bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep Disturbance Induces Increased Cholesterol Level by NR1D1 Mediated CYP7A1 Inhibition
Authors: Xing Chen , Huang Xin , Zhang Yifan , Zhang Chongchong , Wang Wei , Wu Lin , Ding Mengnan , Zhang Min , Song Lun
Published: December 2020

Disturbed sleep is closely associated with an increased risk of metabolic diseases. However, the underlying mechanisms of circadian clock genes linking sleep and lipid profile abnormalities have not been fully elucidated. This study aimed to explore the important role of the circadian clock in regulating impaired cholesterol metabolism at an early stage of sleep deprivation (SD). Sleep disturbance was conducted using an SD instrument. Our results showed that SD increased the serum cholesterol levels. Concentrations of serum leptin and resistin were much lower after SD, but other metabolic hormone concentrations (adiponectin, glucagon, insulin, thyroxine, norepinephrine, and epinephrine) were unchanged before and after SD. Warning signs of cardiovascular diseases [decreased high density lipoprotein (HDL)-cholesterol and increased corticosterone and 8-hydroxyguanosine levels] and hepatic cholestasis (elevated total bile acids and bilirubin levels) were observed after SD. Cholesterol accumulation was also observed in the liver after SD. The expression levels of HMGCR, the critical enzyme for cholesterol synthesis, remained unchanged in the liver. However, the expression levels of liver CYP7A1, the enzyme responsible for the conversion of cholesterol into bile acids, significantly reduced after SD. Furthermore, expression of NR1D1, a circadian oscillator and transcriptional regulator of CYP7A1, strikingly decreased after SD. Moreover, NR1D1 deficiency decreased liver CYP7A1 levels, and SD could exacerbate the reduction of CYP7A1 expression in NR1D1−/− mouse livers. Additionally, NR1D1 deficiency could further increase serum cholesterol levels under SD. These results suggest that sleep disturbance can induce increased serum cholesterol levels and liver cholesterol accumulation by NR1D1 mediated CYP7A1 inhibition.
Expeditious Generation of Biparatopic Common Light Chain Antibodies via Chicken Immunization and Yeast Display Screening
Authors: Bogen Jan P. , Carrara Stefania C. , Fiebig David , Grzeschik Julius , Hock Björn , Kolmar Harald
Published: December 2020

Bispecific (BsAb) and biparatopic (BpAb) antibodies emerged as promising formats for therapeutic biologics exhibiting tailor-made functional properties. Over recent years, chicken-derived antibodies have gained traction for diagnostic and therapeutic applications due to their broad epitope coverage and convenience of library generation. Here we report the first generation of a biparatopic common light chain (cLC) chicken-derived antibody by an epitope binning-based screening approach using yeast surface display. The resulting monospecific antibodies target conformational epitopes on domain II or III of the epidermal growth factor receptor (EGFR) with lower double- or single-digit nanomolar affinities, respectively. Furthermore, the domain III targeting variant was shown to interfere with epidermal growth factor (EGF) binding. Utilizing the Knob-into-Hole technology (KiH), a biparatopic antibody with subnanomolar affinity was generated that facilitates clustering of soluble and cell-bound EGFR and displayed enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) compared to the parental antibodies. This strategy for generating cLC-based biparatopic antibodies from immunized chickens may pave the way for their further development in therapeutic settings.
An Assessment of How Australian Fisheries Management Plans Account for Climate Change Impacts
Authors: Fogarty Hannah E. , Cvitanovic Christopher , Hobday Alistair J. , Pecl Gretta T.
Published: December 2020

For Australian fisheries to remain productive and sustainable (environmentally and commercially), there is a need to incorporate climate change considerations into management and planning, and to implement planned climate adaptation options. Here, we determine the extent to which Australian state fisheries management documents consider issues relating to climate change, as well as how frequently climate change is considered a research funding priority within fisheries research in Australia. We conduct a content analysis of fisheries management documents investigating categories and themes relating to Australian state fisheries, climate, and environmental change. We also reviewed recent Research Priorities from the major fisheries research funding body for reference to climate change related themes, and the number of subsequently funded projects which considered climate change or related topics. Results show that commercial state fisheries management documents consider climate only to a limited degree in comparison to other topics, with less than one-quarter of all fisheries management documents having content relating to climate. However, we find that the south-east and south-west regions of the Australian coastline have the highest incorporation of “climate” and “environmental protection considerations” in their fisheries management documents, and that fisheries are more likely to have more “climate-related mentions” within their related management documents, if they (i) primarily target species with higher economic commercial catch values, (ii) commercial catch weights, or (iii) a greater number of commercial fish stocks existing. Only a small number of recently funded fisheries research projects considered climate change, representing only a small proportion of fisheries research investment. Given the extensive climate-driven impacts recently documented among key Australian fisheries species and associated ecosystems, we conclude that there is a clear need for fisheries management in Australia to consider longer-term climate adaptation strategies for Australian commercial state fisheries to remain sustainable into the future. We suggest that without additional climate-related fisheries research and funding, many Australian agencies and fisheries may not be prepared for the impacts and subsequent adaptation efforts required for sustainable fisheries under climate change.
The First Cut Is the Deepest: Trawl Effects on a Deep-Sea Sponge Ground Are Pronounced Four Years on
Authors: Morrison Katelin M. , Meyer Heidi Kristina , Roberts Emyr Martyn , Rapp Hans Tore , Colaço Ana , Pham Christopher Kim
Published: December 2020

