bluuebunny/crossref_metadata_2025_split huggingface dataset:
Instant diagnosis of gastroscopic biopsy via deep-learned single-shot femtosecond stimulated Raman histology
Authors: Liu Zhijie , Su Wei , Ao Jianpeng , Wang Min , Jiang Qiuli , He Jie , Gao Hua , Lei Shu , Nie Jinshan , Yan Xuefeng , Guo Xiaojing , Zhou Pinghong , Hu Hao , Ji Minbiao 
Published: December 2021

Abstract
Gastroscopic biopsy provides the only effective way for gastric cancer diagnosis, but the gold standard histopathology is time-consuming and incompatible with gastroscopy. Conventional stimulated Raman scattering (SRS) microscopy has shown promise in label-free diagnosis on human tissues, yet it requires the tuning of picosecond lasers to achieve chemical specificity at the cost of time and complexity. Here, we demonstrated single-shot femtosecond SRS (femto-SRS) could reach the maximum speed and sensitivity with preserved chemical resolution by integrating with U-Net. Fresh gastroscopic biopsy was imaged in < 60 seconds, revealing essential histoarchitectural hallmarks perfectly agreed with standard histopathology. Moreover, a diagnostic neural network (CNN) was constructed based on images from 279 patients that predicts gastric cancer with accuracy > 96%. We further demonstrated semantic segmentation of intratumor heterogeneity and evaluation of resection margins of endoscopic submucosal dissection (ESD) tissues to simulate rapid and automated intraoperative diagnosis. Our method holds potential for synchronizing gastroscopy and histopathological diagnosis.
Alterations in Co-abundant Bacteriome in Colorectal Cancer and Persistent Microbial Dysbiosis After Surgery
Authors: Png Chin-Wen , Chua Yong-Kang , Law Jia-Hao , Zhang Yongliang , Tan Ker-Kan 
Published: December 2021

Abstract
ObjectiveThere is growing interest in the role of gut microbiome in colorectal cancer (CRC), ranging from screening to disease recurrence. Our study aims to identify microbial markers characteristic of CRC and to examine if changes in bacteriome persist after surgery. Design49 fecal samples from non-cancer (NC) individuals and CRC patients, before and after surgery, were collected for analysis by bacterial 16S rRNA gene sequencing. ResultsBacterial richness and diversity were reduced in the CRC patients compared to NC individuals. Pro-carcinogenic bacteria such as Bacteroides fragilis and Odoribacter splanchnicus were increased in pre-op CRC compared to NC group. These differences were no longer observed after surgery. Comparison between post- and pre-op CRC showed increased abundance of probiotic bacteria after surgery. Concomitantly, bacteria associated with CRC progression were observed to have increased after surgery, implying persistent dysbiosis. ConclusionMicrobiome signatures characteristic of CRC likely comprise a set of significant alteration in specific bacterial strains. Elements of these dysbiotic signatures persists even after surgery, suggesting possible field-change in remnant non-diseased colon. Future studies should seek to examine if these signatures are also associated with pre-malignant colonic polyps and, explore if these profiles can be used to guide CRC screening and surveillance.
Selecting Essential Factors for Predicting Reference Crop Evapotranspiration Through Tree-based Machine Learning and Bayesian Optimisation
Authors: Zhao Long , Zhao Xinbo , Shi Yi , Wang Yuhang , Cui Ningbo , Zhang Shuo 
Published: December 2021

Abstract
Reference crop evapotranspiration (ETO) is a basic component of the hydrological cycle, and its estimation is critical for agricultural water resource management and scheduling. In this study, three tree-based machine learning algorithms (random forest [RF], gradient boosting decision tree [GBDT], and extreme gradient boosting [XGBoost]) were adopted to determine the essential factors for ETO prediction. The tree-based models were optimised using the Bayesian optimisation (BO) algorithm, and they were compared with three standalone models in terms of daily ETO and monthly mean ETO estimation in North China, with different input combinations of essential variables. The results indicated that solar radiation (Rs) and air temperature (Ts), including the maximum, minimum, and average temperature, in daily ETO were the key parameters affecting model prediction accuracy. Rs was the most influential factor in the monthly average ETO model, followed by Ts. Both relative humidity (RH) and wind speed at 2 m (U2) had little impact on ETO prediction at different scales, although their importance differed. Compared with the GBDT and RF models, the XGBoost model exhibited the highest performance for daily ETO and monthly mean ETO estimation. The hybrid tree-based models with the BO algorithm outperformed the standalone tree-based models. Overall, compared with other inputs, the model with three inputs (Rs, Ts, and RH/U2) had the highest accuracy. The BO-XGBoost model exhibited superior performance in terms of the global performance index (GPI) for daily ETO and monthly mean ETO prediction and it is recommended as a more accurate model predicting daily ETO and monthly mean ETO in North China or areas with a similar climate.
Higher Expectancy of Acupuncture Treatment is Associated with Significant Higher Ovulation, Less Bruising and Lower Dropout in Infertile Women with PCOS Receiving Acupuncture
Authors: Gong Yi , Li Jian , Ma Hong-Li , He Hui , Wu Xiao-Ke 
Published: December 2021

