bluuebunny/crossref_metadata_2025 huggingface dataset:
New Tetramic Acid Derivatives From the Deep-Sea-Derived Fungus Penicillium sp. SCSIO06868 With SARS-CoV-2 Mpro Inhibitory Activity Evaluation
Authors: Pang Xiaoyan , Chen Weihao , Wang Xin , Zhou Xuefeng , Yang Bin , Tian Xinpeng , Wang Junfeng , Xu Shihai , Liu Yonghong
Published: September 2021

Three new tetramic acid derivatives (1–3) and a new polyketide (4) along with eight known compounds (5–12) were isolated from cultures of the deep-sea-derived fungus Penicillium sp. SCSIO06868. Four new structures were elucidated by analysis of one-dimensional/two-dimensional nuclear magnetic resonance (NMR) data and high-resolution electrospray ionization mass spectrometry. Their absolute configurations were established by X-ray crystallography analysis and comparison of the experimental and reported electronic circular dichroism (ECD) values or specific optical rotation. Compound 3 exhibited potent, selective inhibitory activities against Staphylococcus aureus and methicillin-resistant S. aureus with minimum inhibitory concentration values of both 2.5 μg/ml. Also, compound 3 showed weak antiviral activity against severe acute respiratory syndrome coronavirus 2 main protease, which was responsible for the coronavirus disease 2019 pandemic.
Biological and Molecular Characterization of a Jumbo Bacteriophage Infecting Plant Pathogenic Ralstonia solanacearum Species Complex Strains
Authors: Ahmad Abdelmonim Ali , Addy Hardian Susilo , Huang Qi
Published: September 2021

A jumbo phage infecting Ralstonia solanacearum species complex strains, designated RsoM2USA, was isolated from soil of a tomato field in Florida, United States, and belongs to the family Myoviridae. The phage has a long latent period of 270 min and completed its infection cycle in 360 min with a burst size of approximately 32 particles per cell. With a genome size of 343,806 bp, phage RsoM2USA is the largest Ralstonia-infecting phage sequenced and reported to date. Out of the 486 ORFs annotated for RsoM2USA, only 80 could be assigned putative functions in replication, transcription, translation including 44 tRNAs, and structure with the main structural proteins experimentally confirmed. Phylogenetic analyses placed RsoM2USA in the same clade as Xanthomonas phage XacN1, prompting a proposal of a new genus for the two jumbo phages. Jumbo phage RsoM2USA is a lytic phage and has a wide host range, infecting each of the three newly established Ralstonia species: R. solanacearum, R. pseudosolanacearum, and R. syzygii, and significantly reduced the virulence of its susceptible R. solanacearum strain RUN302 in tomato plants, suggesting that this jumbo phage has the potential to be developed into an effective control against diseases caused by R. solanacearum species complex strains.
Mitigating Long-Term COVID-19 Consequences on Brain Health
Authors: D'Arcy Ryan C. N. , Sandhu Jagdeep K. , Marshall Shawn , Besemann Markus
Published: September 2021

COVID-19 is increasingly being linked to brain health impacts. The emerging situation is consistent with evidence of immunological injury to the brain, which has been described as a resulting “brain fog.” The situation need not be medicalized but rather clinically managed in terms of improving resilience for an over-stressed nervous system. Pre-existing comparisons include managing post-concussion syndromes and/or brain fog. The objective evaluation of changes in cognitive functioning will be an important clinical starting point, which is being accelerated through pandemic digital health innovations. Pre-morbid brain health can significantly optimize risk factors and existing clinical frameworks provide useful guidance in managing over-stressed COVID-19 nervous systems.
Application of Machine Learning Techniques to Identify Data Reliability and Factors Affecting Outcome After Stroke Using Electronic Administrative Records
Authors: Rana Santu , Luo Wei , Tran Truyen , Venkatesh Svetha , Talman Paul , Phan Thanh , Phung Dinh , Clissold Benjamin
Published: September 2021

Aim: To use available electronic administrative records to identify data reliability, predict discharge destination, and identify risk factors associated with specific outcomes following hospital admission with stroke, compared to stroke specific clinical factors, using machine learning techniques.

Method: The study included 2,531 patients having at least one admission with a confirmed diagnosis of stroke, collected from a regional hospital in Australia within 2009–2013. Using machine learning (penalized regression with Lasso) techniques, patients having their index admission between June 2009 and July 2012 were used to derive predictive models, and patients having their index admission between July 2012 and June 2013 were used for validation. Three different stroke types [intracerebral hemorrhage (ICH), ischemic stroke, transient ischemic attack (TIA)] were considered and five different comparison outcome settings were considered. Our electronic administrative record based predictive model was compared with a predictive model composed of “baseline” clinical features, more specific for stroke, such as age, gender, smoking habits, co-morbidities (high cholesterol, hypertension, atrial fibrillation, and ischemic heart disease), types of imaging done (CT scan, MRI, etc.), and occurrence of in-hospital pneumonia. Risk factors associated with likelihood of negative outcomes were identified.

Results: The data was highly reliable at predicting discharge to rehabilitation and all other outcomes vs. death for ICH (AUC 0.85 and 0.825, respectively), all discharge outcomes except home vs. rehabilitation for ischemic stroke, and discharge home vs. others and home vs. rehabilitation for TIA (AUC 0.948 and 0.873, respectively). Electronic health record data appeared to provide improved prediction of outcomes over stroke specific clinical factors from the machine learning models. Common risk factors associated with a negative impact on expected outcomes appeared clinically intuitive, and included older age groups, prior ventilatory support, urinary incontinence, need for imaging, and need for allied health input.