Few studies have described the effects of physical disturbance and post-recovery of deep-sea benthic communities. Here, we explore the status of deep-sea sponge ground communities four years after being impacted by an experimental bottom trawl. The diversity and abundance of epibenthic megafauna of two distinct benthic communities in disturbed versus control areas were surveyed using a remotely operated vehicle on the Schulz Bank, Arctic Ocean. Four years after disturbance, megafaunal densities of the shallow (∼600 m depth) and deep (∼1,400 m depth) sites were significantly lower on the disturbed patches compared to the control areas. Multivariate analyses revealed a distinct separation between disturbed and control communities for both sites, with trawling causing 29–58% of the variation. Many epibenthic morphotypes were significantly impacted by the trawl, including ascidians, Geodia parva, Hexactinellida spp., Craniella infrequens, Lissodendoryx complicata, Haliclonia sp. Stylocordyla borealis, Gersemia rubiformis and Actiniaria sp. However, we found some smaller morphospecies to be equally abundant with control transects, including Polymastia thielei, Geodia hentscheli, and Stelletta rhaphidiophora, reflecting lower trawl impact for these morphotypes. Overall, our results suggest that these are fragile ecosystems that require much more time than four years to recover from physical disturbance typical of trawling activities.
The Voice of Science on Marine Biodiversity Negotiations: A Systematic Literature Review
Authors: Tessnow-von Wysocki Ina , Vadrot Alice B. M.
Published: December 2020

Over one hundred governments are currently negotiating a new legally binding instrument for the conservation and sustainable use of marine biological diversity in areas beyond national jurisdiction (BBNJ). The new agreement is to address four broad themes: marine genetic resources (MGRs); area-based management tools (ABMTs), including marine protected areas (MPAs); environmental impact assessments (EIAs); and capacity building and the transfer of marine technology (CB&TT). Although a large corpus of scientific BBNJ literature exists, a comprehensive overview and critical analysis of the academic debate is currently missing. This systematic review seeks to fill this gap by examining the main priority topics and recommendations in a sample of 140 multidisciplinary, geographically diverse publications. As an up-to-date summary and analysis, it is intended for researchers from diverse academic disciplines in the natural and social sciences, policy-makers, and practitioners. It untangles the complex BBNJ negotiations, highlights the policy relevance of existing work, and facilitates links between science, policy, and practice. It presents recommendations made in the literature sample for each of the four package elements of the future treaty and identifies four overarching themes: ocean connectivity, institutional design, the role of science, and digital technology. This paper identifies two important gaps that need to be addressed if we are to conserve marine biodiversity in international waters: the science-policy interfaces and the need for transformative change.
Clinical Utility of a Nomogram for Predicting 30-Days Poor Outcome in Hospitalized Patients With COVID-19: Multicenter External Validation and Decision Curve Analysis
Authors: Zhang Bin , Liu Qin , Zhang Xiao , Liu Shuyi , Chen Weiqi , You Jingjing , Chen Qiuying , Li Minmin , Chen Zhuozhi , Chen Luyan , Chen Lv , Dong Yuhao , Zeng Qingsi , Zhang Shuixing
Published: December 2020

Aim: Early detection of coronavirus disease 2019 (COVID-19) patients who are likely to develop worse outcomes is of great importance, which may help select patients at risk of rapid deterioration who should require high-level monitoring and more aggressive treatment. We aimed to develop and validate a nomogram for predicting 30-days poor outcome of patients with COVID-19.

Methods: The prediction model was developed in a primary cohort consisting of 233 patients with laboratory-confirmed COVID-19, and data were collected from January 3 to March 20, 2020. We identified and integrated significant prognostic factors for 30-days poor outcome to construct a nomogram. The model was subjected to internal validation and to external validation with two separate cohorts of 110 and 118 cases, respectively. The performance of the nomogram was assessed with respect to its predictive accuracy, discriminative ability, and clinical usefulness.

Results: In the primary cohort, the mean age of patients was 55.4 years and 129 (55.4%) were male. Prognostic factors contained in the clinical nomogram were age, lactic dehydrogenase, aspartate aminotransferase, prothrombin time, serum creatinine, serum sodium, fasting blood glucose, and D-dimer. The model was externally validated in two cohorts achieving an AUC of 0.946 and 0.878, sensitivity of 100 and 79%, and specificity of 76.5 and 83.8%, respectively. Although adding CT score to the clinical nomogram (clinical-CT nomogram) did not yield better predictive performance, decision curve analysis showed that the clinical-CT nomogram provided better clinical utility than the clinical nomogram.

Conclusions: We established and validated a nomogram that can provide an individual prediction of 30-days poor outcome for COVID-19 patients. This practical prognostic model may help clinicians in decision making and reduce mortality.
Accuracy Improvement of IOL Power Prediction for Highly Myopic Eyes With an XGBoost Machine Learning-Based Calculator
Authors: Wei Ling , Song Yunxiao , He Wenwen , Chen Xu , Ma Bo , Lu Yi , Zhu Xiangjia
Published: December 2020

Purpose: To develop a machine learning-based calculator to improve the accuracy of IOL power predictions for highly myopic eyes.

