett Cynthia C.
Published: January 2019

In this novel study, the researchers quantify cadaver information provided to Physical Therapy (PT) and Physician Assistant (PA) anatomy faculty and ask what portion of that information is then shared with students. Descriptive statistics were used to the describe demographics of the study respondents and to report survey responses. The majority (60% or greater) of faculty who teach anatomy to PT and PA students have clinical degrees matching the student groups they teach. Chi‐square analysis showed no appreciable difference (P < 0.001) between PT and PA anatomy faculty in the amount of cadaver information they receive or then share with students. There was a difference in the type of cadaver information (identifying vs. non‐identifying) that is received and then shared by these faculty. Faculty are more likely to receive non‐identifying cadaver information (93%) than identifying information (40%) (P < 0.0001) and share non‐identifying information (83%) than identifying information (26%) with students (P < 0.0003). Interestingly, there is no consensus as to whether sharing cadaver information is respectful or disrespectful to those who donate their bodies for anatomy education and research. Further research is warranted into the reasons anatomy faculty withhold cadaver information from students and in the value, if any, for students knowing more about the cadavers they are learning from.
Skilful seasonal prediction of Korean winter temperature
Authors: Lim Juyoun , Dunstone Nick J. , Scaife Adam A. , Smith Doug M.
Published: January 2019

Korean winter temperature exhibits significant year‐to‐year variability, an extreme example of which was the severe cold winter of 2012/2013. Such events can have significant societal and financial impacts. We investigate the seasonal forecast skill for Korean winter temperature using Met Office initialised climate prediction systems. We find significant skill using two independent hindcasts covering the last decades. Observed Korean winter temperature variability appears to be driven by large‐scale dynamical circulation anomalies with centers over the northwest Pacific High (PH) and the Siberian High (SH). While the model has a good simulation of these observed teleconnections, we find that skilfully predicted PH variability dominates the model skill. This is due to the relatively strong PH teleconnection to highly predictable tropical Pacific and Indian Ocean variability. Whereas, observed SH variability is currently much less predictable in seasonal forecast systems. Furthermore, we find that the modelled SH exhibits lower predictability than the observed SH, suggesting a model “signal‐to‐noise” problem over extratropical East Asia which is similar to that reported over northern Europe. We explore one possible pathway, the representation of stratosphere–troposphere coupling, by examining the model simulation of stratospheric sudden warming (SSWs) events. While the SSW frequency and the spatial pattern of surface circulation response appears well simulated, the amplitude of the model response over SH appears anomalously weak. Nevertheless, we conclude that current seasonal forecasts of Korean winter temperature are skilful and have the potential to provide useful climate services.
Beyond ethanol, sugar, and electricity: a critical review of product diversification in Brazilian sugarcane mills
Authors: Klein Bruno Colling , de Mesquita Sampaio Isabelle Lobo , Mantelatto Paulo Eduardo , Filho Rubens Maciel , Bonomi Antonio
Published: January 2019

Process integration is an interesting option to reduce costs and improve the economic viability of new processes in sugarcane mills. Brazil has a prolific sugar‐energy sector, with hundreds of sugarcane mills that could possibly act as sources of carbon, energy, and water for annexed plants. While many studies analyze the integration of new technologies into sugarcane biorefineries as greenfield plants, the assessment and establishment of integrated processes into existing plants will help detecting process bottlenecks and enabling the required levels of integration to be better understood prior to designing a full‐scale, greenfield biorefinery. The present review provides an overview of the possibilities for sugarcane mills to diversify the portfolio of products from sugarcane biomass – beyond ethanol, sugar, and electric energy. The work initially considers the integrated production of market‐ready sugarcane‐derived products, such as animal feed, industrial salts, and hydrocarbons in existing Brazilian plants. Finally, the study outlines the prospects for future integration of non‐traditional process alternatives in sugarcane mills, namely bioplastics, organic acids, molecular hydrogen, and advanced lignocellulosic compounds. © 2019 Society of Chemical Industry and John Wiley & Sons, Ltd.
Efficacy of adjuvant radiotherapy for atypical and anaplastic meningioma
Authors: Zhu Hongda , Bi Wenya Linda , Aizer Ayal , Hua Lingyang , Tian Mi , Den Jiaojiao , Tang Hailiang , Chen Hong , Wang Yin , Mao Ying , Dunn Ian F. , Xie Qing , Gong Ye
Published: January 2019

