bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrogenotrophic Methanogenesis Under Alkaline Conditions
Authors: Wormald Richard M. , Rout Simon P. , Mayes William , Gomes Helena , Humphreys Paul N.
Published: December 2020

A cement-based geological disposal facility (GDF) is one potential option for the disposal of intermediate level radioactive wastes. The presence of both organic and metallic materials within a GDF provides the opportunity for both acetoclastic and hydrogenotrophic methanogenesis. However, for these processes to proceed, they need to adapt to the alkaline environment generated by the cementitious materials employed in backfilling and construction. Within the present study, a range of alkaline and neutral pH sediments were investigated to determine the upper pH limit and the preferred route of methane generation. In all cases, the acetoclastic route did not proceed above pH 9.0, and the hydrogenotrophic route dominated methane generation under alkaline conditions. In some alkaline sediments, acetate metabolism was coupled to hydrogenotrophic methanogenesis via syntrophic acetate oxidation, which was confirmed through inhibition studies employing fluoromethane. The absence of acetoclastic methanogenesis at alkaline pH values (>pH 9.0) is attributed to the dominance of the acetate anion over the uncharged, undissociated acid. Under these conditions, acetoclastic methanogens require an active transport system to access their substrate. The data indicate that hydrogenotrophic methanogenesis is the dominant methanogenic pathway under alkaline conditions (>pH 9.0).
Deficiency of Mitochondrial Functions and Peroxidation of Frontoparietal Cortex Enhance Isoflurane Sensitivity in Aging Mice
Authors: Gong Cansheng , Zhang Donghang , Ou Wei , Ou Mengchan , Liang Peng , Liao Daqing , Zhang Weiyi , Zhu Tao , Liu Jin , Zhou Cheng
Published: December 2020

Background: Hypersensitivity to general anesthetics may predict poor postoperative outcomes, especially among the older subjects. Therefore, it is essential to elucidate the mechanism underlying hypersensitivity to volatile anesthetics in the aging population. Given the fact that isoflurane sensitivity increases with aging, we hypothesized that deficiencies of mitochondrial function and elevated oxidative levels in the frontoparietal cortex may contribute to the enhanced sensitivity to isoflurane in aging mice.

Methods: Isoflurane sensitivity in aging mice was determined by the concentration of isoflurane that is required for loss of righting reflex (LORR). Mitochondrial bioenergetics of the frontoparietal cortex was measured using a Seahorse XFp analyzer. Protein oxidation and lipid oxidation in the frontoparietal cortex were assessed using the Oxyblot protein oxidation detection kit and thiobarbituric acid reactive substance (TBARS) assay, respectively. Contributions of mitochondrial complex II inhibition by malonate and peroxidation by ozone to isoflurane sensitivity were tested in vivo. Besides, effects of antioxidative therapy on mitochondrial function and isoflurane sensitivity in mice were also measured.

Results: The mean concentration of isoflurane that is required for LORR in aging mice (14–16 months old) was 0.83% ± 0.13% (mean ± SD, n = 80). Then, the mice were divided into three groups as sensitive group (S group, mean − SD), medium group (M group), and resistant group (R group, mean + SD) based on individual concentrations of isoflurane required for LORR. Activities of mitochondrial complex II and complex IV in mice of the S group were significantly lower than those of the R group, while frontoparietal cortical malondialdehyde (MDA) levels were higher in the mice of S group. Both inhibition of mitochondrial complexes and peroxidation significantly decreased the concentration of isoflurane that is required for LORR in vivo. After treatment with idebenone, the levels of lipid oxidation were alleviated and mitochondrial function was restored in aging mice. The concentration of isoflurane that required for LORR was also elevated after idebenone treatment.

Conclusions: Decreased mitochondrial functions and higher oxidative stress levels in the frontoparietal cortex may contribute to the hypersensitivity to isoflurane in aging mice.
Regional Gray Matter Volume Identifies High Risk of Unsafe Driving in Healthy Older People
Authors: Yamamoto Yasuharu , Yamagata Bun , Hirano Jinichi , Ueda Ryo , Yoshitake Hiroshi , Negishi Kazuno , Yamagishi Mika , Kimura Mariko , Kamiya Kei , Shino Motoki , Mimura Masaru
Published: December 2020

In developed countries, the number of traffic accidents caused by older drivers is increasing. Approximately half of the older drivers who cause fatal accidents are cognitively normal. Thus, it is important to identify older drivers who are cognitively normal but at high risk of causing fatal traffic accidents. However, no standardized method for assessing the driving ability of older drivers has been established. We aimed to establish an objective assessment of driving ability and to clarify the neural basis of unsafe driving in healthy older people. We enrolled 32 healthy older individuals aged over 65 years and classified unsafe drivers using an on-road driving test. We then utilized a machine learning approach to distinguish unsafe drivers from safe drivers based on clinical features and gray matter volume data. Twenty-one participants were classified as safe drivers and 11 participants as unsafe drivers. A linear support vector machine classifier successfully distinguished unsafe drivers from safe drivers with 87.5% accuracy (sensitivity of 63.6% and specificity of 100%). Five parameters (age and gray matter volume in four cortical regions, including the left superior part of the precentral sulcus, the left sulcus intermedius primus [of Jensen], the right orbital part of the inferior frontal gyrus, and the right superior frontal sulcus), were consistently selected as features for the final classification model. Our findings indicate that the cortical regions implicated in voluntary orienting of attention, decision making, and working memory may constitute the essential neural basis of driving behavior.
In situ Electron Microscopy of Complex Biological and Nanoscale Systems: Challenges and Opportunities
Authors: Han Zexiang , Porter Alexandra E.
Published: December 2020

