bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of APOE ε4 Genotype on Amyloid-β and Tau Accumulation in Alzheimer’s Disease
Authors: Baek Min Seok , Cho Hanna , Lee Hye Sun , Lee Jae Hoon , Ryu Young Hoon , Lyoo Chul Hyoung
Published: August 2020

Background
To assess effects of apolipoprotein E (ApoE) ε4 genotype on Aβ and tau burden and their longitudinal changes in Alzheimer’s disease (AD) spectrum.
Methods
Among 272 individuals who underwent PET scans (18F-florbetaben for Aβ and 18F-flortaucipir for tau) and ApoE genotyping, 187 individuals completed 2-year follow-up PET scans. After correcting for partial-volume effect, we compared the standardized uptake value ratio (SUVR) for Aβ and tau burden between the ε4 + and ε4- groups. By using a linear mixed-effect model, we measured changes in SUVR in the ApoE ε4 + and ε4- groups.
Results
The ε4 + group showed greater baseline Aβ burden in the diffuse cortical regions and greater tau burden in the lateral, and medial temporal, cingulate, and insula cortices. Tau accumulation rate was higher in the parietal, occipital, lateral, and medial temporal cortices in the ε4 + group. In Aβ + individuals, baseline tau burden was greater in the medial temporal cortex, while Aβ burden was conversely greater in the ε4- group. Tau accumulation rate was higher in the ε4 + group in a small region in the lateral temporal cortex. The effect of ApoE ε4 on enhanced tau accumulation persisted even after adjusting for the global cortical Aβ burden.
Conclusions
Progressive tau accumulation may be more prominent in ε4 carriers, particularly in the medial and lateral temporal cortices. ApoE ε4 allele has differential effects on Aβ burden depending on the existing amyloidosis and enhances vulnerability to progressive tau accumulation in the AD spectrum independent of Aβ.
A Patient-guided Measure of Functional Status Following Traumatic Brain Injury: The Bob Brown Scale
Authors: Carney Nancy Ann , Stillwell Molly , Coudray Hugo du
Published: August 2020

Background: While technology for treating traumatic brain injury (TBI) continues to improve, unexplained variation in outcomes persists. A growing body of literature provides evidence for the influence of subjective experience on objective physiological processes. We worked with TBI survivors and their family/caregivers to develop a model of recovery that incorporates patients’ subjective experience with objective measures of functional status (FS) to investigate factors that foster recovery. We then developed a measure of FS that reflects the priorities and perspectives of the patient population. The purpose of this report is to present our process for establishing the reliability and validity of the FS measure.Methods: Through an iterative process we elicited from TBI survivors their priorities for evaluation and measurement of FS. We assembled their responses into an 18-item measure and administered the pilot survey to 68 people with TBI from support groups in Oregon. Final administration was a survey mailed to 837 TBI survivors. Reliability analyses were conducted to evaluate internal consistency. A Cronbach’s Alpha was calculated for each sub-construct of the scale. A Difficulty Function was calculated to compare patient responses to family responses within each construct. Content validity analysis was conducted comparing constructs and items from the measure to those of 11 established, validated TBI outcome measures. an Analysis of Variance (ANOVA) was conducted to investigate the relationship between survivors’ FS scores and their post-trauma socio-economic status.Results: There were 248 complete cases in the sample. Reliability analysis provided adequate inter-item correlations. Difficulty functions ranged from .69 to .47. Construct validity was established with 11 validated instruments used to evaluate TBI. The ANOVA revealed a significant difference between FS scores and post-trauma SES; survivors with lower FS scores experienced lower post-trauma SES.Conclusions: Our goal was to develop a measure of functional status following TBI using the advice and assistance of survivors of TBI and their families. In this paper we present our process for developing and assessing the reliability and validity of the Functional Status measure of the Bob Brown Scale. Future research will be use of the BBS in a prospective sample of TBI survivors.
Value of AFP and PIVKA-II in Diagnosis of Primary Hepatocellular Carcinoma and Prediction of Vascular Invasion and Tumor Differentiation
Authors: Si Yuan-quan , Wang Xiu-Qin , Fan Gang , Wang Chang-Yin , Zheng Yuan-Wen , Song Xie , Pan Cui-Cui , Chu Fu-Lu , Liu Zhan-Feng , Lu Bing-Ru , Lu Zhi-Ming
Published: August 2020