Abstract
Object: To study the expectancy of acupuncture treatment on fertility outcomes and adverse events in infertile women with polycystic ovary syndrome (PCOS) receiving acupuncture. Method: This analysis including 1000 infertile women with PCOS. Women with available expectancy of acupuncture treatment were included in analysis, of whom were subdivided into low and high expectancy groups. The anthropometric and endocrinal parameters, fertility outcomes as well as adverse events and dropout were compared. The risk of low expectancy of acupuncture treatment on ovulation and correspondent 95% confidence interval was computed by multivariable logistic regression model. The Kaplan Meier survival curve was employed to plot the time to ovulation and Cox regression model was used to compare the difference of time to ovulation between groups, adjusting by interventions. Results: 827 women were included in analysis, of whom 373 and 454 women were identified as low and high expectancy, respectively. Compared with low expectancy, women with high expectancy had higher BMI (24.56 vs 23.77 kg/m2, p = 0.03), shorter time to attempt to conception (22.97 vs. 25.00 months, p = 0.03), earlier menarche (13.61vs.13.68 years, p = 0.03) and lower estradiol (256.68 vs. 284.13 pmol/L, p = 0.03). There was not interaction between acupuncture treatment and expectancy of acupuncture treatment regarding ovulation (p = 0.07). High expectancy was associated with significant higher ovulation (adjusted odds ratio (OR) 2.33, 95% CI 1.31 to 4.16, p = 0.004) and lower dropout (adjusted OR 0.13, 95%CI 0.03 to 0.57) in women receiving control acupuncture, even after adjustment by BMI, estradiol, and clomiphene, while it was associated with significant less bruising (adjusted OR 0.28, 95%CI 0.13-0.61) and lower dropout (adjusted OR 0.42, 95%CI 0.18-0.96) in those receiving active acupuncture. High expectancy was associated with significant shorter time to ovulation (median 28 vs 49 days, P < 0.001) in women received control acupuncture, yet it was no longer significant after adjustment for clomiphene. Conclusion: High expectancy of acupuncture treatment was associated with significant higher ovulation, less bruising and lower dropout, but not other fertility outcome in infertile women with PCOS receiving acupuncture. Trial Registration:ClinicalTrial.gov number: NCT01573858 and chictr.org.cn number: ChiCTR-TRC-12002081.
Assessing The Performance of Physician’s Prescribing Preference As An Instrumental Variable in Comparative Effectiveness Research With Moderate and Small Sample Sizes: A Simulation Study
Authors: Zhang Lisong , Lewsey Jim , McAllister David 
Published: December 2021

Abstract
BackgroundInstrumental variable (IV) analyses are used to account for unmeasured confounding in Comparative Effectiveness Research (CER) in pharmacoepidemiology. To date, simulation studies assessing the performance of IV analyses have been based on large samples. However, in many settings, sample sizes are not large.Objective In this simulation study, we assess the utility of Physician’s Prescribing Preference (PPP) as an IV for moderate and smaller sample sizes.MethodsWe designed a simulation study in a CER setting with moderate (around 2500) and small (around 600) sample sizes. The outcome and treatment variables were binary and three variables were used to represent confounding (a binary and a continuous variable representing measured confounding, and a further continuous variable representing unmeasured confounding). We compare the performance of IV and non-IV approaches using two-stage least squares (2SLS) and ordinary least squares (OLS) methods, respectively. Further, we test the performance of different forms of proxies for PPP as an IV.ResultsThe PPP IV approach results in a percent bias of approximately 20%, while the percent bias of OLS is close to 60%. The sample size is not associated with the level of bias for the PPP IV approach. However, smaller sample sizes led to lower statistical power for the PPP IV. Using proxies for PPP based on longer prescription histories result in stronger IVs, partly offsetting the effect on power of smaller sample sizes.Conclusion Irrespective of sample size, the PPP IV approach leads to less biased estimates of treatment effectiveness than conventional multivariable regression adjusting for known confounding only. Particularly for smaller sample sizes, we recommend constructing PPP from long prescribing histories to improve statistical power.
Atomistic Mechanisms of Human TRPA1 Activation By Electrophile Irritants Through Molecular Dynamics Simulation and Mutual Information Analysis
Authors: Habgood Matthew , Seiferth David , Zaki Afroditi-Maria , Alibay Irfan , Biggin Philip 
Published: December 2021

