bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the Effects of 1,25VitD3 on Inflammatory Responses and IL-25 Expression
Authors: Li Nana , Saghafi Nafiseh , Ghaneifar Zahra , Rezaee Seyed Abdorahim , Rafatpanah Houshang , Abdollahi Elham 
Published: December 2021

VitD3 may contribute to a successful pregnancy through modulation of immune responses, so VitD3 deficiency may have a role in the immunopathogenesis of unexplained recurrent spontaneous abortion (URSA). However, the mechanisms of immunomodulatory actions of VitD3 in decreasing the risk of recurrent spontaneous abortion have not been understood well.Objective: The purpose of this research was to investigate the influence of 1,25VitD3 on IL-25 and related cytokines of Th17 cells including IL-17A, IL-6, and IL-23 in peripheral blood mononuclear cells of healthy women as a control group and women with unexplained recurrent spontaneous abortion.Method: Isolation of peripheral blood mononuclear cells (PBMCs) was performed from peripheral blood of the subjects of the studied groups (20 women with URSA as a case group, and 20 control women). The effects of 1,25VitD3 (50 nM, for 24 h) on the studied parameters were evaluated and were compared to the positive and negative controls in vitro. Flow cytometry analysis was used to determine the percentages of regulatory T cells and Th17 cells. For gene expression measurement and cytokines assay, real-time PCR and ELISA were carried out.Results: The proportion of Th17 cells in women with URSA was considerably higher than in the control group. IL-25 mRNA and protein levels in cultured PBMCs from women with URSA were lower than the controls. 1,25VitD3 increased IL-25 expressions at both the protein and mRNA levels in PBMCs from women with URSA relative to the control group. Additionally, 1,25VitD3 treatment not only significantly decreased the percentage of Th17 cells frequency but also reduced expressions of IL-6, IL-17A, and IL-23 in PBMCs from women with URSA.Conclusion: 1,25VitD3 may diminish inflammatory responses cells via downregulation of IL-25 expression. It could be an interesting subject for future researches in the field of the immunopathology of URSA to identify molecular pathways in URSA treatment.
Constructing Prediction Models for Freezing of Gait by Nomogram and Machine Learning: A Longitudinal Study
Authors: Xu Kun , Zhou Xiao-xia , He Run-cheng , Zhou Zhou , Liu Zhen-hua , Xu Qian , Sun Qi-ying , Yan Xin-xiang , Wu Xin-yin , Guo Ji-feng , Tang Bei-sha 
Published: December 2021

Objectives: Although risk factors for freezing of gait (FOG) have been reported, there are still few prediction models based on cohorts that predict FOG. This 1-year longitudinal study was aimed to identify the clinical measurements closely linked with FOG in Chinese patients with Parkinson's disease (PD) and construct prediction models based on those clinical measurements using Cox regression and machine learning.Methods: The study enrolled 967 PD patients without FOG in the Hoehn and Yahr (H&amp;Y) stage 1–3 at baseline. The development of FOG during follow-up was the end-point. Neurologists trained in movement disorders collected information from the patients on a PD medication regimen and their clinical characteristics. The cohort was assessed on the same clinical scales, and the baseline characteristics were recorded and compared. After the patients were divided into the training set and test set by the stratified random sampling method, prediction models were constructed using Cox regression and random forests (RF).Results: At the end of the study, 26.4% (255/967) of the patients suffered from FOG. Patients with FOG had significantly longer disease duration, greater age at baseline and H&amp;Y stage, lower proportion in Tremor Dominant (TD) subtype, a higher proportion in wearing-off, levodopa equivalent daily dosage (LEDD), usage of L-Dopa and catechol-O-methyltransferase (COMT) inhibitors, a higher score in scales of Unified Parkinson's Disease Rate Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), Non-Motor Symptoms Scale (NMSS), Hamilton Depression Rating Scale (HDRS)-17, Parkinson's Fatigue Scale (PFS), rapid eye movement sleep behavior disorder questionnaire-Hong Kong (RBDQ-HK), Epworth Sleepiness Scale (ESS), and a lower score in scales of Parkinson's Disease Sleep Scale (PDSS) (P &lt; 0.05). The risk factors associated with FOG included PD onset not being under the age of 50 years, a lower degree of tremor symptom, impaired activities of daily living (ADL), UPDRS item 30 posture instability, unexplained weight loss, and a higher degree of fatigue. The concordance index (C-index) was 0.68 for the training set (for internal validation) and 0.71 for the test set (for external validation) of the nomogram prediction model, which showed a good predictive ability for patients in different survival times. The RF model also performed well, the C-index was 0.74 for the test set, and the AUC was 0.74.Conclusions: The study found some new risk factors associated with the FOG including a lower degree of tremor symptom, unexplained weight loss, and a higher degree of fatigue through a longitudinal study, and constructed relatively acceptable prediction models.
Cost-Effectiveness Analysis of Fourth- or Further-Line Ripretinib in Advanced Gastrointestinal Stromal Tumors
Authors: Liao Weiting , Xu Huiqiong , Hutton David , Wu Qiuji , Zhou Kexun , Luo Hui , Lei Wanting , Feng Mingyang , Yang Yang , Wen Feng , Li Qiu 
Published: December 2021