Conclusion: Electronic administrative records from this cohort produced reliable outcome prediction and identified clinically appropriate factors negatively impacting most outcome variables following hospital admission with stroke. This presents a means of future identification of modifiable factors associated with patient discharge destination. This may potentially aid in patient selection for certain interventions and aid in better patient and clinician education regarding expected discharge outcomes.
Online Statistical Learning in Developmental Language Disorder
Authors: Lukács Ágnes , Lukics Krisztina Sára , Dobó Dorottya
Published: September 2021

Purpose: The vulnerability of statistical learning (SL) in developmental language disorder (DLD) has mainly been demonstrated with metacognitive offline measures which give little insight into the more specific nature and timing of learning. Our aims in this study were to test SL in children with and without DLD with both online and offline measures and to compare the efficiency of SL in the visual and acoustic modalities in DLD.

Method: We explored SL in school-age children with and without DLD matched on age and sex (n = 36). SL was investigated with the use of acoustic verbal and visual nonverbal segmentation tasks relying on online (reaction times and accuracy) and offline (two-alternative forced choice, 2AFC and production) measures.

Results: In online measures, learning was evident in both groups in both the visual and acoustic modalities, while offline measures showed difficulties in DLD. The visual production task showed a significant learning effect in both groups, while the visual two-alternative forced choice (2AFC) and the two acoustic offline tasks only showed evidence of learning in the control group. The comparison of learning indices revealed an SL impairment in DLD, which is present in both modalities.

Conclusions: Our findings suggest that children with DLD are comparable to typically developing (TD) children in their ability to extract acoustic verbal and visual nonverbal patterns that are cued only by transitional probabilities in online tasks, but they show impairments on metacognitive measures of learning. The pattern of online and offline measures implies that online tests can be more sensitive and valid indices of SL than offline tasks, and the combined use of different measures provides a better picture of learning efficiency, especially in groups where metacognitive tasks are challenging.
Acute Hepatic Porphyria: Pathophysiological Basis of Neuromuscular Manifestations
Authors: de Souza Paulo Victor Sgobbi , Badia Bruno de Mattos Lombardi , Farias Igor Braga , Pinto Wladimir Bocca Vieira de Rezende , Oliveira Acary Souza Bulle
Published: September 2021

Acute hepatic porphyria represents a rare, underdiagnosed group of inherited metabolic disorders due to hereditary defects of heme group biosynthesis pathway. Most patients have their definite diagnosis after several years of complex and disabling clinical manifestations and commonly after life-threatening acute neurovisceral episodes or severe motor handicap. Many key studies in the last two decades have been performed and led to the discovery of novel possible diagnostic and prognostic biomarkers and to the development of new therapeutic purposes, including small interfering RNA-based therapy, specifically driven to inhibit selectively delta-aminolevulinic acid synthase production and decrease the recurrence number of severe acute presentation for most patients. Several distinct mechanisms have been identified to contribute to the several neuromuscular signs and symptoms. This review article aims to present the current knowledge regarding the main pathophysiological mechanisms involved with the acute and chronic presentation of acute hepatic porphyria and to highlight the relevance of such content for clinical practice and in decision making about therapeutic options.
Expression Analysis of SOCS Genes in Migraine
Authors: Ghafouri-Fard Soudeh , Honarmand Tamizkar Kasra , Sayad Arezou , Taheri Mohammad , Samadian Mohammad
Published: September 2021

Migraine is a complex neurological condition affecting a large proportion of persons. Dysregulation of several immune-related transcripts has been noted in migraineurs suggesting an immune-based background for this condition. We measured expression levels suppressor of cytokine signaling (SOCS) genes in the venous blood of migraineurs compared with controls. SOCS1 was down-regulated in patients without aura compared with controls [Ratio of mean expression (RME) = 0.08, P value < 0.001]. This pattern was also detected among female subgroups (RME = 0.06, P value = 0.010), but not among male subgroups (RME = 0.22, P value = 0.114). Expression of SOCS1 was significantly higher in patients with aura compared with those without aura (RME = 5.89, P value = 0.037). Meanwhile, expression of SOCS2 was lower in migraineurs with aura compared with controls (RME = 0.03, P value < 0.001). In addition, this gene was under-expressed in patients without aura compared with controls and in both sex-based subgroups of this group of patients (RME = 0.01, P value < 0.001 for all comparisons). However, its expression was higher in male patients with aura compared with those without aura (P value < 0.001). For SOCS3, we detected a lower level of expression in patients without aura compared with controls (RME = 0.07, P value < 0.001). However, the expression of SOCS3 was higher in patients with aura compared with those without aura (RME = 7.46, P value = 0.001). SOCS5 was down-regulated in patients without aura compared with controls (RME = 0.10, P value < 0.001). Expression of this gene was also lower in patients with aura compared with controls (RME = 0.03, P value < 0.001), and in male patients of this group compared with controls (RME = 0.03, P value = 0.004). On the other hand, expression of SOCS5 was higher in male patients with aura compared with sex-matched patients without aura (RME = 6.67, P value = 0.001). SOCS2 levels could appropriately differentiate migraineurs from healthy subjects. The current study suggests the role of SOCS genes in the pathoetiology of migraine.
Blocking of EGFR Signaling Is a Latent Strategy for the Improvement of Prognosis of HPV-Induced Cancer
Authors: Qiu Jianfa , Hu Feifei , Shao Tingting , Guo Yuqiang , Dai Zongmao , Nie Huanhuan , Olasunkanmi Oluwatayo Israel , Qi Yue , Chen Yang , Lin Lexun , Zhao Wenran , Zhong Zhaohua , Wang Yan
Published: September 2021