Abstract
The ion channel TRPA1 is a promiscuous chemosensor, with reported response to a wide spectrum of noxious electrophilic irritants, as well as cold, heat, and mechanosensation. It is also implicated in the inception of itch and pain and has hence been investigated as a drug target for novel analgesics. The mechanism of electrophilic activation for TRPA1 is therefore of broad interest. TRPA1 structures with the pore in both open and closed states have recently been published as well as covalent binding modes for electrophile agonists. However, the detailed mechanism of coupling between electrophile binding sites and the pore remains speculative. In addition, while two different cysteine residues (C621 and C665) have been identified as critical for electrophile bonding and activation, the bound geometry has only been resolved at C621. Here, we use molecular dynamics simulations of TRPA1 in both pore-open and pore-closed states to explore the allosteric link between the electrophile binding sites and pore stability. Our simulations reveal that an open pore is structurally stable in the presence of open ‘pockets’ in the C621 / C665 region, but rapidly collapses and closes when these pockets are shut. Binding of electrophiles at either C621 or C665 provides stabilisation of the pore-open state, but molecules bound at C665 are shown to be able to rotate in and out of the pocket, allowing for immediate stabilisation of transient open states. Finally, mutual information analysis of trajectories reveals an informational path linking the electrophile binding site pocket to the pore via the voltage-sensing-like domain, giving a detailed insight into the how the pore is stabilized in the open state.
Identification of Novel Chemical Entities for Mirk/Dyrk1B Receptor Using Molecular Modeling and Molecular Dynamic Approaches
Authors: Vanajothi Ramar , Bhavaniramya Sundaresan , Umadevi Muthu , Vijayakumar Rajendran , Alqurashi Yaser E. , Premkumar Kumpati 
Published: December 2021

Abstract
Cancer is a major health problem worldwide and one of the leading death-causing diseases. Mirk (Minibrain-related kinase is a member of the dual-specificity tyrosine-phosphorylation-regulated kinase (Dyrk) family that is highly upregulated in various solid tumors and mediates cell survival including lung cancer. Mirk effectively increases the expression of a series of antioxidant genes, which scavenge the reactive oxygen species and stabilize the p27kip1 that maintain the viability of the quiescent cancer cell and also mediates the cell cycle and survival of cancer cells by influencing the MAPK/ERK signaling pathway. Hence, Mirk acts as a novel therapeutic target for cancer prevention. Owing to the unavailability of the three-dimensional structure of Mirk, in the present study, we have modeled the 3D structure of Mirk, based on the crystal structure of Dyrk1a as a template, and subsequently used it as a target for virtual screening and molecular docking against a small molecule database. Based on the visual inspection, four best hits such as Chembridge_ID 7768949, 7771055, 7758866, and 7764195 have high binding affinity, good docking score, and pharmacokinetic properties were shortlisted. Further, the dynamic stability of lead molecules with modeled Mirk/Dyrk1B was evaluated using 10 ns molecular dynamics simulation approach. The four hit molecules exhibited good and stable binding complex in the binding pocket of the target protein. Collectively the finding of this study suggested that the identified molecules may serve as potential effective anti-cancer inhibitors for cancer prevention.
Ultrasound-guided Serratus Anterior Plane Block Versus Thoracic Paravertebral Block on Alleviating the Acute and Chronic Pain Following the Video-assisted Thoracic Surgery: a Prospective, Randomized, Double-blinded Non-inferiority Clinical Trial
Authors: Wang Yan , Hao Jing , Huang Simin , Gu Xiaoping , Ma Zhengliang 
Published: December 2021

Abstract
The authors have requested that this preprint be removed from Research Square.
Design, Synthesis and Biological Evaluation of Indoline Derivatives as Multifunctional Agents for the Treatment of Ischemic Stroke
Authors: Du Shuaishuai , Jin Fan , Li Jiaming , Ma Xiaodong , Wang Hongwei , Qian Shihu 
Published: December 2021

