bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examination of WHO/INRUD Core Drug Use Indicators at Public Primary Healthcare Centers in Kisii County, Kenya
Authors: Okalebo Faith A. , Guantai Eric M. , Nyabuti Aggrey O. 
Published: March 2020

ABSTRACTBackgroundIrrational drug use is a global problem. However, the extent of the problem is higher in low-income countries. This study set out to assess and characterize drug use at the public primary healthcare centers (PPHCCs) in a rural county in Kenya, using the World Health Organization/ International Network for the Rational Use of Drugs (WHO/INRUD) core drug use indicators methodology.MethodsTen PPHCCs were randomly selected. From each PPHCC, ninety prescriptions from October to December 2018 were sampled and data extracted. Three-hundred (30 per PPHCC) patients and ten (1 per PPHCC) dispensers were also observed and interviewed. The WHO/INRUD core drug use indicators were used to assess the patterns of drug use.ResultsThe average number of drugs per prescription was 2.9 (SD 0.5) (recommended: 1.6– 1.8), percentage of drugs prescribed by generic names was 27.7% (recommended: 100%); the percentage of prescriptions with an antibiotic was 84.8% (recommended: 20.0–26.8%), and with an injection prescribed was 24.9% (recommended: 13.4–24.1%). The percentage of prescribed drugs from the Kenya Essential Medicines List was 96.7% (recommended: 100%). The average consultation time was 4.1 min (SD 1.7) (recommended: ≥10 min), the average dispensing time was 131.5 sec (SD 41.5) (recommended: ≥90 sec), the percentage of drugs actually dispensed was 76.3% (recommended: 100%), the percentage of drugs adequately labeled was 22.6% (recommended: 100%) and percentage of patients with correct knowledge of dispensed drugs was 54.7% (recommended: 100%). Only 20% of the PPHCCs had a copy of KEML available, and 80% of the selected essential drugs assessed were available.ConclusionThe survey shows irrational drug use practices, particularly polypharmacy, non-generic prescribing, overuse of antibiotics, short consultation time and inadequacy of drug labeling. Effective programs and activities promoting the rational use of drugs are the key interventions suggested at all the health facilities.
Transmissibility of coronavirus disease 2019 (COVID-19) in Chinese cities with different transmission dynamics of imported cases
Authors: Chong Ka Chun , Cheng Wei , Zhao Shi , Ling Feng , Mohammad Kirran N. , Wang Maggie Haitian , Zee Benny Chung Ying , Wei Lei , Xiong Xi , Liu Hengyan , Wang Jingxuan , Chen Enfu 
Published: March 2020

AbstractBackgroundMonitoring the time-varying reproduction number (Rt) of the disease is useful in determining whether there is sustained transmission in a population. In this study, we examinedRtof COVID-19 and compared its transmissibility between different intervention periods in Hangzhou and Shenzhen.MethodsDaily aggregated counts of confirmed imported and local cases between January 1, 2020 and March 13, 2020 were analysed. A likelihood function was constructed to estimateRt, accounting for imported cases.ResultsAlthough Hangzhou had fewer number of cases than Shenzhen, Shenzhen had higher proportion of imported cases than Hangzhou (83% vs 29%). Since the epidemic of COVID-19 in Shenzhen was dominated by imported cases,Rtwas kept below unity through time. On the contrary,Rtwas greater than unity in Hangzhou from 16 January to 7 February due to the surge in local cases. Credits to the Wuhan lockdown and outbreak response measures following the local lockdown,Rtdecreased steadily and dropped below unity in mid-February.ConclusionThe lockdown measures and local outbreak responses helped reduce the potential of local transmission in Hangzhou and Shenzhen. Meanwhile, cities with similar epidemic trend could have different transmission dynamics given the variation in imported cases.
Population-wide Screening for Germline Variants of Hereditary Cancer Genes in 12K Unselected Japanese Colorectal Cancers and 27K Controls
Authors: Fujita Masashi , Liu Xiaoxi , Iwasaki Yusuke , Terao Chikashi , Takata Sadaaki , Inai Chihiro , Aoi Tomomi , Maejima Kazuhiro , Hirata Makoto , Murakami Yoshinori , Kamatani Yoichiro , Kubo Michiaki , Akagi Kiwamu , Matsuda Koichi , Nakagawa Hidewaki , Momozawa Yukihide 
Published: March 2020