Human papillomavirus (HPV) is a double-stranded DNA (dsDNA) virus, and its high-risk subtypes increase cancer risks. However, the mechanism of HPV infection and pathogenesis still remain unclear. Therefore, understanding the molecular mechanisms and the pathogenesis of HPV are crucial in the prevention of HPV-related cancers. In this study, we analyzed cervix squamous cell carcinoma (CESC) and head and neck carcinoma (HNSC) combined data to investigate various HPV-induced cancer common features. We showed that epidermal growth factor receptor (EGFR) was downregulated in HPV-positive (HPV+) cancer, and that HPV+ cancer patients exhibited better prognosis than HPV-negative (HPV−) cancer patients. Our study also showed that TP53 mutation rate is lower in HPV+ cancer than in HPV− cancer and that TP53 can be modulated by HPV E7 protein. However, there was no significant difference in the expression of wildtype TP53 in both groups. Subsequently, we constructed HPV-human interaction network and found that EGFR is a critical factor. From the network, we also noticed that EGFR is regulated by HPV E7 protein and hsa-miR-944. Moreover, while phosphorylated EGFR is associated with a worse prognosis, EGFR total express level is not significantly correlated with prognosis. This indicates that EGFR activation will induce a worse outcome in HPV+ cancer patients. Further enrichment analysis showed that EGFR downstream pathway and cancer relative pathway are diversely activated in HPV+ cancer and HPV− cancer. In summary, HPV E7 protein downregulates EGFR that downregulates phosphorylated EGFR and inhibit EGFR-related pathways which in turn and consequently induce better prognosis.
Integrative Analysis of Histopathological Images and Genomic Data in Colon Adenocarcinoma
Authors: Li Hui , Chen Linyan , Zeng Hao , Liao Qimeng , Ji Jianrui , Ma Xuelei
Published: September 2021

Background

Colon adenocarcinoma (COAD) is one of the most common malignant tumors in the world. The histopathological features are crucial for the diagnosis, prognosis, and therapy of COAD.

Methods

We downloaded 719 whole-slide histopathological images from TCIA, and 459 corresponding HTSeq-counts mRNA expression and clinical data were obtained from TCGA. Histopathological image features were extracted by CellProfiler. Prognostic image features were selected by the least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM) algorithms. The co-expression gene module correlated with prognostic image features was identified by weighted gene co-expression network analysis (WGCNA). Random forest was employed to construct an integrative prognostic model and calculate the histopathological-genomic prognosis factor (HGPF).

Results

There were five prognostic image features and one co-expression gene module involved in the model construction. The time-dependent receiver operating curve showed that the prognostic model had a significant prognostic value. Patients were divided into high-risk group and low-risk group based on the HGPF. Kaplan-Meier analysis indicated that the overall survival of the low-risk group was significantly better than the high-risk group.

Conclusions

These results suggested that the histopathological image features had a certain ability to predict the survival of COAD patients. The integrative prognostic model based on the histopathological images and genomic features could further improve the prognosis prediction in COAD, which may assist the clinical decision in the future.
A Novel and Rapid Serum Detection Technology for Non-Invasive Screening of Gastric Cancer Based on Raman Spectroscopy Combined With Different Machine Learning Methods
Authors: Li Mengya , He Haiyan , Huang Guorong , Lin Bo , Tian Huiyan , Xia Ke , Yuan Changjing , Zhan Xinyu , Zhang Yang , Fu Weiling
Published: September 2021

Gastric cancer (GC) is the fifth most common cancer in the world and a serious threat to human health. Due to its high morbidity and mortality, a simple, rapid and accurate early screening method for GC is urgently needed. In this study, the potential of Raman spectroscopy combined with different machine learning methods was explored to distinguish serum samples from GC patients and healthy controls. Serum Raman spectra were collected from 109 patients with GC (including 35 in stage I, 14 in stage II, 35 in stage III, and 25 in stage IV) and 104 healthy volunteers matched for age, presenting for a routine physical examination. We analyzed the difference in serum metabolism between GC patients and healthy people through a comparative study of the average Raman spectra of the two groups. Four machine learning methods, one-dimensional convolutional neural network, random forest, support vector machine, and K-nearest neighbor were used to explore identifying two sets of Raman spectral data. The classification model was established by using 70% of the data as a training set and 30% as a test set. Using unseen data to test the model, the RF model yielded an accuracy of 92.8%, and the sensitivity and specificity were 94.7% and 90.8%. The performance of the RF model was further confirmed by the receiver operating characteristic (ROC) curve, with an area under the curve (AUC) of 0.9199. This exploratory work shows that serum Raman spectroscopy combined with RF has great potential in the machine-assisted classification of GC, and is expected to provide a non-destructive and convenient technology for the screening of GC patients.
Bone Marrow Soluble Immunological Mediators as Clinical Prognosis Biomarkers in B-Cell Acute Lymphoblastic Leukemia Patients Undergoing Induction Therapy
Authors: Kerr Marlon Wendell Athaydes , Magalhães-Gama Fábio , Ibiapina Hiochelson Najibe Santos , Hanna Fabíola Silva Alves , Xabregas Lilyane Amorim , Alves Eliana Brasil , Pimentel João Paulo Diniz , Carvalho Maria Perpétuo Socorro Sampaio , Tarragô Andréa Monteiro , Teixeira-Carvalho Andréa , Martins-Filho Olindo Assis , da Costa Allyson Guimarães , Malheiro Adriana
Published: September 2021