Methods: Data of 1,450 highly myopic eyes from 1,450 patients who had cataract surgeries at our hospital were used as internal dataset (train and validate). Another 114 highly myopic eyes from other hospitals were used as external test dataset. A new calculator was developed using XGBoost regression model based on features including demographics, biometrics, IOL powers, A constants, and the predicted refractions by Barrett Universal II (BUII) formula. The accuracies were compared between our calculator and BUII formula, and axial length (AL) subgroup analysis (26.0–28.0, 28.0–30.0, or ≥30.0 mm) was further conducted.

Results: The median absolute errors (MedAEs) and median squared errors (MedSEs) were lower with the XGBoost calculator (internal: 0.25 D and 0.06 D2; external: 0.29 D and 0.09 D2) vs. the BUII formula (all P ≤ 0.001). The mean absolute errors and were 0.33 ± 0.28 vs. 0.45 ± 0.31 (internal), and 0.35 ± 0.24 vs. 0.43 ± 0.29 D (external). The mean squared errors were 0.19 ± 0.32 vs. 0.30 ± 0.36 (internal), and 0.18 ± 0.21 vs. 0.27 ± 0.29 D2 (external). The percentages of eyes within ±0.25 D of the prediction errors were significantly greater with the XGBoost calculator (internal: 49.66 vs. 29.66%; external: 78.28 vs. 60.34%; both P < 0.05). The same trend was in MedAEs and MedSEs in all subgroups (internal) and in AL ≥30.0 mm subgroup (external) (all P < 0.001).

Conclusions: The new XGBoost calculator showed promising accuracy for highly or extremely myopic eyes.
Development and Validation of Nomograms Predicting the Overall and the Cancer-Specific Survival in Endometrial Cancer Patients
Authors: Li Xingchen , Fan Yuan , Dong Yangyang , Cheng Yuan , Zhou Jingyi , Wang Zhiqi , Li Xiaoping , Wang Jianliu
Published: December 2020

Background: The present study was aimed at developing nomograms estimating the overall survival (OS) and cancer-specific survival (CSS) of endometrial cancer (EC)-affected patients.

Patients and Methods: We retrospectively collected 145,445 EC patients between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Independent prognostic factors were identified via univariate and multivariate Cox analyses. These risk factors were used to establish nomograms to predict 3- and 5-year OS and CSS rates. Internal and external data were used for validation. The predictive accuracy and discriminative ability were measured by using concordance index (C-index) and risk group stratification.

Results: A total of 63,510 patients were collected and randomly assigned into the training cohort (n = 42,340) and the validation cohort (n = 21,170). Age at diagnosis, marital status, tumor size, histologic type, lymph node metastasis, tumor grade, and clinical stage were identified as independent prognostic factors for OS and CSS (p < 0.05 according to multivariate Cox analysis) and were further used to construct the nomograms. The area under the receiver operating characteristics (ROC) curve was greater than that of International Federation of Gynecology and Obstetrics (FIGO) staging system for predicting OS (0.83 vs. 0.73, p < 0.01) and CSS (0.87 vs. 0.79, p < 0.01) in the training cohort. The stratification into different risk groups ensured a significant distinction between survival curves within different FIGO staging categories.

Conclusion: We constructed and validated nomograms that accurately predicting OS and CSS in EC patients. The nomograms can be used for estimating OS and CSS of individual patients and establishing their risk stratification.
Stochastic Analysis Demonstrates the Dual Role of Hfq in Chaperoning E. coli Sugar Shock Response
Authors: Bianchi David M. , Brier Troy A. , Poddar Anustup , Azam Muhammad S. , Vanderpool Carin K. , Ha Taekjip , Luthey-Schulten Zaida
Published: December 2020

Small RNAs (sRNAs) play a crucial role in the regulation of bacterial gene expression by silencing the translation of target mRNAs. SgrS is an sRNA that relieves glucose-phosphate stress, or “sugar shock” in E. coli. The power of single cell measurements is their ability to obtain population level statistics that illustrate cell-to-cell variation. Here, we utilize single molecule super-resolution microscopy in single E. coli cells coupled with stochastic modeling to analyze glucose-phosphate stress regulation by SgrS. We present a kinetic model that captures the combined effects of transcriptional regulation, gene replication and chaperone mediated RNA silencing in the SgrS regulatory network. This more complete kinetic description, simulated stochastically, recapitulates experimentally observed cellular heterogeneity and characterizes the binding of SgrS to the chaperone protein Hfq as a slow process that not only stabilizes SgrS but also may be critical in restructuring the sRNA to facilitate association with its target ptsG mRNA.
Dynamic Modulation of a Learned Motor Skill for Its Recruitment
Authors: Min Kyuengbo , Lee Jongho , Kakei Shinji
Published: December 2020