AbstractBackground & AimsColorectal cancer (CRC) is one of the most common cancers in Western countries and Japan. Currently, a few % of CRCs can be attributed to recognizable hereditary germline variants of known CRC susceptibility genes, predominantly the DNA mismatch repair genes. To establish a universal screening strategy for hereditary CRCs, it is necessary to explore the prevalence of hereditary CRC and pathogenic variants of multiple cancer-predisposing genes in non-European populations.MethodsWe analyzed the coding regions of 27 cancer-predisposing genes, including mismatch repair genes,APC, andBRCA1/2, in 12,503 unselected Japanese CRC patients and 23,705 controls aged ≥ 60 years without any personal or family history of cancer by target sequencing and genome-wide SNP chip data. Their clinical significance was assessed using ClinVar and the guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP).ResultsWe identified 4,804 variants in the 27 genes and annotated them as 397 pathogenic variants, 941 benign variants, and 3,466 variants of uncertain significance, of which 43.6% were registered in neither ClinVar nor dbSNP. In total, 3.3% of the unselected CRC patients and 1.5% of the controls had a pathogenic variant of the 27 genes. The pathogenic variants ofMSH2(odds ratio (OR) =18.1),MLH1(OR=8.6),MSH6(OR=4.9),APC(OR=49.4),BRIP1(OR=3.6),BRCA1(OR=2.6),BRCA2(OR=1.9), andTP53(OR=1.7) were significantly associated with CRC development in the Japanese population (P-values < 0.01, FDR<0.05). Furthermore, we confirmed copy number variants (CNVs) ofMSH2/EPCAM, MLH1, andAPCby multiplex ligation-dependent probe amplification (MLPA) and quantitative PCR in this cohort (n = 23), including whole gene duplications ofMSH2andAPC.These pathogenic variants were significantly associated with the diagnostic age and personal/family history of other types of cancer. In total, at least 3.5% of the Japanese CRC population had a pathogenic variant or CNV of the 27 cancer-predisposing genes.ConclusionsThis is the largest study of CRC heredity in the Asian population and would contribute to the development of guidelines for genetic testing and variant interpretation for heritable CRCs. Universal screening for CRC risk should be assessed in multiple genes, includingBRCA1/2andBRIP1. These data would facilitate risk assessment of cancer and optimize the screening strategy.
Autism and Williams syndrome: dissimilar socio-cognitive profiles with similar patterns of abnormal gene expression in the blood
Authors: Niego Amy , Benítez-Burraco Antonio 
Published: March 2020

AbstractAutism Spectrum Disorders (ASD) and Williams Syndrome (WS) exhibit quite opposite features in the social domain, but also share some common underlying behavioral and cognitive deficits. It is not clear, however, which genes account for the attested differences (and similarities) in the socio-cognitive domain. In this paper we adopted a comparative-molecular approach and looked for genes that might be differentially (or similarly) regulated in the blood of people with these two conditions. We found a significant overlap between differentially-expressed genes compared to neurotypical controls, with most of them exhibiting a similar trend in both conditions, but with genes being more dysregulated in WS than in ASD. These genes are involved in aspects of brain development and function (particularly, dendritogenesis) and are expressed in brain areas (particularly, the cerebellum, the thalamus and the striatum) of relevance for the ASD and the WS etiopathogenesis.
Quality versus quantity: The balance between egg and clutch size among Australian amphibians is related to life history and environmental conditions
Authors: Gould John , Beranek Chad , Valdez Jose , Mahony Michael 
Published: March 2020