Different factors are used as predictors of unfavorable clinical outcomes in B-Cell Acute Lymphoblastic Leukemia (B-ALL) patients. However, new prognostic markers are needed in order to allow treatment to be more accurate, providing better results and an improved quality of life. In the present study, we have characterized the profile of bone marrow soluble mediators as possible biomarkers for risk group stratification and minimal residual disease (MRD) detection during induction therapy. The study featured 47 newly-diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients that were categorized into subgroups during induction therapy according to risk stratification at day 15 [Low Risk (LR), Low Risk increasing to High Risk (LR→HR) and High Risk (HR)] and the MRD detection on day 35 (MRD(-) and MRD(+)). Soluble immunological mediators (CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1β, IL-6, TNF, IFN-γ, IL-17A, IL-4, IL-5, IL-10 and IL-2) were quantified by cytometric bead array and ELISA. Our findings demonstrated that increased levels of CCL5, IFN-γ and IL-2 at baseline appeared as putative candidates of good prognosis in LR and MRD(-) subgroups, while CCL2 was identified as a consistent late biomarker associated with poor prognosis, which was observed on D35 in HR and MRD(+) subgroups. Furthermore, apparently controversial data regarding IL-17A and TNF did not allow the definition of these molecules as either positive or negative biomarkers. These results contribute to the search for novel prognostic indicators, and indicate the potential of bone marrow soluble mediators in prognosis and follow-up of B-ALL patients during induction therapy.
Dose-Response Reduction in Risk of Nasopharyngeal Carcinoma From Smoking Cessation: A Multicenter Case-Control Study in Hong Kong, China
Authors: Wang Lijun , Mai Zhi-Ming , Ngan Roger Kai-Cheong , Ng Wai-Tong , Lin Jia-Huang , Kwong Dora Lai-Wan , Chiang Shing-Chun , Yuen Kam-Tong , Ng Alice Wan-Ying , Ip Dennis Kai-Ming , Chan Yap-Hang , Lee Anne Wing-Mui , Lung Maria Li , Ho Sai Yin , Lam Tai-Hing
Published: September 2021

Background

Cigarette smoking is associated with nasopharyngeal cancer (NPC) risk. Whether quitting reduces the risk is unclear. We investigated the associations of NPC with duration of and age at quitting in an endemic region.

Methods

We investigated the associations between NPC and quitting in a multicenter case-control study in Hong Kong with 676 newly diagnosed NPC cases and 1,285 hospital controls between 2014 and 2017, using a computer-assisted self-administered questionnaire. Multivariable unconditional logistic regression yielded adjusted odds ratios (AORs) of NPC by quitting status, duration and age of quitting, combinations of duration and age of quitting, and quitting to smoking duration ratio, compared with current smoking.

Results

Quitting (AOR: 0.72; 95% CI: 0.53–0.98) and never smoking (0.73, 0.56–0.95) were associated with lower NPC risk. NPC risk decreased with (i) longer quitting duration (p < 0.01), reaching significance after 11–20 (0.62, 0.39–0.99) and 21+ years (0.54, 0.31–0.92) of quitting; (ii) younger quitting age (p = 0.01), reaching significance for quitting at <25 years (0.49, 0.24–0.97); and (iii) higher quitting to smoking duration ratio (p < 0.01), reaching significance when the ratio reached 1 (0.60, 0.39–0.93). Quitting younger (age <25) appeared to confer larger reductions (49% for ≤10 years of quitting, 50% for 11+ years) in NPC risk than quitting at older ages (25+) regardless of quitting duration (16% for ≤10 years, 39% for 11+ years).

Conclusions

We have shown longer duration and younger age of quitting were associated with lower NPC risk, with dose-response relations. Our findings support including smoking as a cause of NPC. Stronger tobacco control measures and quitting services are needed to prevent NPC.
Computed Tomography-Based Radiomics for Preoperative Prediction of Tumor Deposits in Rectal Cancer
Authors: Jin Yumei , Li Mou , Zhao Yali , Huang Chencui , Liu Siyun , Liu Shengmei , Wu Min , Song Bin
Published: September 2021

Objective

To develop and validate a computed tomography (CT)-based radiomics model for predicting tumor deposits (TDs) preoperatively in patients with rectal cancer (RC).

Methods

This retrospective study enrolled 254 patients with pathologically confirmed RC between December 2017 and December 2019. Patients were divided into a training set (n = 203) and a validation set (n = 51). A large number of radiomics features were extracted from the portal venous phase images of CT. After selecting features with L1-based method, we established Rad-score by using the logistic regression analysis. Furthermore, a combined model incorporating Rad-score and clinical factors was developed and visualized as the nomogram. The models were evaluated by the receiver operating characteristic curve (ROC) analysis and area under the ROC curve (AUC).

Results

One hundred and seventeen of 254 patients were eventually found to be TDs+. Rad-score and clinical factors including carbohydrate antigen (CA) 19-9, CT-reported T stage (cT), and CT-reported peritumoral nodules (+/-) were significantly different between the TDs+ and TDs- groups (all P < 0.001). These factors were all included in the combined model by the logistic regression analysis (odds ratio = 2.378 for Rad-score, 2.253 for CA19-9, 2.281 for cT, and 4.485 for peritumoral nodules). This model showed good performance to predict TDs in the training and validation cohorts (AUC = 0.830 and 0.832, respectively). Furthermore, the combined model outperformed the clinical model incorporating CA19-9, cT, and peritumoral nodules (+/-) in both training and validation cohorts for predicting TDs preoperatively (AUC = 0.773 and 0.718, P = 0.008 and 0.039).