In situ imaging for direct visualization is important for physical and biological sciences. Research endeavors into elucidating dynamic biological and nanoscale phenomena frequently necessitate in situ and time-resolved imaging. In situ liquid cell electron microscopy (LC-EM) can overcome certain limitations of conventional electron microscopies and offer great promise. This review aims to examine the status-quo and practical challenges of in situ LC-EM and its applications, and to offer insights into a novel correlative technique termed microfluidic liquid cell electron microscopy. We conclude by suggesting a few research ideas adopting microfluidic LC-EM for in situ imaging of biological and nanoscale systems.
The Monarch Butterfly as a Model for Understanding the Role of Environmental Sensory Cues in Long-Distance Migratory Phenomena
Authors: Guerra Patrick A.
Published: December 2020

The awe-inspiring annual migration of monarch butterflies (Danaus plexippus) is an iconic example of long-distance migratory phenomena in which environmental sensory cues help drive successful migration. In this mini-review article, I begin by describing how studies on monarch migration can provide us with generalizable information on how sensory cues can mediate key aspects of animal movement. I describe how environmental sensory cues can trigger the development and progression of the monarch migration, as well as inform sensory-based movement mechanisms in order to travel to and reach their goal destination, despite monarchs being on their maiden voyage. I also describe how sensory cues can trigger season-appropriate changes in migratory direction during the annual cycle. I conclude this mini-review article by discussing how contemporary environmental challenges threaten the persistence of the monarch migration. Environmental challenges such as climate change and shifting land use can significantly alter the sensory environments that monarchs migrate through, as well as degrade or eliminate the sources of sensory cues that are necessary for successful migration.
Monitoring Astrocytic Ca2+ Activity in Freely Behaving Mice
Authors: Qin Han , He Wenjing , Yang Chuanyan , Li Jin , Jian Tingliang , Liang Shanshan , Chen Tunan , Feng Hua , Chen Xiaowei , Liao Xiang , Zhang Kuan
Published: December 2020

Monitoring astrocytic Ca2+ activity is essential to understand the physiological and pathological roles of astrocytes in the brain. However, previous commonly used methods for studying astrocytic Ca2+ activities can be applied in only anesthetized or head-fixed animals, which significantly affects in vivo astrocytic Ca2+ dynamics. In the current study, we combined optic fiber recordings with genetically encoded Ca2+ indicators (GECIs) to monitor astrocytic activity in freely behaving mice. This approach enabled selective and reliable measurement of astrocytic Ca2+ activity, which was verified by the astrocyte-specific labeling of GECIs and few movement artifacts. Additionally, astrocytic Ca2+ activities induced by locomotion or footshock were stably recorded in the cortices and hippocampi of freely behaving mice. Furthermore, this method allowed for the longitudinal study of astrocytic activities over several weeks. This work provides a powerful approach to record astrocytic activity selectively, stably, and chronically in freely behaving mice.
The Pain–to–Well-Being Relationship in Patients Experiencing Chronic Orofacial Pain
Authors: Bhalang Kanokporn , Steiger Beat , Lukic Nenad , Zumbrunn Wojczyńska Aleksandra , Hovijitra Ray S. , Ettlin Dominik A.
Published: December 2020

Introduction: Orofacial pain features may negatively influence a person's well-being and vice versa. Some aspects of well-being can be measured with axis II instruments that assess patients' psychosocial and behavioral status. The aim of this study was to investigate associations between pain features and psychosocial variables as indicators of well-being.

Materials and Methods: Seven hundred ninety-nine anonymized datasets collected using the Web-based Interdisciplinary Symptom Evaluation (WISE) of patients reporting to the Interdisciplinary Orofacial Pain Unit, University of Zurich, between March 19, 2017 and May 19, 2019, were analyzed. Pain features including intensity, number of locations, impact, and duration were evaluated. Psychometric measures assessed pain-related catastrophizing and disability, illness perception, distress, anxiety, depression, injustice experience, dysmorphic concerns, and insomnia.

Results: Most patients were between 30 and 59 years old (58.3%), female (69.8%), working (66.0%), and experienced pain for more than 6 months (68.5%). Pain intensities were higher in women than men and higher in disabled than working patients. Scores indicating elevated stress and depression were also observed in disabled patients. The sample prevalence rates of clinically relevant axis II instrument scores were as follows: Graded Chronic Pain Scale for the Head (GCPS-H), 27%; Patient Health Questionnaire 4 (PHQ4), 21%; PHQ9, 21%; Pain Catastrophizing Scale (PCS), 20%; General Anxiety Disorder 7 (GAD7), 15%; Insomnia Severity Index (ISI), 15%; Injustice Experience Questionnaire (IEQ), 14%; GCPS for the Body (GCPS-B), 13%; PHQ for Stress (PHQstr), 6%; and Dysmorphic Concern Questionnaire (DCQ), 2%. Noteworthy results of correlation analysis of the clinically relevant axis II scores and pain measures were as follows: the PHQstr had moderate associations (0.34–0.43) with the sum of pain intensity at rest and during function, number of pain locations, and typical pain intensity. The IEQ scores were moderately associated with typical pain intensity at 0.39. The DCQ scores were moderately associated with pain extension at 0.41.