BackgroundThe INVICTUS trial assessed the efficacy and safety of ripretinib compared with placebo in the management of advanced gastrointestinal stromal tumors.MethodWe used a Markov model with three health states: progression-free disease, progression disease and death. We parameterized the model from time-to-event data (progression-free survival, overall survival) of ripretinib and placebo arms in the INVICTUS trial and extrapolated to a patient’s lifetime horizon. Estimates of health state utilities and costs were based on clinical trial data and the published literature. The outcomes of this model were measured in quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Uncertainty was tested via univariate and probabilistic sensitivity analyses.ResultsThe base-case model projected improved outcomes (by 0.29 QALYs) and additional costs (by $70,251) and yielded an ICER of $244,010/QALY gained for ripretinib versus placebo. The results were most sensitive to progression rates, the price of ripretinib, and health state utilities. The ICER was most sensitive to overall survival. When overall survival in the placebo group was lower, the ICER dropped to $127,399/QALY. The ICER dropped to $150,000/QALY when the monthly cost of ripretinib decreased to $14,057. Probabilistic sensitivity analyses revealed that ripretinib was the cost-effective therapy in 41.1% of simulations at the willingness-to-pay (WTP) threshold of $150,000.ConclusionAs the fourth- or further-line therapy in advanced gastrointestinal stromal tumors, ripretinib is not cost-effective in the US. Ripretinib would achieve its cost-effectiveness with a price discount of 56% given the present effectiveness.
Hyperactivity and Inattention in Young Patients Born With an Atrial Septal or Ventricular Septal Defect
Authors: Lau-Jensen Sara Hirani , Asschenfeldt Benjamin , Evald Lars , Hjortdal Vibeke E. 
Published: December 2021

Background: Patients with congenital heart defects have a well-established risk of neuropsychiatric comorbidities. Inattention and hyperactivity are three to four times more frequent in children with complex congenital heart defects. We have previously shown a higher burden of overall attention deficit/hyperactivity disorder (ADHD) symptoms in adults with simple congenital heart defects as well. However, it is unknown whether the higher burden of ADHD symptoms is mainly driven by hyperactivity, inattention, or both.Methods: The participants [simple congenital heart defect = 80 (26.6 years old), controls = 36 (25.3 years old)] and a close relative for each (n = 107) responded to the long version of the Conners' Adults ADHD Rating Scales questionnaire. Our primary and secondary outcomes are mean T-scores in the ADHD scores and symptom sub-scores.Results: Patients with simple congenital heart defects reported a higher mean T-score at all three DSM-IV ADHD scores (ADHD—combined: 52.8 vs. 44.9, p = 0.007, ADHD—inattention: 55.5 vs. 46.4, p = 0.002, and ADHD—hyperactivity: 49.4 vs. 44.0, p = 0.03) and in all four ADHD symptom sub-scores (inattention/memory problems: 50.3 vs. 44.2, p = 0.001, hyperactivity/restlessness: 49.7 vs. 45.9, p = 0.03, impulsivity/emotional lability: 50.0 vs. 41.3, p = 0.001, and self-esteem problems: 53.8 vs. 46.3, p = 0.003). The results were maintained after the removal of outliers (incongruent responses), albeit the hyperactivity/restlessness ADHD symptom sub-score lost significance. Self- and informant ratings differed significantly on the ADHD—inattention score for the congenital heart defect group, where informants rated the ADHD—inattention scores better than the congenital heart defect patients rated themselves.Conclusions: Patients with a simple congenital heart defect have a higher symptom burden across all ADHD scores and all symptom sub-scores. The higher burden of ADHD is driven by both inattention and hyperactivity symptoms, though the inattention symptoms seem more prominent. Close relatives were less aware of the inattention symptoms than the congenital heart defect patients themselves. Routine screening for ADHD symptoms may be warranted to facilitate adequate help and guidance as these symptoms are easily overlooked.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03871881.
Coumarin Derivative N6 as a Novel anti-hantavirus Infection Agent Targeting AKT
Authors: Li Zhoupeng , Wang Fang , Liu Yongsheng , Zhai Dongshen , Zhang Xiaoxiao , Ying Qikang , Jia Min , Xue Xiaoyan , Meng Jingru , Li Jing , Wu Xingan , Li Mingkai 
Published: December 2021