Conclusions

The combined model incorporating Rad-score and clinical factors could provide a preoperative prediction of TDs and help clinicians guide individualized treatment for RC patients.
Identification of a Prognostic Model Based on 2-Gene Signature and Analysis of Corresponding Tumor Microenvironment in Alcohol-Related Hepatocellular Carcinoma
Authors: Guo Yong , Hu Jiejun , Zhao Zhibo , Zhong Guochao , Gong Jianping , Cai Dong
Published: September 2021

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors with the poor prognosis. Nowadays, alcohol is becoming a leading risk factor of HCC in many countries. In our study, we obtained the DEGs in alcohol-related HCC through two databases (TCGA and GEO). Subsequently, we performed enrichment analyses (GO and KEGG), constructed the PPI network and screened the 53 hub genes by Cytoscape. Two genes (BUB1B and CENPF) from hub genes was screened by LASSO and Cox regression analyses to construct the prognostic model. Then, we found that the high risk group had the worse prognosis and verified the clinical value of the risk score in alcohol-related HCC. Finally, we analyzed the tumor microenvironment between high and low risk groups through CIBERSORT and ESTIMATE. In summary, we constructed the two-gene prognostic model that could predict the poor prognosis in patients with alcohol-related HCC.
Detection of Metastatic Tumor Cells in the Bone Marrow Aspirate Smears by Artificial Intelligence (AI)-Based Morphogo System
Authors: Chen Pu , Chen Xu Run , Chen Nan , Zhang Lan , Zhang Li , Zhu Jianfeng , Pan Baishen , Wang Beili , Guo Wei
Published: September 2021

Introduction

Metastatic carcinomas of bone marrow (MCBM) are characterized as tumors of non-hematopoietic origin spreading to the bone marrow through blood or lymphatic circulation. The diagnosis is critical for tumor staging, treatment selection and prognostic risk stratification. However, the identification of metastatic carcinoma cells on bone marrow aspiration smears is technically challenging by conventional microscopic screening.

Objective

The aim of this study is to develop an automatic recognition system using deep learning algorithms applied to bone marrow cells image analysis. The system takes advantage of an artificial intelligence (AI)-based method in recognizing metastatic atypical cancer clusters and promoting rapid diagnosis.

Methods

We retrospectively reviewed metastatic non-hematopoietic malignancies in bone marrow aspirate smears collected from 60 cases of patients admitted to Zhongshan Hospital. High resolution digital bone marrow aspirate smear images were generated and automatically analyzed by Morphogo AI based system. Morphogo system was trained and validated using 20748 cell cluster images from randomly selected 50 MCBM patients. 5469 pre-classified cell cluster images from the remaining 10 MCBM patients were used to test the recognition performance between Morphogo and experienced pathologists.

Results

Morphogo exhibited a sensitivity of 56.6%, a specificity of 91.3%, and an accuracy of 82.2% in the recognition of metastatic cancer cells. Morphogo’s classification result was in general agreement with the conventional standard in the diagnosis of metastatic cancer clusters, with a Kappa value of 0.513. The test results between Morphogo and pathologists H1, H2 and H3 agreement demonstrated a reliability coefficient of 0.827. The area under the curve (AUC) for Morphogo to diagnose the cancer cell clusters was 0.865.

Conclusion

In patients with clinical history of cancer, the Morphogo system was validated as a useful screening tool in the identification of metastatic cancer cells in the bone marrow aspirate smears. It has potential clinical application in the diagnostic assessment of metastatic cancers for staging and in screening MCBM during morphology examination when the symptoms of the primary site are indolent.
Parents' Views to Strengthen Partnerships in Newborn Intensive Care
Authors: Ferreira Alexie , Ferretti Emanuela , Curtis Krista , Joly Cynthia , Sivanthan Myuri , Major Nathalie , Daboval Thierry
Published: September 2021

Background:Parental involvement in their newborn's neonatal intensive care reduces stress and helps with the parent-child attachment, transition to home, and future development. However, parents' perspectives are not often sought or considered when adapting family-centered care in neonatal intensive care units (NICUs).

Aim:To identify what parents believe helps or hinders their involvement in their newborn's care when admitted to our Level 3B NICU.

Methods:Between August and October 2018, nine mothers and one father were interviewed during three 60- to 90-min audiotaped focus groups using a semi-structured interview tool. From the content analysis of the verbatims, three reviewers identified key themes that affected how involved parents could be in their newborn's care.

Results:Parents provided examples of factors that facilitated or restricted their involvement. The analysis identified themes: (1) parent-staff interactions, (2) supportive/trustworthy healthcare professionals, (3) consistency in care and caring staff, (4) family, couple, and peer support, (5) newborn status, (6) resources and education for parents, (7) the NICU environment, and (8) academic and research participation.

Conclusion:We identified a conceptual framework to allow our NICU team to prioritize working strategies to strengthen parental involvement in newborn care. In addition to implementing ways to involve parents, we need to address parents' satisfaction with their participation. These findings may help other investigators explore parents' expectations toward their NICU experience.
The Adverse Cardiovascular Effects and Cardiotoxicity of Kratom (Mitragyna speciosa Korth.): A Comprehensive Review
Authors: Leong Bin Abdullah Mohammad Farris Iman , Singh Darshan
Published: September 2021

Background: Kratom or Mitragyna speciosa (Korth.) has received overwhelming attention recently due to its alleged pain-relieving effects. Despite its potential therapeutic value, kratom use has been linked to many occurrences of multiorgan toxicity and cardiotoxicity. Accordingly, the current narrative review aimed to provide a detailed account of kratom’s adverse cardiovascular effects and cardiotoxicity risk, based on in vitro studies, poison center reports, coroner and autopsy reports, clinical case reports, and clinical studies.