Conclusions: Moderate correlations of certain pain and well-being measures were found in patients reporting clinically relevant stress, injustice experience, and dysmorphic concern, all of which reflect impaired well-being. PHQ4 is suitable for routine distress screening in the clinical setting.
Patient Preference for Antiepileptic Drugs Treatment in China: Evidence From the Discrete Choice Experiment
Authors: Hua Yingjie , Zhu Zhenguo , Li Xueying , Gong Jiaoni , Ding Siqi , Lin Jiahe , Wang Xinshi , Du Yanru , Xia Niange , Zheng Rongyuan , Xu Huiqin
Published: December 2020

Objective: Explore Chinese patients' risk-benefit preferences and willingness-to-pay (WTP) for antiepileptic drugs (AEDs) treatment through the discrete choice experiment (DCE).

Method: Six attributes including the efficacy of AEDs, adverse reactions (digestive system, neuropsychic systems, and the effects on the fetus), dosing frequency and drug costs (to estimate patient WTP) were included in the DCE questionnaire based on results collected from literature reviews, expert consultation, and patient survey. The alternative-specific conditional logit model was used to analyze patient preference and WTP for each attribute and its level and to assess the sociodemographic impact and clinical characteristics.

Results: A total of 151 valid questionnaires were collected. The result shows that five out of the six attributes are significant, except the dosing frequency. Among the six attributes, the efficacy of AEDs (10.0; 95% CI 8.9–11.1) is mostly concerned by patients, followed by the effects of AEDs on the fetus (8.9; 95% CI 7.7–10.1), duration of side effects in the neuropsychic system (4.9; 95% CI 3.7–6.0) and adverse reactions of the digestive system (3.2; 95% CI 1.5–4.2). The patients surveyed are willing to spend ¥ 1,246 (95% CI, ¥ 632- ¥ 1,861) per month to ensure 100% seizure control, and ¥ 1,112 (95% CI, ¥ 586–¥ 1,658) to reduce the risk of the drug affecting the fetus to 3%. Besides, it was found that personal characteristics including the intention for conception and AEDs treatment regimens have statistical significance.

Conclusion: Improving the drug's efficacy and reducing its side effects are predominant considerations for patients with epilepsy in China, especially for those who are concerned about the seizure control and the drug effect on the fetus. This finding is useful to physicians and can encourage shared decision-making between the patients and their doctors in the clinic.
Effects of Computerized Updating and Inhibition Training in Older Adults: The ACTOP Three-Arm Randomized Double-Blind Controlled Trial
Authors: Boujut Arnaud , Verty Lynn Valeyry , Maltezos Samantha , Lussier Maxime , Mellah Samira , Bherer Louis , Belleville Sylvie
Published: December 2020

Background: Working memory (WM) capacity declines with advancing age, which impacts the ability to carry out complex cognitive activities in everyday life. Updating and inhibition processes have been identified as some of the most critical attentional control processes of WM and are linked to age-related WM decline. The general aim of the Attentional Control Training in Older People (ACTOP) study was to perform a side-by-side comparison of updating and inhibition training to examine their respective efficacy and transfer in cognitively healthy older adults.

Method: The study was a three-arm, double-blind, randomized controlled trial registered with the US National Institutes of Health clinical trials registry. Ninety older adults were randomly assigned to 12 half-hour sessions of updating (N-back type exercises), inhibition (Stroop-like exercises) computerized training or active control (general knowledge quiz game). A group of thirty younger adults completed all proximal and WM transfer tasks without training to assess age-related deficits prior to training and whether training reduces these deficits.

Results: Piecewise mixed models show quick improvement of performance during training for both updating and inhibition training. During updating training, the progression was more pronounced for the most difficult (3-back) than for the least (1-back) difficult level until the ninth session. Updating and inhibition training groups improved performance on all proximal and WM transfer measures but these improvements did not differ from the active control group. Younger adults outperformed older ones on all transfer tasks prior to training. However, this was no longer the case following training for two transfer tasks regardless of the training group.

Conclusion: The overall results from this study suggest that attentional control training is effective in improving updating and inhibition performance on training tasks. The optimal dose to achieve efficacy is ~9 half-hour sessions and the dose effect was related to difficulty level for updating training. Despite an overall improvement of older adults on all transfer tasks, neither updating nor inhibition training provided additional improvements in comparison with the active control condition. This suggests that the efficacy of process-based training does not directly affect transfer tasks.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03532113
Uric Acid and Clinical Outcomes Among Intracerebral Hemorrhage Patients: Results From the China Stroke Center Alliance
Authors: Liu Xinmin , Cao Zhentang , Gu Hongqiu , Yang Kaixuan , Ji Ruijun , Li Zixiao , Zhao Xingquan , Wang Yongjun
Published: December 2020

Background and Purpose: The effect of uric acid (UA) levels on severity and prognosis of spontaneous intracerebral hemorrhage (ICH) remains controversial. We aimed to explore the association of admission UA levels with stroke severity and outcomes in ICH patients.