The effect of adjuvant radiotherapy in management for high‐grade meningiomas, especially atypical meningiomas, remains controversial. We aimed to explore the role of adjuvant radiotherapy in this population. A total of 162 adults with high‐grade meningiomas (99 atypical meningiomas and 63 anaplastic meningiomas) were treated from 2003 to 2008 at Huashan Hospital. One hundred and seventeen patients presented with primary and 45 with recurrent disease. One hundred and fifteen patients (70.9%) were treated with adjuvant radiotherapy after surgical resection. The median follow‐up was 76.5 months (range 1‐142 months). Kaplan‐Meier survival curve and Cox proportional hazards modeling were used for analyses. Adjuvant radiotherapy was associated with prolonged progression‐free survival (PFS) and overall survival (OS) in patients with newly diagnosed anaplastic meningiomas irrespective of extent of resection (PFS, P = .001; OS, P = .003). Gross total resection was the only independent prognostic factor for those with newly diagnosed atypical meningiomas (PFS, P < .001; OS, P = .012). A survival benefit for adjuvant radiation was also found in subgroup analysis of patients with high‐grade meningiomas who underwent subtotal resection (PFS, P = .023; OS, P = .013). Among recurrent high‐grade meningiomas, radiotherapy offered no statistically significant improvement in either PFS or OS. Adjuvant radiotherapy is associated with improved survival in patients with newly diagnosed anaplastic meningiomas and those high‐grade meningiomas following subtotal resection. However, there was no significant correlation identified between postoperative radiation and outcome for recurrent high‐grade meningiomas. Future prospective randomized trials may help clarify the optimal tailored treatment for patients with high‐grade meningioma.
Elevated serum HER‐2 predicts poor prognosis in breast cancer and is correlated to ADAM10 expression
Authors: Zheng Hui , Zhong Ailing , Xie Suhong , Wang Yanchun , Sun Jiajun , Zhang Jie , Tong Ying , Chen Miaomiao , Zhang Guihong , Ma Qian , Kai Jinyan , Guo Lin , Lu Renquan
Published: January 2019

Human epidermal growth factor receptor‐2 (HER‐2) overexpression in breast tumor tissues is associated with a poor prognosis but may benefit from treatment with trastuzumab. The extracellular domain (ECD) of HER‐2 can be measured in serum and which has been a new inspection item in clinical laboratory of several hospitals. However, whether serum HER‐2 ECD can be a marker of HER‐2 status in tumor tissues still confused clinicians. This study is a retrospective observation to explore the correlation between serum HER‐2 ECD shedding and tissue HER‐2 status in breast cancer patients. Meanwhile, we will further uncover the potential clinical significance of serum HER‐2 ECD detection. A total of 545 unselected breast cancer patients from Fudan University Shanghai Cancer Center were enrolled in this study. At primary diagnosis without any treatment, serum HER‐2 ECD was measured on ADVIA Centaur assay; meanwhile, tissue HER‐2 from core needle biopsy was tested through immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). We showed that serum HER‐2 ECD concentration was related to tissue HER‐2 status. Nevertheless, 36.9% of patients with tissue HER‐2 overexpression had low levels of HER‐2 ECD shedding (<15 ng/mL) in serum. Here, we demonstrated that HER‐2 ECD shedding was also associated with protein expression and alpha‐secretase activity of a disintegrin and metalloproteinase 10 (ADAM10) using tumor tissues and cell lines. Progression‐free survival (PFS) data from breast cancer patients in TNM phase II and III with tissue HER‐2 IHC 3+ were analyzed using Kaplan‐Meier plotter. The patients with serum HER‐2 ECD above 15 ng/mL had lower progression‐free survival than those with serum HER‐2 ECD <15 ng/mL. Thus, serum HER‐2 ECD could be a biomarker to identify the subgroup of poorer outcome among HER‐2 overexpression breast cancer patients. Inhibition of ADAM10 activity may have potential therapeutic benefit for this most aggressive tumor subgroup.
Role of promoters and catalyst supports for selective synthesis of higher alcohols over molybdenum carbides
Authors: Aslam Waqas , Beltramini Jorge , Atanda Luqman , Rashidi Masih , Konarova Muxina
Published: January 2019