Hantaviruses are globally emerging zoonotic viruses that can cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe, which is primarily caused by Hantaan virus (HTNV) infection, results in profound morbidity and mortality. However, no specific treatment is available for this disease. Coumarin derivatives have been reported as antiviral molecules, while studies about the bioactivity of coumarin derivatives against HTNV infection are limited. To study the potential antiviral activity of coumarin derivatives, 126 coumarin derivatives are synthesized, and their inhibitory activity against HTNV is analyzed in vitro. Among these compounds, N6 inhibits HTNV with relatively high selectivity index at 10.9, and the viral titer of HTNV is reduced significantly after 5, 10, and 20 μM N6 treatments. Furthermore, the administration of N6 at the early stage of HTNV infection can inhibit the replication and production of infectious HTNV in host cell, this therapeutic efficacy is confirmed in HTNV-infected newborn mice at the early stage of infection. The molecular docking results show that N6 forms interactions with the key amino acid residues at its active site, and reveals several molecular interactions responsible for the observed affinity, and the treatment of N6 can inhibit the expression of p (Ser473)Akt and HTNV nucleocapsid protein significantly. As such, these observations demonstrate that coumarin derivative N6 might be used as a potential agent against HTNV infection.
BERT-Based Natural Language Processing of Drug Labeling Documents: A Case Study for Classifying Drug-Induced Liver Injury Risk
Authors: Wu Yue , Liu Zhichao , Wu Leihong , Chen Minjun , Tong Weida 
Published: December 2021

Background &amp; Aims: The United States Food and Drug Administration (FDA) regulates a broad range of consumer products, which account for about 25% of the United States market. The FDA regulatory activities often involve producing and reading of a large number of documents, which is time consuming and labor intensive. To support regulatory science at FDA, we evaluated artificial intelligence (AI)-based natural language processing (NLP) of regulatory documents for text classification and compared deep learning-based models with a conventional keywords-based model.Methods: FDA drug labeling documents were used as a representative regulatory data source to classify drug-induced liver injury (DILI) risk by employing the state-of-the-art language model BERT. The resulting NLP-DILI classification model was statistically validated with both internal and external validation procedures and applied to the labeling data from the European Medicines Agency (EMA) for cross-agency application.Results: The NLP-DILI model developed using FDA labeling documents and evaluated by cross-validations in this study showed remarkable performance in DILI classification with a recall of 1 and a precision of 0.78. When cross-agency data were used to validate the model, the performance remained comparable, demonstrating that the model was portable across agencies. Results also suggested that the model was able to capture the semantic meanings of sentences in drug labeling.Conclusion: Deep learning-based NLP models performed well in DILI classification of drug labeling documents and learned the meanings of complex text in drug labeling. This proof-of-concept work demonstrated that using AI technologies to assist regulatory activities is a promising approach to modernize and advance regulatory science.
Development of Gram Stain Scoring System Based on Pro-Inflammatory Cytokines in the Sheep Model for Testing Toxicity of Vaginal Products
Authors: Vincent Kathleen L. , Miller Aaron L. , Maxwell Carrie , Richardson-Harman Nicola , O'Neill Cynthia , Dawson Lauren N. , Madsen Timothy , Walker Cattlena , Swartz Glenn , Pyles Richard B. 
Published: December 2021