Humans learn motor skills (MSs) through practice and experience and may then retain them for recruitment, which is effective as a rapid response for novel contexts. For an MS to be recruited for novel contexts, its recruitment range must be extended. In addressing this issue, we hypothesized that an MS is dynamically modulated according to the feedback context to expand its recruitment range into novel contexts, which do not involve the learning of an MS. The following two sub-issues are considered. We previously demonstrated that the learned MS could be recruited in novel contexts through its modulation, which is driven by dynamically regulating the synergistic redundancy between muscles according to the feedback context. However, this modulation is trained in the dynamics under the MS learning context. Learning an MS in a specific condition naturally causes movement deviation from the desired state when the MS is executed in a novel context. We hypothesized that this deviation can be reduced with the additional modulation of an MS, which tunes the MS-produced muscle activities by using the feedback gain signals driven by the deviation from the desired state. Based on this hypothesis, we propose a feedback gain signal-driven tuning model of a learned MS for its robust recruitment. This model is based on the neurophysiological architecture in the cortico-basal ganglia circuit, in which an MS is plausibly retained as it was learned and is then recruited by tuning its muscle control signals according to the feedback context. In this study, through computational simulation, we show that the proposed model may be used to neurophysiologically describe the recruitment of a learned MS in novel contexts.
Speech Discrimination Tasks: A Sensitive Sensory and Cognitive Measure in Early and Mild Multiple Sclerosis
Authors: Iva Pippa , Fielding Joanne , Clough Meaghan , White Owen , Godic Branislava , Martin Russell , Rajan Ramesh
Published: December 2020

There is a need for reliable and objective measures of early and mild symptomology in multiple sclerosis (MS), as deficits can be subtle and difficult to quantify objectively in patients without overt physical deficits. We hypothesized that a speech-in-noise (SiN) task would be sensitive to demyelinating effects on precise neural timing and diffuse higher-level networks required for speech intelligibility, and therefore be a useful tool for monitoring sensory and cognitive changes in early MS. The objective of this study was to develop a SiN task for clinical use that sensitively monitors disease activity in early (<5 years) and late (>10 years) stages of MS subjects with mild severity [Expanded Disability Status Scale (EDSS) score < 3]. Pre-recorded Bamford-Kowal-Bench sentences and isolated keywords were presented at five signal-to-noise ratios (SNR) in one of two background noises: speech-weighted noise and eight-talker babble. All speech and noise were presented via headphones to controls (n = 38), early MS (n = 23), and late MS (n = 12) who were required to verbally repeat the target speech. MS subjects also completed extensive neuropsychological testing which included: Paced Auditory Serial Addition Test, Digit Span Test, and California Verbal Learning Test. Despite normal hearing thresholds, subjects with early and late mild MS displayed speech discrimination deficits when sentences and words were presented in babble – but not speech-weighted noise. Significant correlations between SiN performance and standardized neuropsychological assessments indicated that MS subjects with lower functional scores also had poorer speech discrimination. Furthermore, a quick 5-min task with words and keywords presented in multi-talker babble at an SNR of −1 dB was 82% accurate in discriminating mildly impaired MS individuals (median EDSS = 0) from healthy controls. Quantifying functional deficits in mild MS will help clinicians to maximize the opportunities to preserve neurological reserve in patients with appropriate therapeutic management, particularly in the earliest stages. Given that physical assessments are not informative in this fully ambulatory cohort, a quick 5-min task with words and keywords presented in multi-talker babble at a single SNR could serve as a complementary test for clinical use due to its ease of use and speed.
Purification and Functional Characterization of the Chloroform/Methanol-Soluble Protein 3 (CM3) From Triticum aestivum in Drosophila melanogaster
Authors: Thiel Anna-Lena , Ragab Mohab , Wagner Anika E. , Divanovic Senad , Derer Stefanie , Sina Christian
Published: December 2020

Non-celiac wheat sensitivity (NCWS) has been proposed to be an independent disease entity that is characterized by intestinal (e.g., abdominal pain, flatulence) and extra-intestinal symptoms (e.g., headache, fatigue), which are propagated following the ingestion of wheat products. Increased activity of amylase trypsin inhibitors (ATIs) in modern wheat is suggested to be major trigger of NCWS, while underlying mechanisms still remain elusive. Here, we aimed to generate and functionally characterize the most abundant ATI in modern wheat, chloroform/methanol-soluble protein 3 (CM3), in vitro and in Drosophila melanogaster. We demonstrate that CM3 displays α-glucosidase but not α-amylase or trypsin inhibitory activity in vitro. Moreover, fruit flies fed a sucrose-containing diet together with CM3 displayed significant overgrowth of intestinal bacteria in a sucrose-dependent manner while the consumption of α-amylase and α-glucosidase inhibitors was sufficient to limit bacterial quantities in the intestine. Notably, both CM3 and acarbose-treated flies showed a reduced lifespan. However, this effect was absent in amylase inhibitor (AI) treated flies. Together, given α-glucosidase is a crucial requirement for disaccharide digestion, we suggest that inhibition of α-glucosidase by CM3 enhances disaccharide load in the distal gastrointestinal tract, thereby promoting intestinal bacteria overgrowth. However, it remains speculative if this here described former unknown function of CM3 might contribute to the development of gastrointestinal symptoms observed in NCWS patients which are very similar to symptoms of patients with small intestinal bacterial overgrowth.
Cancer During Pregnancy: How to Handle the Bioethical Dilemmas?—A Scoping Review With Paradigmatic Cases-Based Analysis
Authors: Alpuim Costa Diogo , Nobre José Guilherme , de Almeida Susana Baptista , Ferreira Marisa Horta , Gonçalves Inês , Braga Sofia , Pais Diogo
Published: December 2020