Materials and Methods: The patients enrolled in this study were from the China Stroke Center Alliance study (CSCA). Patients were divided into four groups (Q1–Q4) according to the quartiles of UA levels at admission. The primary outcome was in-hospital mortality. The secondary outcomes included stroke severity, in-hospital complications, and discharge disposition. Multivariate logistic regression was adopted to explore the association of UA levels with outcomes after ICH.

Results: Patients (84,304) with acute ICH were included in the final analysis; the median (interquartile range) of UA was 277 (210, 354) μmol/L. The four groups were defined as follows: Q1 ≤ 210 μmol/L, 210 μmol/L < Q2 ≤ 277 μmol/L, 277 μmol/L < Q3 ≤ 354 μmol/L, Q4 > 354 μmol/L. There was no significant evidence indicating that UA levels were correlated with the discharge disposition and in-hospital mortality after ICH. However, compared to Q1, the patients with higher UA levels had decreased odds of severe stroke (NIHSS ≥ 16) at admission (OR 0.89, 95% CI 0.86–0.92). An L-shaped association was found between UA and severe stroke. Among in-hospital complications, decrease in pneumonia, poor swallow function, gastrointestinal bleeding, and deep vein thrombosis (DVT) were significantly associated with higher UA levels compared to Q1 (P for trend < 0.0001).

Conclusions: UA was a protective factor for stroke severity and in-hospital complications such as pneumonia, poor swallow function, gastrointestinal bleeding, and DVT. However, no significant evidence indicated that UA levels were predictive of the discharge disposition and in-hospital mortality after ICH.
Picking Your Brains: Where and How Neuroscience Tools Can Enhance Marketing Research
Authors: Alvino Letizia , Pavone Luigi , Abhishta Abhishta , Robben Henry
Published: December 2020

The use of neuroscience tools to study consumer behavior and the decision making process in marketing has improved our understanding of cognitive, neuronal, and emotional mechanisms related to marketing-relevant behavior. However, knowledge about neuroscience tools that are used in consumer neuroscience research is scattered. In this article, we present the results of a literature review that aims to provide an overview of the available consumer neuroscience tools and classifies them according to their characteristics. We analyse a total of 219 full-texts in the area of consumer neuroscience. Our findings suggest that there are seven tools that are currently used in consumer neuroscience research. In particular, electroencephalography (EEG) and eye tracking (ET) are the most commonly used tools in the field. We also find that consumer neuroscience tools are used to study consumer preferences and behaviors in different marketing domains such as advertising, branding, online experience, pricing, product development and product experience. Finally, we identify two ready-to-use platforms, namely iMotions and GRAIL that can help in integrating the measurements of different consumer neuroscience tools simultaneously. Measuring brain activity and physiological responses on a common platform could help by (1) reducing time and costs for experiments and (2) linking cognitive and emotional aspects with neuronal processes. Overall, this article provides relevant input in setting directions for future research and for business applications in consumer neuroscience. We hope that this study will provide help to researchers and practitioners in identifying available, non-invasive and useful tools to study consumer behavior.
A P300 Brain-Computer Interface With a Reduced Visual Field
Authors: Kirasirova Luiza , Bulanov Vladimir , Ossadtchi Alexei , Kolsanov Alexander , Pyatin Vasily , Lebedev Mikhail
Published: December 2020

A P300 brain-computer interface (BCI) is a paradigm, where text characters are decoded from event-related potentials (ERPs). In a popular implementation, called P300 speller, a subject looks at a display where characters are flashing and selects one character by attending to it. The selection is recognized as the item with the strongest ERP. The speller performs well when cortical responses to target and non-target stimuli are sufficiently different. Although many strategies have been proposed for improving the BCI spelling, a relatively simple one received insufficient attention in the literature: reduction of the visual field to diminish the contribution from non-target stimuli. Previously, this idea was implemented in a single-stimulus switch that issued an urgent command like stopping a robot. To tackle this approach further, we ran a pilot experiment where ten subjects operated a traditional P300 speller or wore a binocular aperture that confined their sight to the central visual field. As intended, visual field restriction resulted in a replacement of non-target ERPs with EEG rhythms asynchronous to stimulus periodicity. Changes in target ERPs were found in half of the subjects and were individually variable. While classification accuracy was slightly better for the aperture condition (84.3 ± 2.9%, mean ± standard error) than the no-aperture condition (81.0 ± 2.6%), this difference was not statistically significant for the entire sample of subjects (N = 10). For both the aperture and no-aperture conditions, classification accuracy improved over 4 days of training, more so for the aperture condition (from 72.0 ± 6.3% to 87.0 ± 3.9% and from 72.0 ± 5.6% to 97.0 ± 2.2% for the no-aperture and aperture conditions, respectively). Although in this study BCI performance was not substantially altered, we suggest that with further refinement this approach could speed up BCI operations and reduce user fatigue. Additionally, instead of wearing an aperture, non-targets could be removed algorithmically or with a hybrid interface that utilizes an eye tracker. We further discuss how a P300 speller could be improved by taking advantage of the different physiological properties of the central and peripheral vision. Finally, we suggest that the proposed experimental approach could be used in basic research on the mechanisms of visual processing.
Delta Radiomics Can Predict Distant Metastasis in Locally Advanced Rectal Cancer: The Challenge to Personalize the Cure
Authors: Chiloiro Giuditta , Rodriguez-Carnero Pablo , Lenkowicz Jacopo , Casà Calogero , Masciocchi Carlotta , Boldrini Luca , Cusumano Davide , Dinapoli Nicola , Meldolesi Elisa , Carano Davide , Damiani Andrea , Barbaro Brunella , Manfredi Riccardo , Valentini Vincenzo , Gambacorta Maria Antonietta
Published: December 2020

