Category: Statistics

J Med Virol. 2021 Aug 30. doi: 10.1002/jmv.27311. Online ahead of print.

ABSTRACT

OBJECTIVE: to analyze the distribution of HPV genotype, cytology and the clinical characteristics of VaIN.

METHODS: All patients with histological-proven VaIN at West China Second University Hospital, between January 1, 2014, and October 1, 2020 were retrospectively identified. Demographics, medical history, HPV genotype, viral load and cytology results were retrieved. Standard statistical analyses were conducted.

RESULTS: Of 3229 patients included, 42.3% were diagnosed with VaIN 1, 30.3% with VaIN 2 and 27.4% with VaIN 3. Patients with VaIN 3 were the oldest (p<0.001). The leading HPV genotypes were HPV 16, 52, 58, 53, 56 and 81. The positive rate HPV 16 was positively correlated with the grade of VaIN and infected most of VaIN 3 patients (76.0%). The sensitivities of cytology for VaIN only, concomitant VaIN and VaIN after hysterectomy were 75.6%, 78.8% and 82.9%, respectively (p=0.013), and the sensitivities of HPV were 91.1%, 93.5% and 91.7%, respectively (p=0.205). Cotesting improved the sensitivities, up to 96.9%, 97.1% and 98.1%, respectively.

CONCLUSIONS: VaIN can occur alone or be concomitant with cervical or vulvar intraepithelial neoplasia. Most of VaIN 2/3 are infected with HPV 16. The sensitivity of cytology and HPV testing is non-inferior to that of CIN 2+. Therefore, these testing might be helpful in the early detection of VaIN. This article is protected by copyright. All rights reserved.

PMID:34460120 | DOI:10.1002/jmv.27311

J Orthop Res. 2021 Aug 30. doi: 10.1002/jor.25176. Online ahead of print.

ABSTRACT

Injured tendons do not regain their native structure except at fetal or very young ages. Healing tendons often show mucoid degeneration involving accumulation of sulfated glycosaminoglycans (GAGs), but its etiology and molecular base have not been studied substantially. We hypothesized that quality and quantity of gene expression involving synthesis of proteoglycans having sulfated GAGs are altered in injured tendons and that a reduction in synthesis of sulfated GAGs improves structural and functional recovery of injured tendons. C57BL6/j mice were subjected to the Achilles tendon tenotomy surgery. The injured tendons accumulated sulfate proteoglycans as early as 1-week postsurgery and continued so by 4-week postsurgery. Transcriptome analysis revealed upregulation of a wide range of proteoglycan genes that have sulfated GAGs in the injured tendons 1 and 3 weeks postsurgery. Genes critical for enzymatic reaction of initiation and elongation of chondroitin sulfate GAG chains were also upregulated. After the surgery, mice were treated with the 2-deoxy-D-glucose (2DG) that inhibits conversion of glucose to glucose-6-phosphate, an initial step of glucose metabolism as an energy source and precursors of monosaccharides of GAGs. The 2DG treatment reduced accumulation of sulfated proteoglycans, improved collagen fiber alignment and reduced the cross-sectional area of the injured tendons. The modulus of the 2DG-treated groups were higher than that in the vehicle group, but not of statistical significance. Our findings suggest that mucoid degeneration in injured tendons may result from upregulated expression of genes involved synthesis of sulfate proteoglycans and can be inhibited by reduction of glucose utilization. This article is protected by copyright. All rights reserved.

PMID:34460123 | DOI:10.1002/jor.25176

Ther Innov Regul Sci. 2021 Aug 30. doi: 10.1007/s43441-021-00336-2. Online ahead of print.

ABSTRACT

BACKGROUND: Growing interest in improving patient participation convenience and the feasible execution of clinical trials has increased demand for new approaches to leverage patient input in the protocol design process.

METHODS: This study builds on prior work conducted by the Tufts Center for the Study of Drug Development in collaboration with ZS. A comprehensive participant burden algorithm based on protocol procedures, participation requirements and lifestyle preferences was developed and tested. Clinical trial preferences and perceptions from 3002 global patients were analyzed to inform and derive the algorithm. It was next tested against a convenience sample of 266 completed protocols. Descriptive statistics, significance tests, and regression analyses were performed.