Abstract
In this work, a series of indoline derivatives as multifunctional neuroprotective agents for battling ischemic stroke were designed, synthesized, and biologically evaluated. In antioxidant assay, all compounds showed significant protective effects against H2O2-induced death of RAW 264.7 cells. In oxygen glucose deprivation/reperfusion (OGD/R)-induced neuronal damage, some compounds significantly elevated the cell survival rate. Among them, 7i, 7j and 7r exerted comparable neuroprotective effects to Ifenprodil, and exhibited binding affinity to N-methyl-D-aspartic acid receptors 2B (NMDA-GluN2B). At the concentrations of 0.1, 1 and 10 μM, 7i, 7j and 7r dose-dependently lowered the LPS-induced secretion of inflammatory cytokines, including TNF-α, IL-6 and NO, by BV-2 cells. Importantly, 7i and 7j can dramatically reduce the cerebral infarction rate and improve neurological deficit scores in middle cerebral artery occlusion (MCAO) rat model. As demonstrated by the above results, 7i and 7j are potential neuroprotective agents for the treatment of ischemic stroke.
Hyperbaric Oxygen Combined with Alginate Oligosaccharide Delay D-gal-induced Liver, Kidney and Spleen Senescence in Mice by Attenuating Oxidative Stress
Authors: Wang Gui-Mei , Zheng Xiao-yue , Wang Pei-Song , Wan Jin-E , Gu Jian , Chen Ming , Long Ying , Mao Yongjun 
Published: December 2021

Abstract
Objectives Hyperbaric oxygen treatment (HBOT) is an adjuvant therapy progressively applied in the treatment of clinical diseases, and alginate oligosaccharide (AOS) is a natural polysaccharide with excellent antioxidant property. In this study, the effects of HBOT combined with AOS on the senescence on liver, kidney and spleen were investigated in a D-galactose (D-gal) -induced senescent mice model. Results The findings indicated that HBOT combined with AOS could delay D-gal-induced aging of liver, kidney and spleen in mice. Specifically, HBOT combined with AOS improved the daily behavior and organ indices of mice. Biochemical and morphological analyses of all tissues indicated that HBOT combined with AOS markedly decreased the unusual elevation of ALT, AST and CREA induced by D-gal, alleviated pathological injury, and significantly enhanced the capacity of antioxidant defense system of mice, including increaing T-SOD, CAT AND GSH-Px activities and decreasing MDA content . In addition, Western Blot results indicated that HBOT combined with AOS also inhibited the overexpression of aging-related proteins p53 and p16. Conclusions To some extent, these findings suggest that HBOT combined with AOS has significant anti-senescence potential in D-gal-induced senescent mice, and the underlying factors may be correlated with the enhancement of antioxidant defense capacity.
Development and Validation of a Risk Score to Predict the Frequent use of Emergency House Calls among Older People who Receive Regular Home Visits
Authors: Sun Yu , Iwagami Masao , Sakata Nobuo , Ito Tomoko , Inokuchi Ryota , Uda Kazuaki , Hamada Shota , Ishimaru Miho , Komiyama Jun , Kuroda Naoaki , Yoshie Satoru , Ishizaki Tatsuro , Iijima Katsuya , Tamiya Nanako 
Published: December 2021

Abstract
Background: Demand for home care services is increasing in Japan, and a 24-hour on-call system could be a burden for primary care physicians. Identifying high-risk patients who need frequent emergency house calls could help physicians prepare and allocate medical resources. The aim of the present study was to develop a risk score to predict the frequent use of emergency house calls in patients who receive regular home visits.Methods: We conducted a retrospective cohort study with linked medical and long-term care claims data from two Japanese cities. Participants were ≥65 years of age and had newly started regular home visits between July 2014 and March 2018 in Tsukuba city and between July 2012 and March 2017 in Kashiwa city. A total of 4,888 eligible patients were randomly divided into a derivation cohort (n=3,259) and a validation cohort (n=1,629). The primary outcome was the frequent use of emergency house calls, defined as the use once per month or more on average during each observation period. We considered pre-specified variables, such as age, gender, medical procedure performed in home health care, long-term care need level, and medical diagnosis at the start of the regular home visit. We used the least absolute shrinkage and selection operator (Lasso) method to select predictor variables. Results: The frequent use of emergency house calls was observed in 13.0% participants (424/3,259) in the derivation cohort and 12.9% participants (210/1,629) in the validation cohort. The risk score included three variables with the following point assignments: home oxygen therapy (4 points); care need level 4-5 (2 point); cancer (5 point). The area under the curve (AUC) in the derivation cohort was 0.708, whereas the AUC of a model that included all pre-specified variables was 0.729. The AUC in the derivation cohort was 0.708, showing moderate discrimination. Conclusions: This easy-to-use risk score would be useful for assessing high-risk patients and would allow the burden on primary care physicians to be reduced through measures such as clustering high-risk patients in well-equipped medical facilities.
DHCR24 Promotes Melanoma Stem-Like Cells Formation and Mediates Vemurafenib Resistance by Accumulating 27-Hydroxycholesterol
Authors: Zhong Feiliang , Chen Tingting , Liu Jia , Wang Ying , Yao Mingdong , Li Bo 
Published: December 2021