Purpose

Distant metastases are currently the main cause of treatment failure in locally advanced rectal cancer (LARC) patients. The aim of this research is to investigate a correlation between the variation of radiomics features using pre- and post-neoadjuvant chemoradiation (nCRT) magnetic resonance imaging (MRI) with 2 years distant metastasis (2yDM) rate in LARC patients.

Methods and Materials

Diagnostic pre- and post- nCRT MRI of LARC patients, treated in a single institution from May 2008 to June 2015 with an adequate follow-up time, were retrospectively collected. Gross tumor volumes (GTV) were contoured by an abdominal radiologist and blindly reviewed by a radiation oncologist expert in rectal cancer. The dataset was firstly randomly split into 90% training data, for features selection, and 10% testing data, for the validation. The final set of features after the selection was used to train 15 different classifiers using accuracy as target metric. The models’ performance was then assessed on the testing data and the best performing classifier was then selected, maximising the confusion matrix balanced accuracy (BA).

Results

Data regarding 213 LARC patients (36% female, 64% male) were collected. Overall 2yDM was 17%. A total of 2,606 features extracted from the pre- and post- nCRT GTV were tested and 4 features were selected after features selection process. Among the 15 tested classifiers, logistic regression proved to be the best performing one with a testing set BA, sensitivity and specificity of 78.5%, 71.4% and 85.7%, respectively.

Conclusions

This study supports a possible role of delta radiomics in predicting following occurrence of distant metastasis. Further studies including a consistent external validation are needed to confirm these results and allows to translate radiomics model in clinical practice. Future integration with clinical and molecular data will be mandatory to fully personalized treatment and follow-up approaches.
Comparison of Machine Learning Models for Prediction of Initial Intravenous Immunoglobulin Resistance in Children With Kawasaki Disease
Authors: Kuniyoshi Yasutaka , Tokutake Haruka , Takahashi Natsuki , Kamura Azusa , Yasuda Sumie , Tashiro Makoto
Published: December 2020

We constructed an optimal machine learning (ML) method for predicting intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD) using commonly available clinical and laboratory variables. We retrospectively collected 98 clinical records of hospitalized children with KD (2–109 months of age). We found that 20 (20%) children were resistant to initial IVIG therapy. We trained three ML techniques, including logistic regression, linear support vector machine, and eXtreme gradient boosting with 10 variables against IVIG resistance. Moreover, we estimated the predictive performance based on nested 5-fold cross-validation (CV). We also selected variables using the recursive feature elimination method and performed the nested 5-fold CV with selected variables in a similar manner. We compared ML models with the existing system regardless of their predictive performance. Results of the area under the receiver operator characteristic curve were in the range of 0.58–0.60 in the all-variable model and 0.60–0.75 in the select model. The specificities were more than 0.90 and higher than those in existing scoring systems, but the sensitivities were lower. Three ML models based on demographics and routine laboratory variables did not provide reliable performance. This is possibly the first study that has attempted to establish a better predictive model. Additional biomarkers are probably needed to generate an effective prediction model.
The Expression of Glycoprotein Genes in the Inflammatory Process of Kawasaki Disease
Authors: Kuo Kuang-Che , Yang Ya-Ling , Lo Mao-Hung , Cai Xin-Yuan , Kuo Ho-Chang , Huang Ying-Hsien
Published: December 2020

Background: Kawasaki disease (KD) is the most common form of febrile coronary vasculitis disease to occur in children. Early diagnosis and proper therapy can prevent the complication of coronary artery lesions (CAL). The main pathogenesis of KD is an inflammatory process related to the host's genetic characteristics. In innate human immunity, the interaction of leukocytes and glycoprotein plays an important role against microbes. The purpose of our study was to understand the role of leukocytes' glycoprotein genes during the acute phase of KD.

Materials and Methods: We enrolled a total of 97 subjects from a medical center. Of those, 24 subjects were healthy controls, and 24 subjects were fever controls; the other 49 subjects were KD patients who had had blood samples taken both before and after IVIG treatment. We collected the total RNA from leukocytes and performed a quantitative polymerase chain reaction for the HP, GRP84, and CLEC4D genes in real time.