RESULTS: Mean participant burden scores were highly associated with, and predictive (p < 0.01) of, screen failure rates, overall clinical trial duration and the number of substantial protocol amendments; and predictive (p < 0.05) of protocol treatment duration. Of 11 subgroups assessed, those that most influenced the algorithm and drove higher overall burden scores included disease condition, caregiver reliance, race, prior experience as a clinical trial participant and participant age. Geographic area and participant sex showed only minimal influence.

CONCLUSION: This study presents advancement and refinement in measuring participation burden that will assist drug development teams and protocol authors in retrospectively understanding clinical trial performance outcomes and in prospectively informing protocol design decisions.

PMID:34460095 | DOI:10.1007/s43441-021-00336-2

Int J Cancer. 2021 Aug 30. doi: 10.1002/ijc.33786. Online ahead of print.

ABSTRACT

Acidity in the tumor microenvironment has been reported to promote cancer growth and metastasis. In this study, we examined a potential relation between extracellular acidity and expression level of the immune checkpoint molecule PD-L1 in murine squamous cell carcinoma (SCC) and melanoma cell lines. PD-L1 expression in the tumor cells was upregulated by culturing in a low pH culture medium. Tumor-bearing mice were allowed to ingest sodium bicarbonate, resulting in neutralization of acidity in the tumor tissue, a decrease in PD-L1 expression in tumor cells, and suppression of tumor growth in vivo. Proton-sensing G protein-coupled receptors (GPCRs), T cell death-associated gene 8 (TDAG8) and ovarian cancer G-protein-coupled receptor 1 (OGR1), were upregulated by low pH, and essentially involved in the acidity-induced elevation of PD-L1 expression in the tumor cells. Human head and neck SCC RNAseq data from the Cancer Genome Atlas also suggested a statistically significant correlation between expression levels of the proton sensors and PD-L1 mRNA expression. These findings strongly suggest that neutralization of acidity in tumor tissue may result in reduction of PD-L1 expression, potentially leading to inhibition of an immune check point and augmentation of anti-tumor immunity.

PMID:34460096 | DOI:10.1002/ijc.33786

Inflammation. 2021 Aug 30. doi: 10.1007/s10753-021-01520-0. Online ahead of print.

ABSTRACT

Plasminogen activator inhibitor-1 (PAI-1) antagonists are known for their neuroprotective effects. In this study, it was aimed to investigate the possible protective effects of PAI-1 antagonists in a rat mild traumatic brain injury (TBI) model. Sprague-Dawley male rats were grouped as sham (n = 7), TBI (n = 9), and TBI + PAI-1 antagonist (5 and 10 mg/kg TM5441 and TM5484; n = 6-7). Under anesthesia, TBI was induced by dropping a metal 300-g weight from a height of 1 m on the skull. Before and 24-h after trauma neurological examination, tail suspension, Y-maze, and novel object recognition tests were performed. Twenty-four hours after TBI, the rats were decapitated and activities of myeloperoxidase, nitric oxide release, luminol-, and lucigenin-enhanced chemiluminescence were measured. Also, interleukin-1β, interleukin-6, tumor necrosis factor, interleukin-10, tumor growth factor-β, caspase-3, cleaved caspase-3, and PAI levels were measured with the ELISA method in the brain tissue. Brain injury was graded histopathologically following hematoxylin-eosin staining. Western blot and immunohistochemical investigation for low-density lipoprotein receptor, matrix metalloproteinase-3, and nuclear factor-κB were also performed. Data were analyzed using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA) and expressed as means ± SEM. Values of p < 0.05 were considered to be statistically significant. Higher levels of myeloperoxidase activity in the TBI group (p < 0.05) were found to be suppressed in 5 and 10 mg/kg TM5441 treatment groups (p < 0.05-p < 0.01). The tail suspension test score was increased in the TBI group (p < 0.001) and decreased in all treatment groups (p < 0.05-0.001). The histologic damage score was increased statistically significantly in the cortex, dentate gyrus, and CA3 regions in the TBI group (p < 0.01-0.001), decreased in the treatment groups in the cortex and dentate gyrus (p < 0.05-0.001). PAI antagonists, especially TM5441, have antioxidant and anti-inflammatory properties against mild TBI in the acute period. Behavioral test results were also improved after PAI antagonist treatment after mild TBI.