Background: To explore the value of alpha fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in diagnosis of primary hepatocellular carcinoma (HCC) and their relationship with vascular invasion, tumor differentiation and size. Methods: A total of 433 participants were enrolled in this study including 266 cases with HCC, 87 cases with liver cirrhosis and 80 healthy individuals. Then we explored the correlation between AFP, PIVKA-II serum level and several pathological features such as vascular invasion, tumor differentiation and size. The value of these two markers used singly or jointly in diagnosing HCC was evaluated by receiver operating characteristic (ROC) curve. The ROC curve was also plotted to identify AFP, PIVKA-II serum cut-off values that would best distinguish HCC patients with and without vascular invasion.Results: The level of AFP and PIVKA-II in HCC group was significantly higher (Z was 7.428, 11.243 respectively, all P<0.01). When AFP and PIVKA-II were used as the individual tumor marker, the areas under the ROC curve (AUC) of HCC diagnosis were 0.765 (95% CI, 0.713～0.8170) for AFP, 0.901 (95% CI, 0.868～0.935) for PIVKA-II, and 0.917 (95% CI, 0.886～0.948) for AFP and PIVKA-II simultaneously. The serum levels of AFP and PIVKA-II were positively correlated with tumor differentiation and size. High AFP and PIVKA-II expression was signiﬁcantly associated with the presence of vascular invasion (P was 0.007 and 0.014 respectively). The AFP level >64.4ng/ml or PIVKA-II level >957.61mAU/ml was the best critical value to predict the presence of vascular invasion. Conclusion: Our results validate that AFP and PIVKA-II play a significant role in the diagnosis of HCC. The diagnostic value of AFP and PIVKA-II combined detection or single assay of PIVKA-II is higher than that of separate assay of AFP. Moreover, their concentration has important clinical value in judging tumor size, tumor cell differentiation and vascular invasion.
The impact of fluid status and decremental PEEP strategy on cardiac function and lung and kidney damage in mild-moderate experimental acute respiratory distress syndrome.
Authors: Rocha Nazareth N. , Samary Cynthia S. , Antunes Mariana A. , Oliveira Milena V. , Hemerly Matheus R. , Santos Patrine S. , Capelozzi Vera L. , Cruz Fernanda F. , Marini John J. , Silva Pedro L. , Pelosi Paolo , Rocco Patricia R. M.
Published: August 2020

Background

We evaluated the effects of abrupt versus gradual positive end-expiratory pressure (PEEP) decrease, combined with standard versus high-volume fluid administration, on lung, heart, and kidney damage in an established model of acute respiratory distress syndrome (ARDS).
Methods

Thirty-five Wistar rats received endotoxin intratracheally. After 24 h, they were treated with Ringer´s lactate [standard (10 mL/kg/h) or high (30 mL/kg/h) fluids]. For 30 min, all animals were mechanically ventilated with tidal volume = 6 mL/kg and PEEP = 9 cmH2O (to keep alveoli open), then randomized to undergo abrupt or gradual (0.2 cmH2O/min for 30 min) PEEP decrease, from 9 to 3 cmH2O. After this period, animals were further ventilated for 10 minutes at PEEP = 3 cmH2O, euthanized, and then lungs and kidney removed for molecular biology analysis.
Results

At the end of the experiment, left and right ventricular end-diastolic areas were greater in animals treated with high compared to standard fluid administration, regardless of PEEP decrease rate. The PAT (pulmonary acceleration time)/PET (pulmonary ejection time) ratio was lower in abrupt compared to gradual PEEP decrease, independent of fluid status, suggesting higher pulmonary arterial pressure in rats undergo abrupt PEEP decrease. Animals treated with high fluids and abrupt PEEP decrease exhibited greater diffuse alveolar damage and higher expression of interleukin-6 (pro-inflammatory marker) and vascular endothelial growth factor (endothelial cell damage marker) compared to the other groups. Standard fluid administration associated with gradual PEEP decrease increased zonula occludens-1 expression, suggesting epithelial cell preservation. Club cell-16 protein expression, an alveolar epithelial cell damage marker, was higher in abrupt compared to gradual PEEP decrease, regardless of fluid status. Acute kidney injury score and gene expression of kidney injury molecule-1 was higher in high compared to standard fluid administration, independent of PEEP strategy.
Conclusion

In experimental mild-moderate ARDS, decreasing PEEP abruptly increased pulmonary arterial hypertension, independent of fluid status. The combination of abrupt PEEP decrease and high fluid administration led to greater lung and kidney damage. This information adds to the growing body of evidence that supports gradual transitioning of ventilatory patterns and warrants directing additional investigative effort into vascular and deflation issues that impact lung protection.
Endoscopic submucosal dissection for treatment of stromal tumor of descending duodenum in association with postoperative perforation and retroperitoneal abscess: a case report
Authors: Wei Wei , Gong Hang , Huang Zhong , Wang Tingyu , Chen Xinlian
Published: August 2020

Background: With the development of endoscopic technology, the clinical detection rates of duodenal lesions have been significantly increased. Endoscopic submucosal dissection (ESD) has been increasingly applied to the minimally invasive treatment of duodenal space-occupying lesions and has similar therapeutic effects as surgery. However, postoperative complications such as perforation and bleeding easily occur after ESD, but there were few reports about it. We report a case, which we designed to evaluate the efficacy and safety of ESD treatment for stromal tumor in descending duodenum. Case presentation: A 64-year-old woman suffered from duodenal fistula and retroperitoneal abscess after ESD for stromal tumor in descending duodenum. The purse-string suture therapy of the wound was not very effective for the patient during the operation. Thus, the patient underwent a series of treatment measures successfully, such as endoscopic jejunum feeding tube placement, anti-infection, endoscopic closure of duodenal fistula, etc, and without evidence of perforation of duodenum. Follow-up was done for 6 months without recurrence. Conclusions: ESD is a efficient and promising strategy for treating of stromal tumor in descending duodenum, while the ESD of security needs to be further evaluated.
Smaller Pineal Gland is Associated With Rapid Eye Movement Sleep Behavior Disorder in Alzheimer’s Disease
Authors: Park Jeongbin , Suh Seung Wan , Kim Grace Eun , Lee Subin , Kim Jun Sung , Kim Hye Sung , Byun Seonjeong , Bae Jong Bin , Kim Jae Hyoung , Kim Sang Eun , Han Ji Won , Kim Ki Woong
Published: August 2020