The synthesis of higher alcohols from syngas is a very promising avenue as syngas can be derived from renewable (biomass) and non‐renewable feedstock (coal, natural gas). To date no commercial process exists for the conversion of syngas into higher alcohols due to poor alcohols yield and selectivity. The search for selective catalysts requires fundamental insight into how to enhance active sites for the formation of alcohols. In the present work, the dispersion of K2CO3 promoted molybdenum carbides over three different supports i.e., highly acidic (ɣ‐alumina), neutral (activated carbon), and basic (magnesium oxide) has been studied. The results revealed that acid sites of ɣ‐alumina expedited the dispersion of the K2CO3 promoter over the molybdenum carbide catalyst and facilitated carbon monoxide dissociation to form C2+ alcohols. The effect of the incorporation of cobalt into the textural and catalytic properties of alumina supported K‐Mo2C was also investigated. The elemental mapping of Co into the K‐Mo2C structure showed the presence of segregated Co and Mo2C islands, but an interaction was observed at the molecular level, resulting in a different H2 temperature‐programmed desorption pattern. With the decreased availability of surface adsorbed hydrogen of the Co promoted K‐Mo2C/Al2O3, the concentration of methanol was significantly reduced and the product selectivity shifted more towards higher alcohols.
High‐risk HPV and neuroendocrine carcinomas of the head and neck
Authors: Faquin William C.
Published: January 2019

Over the past 20 years, a subset of head and neck cancers associated with transcriptionally active high‐risk human papillomavirus has been recognized, a majority of which are squamous cell carcinomas originating in the oropharynx. Two original articles published in this issue of Cancer Cytopathology describe the clinical and cytologic features of human papillomavirus–positive neuroendocrine carcinomas of the head and neck.
Cryptococcus neoformans Mating and Genetic Crosses
Authors: Sun Sheng , Priest Shelby J. , Heitman Joseph
Published: January 2019

The Cryptococcus pathogenic species complex is a group of opportunistic human fungal pathogens that cause cryptococcal meningoencephalitis, an infection associated with unacceptably high mortality rates. The public health relevance of these pathogens has galvanized extensive research over the past several decades and led to characterization of their sexual cycles. This research has allowed several Cryptococcus species to develop into model fungal organisms for both pathogenesis and basic science studies. Many of these studies require observation of the meiotic process and its associated mating structures as well as generation of meiotic progeny with novel phenotypes and genotypes. Herein, we describe how to set up genetic crosses between Cryptococcus strains and observe their mating phenotypes as well as how to recover progeny from these crosses for further analysis. © 2019 by John Wiley & Sons, Inc.
Relationship Between Benralizumab Exposure and Efficacy for Patients With Severe Eosinophilic Asthma
Authors: Chia Yen Lin , Yan Li , Yu Binbing , Wang Bing , Barker Peter , Goldman Mitchell , Roskos Lorin
Published: January 2019

We evaluated the relationship between benralizumab (30 mg every 4 and 8 weeks (Q4W, Q8W)) pharmacokinetic (PK) exposure and end points of asthma exacerbation rates (AERs) and change from baseline in prebronchodilator forced expiratory volume in 1 second (FEV1) for patients with severe, uncontrolled eosinophilic asthma in the SIROCCO/CALIMA phase III trials. In empirical assessment, AER ratios in SIROCCO were similar across PK quartiles. However, the lowest PK quartile in CALIMA had reduced efficacy; low CALIMA placebo AER possibly confounded this result. In population modeling, estimated benralizumab 90% effective concentration for AER reduction was 927 ng/mL, below the Q8W dosage steady‐state average PK concentration (1,066 ng/mL). Benralizumab treatment resulted in more rapid FEV1 improvement vs. placebo (estimated half‐maximum time: 7.6 vs. 18 days); this response was greater for patients with greater baseline eosinophil counts. These results confirmed 30 mg Q8W is the optimal benralizumab dosage for patients with severe eosinophilic asthma.
Demonstrating Heterogeneity of Treatment Effects Among Patients: An Overlooked but Important Step Toward Precision Medicine
Authors: Gewandter Jennifer S. , McDermott Michael P. , He Hua , Gao Shan , Cai Xueya , Farrar John T. , Katz Nathaniel P. , Markman John D. , Senn Stephen , Turk Dennis C. , Dworkin Robert H.
Published: January 2019

Although heterogeneity in the observed outcomes in clinical trials is often assumed to reflect a true heterogeneous response, it could actually be due to random variability. This retrospective analysis of four randomized, double‐blind, placebo‐controlled multiperiod (i.e., episode) crossover trials of fentanyl for breakthrough cancer pain illustrates the use of multiperiod crossover trials to examine heterogeneity of treatment response. A mixed‐effects model, including fixed effects for treatment and episode and random effects for patient and treatment‐by‐patient interaction, was used to assess the heterogeneity in patients’ responses to treatment during each episode. A significant treatment‐by‐patient interaction was found for three of four trials (P < 0.05), suggesting heterogeneity of the effect of fentanyl among different patients in each trial. Similar analyses in other therapeutic areas could identify conditions and therapies that should be investigated further for predictors of treatment response in efforts to maximize the efficiency of developing precision medicine strategies.
Progress of Pharmacological Approaches in Parkinson's Disease
Authors: Zeuner Kirsten E. , Schäffer Eva , Hopfner Franziska , Brüggemann Norbert , Berg Daniela
Published: January 2019