AbstractAn inverse relationship between egg and clutch size has been found repeatedly across animal groups, including birds, reptiles and amphibians, and is considered to be a result of resource limitations and physical constraints on the reproducing female. However, few studies have contextualised this relationship with respect to various environmental selecting pressures and life history traits that have also likely influenced the selection of an optimal egg/clutch size combination, while even fewer have tested these interrelationships using robust natural history datasets. In this study, we aimed to test current hypothesises regarding these relationships on both egg and clutch sizes among the Australian Anurans, which to date have not received this kind of investigation. Specifically, we looked at the influence of environmental selecting pressures (egg laying location, environment persistence and bioregion) and life history traits (adult female body size, egg development type, parental care level, breeding period and temporal breeding pattern). As expected, a clear inverse relationship was found between egg and clutch size, while female body size was positively related to both. Generally speaking, smaller clutches of larger eggs tended to be produced by species that i) oviposit terrestrially, ii) showcase direct development and iii) possess high levels of parental care. Temporal breeding pattern was strongly related to clutch size only, with large clutches occurring in explosive breeding species, while breeding habitat was strongly related to egg size only, with large eggs sizes occurring in terrestrial species. Altogether, these findings indicate that numerous factors have likely influenced the evolution of an optimal clutch type in this group, highlighting the importance of incorporating such variables into animal studies on egg and clutch sizes.
An emergent clade of SARS-CoV-2 linked to returned travellers from Iran
Authors: Eden John-Sebastian , Rockett Rebecca , Carter Ian , Rahman Hossinur , de Ligt Joep , Hadfield James , Storey Matthew , Ren Xiaoyun , Tulloch Rachel , Basile Kerri , Wells Jessica , Byun Roy , Gilroy Nicky , O’Sullivan Matthew V , Sintchenko Vitali , Chen Sharon C , Maddocks Susan , Sorrell Tania C , Holmes Edward C , Dwyer Dominic E , Kok Jen ,   for the 2019-nCoV Study Group
Published: March 2020

AbstractThe SARS-CoV-2 epidemic has rapidly spread outside China with major outbreaks occurring in Italy, South Korea and Iran. Phylogenetic analyses of whole genome sequencing data identified a distinct SARS-CoV-2 clade linked to travellers returning from Iran to Australia and New Zealand. This study highlights potential viral diversity driving the epidemic in Iran, and underscores the power of rapid genome sequencing and public data sharing to improve the detection and management of emerging infectious diseases.
A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein
Authors: Joyce M. Gordon , Sankhala Rajeshwer S. , Chen Wei-Hung , Choe Misook , Bai Hongjun , Hajduczki Agnes , Yan Lianying , Sterling Spencer L. , Peterson Caroline E. , Green Ethan C. , Smith Clayton , de Val Natalia , Amare Mihret , Scott Paul , Laing Eric D. , Broder Christopher C. , Rolland Morgane , Michael Nelson L. , Modjarrad Kayvon 
Published: March 2020

SUMMARYSARS-CoV-2 is a zoonotic virus that has caused a pandemic of severe respiratory disease—COVID-19— within several months of its initial identification. Comparable to the first SARS-CoV, this novel coronavirus’s surface Spike (S) glycoprotein mediates cell entry via the human ACE-2 receptor, and, thus, is the principal target for the development of vaccines and immunotherapeutics. Molecular information on the SARS-CoV-2 S glycoprotein remains limited. Here we report the crystal structure of the SARS-CoV-2 S receptor-binding-domain (RBD) at a the highest resolution to date, of 1.95 Å. We identified a set of SARS-reactive monoclonal antibodies with cross-reactivity to SARS-CoV-2 RBD and other betacoronavirus S glycoproteins. One of these antibodies, CR3022, was previously shown to synergize with antibodies that target the ACE-2 binding site on the SARS-CoV RBD and reduce viral escape capacity. We determined the structure of CR3022, in complex with the SARS-CoV-2 RBD, and defined a broadly reactive epitope that is highly conserved across betacoronaviruses. This epitope is inaccessible in the “closed” prefusion S structure, but is accessible in “open” conformations. This first-ever resolution of a human antibody in complex with SARS-CoV-2 and the broad reactivity of this set of antibodies to a conserved betacoronavirus epitope will allow antigenic assessment of vaccine candidates, and provide a framework for accelerated vaccine, immunotherapeutic and diagnostic strategies against SARS-CoV-2 and related betacoronaviruses.HIGHLIGHTSHigh resolution structure of the SARS-CoV-2 Receptor-Binding-Domain (RBD).Recognition of the SARS-CoV-2 RBD by SARS-CoV antibodies.Structure of the SARS-COV-2 RBD in complex with antibody CR3022.Identification of a cryptic site of vulnerability on the SARS-CoV-2 Spike.
Accurate Diagnosis of Colorectal Cancer Based on Histopathology Images Using Artificial Intelligence
Authors: Wang Kuan-Song , Yu Gang , Xu Chao , Meng Xiang-He , Zhou Jianhua , Zheng Changli , Deng Zhenghao , Shang Li , Liu Ruijie , Su Shitong , Zhou Xunjian , Li Qingling , Li Juanni , Wang Jing , Ma Kewen , Qi Jialin , Hu Zhenmin , Tang Ping , Deng Jeffrey , Qiu Xiang , Li Bo-Yang , Shen Wen-Di , Quan Ru-Ping , Yang Jun-Ting , Huang Lin-Ying , Xiao Yao , Yang Zhi-Chun , Li Zhongming , Wang Sheng-Chun , Ren Hongzheng , Liang Changjiang , Guo Wei , Li Yanchun , Xiao Heng , Gu Yonghong , Yun Jing-Ping , Huang Dan , Song Zhigang , Fan Xiangshan , Chen Ling , Yan Xiaochu , Li Zhi , Huang Zhong-Chao , Huang Jufang , Luttrell Joseph , Zhang Chao-Yang , Zhou Weihua , Zhang Kun , Yi Chunhui , Shen Hui , Wang Yu-Ping , Xiao Hong-Mei , Deng Hong-Wen 
Published: March 2020

AbstractBackgroundAccurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients’ treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on their daily image analyses.MethodsBased on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC prediction/diagnosis using weakly labeled pathological whole slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, >14,680 WSIs, from >9,631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, U.S., and Germany.ResultsOur innovative AI tool was consistently nearly perfectly agreed with (average Kappa-statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multi-centers. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.981 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells.ConclusionsThis first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. Hence, it will drastically alleviate the heavy clinical burden of daily pathology diagnosis, and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.
Master Regulator Analysis of the SARS-CoV-2/Human interactome
Authors: Guzzi Pietro Hiram , Mercatelli Daniele , Ceraolo Carmine , Giorgi Federico M. 
Published: March 2020

Abstractthe recent epidemic outbreak of a novel human coronavirus called SARS-CoV-2 and causing the respiratory tract disease COVID-19 has reached worldwide resonance and a global effort is being undertaken to characterize the molecular features and evolutionary origins of this virus. In this paper, we set out to shed light on the SARS-CoV-2/host receptor recognition, a crucial factor for successful virus infection. Based on the current knowledge of the interactome between SARS-CoV-2 and host cell proteins, we performed Master Regulator Analysis to detect which parts of the human interactome are most affected by the infection. We detected, amongst others, affected apoptotic and mitochondrial mechanisms, and a downregulation of the ACE2 protein receptor, notions that can be used to develop specific therapies against this new virus.
Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
Authors: Lv Huibin , Wu Nicholas C. , Tsang Owen Tak-Yin , Yuan Meng , Perera Ranawaka A. P. M. , Leung Wai Shing , So Ray T. Y. , Chun Chan Jacky Man , Yip Garrick K. , Hong Chik Thomas Shiu , Wang Yiquan , Chung Choi Chris Yau , Lin Yihan , Ng Wilson W. , Zhao Jincun , Poon Leo L. M. , Malik Peiris J. S. , Wilson Ian A. , Mok Chris K. P. 
Published: March 2020

AbstractThe World Health Organization has recently declared the ongoing outbreak of COVID-19, which is caused by a novel coronavirus SARS-CoV-2, as pandemic. There is currently a lack of knowledge in the antibody response elicited from SARS-CoV-2 infection. One major immunological question is concerning the antigenic differences between SARS-CoV-2 and SARS-CoV. We address this question by using plasma from patients infected by SARS-CoV-2 or SARS-CoV, and plasma obtained from infected or immunized mice. Our results show that while cross-reactivity in antibody binding to the spike protein is common, cross-neutralization of the live viruses is rare, indicating the presence of non-neutralizing antibody response to conserved epitopes in the spike. Whether these non-neutralizing antibody responses will lead to antibody-dependent disease enhancement needs to be addressed in the future. Overall, this study not only addresses a fundamental question regarding the antigenicity differences between SARS-CoV-2 and SARS-CoV, but also has important implications in vaccine development.
GAS6-AXL signaling triggers actin remodeling and macropinocytosis that drive cancer cell invasion
Authors: Zdżalik-Bielecka Daria , Poświata Agata , Kozik Kamila , Jastrzębski Kamil , Schink Kay Oliver , Brewińska-Olchowik Marta , Piwocka Katarzyna , Stenmark Harald , Miączyńska Marta 
Published: March 2020