Background: To investigate the association between pineal gland volume and symptoms of rapid eye movement (REM) sleep behavior disorder (RBD) in Alzheimer’s disease (AD) patients without any feature of dementia with Lewy bodies.Methods: We enrolled 296 community-dwelling probable AD patients who did not meet the diagnostic criteria for possible or probable dementia with Lewy bodies. Among them, 93 were amyloid beta (Aβ) positive on 18F-florbetaben amyloid brain positron emission tomography. We measured RBD symptoms using the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) and defined probable RBD (pRBD) as the RBDSQ of 5 or higher. We manually segmented pineal gland on 3T structural T1-weighted brain magnetic resonance imaging.Results: The participants with pRBD had smaller pineal parenchyma volume (VPP) than those without pRBD (p < 0.001). The smaller the VPP, the more severe the RBD symptoms (p < 0.001). VPP was inversely associated with risk of prevalent pRBD (odds ratio = 0.909, 95% confidence interval [CI] = 0.878–0.942, p < 0.001). Area under the receiver operator characteristic curve for pRBD of VPP was 0.80 (95% CI = 0.750–0.844, p < 0.0001). These results were not changed when we analyzed the 93 participants with Aβ-positive AD separately.Conclusion: In AD patients, reduced pineal gland volume may be associated with RBD.
MRI-Based Alzheimer’s Disease-Resemblance Atrophy Index in the Detection of Preclinical and Prodromal Alzheimer’s Disease
Authors: Liu Wanting , Au Lisa Wing Chi , Abrigo Jill , Luo Yishan , Wong Adrian , Lam Bonnie Yin Ka , Fan Xiang , Kwan Pauline Wing Lam , Ma Hon Wing , Ng Anthea Yee Tung , Chen Sirong , Leung Eric Yim Lung , Ho Chi Lai , Wong Simon Ho Man , Chu Winnie CW , Ko Ho , Lau Alexander Yuk Lun , Shi Lin , Mok Vincent Chung Tong
Published: August 2020

Background: We aimed to validate the performance of an MRI-based machine learning derived Alzheimer’s Disease-resemblance atrophy index (AD-RAI) in detecting preclinical and prodromal AD. Methods: A total of 62 subjects (mild cognitive impairment [MCI]=25, cognitively unimpaired [CU]=37) underwent MRI, 11C- PIB, and 18F-T807 PET. We investigated the performance of AD-RAI at the pre-specified cutoff of ≥ 0.5 in detecting preclinical and prodromal AD and compared its performance with that of visual and volumetric hippocampal measures. Results: AD-RAI achieved the best metrics among all subjects (sensitivity 0.73, specificity 0.91, accuracy 87.10%) and among MCI subgroup (sensitivity 0.91, specificity 0.79, accuracy 84.00%) in detecting A+T+ subjects over other measures. Among CU subgroup, hippocampal volume (sensitivity 0.75, specificity 0.88, accuracy 86.49%) achieved a higher sensitivity than AD-RAI (sensitivity 0.25, specificity 0.97, accuracy 89.19%) in detecting preclinical AD.Conclusions: AD-RAI aids the detection of early AD, in particular at the prodromal stage.
A Novel lncRNA loc339803 acts as CeRNA of miR-30a-5p to promote the migration and invasion of hepatocellular carcinoma cells
Authors: xue cailin , zhang xudong , gao peng , yu weiwei , cui xiaohan , zhu chunfu , qin xihu
Published: August 2020

Background
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and has an unfavorable clinical outcome. Emerging evidences have demonstrated that long noncoding RNAs (lncRNAs) play an important role in the carcinogenesis and progression of HCC. However, the clinical significances, the biological roles of most lncRNAs in HCC remain poorly understood.
Methods
The expression levels of lncRNA loc339803 in HCC tissues and cell lines were determined by quantitative real-time polymerase chain reaction(qRT-PCR) assay. The cellular sublocalization of loc339803 were determined by fluorescence in situ hybridization and nuclear & cytoplasmic RNA isolation assay. Western blot, CCK-8, Edu, colony formation, migration and invasion assays were used to investigate the roles of loc339803 in progression of HCC in vitro. A mouse model for lung metastasis was constructed to evaluate the role of loc339803 in HCC development in vivo. The correlations among loc339803, miR-30a-5p and SNAIL1 were validated by qRT-PCR and a dual- luciferase reporter assay.
Results
The expression of loc339803 was upregulated in HCC tissues and cell lines, and positively correlated with tumor size, advanced tumor stage, higher serum AFP level and poor prognosis of HCC patients. loc339803 can promote the migration and invasion of HCC cells in vivo and in vitro. Further studies demonstrated the loc339803 functioned as a competing endogenous RNA (ceRNA) by directly binding to miR-30a-5p, thus up-regulating the expression of snai1, a target gene of miR-30a-5p. Moreover, miR-30a-5p upregulation blocked the enhancement of migration and invasion of HCC cells induced by loc339803 overexpression.
Conclusions
Loc339803 may be oncogenic in HCC and associated with poor clinical outcomes. LncRNA loc339803 might promote the invasion and migration of HCC cells through regulating miR-30a-5p/ SNAIL1 axis.
Construction and Validation of an Autophagy-related Prognostic Model for Survival Predicting in Colon Cancer Patients
Authors: Zheng Shu-Yue , Chen Faying , Cui Hui-Juan
Published: August 2020