The progressive neurodegenerative process in Parkinson's disease (PD) is not restricted to dopaminergic midbrain neurons but involves the entire nervous system. In this review, we outline established treatment options at different disease stages and address new therapeutic approaches. These include, based on recent advances in the understanding of the pathophysiology of PD, genetic and disease‐modifying approaches to reduce abnormal accumulation and aggregation of alpha‐synuclein (aSYN), mitochondrial dysfunction, and dysfunction of lysosomal proteins. Moreover, we highlight clinical trials to reduce neuroinflammation and increase neurorestoration.
Drug‐Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles
Authors: Nicoletti Paola , Aithal Guruprasad P. , Chamberlain Thomas C. , Coulthard Sally , Alshabeeb Mohammad , Grove Jane I. , Andrade Raul J. , Bjornsson Einar , Dillon John F. , Hallberg Par , Lucena M. Isabel , Maitland‐van der Zee Anke H. , Martin Jennifer H. , Molokhia Mariam , Pirmohamed Munir , Wadelius Mia , Shen Yufeng , Nelson Matthew R. , Daly Ann K. ,   the International Drug‐Induced Liver Injury Consortium (iDILIC)
Published: January 2019

Some patients prescribed flucloxacillin (~ 0.01%) develop drug‐induced liver injury (DILI). HLA‐B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single‐nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA‐B*57:01 was the major risk factor (allelic odds ratio (OR) = 36.62; P = 2.67 × 10−97). HLA‐B*57:03 also showed an association (OR = 79.21; P = 1.2 × 10−6). Within the HLA‐B protein sequence, imputation showed valine97, common to HLA‐B*57:01 and HLA‐B*57:03, had the largest effect (OR = 38.1; P = 9.7 × 10−97). We found no HLA‐B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non‐HLA signals for any penicillin‐related DILI.
A journey on plate tectonics sheds light on European crayfish phylogeography
Authors: Pârvulescu Lucian , Pérez‐Moreno Jorge L. , Panaiotu Cristian , Drăguț Lucian , Schrimpf Anne , Popovici Ioana‐Diana , Zaharia Claudia , Weiperth András , Gál Blanka , Schubart Christoph D. , Bracken‐Grissom Heather
Published: January 2019

Crayfish can be used as model organisms in phylogeographic and divergence time studies if reliable calibrations are available. This study presents a comprehensive investigation into the phylogeography of the European stone crayfish (Austropotamobius torrentium) and includes samples from previously unstudied sites. Two mitochondrial markers were used to reveal evolutionary relationships among haplogroups throughout the species’ distributional range and to estimate the divergence time by employing both substitution rates and geological calibration methods. Our haplotype network reconstruction and phylogenetic analyses revealed the existence of a previously unknown haplogroup distributed in Romania's Apuseni Mountains. This haplogroup is closely related to others that are endemic in the Dinarides, despite their vast geographical separation (~600 km). The separation is best explained by the well‐dated tectonic displacement of the Tisza–Dacia microplate, which started in the Miocene (~16 Ma) and possibly carried part of the A. torrentium population to the current location of the Apuseni Mountains. This population may thus have been isolated from the Dinarides for a period of ca. 11 m.y. by marine and lacustrine phases of the Pannonian Basin. The inclusion of this geological event as a calibration point in divergence time analyses challenges currently accepted crayfish evolutionary time frames for the region, constraining the evolution of this area's crayfish to a much earlier date. We discuss why molecular clock calibrations previously employed to date European crayfish species divergences should therefore be reconsidered.
Toward reliable population density estimates of partially marked populations using spatially explicit mark–resight methods
Authors: Carter Andrew , Potts Joanne M. , Roshier David A.
Published: January 2019

Camera traps are used increasingly to estimate population density for elusive and difficult to observe species. A standard practice for mammalian surveys is to place cameras on roads, trails, and paths to maximize detections and/or increase efficiency in the field. However, for many species it is unclear whether track‐based camera surveys provide reliable estimates of population density.

Understanding how the spatial arrangement of camera traps affects population density estimates is of key interest to contemporary conservationists and managers given the rapid increase in camera‐based wildlife surveys.

We evaluated the effect of camera‐trap placement, using several survey designs, on density estimates of a widespread mesopredator, the red foxVulpes vulpes, over a two‐year period in a semi‐arid conservation reserve in south‐eastern Australia. Further, we used the certainty in the identity and whereabouts of individuals (via GPS collars) to assess how resighting rates of marked foxes affect density estimates using maximum likelihood spatially explicit mark–resight methods.