Methods: An electronic search was conducted to identify all research articles published in English from 1950 to 2021 using the major research databases, such as Google Scholar, Web of Science, PubMed, Scopus, Mendeley, EMBASE, Cochrane Library, and Medline. We then analyzed the literature’s discussion of adverse cardiovascular effects, toxicity, and mortality related to kratom use.

Results: Our findings revealed that, although in vitro studies have found kratom preparations’ most abundant alkaloid—mitragynine—to cause a prolonged QTc interval and an increased risk of torsades de pointes, a clinical study examining humans’ regular consumption of kratom did not report such a risk. However, this latter study did show that regular kratom use could induce an increased QTc interval in a dose-dependent manner. A few case reports also highlighted that kratom consumption is associated with ventricular arrhythmia and cardiopulmonary arrest, but this association could have ensued when kratom was co-administered with another substance. Similarly, analyses of national poison data showed that kratom’s most common adverse acute cardiovascular effects include tachycardia and hypertension. Meanwhile, coroner and autopsy reports indicated that kratom’s cardiovascular sequelae encompass coronary atherosclerosis, myocardial infarction, hypertensive cardiovascular disease, left ventricular hypertrophy, cardiac arrhythmia, cardiomegaly, cardiomyopathy, focal band necrosis in the myocardium, and myocarditis. Given the available data, we deduced that all cardiac eventualities reported in the literature could have been compounded by polysubstance use and unresolved underlying medical illnesses.

Conclusion: Although kratom use has been associated with death and cardiotoxicity, especially at higher doses and when associated with other psychoactive drugs, the dearth of data and methodological limitations reported in existing studies do not allow a definitive conclusion, and further studies are still necessary to address this issue.
Fascin-1 is Highly Expressed Specifically in Microglia After Spinal Cord Injury and Regulates Microglial Migration
Authors: Yu Shuisheng , Cheng Li , Tian Dasheng , Li Ziyu , Yao Fei , Luo Yang , Liu Yanchang , Zhu Zhenyu , Zheng Meige , Jing Juehua
Published: September 2021

Recent research indicates that after spinal cord injury (SCI), microglia accumulate at the borders of lesions between astrocytic and fibrotic scars and perform inflammation-limiting and neuroprotective functions, however, the mechanism of microglial migration remains unclear. Fascin-1 is a key actin-bundling protein that regulates cell migration, invasion and adhesion, but its role during SCI has not been reported. Here, we found that at 7–14 days after SCI in mice, Fascin-1 is significantly upregulated, mainly distributed around the lesion, and specifically expressed in CX3CR1-positive microglia. However, Fascin-1 is not expressed in GFAP-positive astrocytes, NeuN-positive neurons, NG2-positive cells, PDGFRβ-positive cells, or blood-derived Mac2-positive macrophages infiltrating into the lesion core. The expression of Fascin-1 is correspondingly decreased after microglia are specifically depleted in the injured spinal cord by the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. The upregulation of Fascin-1 expression is observed when microglia are activated by myelin debris in vitro, and microglial migration is prominently increased. The inhibition of Fascin-1 expression using small interfering RNA (siRNA) markedly suppresses the migration of microglia, but this effect can be reversed by treatment with myelin. The M1/M2-like polarization of microglia does not affect the expression of Fascin-1. Together, our results suggest that Fascin-1 is highly expressed specifically in microglia after SCI and can play an important role in the migration of microglia and the formation of microglial scars. Hence, the elucidation of this mechanism will provide novel therapeutic targets for the treatment of SCI.
Five-Decade Update on Chemopreventive and Other Pharmacological Potential of Kurarinone: a Natural Flavanone
Authors: Kumar Shashank , Prajapati Kumari Sunita , Shuaib Mohd , Kushwaha Prem Prakash , Tuli Hardeep Singh , Singh Atul Kumar
Published: September 2021

In the present article we present an update on the role of chemoprevention and other pharmacological activities reported on kurarinone, a natural flavanone (from 1970 to 2021). To the best of our knowledge this is the first and exhaustive review of kurarinone. The literature was obtained from different search engine platforms including PubMed. Kurarinone possesses anticancer potential against cervical, lung (non-small and small), hepatic, esophageal, breast, gastric, cervical, and prostate cancer cells. In vivo anticancer potential of kurarinone has been extensively studied in lungs (non-small and small) using experimental xenograft models. In in vitro anticancer studies, kurarinone showed IC50 in the range of 2–62 µM while in vivo efficacy was studied in the range of 20–500 mg/kg body weight of the experimental organism. The phytochemical showed higher selectivity toward cancer cells in comparison to respective normal cells. kurarinone inhibits cell cycle progression in G2/M and Sub-G1 phase in a cancer-specific context. It induces apoptosis in cancer cells by modulating molecular players involved in apoptosis/anti-apoptotic processes such as NF-κB, caspase 3/8/9/12, Bcl2, Bcl-XL, etc. The phytochemical inhibits metastasis in cancer cells by modulating the protein expression of Vimentin, N-cadherin, E-cadherin, MMP2, MMP3, and MMP9. It produces a cytostatic effect by modulating p21, p27, Cyclin D1, and Cyclin A proteins in cancer cells. Kurarinone possesses stress-mediated anticancer activity and modulates STAT3 and Akt pathways. Besides, the literature showed that kurarinone possesses anti-inflammatory, anti-drug resistance, anti-microbial (fungal, yeast, bacteria, and Coronavirus), channel and transporter modulation, neuroprotection, and estrogenic activities as well as tyrosinase/diacylglycerol acyltransferase/glucosidase/aldose reductase/human carboxylesterases 2 inhibitory potential. Kurarinone also showed therapeutic potential in the clinical study. Further, we also discussed the isolation, bioavailability, metabolism, and toxicity of Kurarinone in experimental models.
Cost-Effectiveness of Short-Course Radiation Plus Temozolomide for the Treatment of Newly Diagnosed Glioblastoma Among Elderly Patients in China and the United States
Authors: Chen Jigang , Tong Xin , Han Mingyang , Zhao Songfeng , Ji Linjin , Qin Yongkai , He Zilong , Pan Yuesong , Wang Chunhui , Liu Aihua
Published: September 2021