The authors have requested that this preprint be removed from Research Square.
Screening of Human Epidermal Growth Factor Receptor 2 (HER2) Extracellular Domain for Potential Epitopes by Using Immuno-informatics Tools.
Authors: Odhar Hasanain Abdulhameed , Ahjel Salam Waheed , Odhar Zanan Abdulhameed , Humadi Suhad Sami , Rayshan Ali Mahmood , Hashim Ahmed Fadhil
Published: August 2020

The human epidermal growth factor receptor 2 (HER2) is a well-studied oncoprotein that is overexpressed in a considerable proportion of breast cancer patients. The increased expression of this tyrosine kinase receptor is usually associated with poor clinical prognosis in female patients with breast cancer. In these patients, specific response of immune system against HER2 had been observed. This suggests that immunotherapy approaches can be employed for enhancing the response of tumor infiltrating lymphocytes against HER2 in susceptible tumor microenvironment. In this regard, peptide vaccines are considered one of the most affordable immunotherapy modalities due to their low production cost and long-term effect. For this purpose, we have screened the extracellular domain of HER2 crystal for potential B-cells and T-cells epitopes by using different immuno-informatics tools. The output peptides were then refined and filtered according to their antigenicity, allergenicity and vulnerability to selected proteases. Here, we present multiple B-cells and T-cells epitope candidates against HER2 extracellular domain with high antigenicity, low allergenicity and good resistance for selected proteolytic enzymes. These filtered epitopes can be used for design and construction of anti-HER2 peptide vaccine for potential use in HER2 positive breast cancer patients. Additionally, the sequence of linear B-cells epitopes can be used for the design of monoclonal antibody variable region against HER2 extracellular domain.
Air Quality and Its Relationship with COVID-19 Mortality in Hotspot Places of India: A Post-lockdown Analysis
Authors: Naqvi Hasan Raja , Mutreja Guneet , Shakeel Adnan , Siddiqui Masood Ahsan
Published: August 2020

The COVID-19 pandemic spread over the world like the wind with more than 400,000 documented cases as of March 24th, 2020. In this regard, strict lockdown measures were imposed in India on the same date to stop the virus spread. Thereafter, various lockdown impacts were observed and one of the immediate effects was a reduction in air pollution levels across the world. In this study, we have selected 14 major hotspot places where the COVID-19 cases were >1000 (as of 1st June 2020) that represents more than 70% mortalities of India. We assessed the impact of lockdown on different air quality indicators including ground (PM2.5, PM10, NO2, SO2, O3, and AQI) and tropospheric nitric oxide (NO2) concentrations through ground monitoring stations and Sentinel-5 satellite data respectively. We have found highest reduction in NO2 (-48.68%), PM2.5 (-34.84%) and PM10 (-33.89%) air pollutant (unit in µg/m3) levels post-lockdown. Moreover, tropospheric NO2 (mol/m2) concentrations were also improved over Delhi, Mumbai, Kolkata, Thane, and Ahmedabad metro cities. Interestingly, air pollutant indicators have been correlated with different periods (as of 1st and 15th June 2020) of COVID-19 mortalities data to assess the bounding between these variables. Accordingly, we have found a strong positive correlation of mortalities data with ground PM10 (R2=0.145; r =0.38) and AQI (R2=0.17; r =0.412) indicators and this relationship has been improved significantly on second time point. The correlation finding suggests that the long-term bad air quality may aggravate the clinical symptoms of the disease.
Automated COVID-19 Detection from Chest X-Ray Images : A High Resolution Network (HRNet) Approach 
Authors: Ahmed Sifat , Hossain Tonmoy , Hoque Oishee Bintey , Sarker Sujan , Rahman Sejuti , Shah Faisal Muhammad
Published: August 2020

Background/ introduction: The pandemic, originated by novel coronavirus 2019 (COVID-19), continuing its devastating effect on the health, well-being, and economy of the global population. A critical step to restrain this pandemic is the early detection of COVID-19 in the human body to constraint the exposure and control the spread of the virus. Chest X-Rays are one of the non-invasive tools to detect this disease as the manual PCR diagnosis process is quite tedious and time-consuming. Our intensive background studies show that, the works till now are not efficient to produce an unbiased detection result.Method: In this work, we propose an automated COVID-19 classification method, utilizing available COVID and non-COVID X-Ray datasets, along with High Resolution Network (HRNet) for feature extraction embedding with the UNet for segmentation purposes.Results: To evaluate the proposed method, several baseline experiments have been performed employing numerous deep learning architectures. With extensive experiment, we got a significant result of 99.26% accuracy, 98.53% sensitivity, and 98.82% specificity with HRNet which surpasses the performances of the existing models.Conclusions: Finally, we conclude that our proposed methodology ensures unbiased high accuracy, which increases the probability of incorporating X-Ray images into the diagnosis of the disease.
Mental distress and its associations with behavioral outcomes during the COVID-19 pandemic: A national survey of Chinese adults
Authors: Ma Lu , Gao Liwang , Lau Joseph Tak-fai , Atif Rahman , Johnson Blair T. , Yan Alice Fang , Shi Zumin , Ding Yixin , Nie Peng , Zheng Jinge , Wang Youfa , Wang Weidong , Xue Qian-Li
Published: August 2020