Fox detection rates were much higher at cameras placed on tracks compared with off‐track cameras, yet in the majority of sessions, camera placement had relatively little effect on point estimates of density. However, for each survey design, the precision of density estimates varied considerably across sessions, influenced heavily by the absolute number of marked foxes detected, the number of times marked foxes was resighted, and the number of detection events of unmarked foxes.

Our research demonstrates that the precision of population density estimates using spatially explicit mark–resight models is sensitive to resighting rates of identifiable individuals. Nonetheless, camera surveys based either on‐ or off‐track can provide reliable estimates of population density using spatially explicit mark–resight models. This underscores the importance of incorporating information on the spatial behavior of the subject species when planning camera‐trap surveys.
TLR signals license CD8 T cells to destroy oligodendrocytes expressing an antigen shared with a Listeria pathogen
Authors: Sánchez‐Ruiz Monica , Polakos Noelle Katherine , Blau Tobias , Utermöhlen Olaf , Brunn Anna , Montesinos‐Rongen Manuel , Hünig Thomas , Deckert Martina
Published: January 2019

Increasing evidence suggests a role of CD8 T cells in autoimmune demyelinating CNS disease, which, however, is still controversially discussed. Mice, which express ovalbumin (OVA) as cytosolic self‐antigen in oligodendrocytes (ODC‐OVA mice), respond to CNS infection induced by OVA‐expressing attenuated Listeria with CD8 T cell‐mediated inflammatory demyelination. This model is suitable to decipher the contribution of CD8 T cells and the pathogen in autoimmune CNS disease.

Here, we show that both antigen and pathogen are required in the CNS for disease induction, though not in a physically linked fashion. Intracerebral challenge with combined toll like receptor (TLR) TLR2 and TLR9 as well as TLR7 and TLR9 agonists substituted for the bacterial stimulus, but not with individual TLR agonists (TLR2, TLR3,TLR5,TLR7, TLR9). Furthermore, MyD88 inactivation rendered ODC‐OVA mice resistant to disease induction.

Collectively, CD8 T cell‐mediated destruction of oligodendrocytes is activated if (i) an antigen shared with an infectious agent is provided in the CNS microenvironment and (ii) innate immune signals inform the CNS microenvironment that pathogen removal warrants an immune attack by CD8 T cells, even at the expense of locally restricted demyelination.
A simple electrical approach to monitor dielectrophoretic focusing of particles flowing in a microchannel
Authors: Reale Riccardo , De Ninno Adele , Businaro Luca , Bisegna Paolo , Caselli Federica
Published: January 2019

This paper reports an impedance‐based system for the quantitative assessment of dielectrophoretic (DEP) focusing of single particles flowing in a microchannel. Particle lateral positions are detected in two electrical sensing zones placed before and after a DEP‐focusing region, respectively. In each sensing zone, particle lateral positions are estimated using the unbalance between the opposite pulses of a differential current signal obtained with a straightforward coplanar electrode configuration. The system is used to monitor the focusing of polystyrene beads of 7 or 10 μm diameter, under various conditions of DEP field intensities and flow rates that produce different degrees of focusing. This electrical approach represents a simple and valuable alternative to optical methods for monitoring of particle focusing systems.
Retracted: Design and Experiments of a Hybrid Wind Turbine Drive Train using both Hydraulic and Mechanical Transmissions
Authors: Gu Haigang , Li Wei , Lin Yonggang
Published: January 2019

Retraction: Gu, H., Li, W. and Lin, Y. (2019). Design and Experiments of a Hybrid Wind Turbine Drive Train using both Hydraulic and Mechanical Transmissions. Environmental Progress & Sustainable Energy. DOI: 10.1002/ep.13045

The above article, published online on 20 January 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, Haigang Gu, Wei Li, Yonggang Lin, the journal Editor‐in‐Chief, Professor Martin Abraham, the AIChE, and Wiley Periodicals, LLC. The retraction has been agreed as it was submitted by the submitting author, Xiuxing Yin, who is not listed as an author on the published version, without the consent of the authors listed on the article who were unaware of its submission.
Optimization of process parameters for methylene blue removal by jute stick using response surface methodology
Authors: Ghosh Rakesh Kumar , Ray Deb Prasad , Debnath Sanjoy , Tewari Avisek , Das Ipsita
Published: January 2019