Results: Compared with both the healthy and fever controls, the upregulation of HP, GRP84, and CLEC4D genes was significant in peripheral leukocytes during acute-phase KD. The transcriptional level of these respective genes not only demonstrated a positive correlation with each other, but were also effective predictors for KD (all auROC >0.87) according to the ROC curve analysis. The hyper-expression of these three genes was significantly associated with IVIG resistance, but not CAL formation.

Conclusions: Our study demonstrates that the expression of HP, GRP84, and CLEC4D genes of leukocytes play an important role in the pathogenesis and primary IVIG response during the acute inflammatory process of KD.
Pharmacological Characterization of Orofacial Nociception in Female Rats Following Nitroglycerin Administration
Authors: Caudle Robert M. , Caudle Stephanie L. , Flenor Natalie D. , Rohrs Eric L. , Neubert John K.
Published: December 2020

Rodent models of human disease can be valuable for understanding the mechanisms of a disease and for identifying novel therapies. However, it is critical that these models be vetted prior to committing resources to developing novel therapeutics. Failure to confirm the model can lead to significant losses in time and resources. One model used for migraine headache is to administer nitroglycerin to rodents. Nitroglycerin is known to produce migraine-like pain in humans and is presumed to do the same in rodents. It is not known, however, if the mechanism for nitroglycerin headaches involves the same pathological processes as migraine. In the absence of known mechanisms, it becomes imperative that the model not only translates into successful clinical trials but also successfully reverse translates by demonstrating efficacy of current therapeutics. In this study female rats were given nitroglycerin and nociception was evaluated in OPADs. Estrous was not monitored. Based on the ED50 of nitroglycerin a dose of 10 mg/kg was used for experiments. Sumatriptan, caffeine, buprenorphine and morphine were administered to evaluate the reverse translatability of the model. We found that nitroglycerin did not produce mechanical allodynia in the face of the rats, which is reported to be a consequence of migraine in humans. Nitroglycerin reduced the animals’ participation in the assay. The reduced activity was verified using an assay to measure exploratory behavior. Furthermore, the effects of nitroglycerin were not reversed or prevented by agents that are effective acute therapies for migraine. Two interesting findings from this study, however, were that morphine and nitroglycerin interact to increase the rats’ tolerance of mechanical stimuli on their faces, and they work in concert to slow down the central motor pattern generator for licking on the reward bottle. These interactions suggest that nitroglycerin generated nitric oxide and mu opioid receptors interact with the same neuronal circuits in an additive manner. The interaction of nitroglycerin and morphine on sensory and motor circuits deserves additional examination. In conclusion, based on the results of this study the use of nitroglycerin at these doses in naïve female rats is not recommended as a model for migraine headaches.
Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors
Authors: De Caro Carmen , Di Cesare Mannelli Lorenzo , Branca Jacopo Junio Valerio , Micheli Laura , Citraro Rita , Russo Emilio , De Sarro Giovambattista , Ghelardini Carla , Calignano Antonio , Russo Roberto
Published: December 2020

Epigenetic mechanisms are involved in epilepsy and chronic pain development. About that, we studied the effects of the natural histone deacetylase (HDAC) inhibitor sodium butyrate (BUT) in comparison with valproic acid (VPA) in a validated genetic model of generalized absence epilepsy and epileptogenesis. WAG/Rij rats were treated with BUT (30 mg/kg), VPA (300 mg/kg), and their combination (BUT + VPA) daily per os for 6 months. Rats were subjected at Randall–Selitto, von Frey, hot plate, and tail flick tests after 1, 3, and 6 months of treatment to evaluate hypersensitivity to noxious and non-noxiuous stimuli. Moreover, PPAR-γ (G3335 1 mg/kg), GABA-B (CGP35348 80 mg/kg), and opioid (naloxone 1 mg/kg) receptor antagonists were administrated to investigate the possible mechanisms involved in analgesic activity. The expression of NFkB, glutathione reductase, and protein oxidation (carbonylation) was also evaluated by Western blot analysis. WAG/Rij rats showed an altered pain threshold throughout the study (p < 0.001). BUT and BUT + VPA treatment reduced hypersensitivity (p < 0.01). VPA was significantly effective only after 1 month (p < 0.01). All the three receptors are involved in BUT + VPA effects (p < 0.001). BUT and BUT + VPA decreased the expression of NFkB and enhanced glutathione reductase (p < 0.01); protein oxidation (carbonylation) was reduced (p < 0.01). No effect was reported with VPA. In conclusion BUT, alone or in coadministration with VPA, is a valuable candidate for managing the epilepsy-related persistent pain.
Severe Potential Drug-Drug Interactions and the Increased Length of Stay of Children in Intensive Care Unit
Authors: Lima Elisangela da Costa , Camarinha Barbara Dias , Ferreira Bezerra Nathalia Cristina , Panisset Anderson Gonçalves , Belmino de Souza Raquel , Silva Marcus Tolentino , Lopes Luciane Cruz
Published: December 2020