Background This study primarily aimed to evaluate the associations between mental distress and COVID-19-related changes in behavioral outcomes, and potential modifiers (age, gender, and educational attainment) of such associations.Methods An online survey using anonymous network sampling was conducted in China during April-May, 2020 using a 74-item questionnaire distributed through social media. A national sample of 10,545 adults in 31 provinces provided data on socio-demographic characteristics, COVID-19-related mental distress, and changes in behavioral outcomes. Structural equation models were used for data analyses.Results About 13% of adults reported experiencing at least one symptom of mental distress. After adjusting for covariates, greater mental distress was associated with increased smoking and alcohol consumption (among current smokers and drinkers) and with both increased and decreased physical activity. Underweight adults were more likely to lose body weight (≥ 1 kg) whereas overweight adults were more likely to gain weight by the same amount. Association between mental distress and change in physical activity was stronger in adults aged 40 and above and those with high education.Conclusions Mental distress was associated with increased smoking in males but not females. These findings inform the design of tailored public health interventions aimed to mitigate long-term negative consequences of mental distress on outcomes.
Mathematical Modelling of COVID-19 Pandemic with Demographic Effects
Authors: Kamara Abdul Alimamy , Mouanguissa Lagès N. , Barasa Godfrey
Published: August 2020

In this paper, an asymptomatic infection transmission Susceptible-Exposed-Infectious-Recovered (SEIR) model with demographic effects is used to understand the dynamics of the COVID-19 pandemics. We calculate the basic reproduction number (R0), and prove the global stability of the model by solving the differential equations of the model using the disease-free equilibrium (DFE) and endemic equilibrium (EE) equations, respectively. We showed that when the R0 less than one or less than and equal to one, and greater than one or greater than and equal to one the DFE and EE asymptotic stability exist theoretically and numerically, respectively. We also demonstrate the detrimental impact of the direct and asymptomatic infections for the COVID-19 pandemic.
The Best Commercial Chemical Disinfectant for Swimming Pools Environments Contaminated With Fungi
Authors: Badiee Parisa , Rouein Sara , Zaravar Foroozandeh , Ghasemi Fatemeh
Published: August 2020

Background: Swimming pools are contaminated with different microorganisms. This study aimed to investigate the fungal contamination of the swimming pools and detect the susceptibility of the isolated fungi to routinely used disinfectants.Methods: Surface and water samples were collected from different parts of 13 indoor swimming pools. Isolated fungal species were identified based on respective colony morphology, microscopic examination, and RFLP-PCR. Susceptibilities of fungal species to common disinfectants used in swimming pools were investigated, according to M38-A and M27A3 protocols.Results: Of the 795 collected specimens, 2211 isolates from 35 fungal species were identified. The most isolated fungi were filamentous hyaline hyphomycetes (especially Aspergillus spp.), and dematiaceous (especially Cladosporium spp.), followed by Mucorales, Candida species and dermatophyte species. The most contaminated places were shoes changing and dressing rooms. Sodium hypochlorite (bleach) and chloroxylenol (Dettol) were found to be effective against all isolated fungi after 2.5 and 5 minutes, respectively. Isopropyl alcohol (Afrooz disinfectant solution) was not an effect on Aspergillus spp., dematiaceous fungi, and Candida spp. after 10 minutes’ exposure. The efficacy of hydrochloric acid (liqueur de Javel) showed the most fungicidal activity against dermatophytes at all times. Conclusions: For efficient cleaning, the disinfectant must remain on the surfaces for an appropriate period. Sodium hypochlorite was efficient antifungal activity in a shorter time for killing all species of fungi. Given the different sensitivity and resistance profile of fungi to disinfectants, regular assessment of the disinfectants used for cleaning the pools is suggested.
Development of a chiral HPLC method for the separation and quantification of hydroxychloroquine enantiomers
Authors: Chen Yijun , Xiong Xisheng , Wang Kun , Tang Tao , Fang Jinzhi
Published: August 2020

Hydroxychloroquine (2-[[4-[(7-Chloroquinolin-4-yl) amino]pentyl](ethyl) amino]-ethanol, HCQ), an effective anti-malarial drug, has been applied in the clinics for potential treatment of severe coronavirus disease 2019 (COVID-19). Although the clinical benefits of HCQ require extensive clinical data to confirm, the existence of a chiral center in the molecule to possess two optical isomers suggests that there might be an enantiomeric difference on the treatment of COVID-19. Due to poor resolution and the inability of quantification by previously reported methods for the analysis of HCQ enantiomers, it is necessary to develop an analytical method to achieve baseline separation for quantitative and accurate determination of the enantiomeric purity in order to compare the efficacy and toxicity profiles of different enantiomer. In this study, we developed and validated an accurate and reproducible normal phase chiral HPLC method for the analysis of two enantiomers of HCQ, and the method was further evaluated with biological samples. With this newly developed method, the relative standard deviation of all analytes was lower than 5%, and the limit of quantification was 0.27 μg/ml, 0.34 μg/ml and 0.20 μg/ml for racemate, R- and S-enantiomer, respectively. The present method provides an essential analytical tool for preclinical and clinical evaluation of HCQ enantiomers for potential treatment of COVID-19.
Generation and Selection of Driver-behavior-based Transferable Motion Primitives
Authors: Guan Haijie , Wang Boyang , Wei Jiaming , Lu Yaomin , Chen Huiyan , Gong Jianwei
Published: August 2020