Ethical issues that arise during the care of a pregnant woman with cancer are challenging to physicians, policymakers, lawyers, and the bioethics community. The main purpose of this scoping review is to summarize existing literature regarding the bioethical dilemmas when a conflict arises in the maternal-fetus dyad, like the one related to cancer and pregnancy outcomes. Moreover, we illustrate the decision-making process of real-life case reports. Published data were searched through the PubMed and Google Scholar databases, as well as in grey literature, using appropriate controlled keywords in English and Portuguese. After identification, screening, eligibility and data extraction from the articles, a total of 50 was selected. There are several established ethical frameworks for conflict resolution and decision-making. Pragmatic theoretical approaches include case-based analysis, the ethics of care, feminist theory, and traditional ethical principlism that scrutinizes the framework of autonomy, justice, beneficence, and non-maleficence. In addition, society and practitioner values could mediate this complex ethical interplay. The physician must balance autonomy and beneficence-based obligations to the pregnant woman with cancer, along with beneficence-based obligations to the fetus. Ethical challenges have received less attention in the literature, particularly before the third trimester of pregnancy. Best, unbiased and balanced information must be granted both to the patient and to the family, regarding the benefits and harms for the woman herself as well as for the fetal outcome. Based on a previously validated method for analyzing and working up clinical ethical problems, we suggest an adaptation of an algorithm for biomedical decision-making in cancer during pregnancy, including recommendations that can facilitate counseling and help reduce the suffering of the patient and her family.
An Integrative Pan-Cancer Analysis Revealing LCN2 as an Oncogenic Immune Protein in Tumor Microenvironment
Authors: Xu Wen-Xiu , Zhang Jian , Hua Yu-Ting , Yang Su-Jin , Wang Dan-Dan , Tang Jin-Hai
Published: December 2020

Background

Lipocalin 2 (LCN2), an innate immune protein, plays a pivotal role in promoting sterile inflammation by regulating immune responses. However, the role of LCN2 in diverse cancers remains poorly defined. This research aimed to investigate the correlation between LCN2 expression and immunity and visualize its prognostic landscape in pan-cancer.

Methods

Raw data in regard to LCN2 expression in cancer patients were acquired from TCGA and GTEx databases. Besides, we investigated the genomic alterations, expression pattern, and survival analysis of LCN2 in pan-cancer across numerous databases, including cBioPortal and GEPIA database. The correlation between LCN2 expression and tumor immune infiltration was explored via TIMER, and we utilized CIBERSORT and ESTIMATE computational methods to assess the proportion of tumor-infiltrating immune cells (TIICs) and the amount of stromal and immune components from TCGA database. Protein–Protein Interaction analysis was performed in GeneMANIA database, and gene functional enrichment was performed by Gene Set Enrichment Analysis (GSEA).

Results

On balance, tumor tissue had a higher LCN2 expression level compared with that in normal tissue. Elevated expression of LCN2 was related to poor clinical regimen with OS and RFS. There were significant positive correlations between LCN2 expression and TIICs, including CD8+ T cells, CD4+ T cells, B cells, neutrophils, macrophages, and dendritic cells. Moreover, markers of TIICs exhibited different LCN2-related immune infiltration patterns. GSEA analysis showed that the expression of LCN2 was related to retinol metabolism, drug metabolism cytochrome P450 and metabolism of xenobiotics by cytochrome P450.

Conclusions

These findings suggested that LCN2 might serve as a biomarker for immune infiltration and poor prognosis in cancers, shedding new light on therapeutics of cancers.
Case Report: Two Cases of Chemotherapy Refractory Metastatic Penile Squamous Cell Carcinoma With Extreme Durable Response to Pembrolizumab
Authors: Chahoud Jad , Skelton William Paul , Spiess Philippe E. , Walko Christine , Dhillon Jasreman , Gage Kenneth L. , Johnstone Peter A. S. , Jain Rohit K.
Published: December 2020

Background

Penile squamous cell carcinoma (PSCC) is a rare malignancy, and those patients with metastatic disease have limited treatment options. Treatment is largely comprised of platinum-based chemotherapy; however, patients progressing after initial chemotherapy have a median overall survival (OS) of less than 6 months. Based on a high percentage of PD-L1 expression in patients with PSCC, and its biological similarities to other squamous cell carcinomas, we present two patient cases treated with pembrolizumab with extraordinary durable treatment response far beyond treatment with standard therapy.

Main Body

The first patient is a 64 year old male with PSCC who was treated with neoadjuvant chemotherapy, partial penectomy, and adjuvant radiation prior to developing metastatic disease. He had a high TMB (14 mutations/Mb) and was started on pembrolizumab with a complete response, which has been maintained for 38 months. The second patient is an 85 year old male with PSCC who was treated with partial penectomy and adjuvant chemotherapy and radiation prior to developing metastatic disease. He had positive PD-L1 expression CPS 130) and was started on pembrolizumab with a partial response, which has been maintained for 18 months after starting treatment.