Children are exposed to drug-drug interactions (DDI) risks due to their organism’s complexity and the need for several medicines prescriptions in pediatric intensive care units (PICU). This study aimed to assess the prevalence of potential DDIs in a Brazilian PICU. We carried out a cross-sectional study at a pediatric teaching hospital from Rio de Janeiro (Brazil) over one year. Potential DDIs (pDDIs) between prescribed medicines for hospitalized children in PICU (n = 143) were analyzed according to severity using Micromedex®. Sex, age group, number of drugs prescribed, vasoactive amines use (a proxy of clinical complexity), and the PICU length of stay were summarized using descriptive statistics. Association between the PICU length stay, and variables sex, age, clinical condition complexity, number of drugs prescribed, and severity of pDDI were examined by univariate and multiple linear regression. Seventy percent of patients aged three days to 14 years old were exposed at least one potential DDIs during PICU stay. Two hundred eighty-four different types of pDDIs were identified, occurring 1,123 times. Nervous system drugs were implicated in 55% of the interactions, and fentanyl (10%) was most involving in pDDIs. Most pDDIs were classified as higher severity (56.2%), with reasonable documentation (64.6%) and unspecified onset time (63.8%). Worse clinical condition, ten or more drugs prescribed, and most severe pDDIs were associated with a longer PICU length of stay. Multiple linear regression analysis showed an increase of 9.83 days (95% confidence interval: 3.61–16.05; p = 0.002) in the PICU length of stay in children with major or contraindicated pDDIs. The results of this research may support the monitoring and prevention of pDDIs related to adverse events in children in intensive care and the design and conduction of new studies.
Pharmacokinetics and Bioequivalence of Rasagiline Tablets in Chinese Healthy Subjects Under Fasting and Fed Conditions: An Open, Randomized, Single-Dose, Double-Cycle, Two-Sequence, Crossover Trial
Authors: Li Yinjuan , Qi Lu , Bai Haihong , Liu Ying , Fan Rongxia , Tu Yongrui , Sun Yongqiang , Wang Juxiang , Qi Qi , Feng Xiaohui , Zhou Da , Wang Xinghe
Published: December 2020

Objective: This study evaluated the pharmacokinetics, safety, and bioequivalence (BE) of two formulations of rasagiline tablets in healthy Chinese subjects under fasting and fed conditions.

Methods: An open, randomized, single-dose, double-cycle, two-sequence, self-crossover pharmacokinetic study in healthy Chinese subjects under fasting and high-fat postprandial conditions was performed. A total of 108 healthy subjects (36 in the fasting group and 72 in the postprandial group) were recruited. In each cycle of the study under both conditions, subjects received a single oral dose of 1 mg of a test or reference preparation of rasagiline tablets (1 mg each). A washout period of 3 days was observed. Blood samples were obtained up to 10 h post-intake. Primary endpoints were the BE of major pharmacokinetic parameters (AUC0–t and AUC0–∞) and the maximum observed serum concentration (Cmax). Secondary endpoints were safety parameters.

Results: The 90% confidence interval (CI) of the geometric mean ratio (GMR) of the test drug vs. the reference drug for rasagiline was 94.16–105.35% for the AUC0–t under fasting conditions and 99.88–107.07% under postprandial conditions. The 90% CIs for the AUC0–∞ were 93.55–105.01% and 99.59–107.05% under fasting and postprandial conditions, respectively. The 90% CIs for the Cmax were 88.26–108.46% and 89.54–118.23% under fasting and postprandial conditions, respectively. The 90% CIs for the test/reference AUC ratio and Cmax ratio were within the acceptable range (0.80–1.25) for BE. In this BE study, there were no serious adverse events (AEs).

Conclusion: BE between the test and the reference products was established in both fasting and postprandial conditions. The two formulations of rasagiline showed good tolerability and a similar safety profile.

Clinical Trial Registration:chinaDrugtrials.org.cn, identifier CTR20181466.
A Mass Spectrometry Based Metabolite Profiling Workflow for Selecting Abundant Specific Markers and Their Structurally Related Multi-Component Signatures in Traditional Chinese Medicine Multi‐Herb Formulae
Authors: Houriet Joëlle , Allard Pierre-Marie , Queiroz Emerson Ferreira , Marcourt Laurence , Gaudry Arnaud , Vallin Lennie , Li Songhua , Lin Yu , Wang Ruwei , Kuchta Kenny , Wolfender Jean-Luc
Published: December 2020