In order to achieve the integration of driver experience and heterogeneous vehicle platform characteristics in the motion planning algorithm, based on the driver-behavior-based transferable motion primitives, a general motion planning framework for oine generation and online selection of motion primitives (MPs) is proposed. The optimal control theory is applied to solve the boundary value problems in the process of generating MPs, where the driver behaviors and the vehicle motion characteristics are integrated into the optimization in the form of constraints. Moreover, this paper proposes a layered, unequal-weighted MPs selection framework and utilizes the combination of environmental constraints, nonholonomic vehicle constraints, trajectory smoothness, and collision risk as the single-step extension evaluation index. The library of MPs generated oine demonstrates that the proposed generation method realizes the eective expansion of the MP types and achieves the diverse generation of MPs with various velocity attributes and platform types. We also present how the MP selection algorithm utilizes the unique MP library to achieve the online extension of MP sequences. The results show that the proposed motion planning framework can not only improve the eciency and rationality of the algorithm based on driving experience but also can transfer between heterogeneous vehicle platforms and highlight the unique motion characteristics of the platform.
The New Normal of ENT OPD - Adapting Safe Practices.
Authors: Yeolekar Aditya , Bhalerao Sudhir , Bhalerao Maya
Published: August 2020

The COVID-19 epidemic originating in China has spread rapidly worldwide and converted to pandemic proportions in March 2020. In India and densely populated countries like Brazil and USA the numbers are still rising. Clinicians all over the world are trying to contain it by minimizing the cross-transmission of disease among hospital staff members. In the field of Otorhinolaryngology (ENT) the doctors are exposed to high viral load while examining the patients. Therefore contingency plans are required for dealing with patients in outpatient clinics, and while performing diagnostic endoscopies, minor procedures in OPD and surgeries in operating rooms. Infected patients may shed severe acute respiratory syndrome coronavirus-2 (SARS-CoV- 2) particles into their environment via body secretions. Therefore, Otolaryngologists should be vigilant. In this submission, we share our experience of an innovative practice plan in redesigning the ENT OPD setup, endoscopy set up and OT so as to reduce the risk of transmission of virus not only to doctors but other healthcare workers. We hope that our modifications will serve as a guide for every Otolaryngologist throughout India towards performing their clinical duties confidently without any apprehension and ensuring adequate safety during this testing times in their small set-up/ clinical establishments.
First Principle Study of Silver Nanoparticles Interactions with Antimalarial Drugs Extracted from Artemisia Annua Plant
Authors: Akbari Mahmood , Morad Razieh , Maaza Malik
Published: August 2020

Silver nanoparticles have a great potential in a broad range of applications such as drug-delivery carriers because of their antiviral and antibacterial properties. In this study, the coating properties of silver nanoparticle with three common anti-malarial drugs Artemisinin, Artemether, and Artesunate have been studied by using the quantum mechanical and classical atomistic molecular dynamics simulation in order to use as the drug delivery to treat Malaria and COVID-19 diseases. The optimized structure, frequencies, charge distribution and the electrostatic potential maps of three drug molecules were simulated by using the density functional theory (DFT) at the B3LYP/6-311++g(d,p) level of theory. Then molecular dynamics simulation was used to study the coating of AgNP with each of these drugs. The affinity of interaction was obtained as; Artesunate > Artemether > Artemisinin which is in agreement with the DFT results on the adsorption of drugs on the Ag(111) slab.
Proteinuria in COVID-19: prevalence, characterization and prognostic role
Authors: Huart Justine , Bouquegneau Antoine , Lutteri Laurence , Erpicum Pauline , Grosch Stéphanie , Résimont Guillaume , Wiesen Patricia , Bovy Christophe , Krzesinski Jean-Marie , Thys Marie , Lambermont Bernard , Misset Benoit , Pottel Hans , Mariat Christophe , Cavalier Etienne , Burtey Stéphane , Jouret François , Delanaye Pierre
Published: August 2020

Background: Proteinuria has been commonly reported in patients with COVID-19, suggesting a renal involvement in this infection. However, only dipstick tests have been used thus far. Here, the quantification and characterization of proteinuria and hematuria are investigated. Their potential association with mortality was assessed. Methods: This retrospective, observational and monocentric study includes 153 patients hospitalized with COVID-19 between March 28th and April 30th 2020, in whom total proteinuria and urine α1-microglobulin (a marker of tubular injury) have been measured. Association with mortality was evaluated with a follow-up until May 7th 2020. Results: According to the Kidney Disease Improving Global Outcomes staging, 14% (n=21) had stage 1 proteinuria (<150 mg/g of urine creatinine), 42% (n=64) had stage 2 (between 150 and 500 mg/g) and 44% (n=68) had stage 3 (over 500 mg/g). Urine α1-microglobulin concentration was higher than 10 or 15 mg/g in 94% and 89% of patients, respectively. After a median follow-up of 27 [14;30] days, the mortality rate reached 18%. Total proteinuria and urine α1-microglobulin (as continuous and/or categorical variables) were associated with mortality in unadjusted and adjusted models. This association was even stronger in subgroups of patients with normal renal function or without urinary catheter. Conclusions: Proteinuria is frequent in patients with COVID-19. Its characterization suggests a tubular origin with increased urine α1-microglobulin. Tubular proteinuria seems associated with mortality in COVID-19.
An Improved Method for in Vitro Feeding of Dermanyssus Gallinae (Poultry Red Mite) Using Baudruche Membrane (Goldbeater’s Skin).
Authors: Nunn Francesca G , Baganz Jessica , Bartley Kathryn , Hall Sarah , Burgess Stewart , Nisbet Alasdair J.
Published: August 2020