Conclusions

These two cases of extreme durable response with pembrolizumab (with molecular data including TMB and PD-L1 status) represent a significant clinical benefit in this patient population. With limited treatment options that result in a median OS of less than 6 months, along with the toxicity profile of chemotherapy which may not be tolerated in elderly patients with comorbidities, this survival benefit with pembrolizumab, along with advances in tumor sequencing and clinical trials shows that there is a potentially significant benefit with novel therapies in this patient population.
Magnetic Non-invasive Auricular Acupuncture During Eye-Exam for Retinopathy of Prematurity in Preterm Infants: A Multicentre Randomized Controlled Trial
Authors: Gan Kimberly M. L. , Oei Ju-Lee , Quah-Smith Im , Kamar Azanna A. , Lordudass Alexis A. D. , Liem Kian D. , Lindrea Kwee Bee , Daly Mary , Gaunker Nilima , Mangat Avneet K. , Yaskina Maryna , Schmölzer Georg M.
Published: December 2020

Background: Eye exam for Retinopathy of prematurity (ROP) is a painful procedure and pharmacological analgesia might be ineffective. We hypothesized that magnetic auricular acupuncture (MAA) compared to placebo will decrease pain during ROP exam in preterm infants.

Methods: Multicentre randomized controlled trial conducted in three hospitals (Australia, Canada, and Malaysia). Eligibility: >32 weeks, ROP exam, not sedated, and parental consent. A total of 100 infants were randomized (1:1) to MAA (n = 50) or placebo (n = 50). MAA stickers or placebo were placed on both ears by an unblinded investigator. Pain was assessed using the Premature Infant Pain Profile. Primary analyses were by intention-to-treat. ClinicalTrials.gov:NCT03650621.

Findings: The mean (standard deviation, SD) gestation, birthweight, and postnatal age were (MAA 28(3) vs. placebo 28(2) weeks; MAA 1,057(455) vs. placebo 952(273) g; MAA 7(3) vs. placebo 7(3) weeks. Placebo infants had significantly higher PIPP scores during [mean difference 1.6 points (95%CI 0.1–3.1)] and 1 h mean difference 1.5 points (95%CI 0.7–2.2) after the procedure (p < 0.03). Heart rate was lower (173(22) vs. 184(18)/min) and oxygen saturations were higher (93.8(6.2) vs. 91.7(6.1)%, p = 0.05) in MAA infants. No adverse effects.

Interpretation: MAA may reduce physiological pain responses during and after ROP exam in preterm infants. Assessment of long-term effects are warranted.

Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT03650621.
Age Differences in Preferences for Fear-Enhancing Vs. Fear-Reducing News in a Disease Outbreak
Authors: Villalba Anthony A. , Stanley Jennifer Tehan , Turner Jennifer R. , Vale Michael T. , Houston Michelle L.
Published: December 2020

Older adults (OA) prefer positive over negative information in a lab setting, compared to young adults (YA; i.e., positivity effects). The extent to which OA avoid negative events or information relevant for their health and safety is not clear. We first investigated age differences in preferences for fear-enhancing vs. fear-reducing news articles during the Ebola Outbreak of 2014. We were able to collect data from 15 YA and 13 OA during this acute health event. Compared to YA, OA were more likely to read the fear-enhancing article, select hand-sanitizer over lip balm, and reported greater fear of Ebola. We further investigated our research question during the COVID-19 pandemic with 164 YA (18–30 years) and 171 OA (60–80 years). Participants responded to an online survey about the COVID-19 pandemic across 13 days during the initial peak of the pandemic in the United States (U.S.). Both YA and OA preferred to read positive over negative news about the coronavirus, but OA were even more likely than YA to prefer the positive news article. No age differences in the fear of contraction were found, but OA engaged in more health-protective behaviors compared to YA. Although OA may not always report greater fear than YA or seek out negative information related to a health concern, they still engage in protective health behaviors. Thus, although positivity effects were observed in attention and emotional reports (in the COVID-19 study), OA still modified their behaviors more than YA (giveaway in both studies, and health-protective behavior change in the COVID-19 study), suggesting that positivity effects did not hamper OA ability to respond to a health crisis.
Workaholism and Technostress During the COVID-19 Emergency: The Crucial Role of the Leaders on Remote Working
Authors: Spagnoli Paola , Molino Monica , Molinaro Danila , Giancaspro Maria Luisa , Manuti Amelia , Ghislieri Chiara
Published: December 2020

Although remote working can involve positive outcomes both for employees and organizations, in the case of the sudden and forced remote working situation that came into place during the COVID-19 crisis there have also been reports of negative aspects, one of which is technostress. In this context of crisis, leadership is crucial in sustainably managing and supporting employees, especially employees with workaholic tendencies who are more prone to developing negative work and health outcomes. However, while research on the role of the positive aspects of leadership during crises does exist, the negative aspects of leadership during the COVID-19 crisis have not yet been studied. The present study aimed to explore the role of authoritarian leadership in a sample of 339 administrative university employees who worked either completely from home or from home and the workplace. The study examined the moderating effect of a manager on this relationship and the connections between workaholism and technostress through conditional process analysis. Results pointed out that high authoritarian leadership had an enhancing effect, whereas low authoritarian leadership had a protective effect on the relationship between workaholism and technostress, only in the group of complete remote workers. Thus, authoritarian leadership should be avoided and training leaders to be aware of its effect appears to be essential. Limitations, future directions for the study, and practical implications are also discussed.
A Preliminary Investigation of the Views of People With Parkinson's (With and Without Psychosis) and Caregivers on Participating in Clinical Trials During the Covid-19 Pandemic: An Online Survey
Authors: McGoohan Katie , Amjad Anneesa , Ratcliffe Natasha , Bhattacharyya Sagnik , Granville Gillian , Sullivan Matthew , Gosden Lesley , Aarsland Dag , Chaudhuri K. Ray , ffytche Dominic , Ballard Clive , Velayudhan Latha
Published: December 2020