Background: Glioblastoma multiforme (GBM) is a fatal type of brain tumor with a high incidence among elderly people. Temozolomide (TMZ) has proven to be an effective chemotherapeutic agent with significant survival benefits. This study aimed to evaluate the economic outcomes of radiotherapy (RT) and TMZ for the treatment of newly diagnosed GBM in elderly people in the United States (US) and China.

Methods: A partitioned survival model was constructed for RT plus TMZ and RT alone among patients with methylated and unmethylated tumor status. Base case calculations and one-way and probabilistic sensitivity analyses were performed. Life-years, quality-adjusted life-years (QALYs), costs (in 2021 US dollars [$] and Chinese Yuan Renminbi [¥]), and incremental cost-effectiveness ratios (ICERs) were calculated.

Results: RT plus TMZ was found to be associated with significantly higher costs and QALYs in all groups. Only US patients with methylated status receiving RT plus TMZ had an ICER ($89358.51) less than the willingness-to-pay (WTP) threshold of $100000 per QALY gained when compared with receiving RT alone. When the WTP threshold ranged from $100000 to $150000 from the US perspective, the probability of RT plus TMZ being cost-effective increased from 80.5 to 99.8%. The cost of TMZ must be lower than ¥120 per 20 mg for RT plus TMZ to be cost-effective among patients with methylated tumor status in China.

Conclusion: RT plus TMZ was not cost-effective in China, and a reduction in the TMZ price was justified. However, it is highly likely to be cost-effective for patients with methylated tumor status in the US.
Water-Soluble Tomato Extract Fruitflow Alters the Phosphoproteomic Profile of Collagen-Stimulated Platelets
Authors: Zhang Shenghao , Chen Huilian , Li Chuanbao , Chen Beidong , Gong Huan , Zhao Yanyang , Qi Ruomei
Published: September 2021

Platelet hyperactivity is a risk factor for cardiovascular disease and thrombosis. Recent studies reported that the tomato extract Fruitflow inhibited platelet function, but the molecular mechanism is still unclear. The present study used proteomics to quantitatively analyze the effect of fruitflow on the inhibition of collagen-stimulated platelets and validated the involvement of several signaling molecules. Fruitflow significantly inhibited human platelet aggregation and P-selectin expression that were induced by collagen. Proteomics analysis revealed that compared fruitflow-treated collagen-stimulated platelets with only collagen-stimulated platelets, 60 proteins were upregulated and 10 proteins were downregulated. Additionally, 66 phosphorylated peptides were upregulated, whereas 37 phosphorylated peptides were downregulated. Gene Ontology analysis indicated that fruitflow treatment downregulated phosphoinositide 3-kinase (PI3K)/protein kinase B and guanosine triphosphatase-mediated signal transduction in collagen-activated platelets. Biological validation indicated that fruitflow decreased Akt, glycogen synthase kinase 3β, p38 mitogen-activated protein kinase (MAPK), and heat shock protein (Hsp27) phosphorylation in collagen-stimulated platelets. Fruitflow recovered cyclic adenosine monophosphate levels in collagen-activated platelets and reduced protein kinase A substrate phosphorylation that was induced by collagen. These findings suggest that fruitflow is a functional food that can inhibit platelet function, conferring beneficial effects for people who are at risk for platelet hyperactivity-associated thrombosis.
A Proof of Concept of the Role of TDM-Based Clinical Pharmacological Advices in Optimizing Antimicrobial Therapy on Real-Time in Different Paediatric Settings
Authors: Gatti Milo , Cojutti Pier Giorgio , Campoli Caterina , Caramelli Fabio , Corvaglia Luigi Tommaso , Lanari Marcello , Pession Andrea , Ramirez Stefania , Viale Pierluigi , Pea Federico
Published: September 2021

Introduction: Antimicrobial treatment is quite common among hospitalized children. The dynamic age-associated physiological variations coupled with the pathophysiological alterations caused by underlying illness and potential drug-drug interactions makes the implementation of appropriate antimicrobial dosing extremely challenging among paediatrics. Therapeutic drug monitoring (TDM) may represent a valuable tool for assisting clinicians in optimizing antimicrobial exposure. Clinical pharmacological advice (CPA) is an approach based on the correct interpretation of the TDM result by the MD Clinical Pharmacologist in relation to specific underlying conditions, namely the antimicrobial susceptibility of the clinical isolate, the site of infection, the pathophysiological characteristics of the patient and/or the drug-drug interactions of cotreatments. The aim of this study was to assess the role of TDM-based CPAs in providing useful recommendations for the real-time personalization of antimicrobial dosing regimens in various paediatric settings.

Materials and methods: Paediatric patients who were admitted to different settings of the IRCCS Azienda Ospedaliero-Universitaria of Bologna, Italy (paediatric intensive care unit [ICU], paediatric onco-haematology, neonatology, and emergency paediatric ward), between January 2021 and June 2021 and who received TDM-based CPAs on real-time for personalization of antimicrobial therapy were retrospectively assessed. Demographic and clinical features, CPAs delivered in relation to different settings and antimicrobials, and type of dosing adjustments were extracted. Two indicators of performance were identified. The number of dosing adjustments provided over the total number of delivered CPAs. The turnaround time (TAT) of CPAs according to a predefined scale (optimal, <12 h; quasi-optimal, between 12–24 h; acceptable, between 24–48 h; suboptimal, >48 h).