In this study, jute stick (JS), the underexplored by‐product of jute (Corchorus olitorius) cultivation system, has been used as a novel low‐cost adsorbent to remove methylene blue (MB), a cationic dye, from an aqueous medium. Box–Behnken design matrix and response surface methodology (RSM) have been used to evaluate the effect of four important process factors namely, solution pH (3–11), adsorbent dose (0.5–5 g L−1), initial dye concentration (50–200 mg L−1), and time (60–180 min). JS was characterized by physico‐chemical parameters, pHzpc (zero‐point charge), FTIR for the functional groups and SEM–EDX for surface morphology. The direct and interaction effects of adsorption parameters were studied. The optimum values of pH, dose, initial concentration, and time for maximum % dye removal were 10.27, 5 (g L−1), 200 (mg L−1), and 66.06 min. Regeneration and recycling studies were also carried out. The present study indicated that JS, a bio‐waste of jute cultivation system, can be effectively utilized as an adsorbent to treat MB contaminated aqueous medium/ wastewater before environmental disposal. © 2019 American Institute of Chemical Engineers Environ Prog, 38:e13146, 2019
Efficacy of bergamot: From anti‐inflammatory and anti‐oxidative mechanisms to clinical applications as preventive agent for cardiovascular morbidity, skin diseases, and mood alterations
Authors: Perna Simone , Spadaccini Daniele , Botteri Leonardo , Girometta Carolina , Riva Antonella , Allegrini Pietro , Petrangolini Giovanna , Infantino Vittoria , Rondanelli Mariangela
Published: January 2019

We summarize the effects of bergamot (extract, juice, essential oil, and polyphenolic fraction) on cardiovascular, bone, inflammatory, skin diseases, mood alteration, anxiety, pain, and stress. This review included a total of 31 studies (20 studies on humans with 1709 subjects and 11 in animals (rats and mice)). In humans, bergamot‐derived extract (BE) exerts positive effects on hyperlipidemia with an oral dose from 150 mg to 1000 mg/day of flavonoids administered from 30 to 180 days, demonstrating an effect on body weight and in modulating total cholesterol, triglycerides, LDL, and HDL. Studies in animals confirm promising data on glucose control (500/1000 mg/day of BE with a treatment lasting 30 days) are available in rats. In animals models, bergamot essential oil (BEO, 10 mg/kg or 20 mg/kg daily for 20 weeks) increases bone volume, decreases psoriatic plaques, increases skin collagen content, and promotes hair growth. Bergamot juice (20 mg/kg) is promising in terms of pro‐inflammatory cytokine reduction. In humans, aromatherapy (from 15 to 30 min) does not appear to be useful in order to reduce stress, anxiety, and nausea, compared to placebo. Compared to baseline, BE topical application and BEO aromatherapy reduce blood diastolic and systolic pressure and could have a significant effect on improving mental conditions.
Recovery of high value‐added protein from enzyme‐assisted aqueous extraction (EAE) of soybeans by dead‐end ultrafiltration
Authors: Zhang Qiaozhi , Li Yang , Wang Zhongjiang , Qi Baokun , Sui Xiaonan , Jiang Lianzhou
Published: January 2019

The skim fraction (SF) obtained from enzyme‐assisted aqueous extraction (EAE) of soybeans is a by‐product with high protein content of up to 60.67%. As such, it is of great interest to develop an efficient method to recover protein from this fraction. In this study, the potential of dead‐end ultrafiltration (UF) in recovering skim protein extracted with different proteases was evaluated. Two polyethersulfone (PES) membranes with molecular weight cutoffs (MWCO) of 3 kDa and 5 kDa were utilized. Results revealed that the membrane with the MWCO of 5 kDa exhibited better filtration efficiency, since higher permeate flux values and lower impurity rejections were observed. Compared with Flavourzyme and Protex 7L, Alcalase 2.4L and Protex 6L exhibited stronger hydrolyzing ability, resulting in higher filtration fluxes but lower protein rejection coefficients. The recovered protein showed comparable amino acid profile to SPC, while with significantly reduced levels of trypsin inhibitors and phytate (p < 0.05), indicating high quality of the recovered protein. Overall, UF can be applicable to recover high value‐added protein from EAE of soybeans and remove undesired components from the resulting protein products.
The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS‐9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis
Authors: Trauner Michael , Gulamhusein Aliya , Hameed Bilal , Caldwell Stephen , Shiffman Mitchell L. , Landis Charles , Eksteen Bertus , Agarwal Kosh , Muir Andrew , Rushbrook Simon , Lu Xiaomin , Xu Jun , Chuang Jen‐Chieh , Billin Andrew N. , Li Georgia , Chung Chuhan , Subramanian G. Mani , Myers Robert P. , Bowlus Christopher L. , Kowdley Kris V.
Published: January 2019

Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double‐blind, placebo‐controlled study, we tested the safety and efficacy of cilofexor (formerly GS‐9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large‐duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) > 1.67 × upper limit of normal and total bilirubin ≤ 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7α‐hydroxy‐4‐cholesten‐3‐one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U/L (interquartile range 288‐439) and 0.7 mg/dL (0.5‐1.0), respectively. Dose‐dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction −21%; P = 0.029 versus placebo), gamma‐glutamyl transferase (−30%; P < 0.001), alanine aminotransferase (ALT) (−49%; P = 0.009), and aspartate aminotransferase (−42%; P = 0.019). Cilofexor reduced serum C4 compared with placebo; reductions in bile acids were greatest with 100 mg. Relative reductions in ALP were similar between ursodeoxycholic acid–treated and untreated patients. At week 12, cilofexor‐treated patients with a 25% or more relative reduction in ALP had greater reductions in serum alanine aminotransferase, aspartate aminotransferase, gamma‐glutamyl transferase, tissue inhibitor of metalloproteinase 1, C‐reactive protein, and bile acids than nonresponders. Adverse events were similar between cilofexor and placebo‐treated patients. Rates of grade 2 or 3 pruritus were 14% with 100 mg, 20% with 30 mg, and 40% with placebo. Conclusion: In this 12‐week, randomized, placebo‐controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries and markers of cholestasis in patients with PSC.
Lymphocyte Antigen 6 Complex, Locus C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice
Authors: Wu Li‐Ling , Peng Wei‐Hao , Wu Hui‐Lin , Miaw Shi‐Chuen , Yeh Shiou‐Hwei , Yang Hung‐Chih , Liao Pei‐Hsuan , Lin Jing‐Shan , Chen Yan‐Rong , Hong Yen‐Tien , Wang Hurng‐Yi , Chen Pei‐Jer , Chen Ding‐Shinn
Published: January 2019

To understand the mechanism(s) of age‐dependent outcomes of hepatitis B virus (HBV) infection in humans, we previously established an age‐related HBV mouse model in which 6‐week‐old (N6W) C3H/HeN mice exhibited virus tolerance whereas 12‐week‐old (N12W) counterparts presented virus clearance. By investigating the hepatic myeloid cell dynamics in mice of these two ages, we aim to identify factors associated with HBV clearance. C3H/HeN mice were transfected with an HBV plasmid by hydrodynamic injection. Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), day 7 (D7), and day 14 after injection. C‐C chemokine receptor type 2 (CCR2) antagonist and clodronate (CLD) were respectively administered to N12W and N6W mice to study the roles of lymphocyte antigen 6 complex, locus C (Ly6C)+ monocytes and Kupffer cells (KCs) in viral clearance. N12W mice had a significantly higher number of TNF‐α–secreting Ly6C+ monocytes and fewer IL‐10–secreting KCs at D3 in the liver than their younger N6W counterparts after HBV transfection. In addition, the elevated number of interferon‐γ+TNF‐α+ CD8+ T cells at D7 was only seen in the older cohort. The enhanced Ly6C+ monocyte induction in N12W mice resulted from elevated C‐C motif chemokine ligand 2 (CCL2) secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C+ monocyte recruitment and degree of KC reduction and delayed HBV clearance in N12W animals. Depletion of KCs by CLD liposomes enhanced Ly6C+ monocyte recruitment and accelerated HBV clearance in N6W mice. Conclusions: Ly6C+ monocytes and KCs may, respectively, represent the resistance and tolerance arms of host defenses. These two cell types play an essential role in determining HBV clearance/tolerance. Manipulation of these cells is a promising avenue for immunotherapy of HBV‐related liver diseases.
Delayed diagnosis of intraperitoneal bladder perforation after blunt trauma
Authors: Wang Lu , Ogawa Soichiro , Onagi Akifumi , Tanji Ryo , Honda Ruriko , Matsuoka Kanako , Hoshi Seiji , Koguchi Tomoyuki , Kurimura Yoshimasa , Onoda Mitsutaka , Hata Junya , Yabe Michihiro , Sato Yuichi , Akaihata Hidenori , Kataoka Masao , Haga Nobuhiro , Ishibashi Kei , Kojima Yoshiyuki
Published: January 2019

Introduction

Intraperitoneal urinary bladder perforation due to blunt trauma in intoxicated patients requires quick and accurate diagnosis. However, this is difficult to correctly diagnose in intoxicated patients because their symptoms can be masked. We describe a rare case of intraperitoneal urinary bladder perforation that occurred after blunt trauma.

Case presentation

A 66‐year‐old intoxicated man stumbled, tripped on a stone step and landed on his lower abdomen, but felt no pain at the time. Two days later, he was diagnosed with intraperitoneal urinary bladder perforation, which was repaired by open surgery.