Background: The coronavirus pandemic is having a profound impact on non-COVID-19 related research, including the delivery of clinical trials for patients with Parkinson's disease.

Objectives: A preliminary investigation to explore the views of Parkinson's disease (PD) patients, with and without experience of psychosis symptoms, and carers on the resumption of clinical research and adaptations to trials in light of COVID-19.

Methods: An anonymous self-administered online survey was completed by 30 PD patients and six family members/carers via the Parkinson's UK Research Support Network to explore current perceptions on taking part in PD research and how a planned clinical trial for psychosis in PD may be adapted so participants feel safe.

Results: Ninety-one percent of respondents were enthusiastic about the continuation of non-COVID-19 related research as long as certain safety measures were in place. Ninety-four percent stated that they would be happy to complete assessments virtually. However, they noted that care should be taken to ensure that this does not exclude participants, particularly those with more advanced PD who may require assistance using portable electronic devices. Regular and supportive communication from the research team was also seen as important for maintaining the psychological well-being of participants while taking part in the trial.

Conclusions: In the era of COVID-19 pandemic, standard approaches will have to be modified and rapid adoption of virtual assessments will be critical for the continuation of clinical research. It is important that alongside the traditional methods, new tools are developed, and older ones validated for virtual assessments, to allow safe and comprehensive assessments vital for ongoing research in people with Parkinson's.
Demographic and Clinical Characteristics of Early Travel-Associated COVID-19 Cases
Authors: Marei Reham M. , Emara Mohamed M. , Elsaied Omar M. , Nasrallah Gheyath K. , Chivese Tawanda , Al-Romaihi Hamad E. , Althani Mohamed H. , Al Thani Asmaa A. , Farag Elmoubasher A. , Yassine Hadi M.
Published: December 2020

Background: SARS-CoV-2 continues to claim hundreds of thousands of people's lives. It mostly affects the elderly and those with chronic illness but can also be fatal in younger age groups. This article is the first comprehensive analysis of the epidemiological and clinical outcomes of the travel-associated SARS-CoV-2 cases until April 19, 2020.

Methods: Demographic and clinical data of travel-associated SARS-CoV-2 cases were collected for the period between January 16, 2020 and April 19, 2020. More than one hundred and eighty databases were searched, including the World Health Organization (WHO) database, countries' ministries websites, and official media sites. Demographic and clinical data were extracted and analyzed.

Results: A total of 1,186 cases from 144 countries meeting the inclusion criteria were reported and included in the analysis. The mean age of the cases was 44 years, with a male to female ratio of 1.6:1. Travel-associated cases originated from more than 40 countries, with China, Italy, and Iran reporting the highest numbers at 208, 225, and 155, respectively. Clinical symptoms varied between patients, with some reporting symptoms during the flights (117 cases; 9.87%). A total of 312 (26.31%) cases were hospitalized, of which 50 cases (4.22%) were fatal.

Conclusion: Major gaps exist in the epidemiology and clinical spectrum of the COVID-19 travel-associated cases due to a lack of reporting and sharing data of many counties. The identification and implementation of methodologies for measuring traveler's risk to coronavirus would help in minimizing the spread of the virus, especially in the next waves.
Feature Guided Search for Creative Problem Solving Through Tool Construction
Authors: Nair Lakshmi , Chernova Sonia
Published: December 2020

Robots in the real world should be able to adapt to unforeseen circumstances. Particularly in the context of tool use, robots may not have access to the tools they need for completing a task. In this paper, we focus on the problem of tool construction in the context of task planning. We seek to enable robots to construct replacements for missing tools using available objects, in order to complete the given task. We introduce the Feature Guided Search (FGS) algorithm that enables the application of existing heuristic search approaches in the context of task planning, to perform tool construction efficiently. FGS accounts for physical attributes of objects (e.g., shape, material) during the search for a valid task plan. Our results demonstrate that FGS significantly reduces the search effort over standard heuristic search approaches by ≈93% for tool construction.
Protective Effects of Korean Herbal Remedy against Airway Inflammation in an Allergic Asthma by Suppressing Eosinophil Recruitment and Infiltration in Lung
Authors: Yoon Soyon , Song Seokcheon , Shin Jae Woo , Kang Sini , Kim Hye Young , You Hyun Ju
Published: December 2020