Results: Overall, 247 CPAs were delivered to 53 paediatric patients (mean 4.7 ± 3.7 CPAs/patient). Most were delivered to onco-haematological patients (39.6%) and to ICU patients (35.8%), and concerned mainly isavuconazole (19.0%) and voriconazole (17.8%). Overall, CPAs suggested dosing adjustments in 37.7% of cases (24.3% increases and 13.4% decreases). Median TAT was 7.5 h (IQR 6.1–8.8 h). Overall, CPAs TAT was optimal in 91.5% of cases, and suboptimal in only 0.8% of cases.

Discussion: Our study provides a proof of concept of the helpful role that TDM-based real-time CPAs may have in optimizing antimicrobial exposure in different challenging paediatric scenarios.
Screening of a Focused Ubiquitin-Proteasome Pathway Inhibitor Library Identifies Small Molecules as Novel Modulators of Botulinum Neurotoxin Type A Toxicity
Authors: Sen Edanur , Kota Krishna P. , Panchal Rekha G. , Bavari Sina , Kiris Erkan
Published: September 2021

Botulinum neurotoxins (BoNTs) are known as the most potent bacterial toxins, which can cause potentially deadly disease botulism. BoNT Serotype A (BoNT/A) is the most studied serotype as it is responsible for most human botulism cases, and its formulations are extensively utilized in clinics for therapeutic and cosmetic applications. BoNT/A has the longest-lasting effect in neurons compared to other serotypes, and there has been high interest in understanding how BoNT/A manages to escape protein degradation machinery in neurons for months. Recent work demonstrated that an E3 ligase, HECTD2, leads to efficient ubiquitination of the BoNT/A Light Chain (A/LC); however, the dominant activity of a deubiquitinase (DUB), VCIP135, inhibits the degradation of the enzymatic component. Another DUB, USP9X, was also identified as a potential indirect contributor to A/LC degradation. In this study, we screened a focused ubiquitin-proteasome pathway inhibitor library, including VCIP135 and USP9X inhibitors, and identified ten potential lead compounds affecting BoNT/A mediated SNAP-25 cleavage in neurons in pre-intoxication conditions. We then tested the dose-dependent effects of the compounds and their potential toxic effects in cells. A subset of the lead compounds demonstrated efficacy on the stability and ubiquitination of A/LC in cells. Three of the compounds, WP1130 (degrasyn), PR-619, and Celastrol, further demonstrated efficacy against BoNT/A holotoxin in an in vitro post-intoxication model. Excitingly, PR-619 and WP1130 are known inhibitors of VCIP135 and USP9X, respectively. Modulation of BoNT turnover in cells by small molecules can potentially lead to the development of effective countermeasures against botulism.
Controlled Ovarian Hyperstimulation Protocol in Infertile Patients During the COVID-19 Pandemic
Authors: Li Fei , Zhang HuiXia , Shi WeiYi , Wu YiFang , Tian Ye , Guo YiHong , Jin HaiXia , Li Gang
Published: September 2021

Objectives: To explore the appropriate controlled ovarian hyperstimulation (COH) protocols in infertility patients who received the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments during the COVID-19 pandemic.

Materials and Methods: This retrospective cohort study evaluated the efficiency of the early follicular-phase long-acting GnRH-agonist long (EFLL) protocol (a new protocol developed by Chinese clinicians), prolonged pituitary down-regulation of EFLL protocol (Pro-EFLL), and the GnRH-ant protocol for couples meeting the study criteria between February 2020 and June 2020 who were treated by the First Affiliated Hospital of Zhengzhou University during the COVID-19 pandemic, and compared the pregnancy rates and miscarriage rates per fresh transfer cycle, number of retrieved oocytes, endometrial thickness on the day of hCG injection and the number of fertilized oocytes, mature oocytes, fertilized oocytes, and transferable embryos among the three protocols.

Results: We found that the prolonged pituitary down-regulation during the COVID-19 pandemic by utilizing a full-dose of GnRH-a administrated in infertility patients were no differences in clinical outcomes than other protocols, The prolonged pituitary down-regulation protocol and EFLL protocol were associated with a higher Endometrial thickness on the day of hCG injection (12.67 ± 2.21 vs. 12.09 ± 2.35 vs. 10.79 ± 2.38, P < 0.001), retrieved oocytes (14.49 ± 6.30 vs. 15.02 ± 7.93 vs. 10.06 ± 7.63, P < 0.001), mature oocytes (11.60 ± 5.71 vs. 11.96 ± 6.00 vs. 7.63 ± 6.50, P < 0.001), fertilized oocytes (9.14 ± 5.43 vs. 8.44 ± 5.34 vs. 5.42 ± 5.20, P < 0.001), and transferable embryos (4.87 ± 2.96 vs. 6.47 ± 5.12 vs. 3.00 ± 3.28 vs. P < 0.001) in the GnRH-antagonist protocol.

Conclusion: We recommend that patients start Gn injections 33–42 days after a pituitary downregulated full dose (3.75 mg) of gonadotropin-releasing hormone agonist during the COVID-19 pandemic, even a delay of 2–4 weeks does not affect the implantation rate. The study can provide a more detailed estimate and clinical management strategies for infertile couples during the COVID-19 pandemic.