Abstract
Background: Melanoma is the most serious skin cancer with gradually increased incidence and poor prognosis mainly as the result of cancer stem cell (CSC) expansion and drug resistance. Some studies have suggested that dysregulated cholesterol homeostasis increasing tumorigenicity and metastasis in cancers. In the present study, our objective was to elucidate the contribution of 24-Dehydrocholesterol reductase (DHCR24) towards melanoma progression and drug resistance.Methods: Immunohistochemistry and HE staining were performed for determing the expression of DHCR24 in melanoma patients, lentivirus perturbation and functional assays were used to evaluate the ability of turmorigenesis of DHCR24 altered melanoma cells and melanoma stem-like cells. RNA sequencing (RNA-seq) and targeted metabolomics were carried out for identifying metabolites which contributes melanoma stem-like cell expansion and vemurafenib treatment resistance.Results: DHCR24 was over-expressed in melanoma patients while knockdown of DHCR24 blocked melanoma cells in S phase and lead to significant inhibition in proliferation and migration. Meanwhile, forced expression of DHCR24 promotes the growth of melanoma cells in xenograft mice. We further demonstrated that DHCR24 promotes the proliferation of melanoma stem-like cell populations by activating Rap1/AKT signaling and result in accumulation of cellular 27-Hydroxycholesterol (27-HC) contents. Next, we validated that both CYP27A1 and 27-HC administration contributed to melanoma stem-like cells formation and vemurafenib resistance through AKT-308/309 phosphorylation. Conclusions: Our data confirmed the oncogenic role of DHCR24 in melanoma stem-like cells proliferation and vemurafenib resistance by regulating 27-HC. These findings established the basis of targeting DHCR24 as a potential therapeutic target for advanced melanoma.
Salvage Techniques for Difficult Biliary Cannulation: A Retrospective Study of 1021 Endoscopic Retrograde Cholangiopancreatography Cases in a Tertiary Referral Center
Authors: Maruta Shikiko , Sugiyama Harutoshi , Ogasawara Sadahisa , Sugihara Chihei , Ouchi Mayu , Kan Motoyasu , Yamada Toshihito , Miura Yoshifumi , Nagashima Hiroki , Takahashi Koji , Kusakabe Yuko , Ohyama Hiroshi , Okitsu Koichiro , Ohno Izumi , Mikata Rintaro , Sakai Yuji , Tsuyuguchi Toshio , Kato Jun , Kato Naoya 
Published: December 2021

Abstract
Although some salvage techniques have been developed to overcome difficult biliary cannulation in endoscopic retrograde cholangiopancreatography (ERCP), few reports analyzed the choice of techniques and their clinical outcomes in large cohorts. This study aimed to evaluate the outcomes of biliary cannulation in patients with initial treatment papillae. We retrospectively identified 1021 patients who underwent initial ERCP from January 2013 to March 2020. We investigated background factors, treatment details, success rates, and adverse event rates. Then we analyzed a series of treatment processes, including salvage techniques such as double guidewire technique (DGT), needle knife pre-cutting (NKP), and transpancreatic pre-cut papillotomy (TPPP). The initial ERCP success rate was 94.3%, and the eventual success rate was 98.3%. Salvage techniques were required in 380 of 1021 patients (37.2%), associated with long oral protrusion (OR, 2.38; 95% CI, 1.80–3.15; p < 0.001). A total of 503 cases (49.3%) had long oral protrusions, 47.5% of which required the salvage techniques, much higher than 27.5% of not-long cases. Patients with long oral protrusions had a higher frequency of NKP. In conclusion, patients with long oral protrusions frequently required salvage techniques. Appropriate strategies and salvage techniques may help to overcome many difficult biliary cannulation cases.