Background: Development of safe, effective products to prevent the sexual transmission of HIV remains a priority. Prior to clinical testing, the products must undergo strict safety evaluations to avoid mucosal drug toxicity, inflammation, and vaginal microbiome (VMB) shifts. Based on the Food and Drug Administration (FDA) guidance, we designed a study to measure the inflammatory markers and VMB changes after intravaginal treatment with products that have been associated with toxicity, with the objective to develop a Gram stain slide scoring system, similar to Nugent scoring, correlated with the proinflammatory cytokines in sheep.Methods: Non-pregnant Dorset ewes (n = 34) were randomized to receive 5 ml intravaginal 4% nonoxynol-9 (N9) contraceptive gel, positive control (0.2% benzalkonium chloride), placebo control [hydroxethyl cellulose (HEC)], or no application daily for 10 days, with 11-day post-treatment follow-up. The vaginal swabs were collected for the cytokines, VMB, and Gram-stained slides. An enzyme-linked immunosorbent assay (ELISA) analysis of cytokines interleukin (IL)-1β, IL-8, CXCL10, and tumor necrosis factor-α (TNF-α) was used to determine inflammatory state of the sample. Vaginal microbiome community types (CT) were utilized to create five equivalent slide subsets for iterative development of a Gram-stained slide scoring system with comparisons with inflammatory state based on the cytokine levels.Results: Digital images of the Gram-stained slides were scored based on Gram staining and morphology of bacteria, presence of sheep epithelial cells, and immune cells. The scoring system was modified in an iterative fashion with weighting based on cytokine categorization of inflamed samples, with three of four cytokine values above the mean indicating that the sample was inflamed. The parameters in the final version of the scoring system included mature epithelial cells, Gram-negative rods, and Gram-positive diplococci indicating normal and immune cells indicating inflammation. The area under the receiver operator characteristic curve (ROC AUC) was 0.725 (ROC AUCs range between 0.5 and 1.0) with a greater area indicating higher diagnostic ability of a test with a binary outcome: inflamed or normal.Conclusion: The scoring system, derived from the advanced VMB and cytokine analyses, provides a validated, practical method for quantification of Gram-stained slides that can be performed in most laboratories, increasing the potential for standardization. The training plan can assist laboratories to determine the safety of intravaginal products in their sheep studies or the methodological approach can be applied to other animal models where such data are also needed.
Orofacial myofunctional disorder characteristics in cerebral palsy and their treatment methods
Authors: Danilova М. A. , Zalazaeva E. A. 
Published: December 2021

Relevance. The variety of clinical manifestations of orofacial myofunctional disorders in cerebral palsy determines the need to improve diagnosis and treatment approaches. According to the authors, the planning of rehabilitation measures for children with cerebral palsy and orofacial pathology should be individual.Materials and methods. 120 children (mean age 8.7 years) with cerebral palsy and orofacial myofunctional disorders participated in the study with subsequent assessment of dental and neurological statuses during treatment, prevention and rehabilitation.Results. The study established correlations between general motor pathology, malocclusion and changes in the speech organs depending on the clinical form of cerebral palsy. Spastic dysarthria and anarthria were detected in 82 cases, age-appropriate speech and language development - in 38. Occlusion assessment revealed malocclusion in 88 subjects, neutral occlusion – in 32.Conclusions. Modern approaches to the treatment of malocclusion and orofacial myofunctional disorders in children with cerebral palsy allow increasing the effectiveness and quality of rehabilitation, organizing the sequence and continuity of specialist actions in a multidisciplinary rehabilitation team.
Evaluation of the preventive care effectiveness in the adults with odontogenic infection given social and hygienic risk factors
Authors: Ulitovskiy S. B. , Kalinina O. V. , Shevcov A. V. , Soloveva E. S. , Fok N. K. 
Published: December 2021