Background: Dermanyssus gallinae, or poultry red mite (PRM), is one of the most economically important ectoparasites in laying hens worldwide with infestations leading to both welfare and economic issues. Research into the testing and validation of novel vaccines and systemic acaricides to control PRM initially requires the use of in vitro methodologies before using in vivo assessments. In vitro methods to date have either involved PRM feeding on hen blood through biological membranes such as chick skin, which can be difficult to obtain and variable in quality, or through synthetic membranes that are unsatisfactory due to breakage and lack of natural feeding cues. The use of hen blood in these systems also requires multiple procedures (bleeds) to provide sufficient material for experimental replicates and the potential for using other species, from which larger blood volumes can be withdrawn in a single procedure (e.g. geese), could improve this technique as a refinement in the use of animals in research.Methods: Using adult female PRM, an initial experiment with an existing in vitro feeding device employing a Parafilm™ M membrane [1] was used to investigate any differences in mite feeding, egg laying and mortality when fed goose or hen blood. Subsequently, any effects on these parameters when PRM were fed through two different membranes; Parafilm™ M and Baudruche membrane, and a combination of these membranes with an overlaid polyester mesh to promote mite attachment, were then tested using goose blood as the food source.Results: PRM fed equally well on goose or hen blood through a Parafilm™ M membrane and there were no statistically significant differences in mortality of PRM fed with either blood type, although a significant increase (p = 0.03) in eggs laid per fed mite when using goose blood was demonstrated, indicating that goose blood is a satisfactory replacement for hens blood. A 70% increase in PRM feeding was observed when mites were fed on goose blood through a Baudruche membrane when compared to the Parafilm™ M membrane. Addition of an overlaid polyester mesh did not further improve feeding rates on either membrane. A significant increase (p = 0.04) in PRM egg laying was observed in mites fed on goose blood through Baudruche membrane, compared to those fed through Parafilm™ M. A mean of 1.22 eggs per fed mite was obtained using the Baudruche feeding device compared to only 0.87 eggs per fed mite using the Parafilm™ M device when neither had a polyester mesh overlay. It was noted that PRM feeding through Baudruche membrane had fed to repletion when compared to those fed through Parafilm™ M.Conclusion: The in vitro feeding of poultry red mite can be readily facilitated through the use of goose blood in feeding devices with Baudruche membrane.
Commercial and public payer opioid analgesic prescribing policies: A case study
Authors: Arfken Cynthia L , Lehr Victoria Tutag
Published: August 2020

Background: One strategy to address the high number of U.S. opioid-related deaths is to restrict high-risk or inappropriate opioid analgesic prescribing and dispensing. Federal and state laws and regulations have implemented restrictions but less is known about commercial and public payers’ policies aside from clinician anecdotal reports that these policies are increasing. To assess the number and types of policies with temporal trends, we examined commercial and public (Medicaid) payer policies in one state, Michigan, that has high opioid-related deaths and implemented opioid analgesic prescribing laws. Between 2015 and 2018 claims paid by commercial payers dropped 30.5% and 15.2% for public payer, suggesting the impact of federal and state laws and regulations, media, advocacy groups, education, and payer policies. Methods: Policies for seven large commercial payers and the public payer for 2012-2018 were reviewed and categorized by actions. Joinpoint regression was used to summarize temporal trends on number of policies for all payers and commercial and public payer subgroups. Results: Across the seven years, there were 529 action policies (75.57 (95% confidence intervals (CI) 35.93, 115.22) actions per year) with a range of 36 to 103 actions by payer. Limitations on number of days for initial prescriptions being most frequently implemented policy (83 policies and implemented at least once by all eight payers). The least frequently used policy was incentives to providers which was implemented once by one payer. The temporal trend showed a decline in new policies from 2012 to 2013 but a steady increase from 2014 to 2018 (average annual percent change=29.6% (95% confidence intervals 13.2%, 48.5%). The public payer (implemented 47 policies) showed no increase in number of policies over time (AAPC=2.9% (95% CI -41.6%, 61.6%). Conclusions: The eight commercial and public payers implemented many new policies to restrict opioid analgesic prescribing with a steady increase in the number of such policies implemented from 2014 to 2018. This case study documented that at least in one state with high opioid-related deaths and multiple commercial payers, new and different policies were increasingly implemented challenging clinicians providing patient care and researchers determining the impact. Key words : opioid prescribing, commercial insurance, public insurance, policies, regulations, temporal trends
Surprising protective mechanisms against severe forms of COVID-19 infection among Common Variable Immunodeficiency Patients- one center experience.
Authors: Petricau Carina , Nedelea Irena , Deleanu Diana
Published: August 2020