The increasing prevalence of allergic asthma has become the world’s major health issue. Current treatments for allergic asthma focus on treating symptoms, while permanent cures still remain undiscovered. In this study, we investigated the effect of Korean traditional herbal remedy, Pyunkang-tang (PGT)—composed of six plants—on asthma alleviation in a mouse model. The PGT mixture was orally gavaged to mice (PM group, 20 mg/mouse/day) from 7 days before sensitization with ovalbumin (OVA) (day −7). On day 0 and day 14, mice from OVA-control (n = 9) and PM group (n = 8) were sensitized with OVA and alum through intraperitoneal injection. On days 18~20, OVA was challenged to mice through nasal injection and sacrificed next day. Cell profile in lung tissue was analyzed by flow cytometry and RT-qPCR analysis, and the number of eosinophils and expression of siglec-F were significantly reduced in the PM group. Lung tissue was examined with hematoxylin and eosin (H&E) and Alcian blue/periodic acid–Schiff (AB-PAS) staining. Noticeably reduced eosinophil infiltration around bronchioles was displayed in the PM group compared to the OVA-control group. Furthermore, PGT-treated mice showed a significant reduction in IL-13 and a mild reduction in IL-5 in lungs. A decreasing tendency of IL-5/13 (+) CD4+ T cells and IL-13(+) innate lymphoid cells (ILCs) and a significant reduction in IL5(+) ILCs were also observed. When treating PGT on murine lung epithelial cells stimulated by papain, there was a significant reduction in IL-33 mRNA expression levels. Taken together, oral delivery of PGT successfully alleviated asthmatic responses provoked by OVA in a mouse model and could lead to novel therapies for allergic asthma.
Degradation Kinetics of Betacyanins during the Pasteurization and Storage of Cactus Pear (Opuntia dillenii Haw.) Juice Using the Arrhenius, Eyring, and Ball Models
Authors: Bassama Joseph , Tamba Abdoulaye , Ndong Moussa , Sarr Khakhila Dieu Donnée , Cissé Mady
Published: December 2020

Betacyanin stability was assessed over temperatures ranging from 60 to 90 °C for cactus pear (Opuntia dillenii Haw.) juice. The juice showed a betacyanin content of 0.76 g/kg. The rate constants for the betacyanin degradation and isothermal kinetic parameters were calculated according to the following three models: Arrhenius, Eyring, and Ball. The fittings of the models were found to be close to one other with SSE values of 0.0964, 0.0964, and 0.0974, respectively. However, because the estimated parameters for the Ball equation happened to be less correlated than the parameters of the other models, this equation was then used for the simulations. The parameters for z and D0 were 42.21 °C and 6.79 × 104 s, respectively. Betacyanins were found to resist typical heat treatment conditions (F70°C values between 100 and 200 min), with a maximum loss of 10% when the temperature was above 80 °C. The time/temperature combinations that could assure both the safety of the product and the preservation of the betacyanins were identified. With Enterococcus faecalis as the reference, when the temperature was 100 °C, the pasteurization time satisfying these two conditions was 0.6 min, whereas it was 180 min when the temperature was 62 °C. The degradation of betacynins during storage was positively correlated with temperature and was accompanied by the appearance of a brown shade.
Optimization of Ultrasound-Assisted Emulsification of Emollient Nanoemulsions of Seed Oil of Passiflora edulis var. edulis
Authors: Guzmán Caterine , Rojas Maritza Adelina , Aragón Marcela
Published: December 2020

Passiflora edulis var. edulis is a plant of commercial interest because of it fruits. The seeds, a by-product in the food industry, can be a source of oil for cosmetic, pharmaceutical and food industries. The aims of this work were to optimize the ultrasonic-assisted emulsification conditions for o/w nanoemulsions and to evaluate the emollient activity of the seed oil. The optimum emulsification conditions were established, using the response surface methodology with a Box-Behnken design (BBD). The emollient activity of seed oil of P. edulis var. edulis was evaluated with healthy volunteers using a cutometer for skin moisture and viscoelasticity measurements. The optimal formulation variables (85.34 W of ultrasonic power, 5.96 irradiation time, 70.65% water and a 5:4 oil:surfactant ratio), resulted in considerable improvement in the properties of the ultrasonically formulated nanoemulsions. Finally, the seed oil of P. edulis var. edulis and the nanoemulsion generated by ultrasound presented emollient activity.
The Effect of Cornering on the Aerodynamics of a Multi-Element Wing in Ground Effect
Authors: Patel Dipesh , Garmory Andrew , Passmore Martin
Published: December 2020

This research investigates the effects of cornering on a multi-element wing in ground effect with the aim to improve the understanding of such in the effort to improve the performance of open-wheel race cars. A numerical validation study was performed to confirm the validity of the Detached Eddy Simulation CFD methodology used. This involved comparing numerical data with wind tunnel experimental data using a force balance and PIV for the velocity field to reveal the trajectory of the trailing vortex system. Once validated, the CFD was used to test the wing within a cornering condition as well as fixed yaw condition and its aerodynamic performance relative to the straight-line condition was analysed. Asymmetry was the general theme concerning the on-surface pressure distribution with this most prominent under the cornering condition. Ultimately, minimal change was observed regarding the downforce generated whilst drag was found to increase in the cornering condition and decrease slightly in the fixed yaw condition. Asymmetry was also observed in the wake of the wing where alterations to the relative strengths of the vortices was observed as well as their downstream paths which was generally governed by the direction of the freestream flow.