In Traditional Chinese Medicine (TCM), herbal preparations often consist of a mixture of herbs. Their quality control is challenging because every single herb contains hundreds of components (secondary metabolites). A typical 10 herb TCM formula was selected to develop an innovative strategy for its comprehensive chemical characterization and to study the specific contribution of each herb to the formula in an exploratory manner. Metabolite profiling of the TCM formula and the extract of each single herb were acquired with liquid chromatography coupled to high-resolution mass spectrometry for qualitative analyses, and to evaporative light scattering detection (ELSD) for semi-quantitative evaluation. The acquired data were organized as a feature-based molecular network (FBMN) which provided a comprehensive view of all types of secondary metabolites and their occurrence in the formula and all single herbs. These features were annotated by combining MS/MS-based in silico spectral match, manual evaluation of the structural consistency in the FBMN clusters, and taxonomy information. ELSD detection was used as a filter to select the most abundant features. At least one marker per herb was highlighted based on its specificity and abundance. A single large-scale fractionation from the enriched formula enabled the isolation and formal identification of most of them. The obtained markers allowed an improved annotation of associated features by manually propagating this information through the FBMN. These data were incorporated in the high-resolution metabolite profiling of the formula, which highlighted specific series of related components to each individual herb markers. These series of components, named multi-component signatures, may serve to improve the traceability of each herb in the formula. Altogether, the strategy provided highly informative compositional data of the TCM formula and detailed visualizations of the contribution of each herb by FBMN, filtered feature maps, and reconstituted chromatogram traces of all components linked to each specific marker. This comprehensive MS-based analytical workflow allowed a generic and unbiased selection of specific and abundant markers and the identification of multiple related sub-markers. This exploratory approach could serve as a starting point to develop more simple and targeted quality control methods with adapted marker specificity selection criteria to given TCM formula.
Natural Xanthones and Skin Inflammatory Diseases: Multitargeting Mechanisms of Action and Potential Application
Authors: Gunter Natalie Vivien , Teh Soek Sin , Lim Yang Mooi , Mah Siau Hui
Published: December 2020

The pathogenesis of skin inflammatory diseases such as atopic dermatitis, acne, psoriasis, and skin cancers generally involve the generation of oxidative stress and chronic inflammation. Exposure of the skin to external aggressors such as ultraviolet (UV) radiation and xenobiotics induces the generation of reactive oxygen species (ROS) which subsequently activates immune responses and causes immunological aberrations. Hence, antioxidant and anti-inflammatory agents were considered to be potential compounds to treat skin inflammatory diseases. A prime example of such compounds is xanthone (xanthene-9-one), a class of natural compounds that possess a wide range of biological activities including antioxidant, anti-inflammatory, antimicrobial, cytotoxic, and chemotherapeutic effects. Many studies reported various mechanisms of action by xanthones for the treatment of skin inflammatory diseases. These mechanisms of action commonly involve the modulation of various pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor α (TNF-α), as well as anti-inflammatory cytokines such as IL-10. Other mechanisms of action include the regulation of NF-κB and MAPK signaling pathways, besides immune cell recruitment via modulation of chemokines, activation, and infiltration. Moreover, disease-specific activity contributed by xanthones, such as antibacterial action against Propionibacterium acnes and Staphylococcus epidermidis for acne treatment, and numerous cytotoxic mechanisms involving pro-apoptotic and anti-metastatic effects for skin cancer treatment have been extensively elucidated. Furthermore, xanthones have been reported to modulate pathways responsible for mediating oxidative stress and inflammation such as PPAR, nuclear factor erythroid 2-related factor and prostaglandin cascades. These pathways were also implicated in skin inflammatory diseases. Xanthones including the prenylated α-mangostin (2) and γ-mangostin (3), glucosylated mangiferin (4) and the caged xanthone gambogic acid (8) are potential lead compounds to be further developed into pharmaceutical agents for the treatment of skin inflammatory diseases. Future studies on the structure-activity relationships, molecular mechanisms, and applications of xanthones for the treatment of skin inflammatory diseases are thus highly recommended.
Companies’ Health Technology Assessment Strategies and Practices in Australia, Canada, England, France, Germany, Italy and Spain: An Industry Metrics Study
Authors: Wang Ting , McAuslane Neil , Liberti Lawrence , Gardarsdottir Helga , Goettsch Wim , Leufkens Hubert
Published: December 2020

Background:Health technology assessment (HTA) has increased in importance in supporting payer decision making by assessing the relative effectiveness and cost effectiveness of new medicines. Thus, pharmaceutical companies need to address the HTA requirements early during development to improve reimbursement outcomes. Currently, there is a lack of research to assess the impact of HTA on development and jurisdictional outcome from companies’ perspectives. This study aimed to assess companies’ HTA strategy and characterise HTA practice in seven jurisdictions.

Methods:A multi-year, annual study collected information for individual products, focusing on development activities regarding inclusion of HTA requirements and selection of global comparators. The generation of local contextual information, submission strategies and predictability of HTA outcomes was examined jurisdictionally in Australia, Canada, England, France, Germany, Italy and Spain. The study questionnaire was built into a secure online data collection platform and data were provided annually by participating companies.

Results:Data for 169 compounds were provided by nine international companies between 2014 and 2018. HTA requirements were implemented in evidence generation plan for 63% of products during development. Global comparators were accepted by HTA bodies for more than half of studied products; Spain showed the highest acceptance rate (85%). Companies took advantages of parallel process in Australia and Canada to shorten product rollout time. Australia demonstrated general consistency in HTA review time, and England had the longest variation (interquartile range, 216 days). Requirements for additional information after submission occurred at all HTA bodies. Germany and Italy showed the highest percentage of products being reimbursed as per regulatory label (80 and 68%, respectively). Canada was the most predictable jurisdiction, with the highest proportion of review outcome (90%) that met companies’ expectations.

Conclusion:Companies are addressing HTA requirements during development for many products; however, they are challenged by varying requirements and practices and product success ultimately depends on how HTA organisations and payers assess added value in the context of the national healthcare systems. This ongoing study created a baseline to help capture fact-based changes for company HTA strategies and HTA body practices.