Conclusion

Urinary bladder perforation should be considered when patients present with abdominal pain and decrease in urine volume following trauma.
Report of the AAPM TG‐256 on the relative biological effectiveness of proton beams in radiation therapy
Authors: Paganetti Harald , Blakely Eleanor , Carabe‐Fernandez Alejandro , Carlson David J. , Das Indra J. , Dong Lei , Grosshans David , Held Kathryn D. , Mohan Radhe , Moiseenko Vitali , Niemierko Andrzej , Stewart Robert D. , Willers Henning
Published: January 2019

The biological effectiveness of proton beams relative to photon beams in radiation therapy has been taken to be 1.1 throughout the history of proton therapy. While potentially appropriate as an average value, actual relative biological effectiveness (RBE) values may differ. This Task Group report outlines the basic concepts of RBE as well as the biophysical interpretation and mathematical concepts. The current knowledge on RBE variations is reviewed and discussed in the context of the current clinical use of RBE and the clinical relevance of RBE variations (with respect to physical as well as biological parameters).

The following task group aims were designed to guide the current clinical practice:

Assess whether the current clinical practice of using a constant RBE for protons should be revised or maintained.

Identifying sites and treatment strategies where variable RBE might be utilized for a clinical benefit.

Assess the potential clinical consequences of delivering biologically weighted proton doses based on variable RBE and/or LET models implemented in treatment planning systems.

Recommend experiments needed to improve our current understanding of the relationships among in vitro, in vivo, and clinical RBE, and the research required to develop models. Develop recommendations to minimize the effects of uncertainties associated with proton RBE for well‐defined tumor types and critical structures.
Multi‐domain features for reducing false positives in automated detection of clustered microcalcifications in digital breast tomosynthesis
Authors: Zhang Fan , Wu Shandong , Zhang Cheng , Chen Qian , Yang Xiaodong , Jiang Ke , Zheng Jian
Published: January 2019

Purpose

In digital breast tomosynthesis (DBT) imaging, a microcalcification (MC) cluster may span across different slices and blurring exists in the out‐of‐focus slices. We developed a radiomics approach to extract features from focus slice and combine multiple spatial domains to reduce false positives (FPs) in an automated pipeline of detecting MC clusters.

Methods

We performed a retrospective study on a cohort of 290 Chinese women patients with a total of 580 DBT volumes. We developed an automated MC detection pipeline that consists of two stages: an initial detection to identify a set of MC candidates that may include many FPs, followed by a radiomics‐based classification model to identify and reduce the FPs. We extract both two‐dimensional (2D) and three‐dimensional (3D) radiomics features from multiple spatial domains, including a focus slice, projection image, and tomographic volume. A linear discriminant classifier was used coupled with a sequential forward feature selection procedure. The free‐response operating characteristics (FROC) curve and partial area under the FROC curve (pAUC) in the FP rate range of 0 to 2 per DBT volume were used to evaluate the model's performance.

Results

At a sensitivity of 90%, the FP rate was reduced from 1.3 to 0.2 per DBT volume after applying the multi‐domain‐based classification on the initial detections. The multi‐domain yielded a significantly higher pAUC compared to the initial detection (increase of pAUC = 0.2278, P < 0.0001), focus slice (increase of pAUC = 0.0345, P = 0.0152), project image (increase of pAUC = 0.1043, P < 0.0001), and tomographic volume (increase of pAUC = 0.0791, P = 0.0032).

Conclusion

The radiomic features extracted from the three domains may provide complementary information and their integration can significantly reduce FPs in automated detection of MCs in DBT volumes on a large Chinese women population.
Improved synthesis on solid phase of dithiocarbamic cRGD‐derivative and 99mTc‐radiolabelling
Authors: Caporale Andrea , Bolzati Cristina , Incisivo Giuseppina Maria , Salvarese Nicola , Grieco Paolo , Ruvo Menotti
Published: January 2019

In the field of angiogenesis, small cyclic pentapeptides containing the RGD motif are playing a relevant role for their high affinity and specificity for integrin receptors and for the possibility to act at both therapeutic and diagnostic level by inhibiting pathological angiogenesis and by serving as shuttles to deliver imaging‐probe including SPECT/PET radionuclides to specific tissues.

In the last decade, several new protocols were reported in literature for the direct synthesis of cyclic RDG either in solution or by SPPS. Here, we have elaborated and tested some alternative approaches using different resins and different protective groups. The introduction of the dithiocarbamate function, useful to complex radio‐metals suitable for nuclear medicine applications, has also been considered and achieved.