In this report we aimed to present the nonthreatening experience of patients diagnosed with Common variable immunodeficiency (CVID) included in the National Rare Disease Program registry and consulted at the Immunology department of the Regional Institute of Gastroenterology and Hepatology “Prof Dr. Octavian Fodor” during the Coronavirus disease 2019 (COVID-19) pandemic as well as to review the current understanding of COVID-19 immunopathology followed by possible protective mechanisms against severe infection in these highly susceptible individuals. We report clinical and laboratory results of patients in a single-center retrospective study after lockdown restrictions were partially lifted (May-June 2020) and patients were able to come into the hospital for routine check-up and immunoglobulin replacement treatment. Of the 49 patients consulted during this period, we identified only one asymptomatic patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, supporting recently published data that not all immune compromised patients are at increased risk. According to recent publications the virus induces an inflammatory response leading to a cytokine storm responsible for severe complications. CVID patients seem to be protected from severe forms of this severe virus through reduced viral susceptibility, deficient B lymphocyte response, loss of Interleukin-6 (IL-6) receptor and impaired toll-like receptor pathway activation. Despite being at high risk for other infectious disease, in the context of SARS-CoV-2 induced pandemic, CVID patient’s lack of immune response is their protection against the dangerous macrophage hyper-activation resulting cytokine storm consequences.
Nanomaterials induce different levels of oxidative stress, depending on the used model system: Comparison of in vitro and in vivo effects
Authors: Karkossa Isabel , Bannuscher Anne , Hellack Bryan , Wohlleben Wendel , Laloy Julie , Stan Miruna S. , Dinischiotu Anca , Wiemann Martin , Luch Andreas , Haase Andrea , von Bergen Martin , Schubert Kristin
Published: August 2020

Background The immense variety and constant development of nanomaterials (NMs) raise the demand for a facilitated risk assessment, for which knowledge on NMs mode of actions (MoAs) is required. For this purpose, a comprehensive data basis is of paramountcy that can be obtained using omics. Furthermore, the establishment of suitable in vitro test systems is indispensable to follow the 3R concept and to master the high number of NMs. In the present study, we aimed at comparing NM effects in vitro and in vivo using a multi-omics approach. We applied an integrated data evaluation strategy based on proteomics and metabolomics to four silica NMs and one titanium dioxide-based NM. For in vitro investigations, alveolar epithelial cells and alveolar macrophages were treated with different doses of NMs, and the results were compared to effects on rat lungs after short-term inhalations and instillations at varying doses with and without a recovery period.Results Since the production of reactive oxygen species (ROS) is described to be a critical biological effect of NMs, and enrichment analyses confirmed oxidative stress as a significant effect upon NM treatment in vitro in the present study, we focused on different levels of oxidative stress. Thus, we found opposite changes for proteins and metabolites that are related to the production of reduced glutathione in alveolar epithelial cells and alveolar macrophages, illustrating that NMs MoAs depend on the used model system. Interestingly, in vivo, pathways related to inflammation were affected to a greater extent than oxidative stress responses. Hence, the assignment of the observed effects to the levels of oxidative stress was different in vitro and in vivo as well. However, the overall classification of “active” and “passive” NMs was consistent in vitro and in vivo.Conclusions The consistent classification indicates both tested cell lines to be suitable for NM toxicity assessment even though the induced levels of oxidative stress strongly depend on the used model systems. Thus, the here presented results highlight that model systems need to be carefully revised to decipher the extent to which they can replace in vivo testing.
Fluid flow exposure promotes Epithelial-to-Mesenchymal Transition and adhesion of breast cancer cells to endothelial cells
Authors: Fuh Kenneth F. , Shepherd Robert D. , Withell Jessica S. , Kooistra Brayden K. , Rinker Kristina D
Published: August 2020

Background: Fluid forces are an integral part of the tumor microenvironment through all phases of development and progression. However, it is not well understood how these forces affect key steps in the progression of breast cancer of Epithelial-to-Mesenchymal Transition (EMT) and adhesion to vascular wall endothelial cells. EMT is associated with the progression of most carcinomas through induction of new transcriptional programs within affected epithelial cells, resulting in cells becoming more motile and adhesive to endothelial cells.Methods: MDA-MB-231, SK-BR-3, BT-474, and MCF-7 cells and normal Human Mammary Epithelial Cells (HMECs) were exposed to fluid flow in a parallel-plate bioreactor system. Changes in gene expression were quantified using microarrays and qPCR, gene-gene interactions were elucidated using network analysis, and key modified genes were examined in clinical datasets. Changes in protein expression of key EMT markers between chemically induced EMT and flow-exposed cells were compared in immunocytochemistry assays. Finally, the ability of flow-stimulated and unstimulated cancer cells to adhere to an endothelial monolayer was evaluated in flow and static adhesion experiments.Results: Fluid flow stimulation resulted in upregulation of EMT inducers and downregulation of repressors. Specifically, Vimentin and Snail were upregulated both at the gene and protein expression levels in flow stimulated HMECs, suggesting progression towards an EMT phenotype. Flow-induced overexpression of a panel of cell adhesion genes was also observed. Network analysis revealed genes involved in cell flow responses including FN1, PLAU, and ALCAM. When evaluated in clinical datasets, overexpression of FN1, PLAU, and ALCAM was observed in patients with most subtypes of breast cancer. We also observed increased adhesion of flow-stimulated breast cancer cells compared to unstimulated controls, suggesting an increased potential to form secondary tumors at metastatic sites. Conclusions: This study shows that prolonged fluid force exposure on the order of 1 Pa promotes EMT and adhesion of breast cancer cells to an endothelial monolayer. Further, identified biomarkers were distinctly expressed in patient populations. A better understanding of how biophysical forces such as shear stress affect cellular processes involved in metastatic progression of breast cancer is important for identifying new molecular markers for disease progression, and for predicting metastatic risk.