AbstractAXL, a member of the TAM (TYRO3, AXL, MER) receptor tyrosine kinase family, and its ligand GAS6 are implicated in oncogenesis and metastasis of many cancer types. However, the exact cellular processes activated by GAS6-AXL remain largely unexplored. Here, we identified an interactome of AXL and revealed its associations with proteins regulating actin dynamics. Consistently, GAS6-mediated AXL activation triggered actin remodeling manifested by peripheral membrane ruffling and circular dorsal ruffles (CDRs). This further promoted macropinocytosis that mediated the internalization of GAS6-AXL complexes and sustained survival of glioblastoma cells grown under glutamine-deprived conditions. GAS6-induced CDRs contributed to focal adhesion (FA) turnover, cell spreading and elongation. Consequently, AXL activation by GAS6 drove invasion of cancer cells in a spheroid model. All these processes required the kinase activity of AXL but not TYRO3, and downstream activation of PI3K. We propose that GAS6-AXL signaling induces multiple actin-driven cytoskeletal rearrangements and macropinocytosis that jointly contribute to cancer cell invasion.
Emergence of evidence during disease outbreaks: lessons learnt from the Zika virus outbreak
Authors: Counotte Michel J , Meili Kaspar W , Low Nicola 
Published: March 2020

AbstractIntroductionOutbreaks of infectious diseases trigger an increase in scientific research and output. Early in outbreaks, evidence is scarce, but it accumulates rapidly. We are continuously facing new disease outbreaks, including the new coronavirus (SARS-nCoV-2) in December 2019.The objective of this study was to describe the accumulation of evidence during the 2013-2016 Zika virus (ZIKV) outbreak in the Pacific and the Americas related to aetiological causal questions about congenital abnormalities and Guillain-Barré syndrome.MethodsWe hypothesised that the temporal sequence would follow a pre-specified order, according to study design. We assessed 1) how long it takes before findings from a specific study design appear, 2) how publication of preprints could reduce the time to publication and 3) how time to publication evolves over time.ResultsWe included 346 publications published between March 6, 2014 and January 1, 2019. In the 2013-–2016 ZIKV outbreak, case reports, case series and basic research studies were published first. Case-control and cohort studies appeared between 400–700 days after ZIKV was first detected in the region of the study origin. Delay due to the publication process were lowest at the beginning of the outbreak. Only 4.6% of the publications was available as preprints.DiscussionThe accumulation of evidence over time in new causal problems generally followed a hierarchy. Preprints reduced the delay to initial publication. Our methods can be applied to new emerging infectious diseases.
Gut microbiota impacts bone via B.vulgatus-valeric acid-related pathways
Authors: Lin Xu , Xiao Hong-Mei , Liu Hui-Min , Lv Wan-Qiang , Greenbaum Jonathan , Yuan Si-Jie , Gong Rui , Zhang Qiang , Chen Yuan-Cheng , Peng Cheng , Xu Xue-Juan , Pan Dao-Yan , Chen Zhi , Li Zhang-Fang , Zhou Rou , Wang Xia-Fang , Lu Jun-Min , Ao Zeng-Xin , Song Yu-Qian , Zhang Yin-Hua , Su Kuan-Jui , Meng Xiang-He , Ge Chang-Li , Lv Feng-Ye , Shi Xing-Ming , Zhao Qi , Guo Bo-Yi , Yi Neng-Jun , Shen Hui , Papasian Christopher J. , Shen Jie , Deng Hong-Wen 
Published: March 2020

AbstractAlthough gut microbiota influences osteoporosis risk, the individual species involved, and underlying mechanisms, are unknown. We performed integrative analyses in a Chinese cohort with metagenomics/targeted metabolomics/whole-genome sequencing. Bacteroides vulgatus was found negatively associated with bone mineral density (BMD), this association was validated in US Caucasians. Serum valeric acid was positively associated with BMD, and B.vulgatus causally downregulated it. Ovariectomized mice fed B.vulgatus had decreased bone formation and increased bone resorption, lower BMD and poorer bone micro-structure. Valeric acid suppressed NF-κB p65 protein production (pro-inflammatory), and enhanced IL-10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells, and enhanced maturation of osteoblasts in vitro. B.vulgatus and valeric acid represent promising targets for osteoporosis prevention/treatment.