Relevance. Odontogenic infection is one of the most important problems of dental science. The variety of anti-inflammatory oral hygiene products determines the need for targeted selection of preventive toothpastes and rinses, balms, foams, elixirs, as well as monitoring and training the algorithm of hygienic measures for a patient with an odontogenic infection. The aim of the study was to study the hygienic status of the adult population for the selection of individual oral hygiene products for odontogenic infection, taking into account social and hygienic factors.Materials and methods. The study examined the prevalence of odontogenic infection in the adult population to determine the need for professional care and dental education. The study involved 198 people without somatic pathology, who were allocated into four groups according to the performed oral care and taking into account the dental status and the intensity of oral microbiota formation in the adult population. The patients were followed-up every week for one month. The study examined the simplified oral hygiene index by GreenVermillion (OHI-S), PMA index and Mühlemann and Son sulcus bleeding index, which allowed calculating the effectiveness of oral care products.Results. The preventive care effectiveness evaluation showed an increase in the cleansing effect in the adult population over the entire study period. The anti-inflammatory effectiveness analysis demonstrated positive changes: by the end of the study, the PMA index was 51.52 ± 3.40% in group 1; it increased by a factor of 3 and amounted to 44.17 ± 2.77% in group 2; 56.51 ± 4.61% – in group 3, 48.95 ± 3.60% – in group 4. The Mühlemann and Son sulcus bleeding index demonstrated the changes in the periodontal tissue condition and amounted to 52.78 ± 3.62% in group 1, 44.11 ± 3.54% in group 2, 54.97 ± 3.98% in group 3, 47.78 ± 2.73% in group 4.Conclusions. The development of oral health promotion measures determines the significance of oral care products for the prevention of odontogenic infection in the adult population, which plays a crucial role in the individual program planning for the main dental disease prevention.
Sagittal expansion of the maxilla in an adult. A clinical case
Authors: Yakoub D. J. , Startceva I. V. , Admakin O. I. , Solop I. A. 
Published: December 2021

Relevance. Skeletal Class III malocclusion is one of the most difficult to correct. Genetics, environmental factors, and postembryonic development influence its etiology. Sagittal expansion of the upper jaw will ensure the correct position of the lower jaw, which in turn will improve the patient's aesthetic parameters and health. The study examines a treatment method using the Fixed anterior growth guidance appliance (FAGGA).Materials and methods. This clinical case presents a 21-year-old male with skeletal class III due to maxillary bone deficiency. The patient refused surgery to increase the size of the upper jaw and opted for orthodontic treatment. The latter was performed using a Fixed anterior growth guidance appliance (FAGGA), followed by a rapid palatal (maxillary) expansion (RME) and brackets. We removed the FAGGA after eight months. The profile and occlusion improved.Results. The change in the inclination and protrusion of the maxillary incisors improved the profile. We received 2mm of space behind the upper right canine and 1.5mm of space behind the left one and the SNA angle increased by 2 degrees. The treatment continues with RME and brackets.Conclusions. An increase in inclination and protrusion of the maxillary incisors and a slight skeletal change improved the aesthetic parameters of the facial area.
The study of the calcium and phosphorus metabolism impact on the development of demineralized enamel areas in adolescents
Authors: Kiselnikova L. P. , Alekseeva I. A. , Danilova I. G. , Kaminskaya L. A. 
Published: December 2021

Relevance. The article presents the current data on the impact of calcium and phosphorus metabolism on the development of demineralized enamel areas in adolescents. The level of vitamin D3, osteocalcin, bone alkaline phosphatase isoenzyme and parathyroid hormone (PTH) in mixed saliva appeared to reflect the risk of the cariogenic situation in the oral cavity and the risk of enamel demineralization development, which are relevant in pediatric dentistry. Purpose – to reveal the relationship between the localized enamel demineralization and the calcium and phosphorus metabolism in teenagers.Materials and methods. In 45 adolescents, the study examined the vulnerability of hard dental tissues, including initial lesions and the mixed saliva mineral metabolism in teenagers. We formed the following groups to study the caries intensity level. Group 1 consisted of 12 adolescents with a DMF index of 3.8. 11 adolescents comprised group 2 and 11 adolescents – group 3 with DMF indices of 4.9 and 6.8, respectively; group 4 contained adolescents without caries.Results. The analysis of caries intensity and permanent enamel demineralization areas in adolescents and the main markers of mixed saliva mineralization revealed a correlation between the activity of the initial carious lesions and the calcium and phosphate metabolism.Conclusions. Evaluating the principal markers of calcium and phosphorus metabolism is relevant for the risk assessment of the cariogenic situation or enamel demineralization development in adolescents and preventive treatment planning.