PMID:34460025 | DOI:10.1007/s10753-021-01520-0

Neurol Ther. 2021 Aug 30. doi: 10.1007/s40120-021-00277-w. Online ahead of print.

ABSTRACT

INTRODUCTION: According to the official Russian source, in 2017 only 0.27% of the population of Russia was diagnosed with International Classification of Diseases, tenth revision (ICD-10) F4 category disorders (neurotic, stress-related and somatoform disorders), despite these disorders being among the most prevalent mental disorders worldwide. Here we report the results of a large-scale survey among Russian psychiatrists with the primary objective to assess the proportion of psychiatrists who use the diagnoses of interest (mixed anxiety and depression disorder [MADD], adjustment disorder [AdD], panic disorder [PD], agoraphobia, generalized anxiety disorder [GAD], social phobia, simple phobia, acute stress disorder and posttraumatic stress disorder) and compare results with those of a recent World Psychiatric Association (WPA) and World Health Organization (WHO) survey. We also compared the incidence of these diagnoses between state and non-state psychiatric services in Russia.

METHODS: Mean proportions and distribution of proportions of participants who made diagnoses of interest at different rates were calculated and compared with the results of the recent WPA and WHO survey. Risk ratios (RR) of the incidence of these diagnoses made at a frequency of at least once a week were calculated to compare state and non-state psychiatric services. The 95% confidence intervals of the RRs were calculated using the Koopman asymptotic score method.

RESULTS: Responses of 960 Russian psychiatrists were included in the analysis. Of these 95, 89 and 87% reported making diagnoses of MADD, AdD and PD, respectively, during the preceding 12 months, a far larger proportion compared to other disorders of interest. In general, a significantly smaller proportion of participants in our survey made diagnoses of anxiety disorders compared to respondents in the international WPA-WHO survey. Based on RRs, diagnoses of MADD, AdD, PD, GAD and acute stress disorder were less frequently made in the state-operated psychiatric service.

CONCLUSION: Our survey revealed a serious underdiagnosis of anxiety disorders in Russia that may be associated with complex factors that include, but are not limited to the current stigma associated with the state-operated psychiatric service, which is still the exclusive source of official statistical data in Russia.

PMID:34460079 | DOI:10.1007/s40120-021-00277-w

AMB Express. 2021 Aug 30;11(1):122. doi: 10.1186/s13568-021-01282-w.

ABSTRACT

Klebsiella pneumoniae is a multidrug-resistant (MDR) opportunistic pathogen that causes nosocomial infections. Virulence analysis and molecular typing as powerful approaches can provide relevant information on K. pneumoniae infection. In the current study, antibiotic resistance, virulence-associated genes analysis, as well as molecular typing of K. pneumoniae strains were investigated. Out of 505 clinical samples collected from hospitalized patients, 100 K. pneumoniae strains were isolated by standard microbiological methods and subjected to the phenotypic and genotyping analysis. The highest prevalence of resistance was observed against ciprofloxacin (75%), trimethoprim-sulfamethoxazole (73%) and nitrofurantoin (68%). Virulence associated genes including entB, traT, ybts, magA, iucC, htrA and rmpA were found in 80%, 62%, 75%, 5%, 30%, 72% and 48%, of the isolates, respectively. The prevalence of biofilm-associated genes including mrkA, fimH, and mrkD were equally 88% for all tested isolates. Moreover, the efflux pump genes including AcrAB, TolC and mdtK were observed in 41 (41%), 33 (33%) and 26 (26%) of the strains respectively. A significant statistical association was observed between MDR strains and high expression of efflux pump and biofilm genes. The K. pneumoniae strains were differentiated into 11 different genetic patterns using the repetitive element sequence-based PCR (rep-PCR) technique. High prevalence of resistance, presence of various virulence factors, high level of efflux pump, and biofilm gene expression in diverse clones of K. pneumoniae strains pose an important health issue in clinical settings.

PMID:34460016 | DOI:10.1186/s13568-021-01282-w

Bull Math Biol. 2021 Aug 30;83(10):102. doi: 10.1007/s11538-021-00931-2.

NO ABSTRACT

PMID:34460011 | DOI:10.1007/s11538-021-00931-2

Clin Oral Investig. 2021 Aug 30. doi: 10.1007/s00784-021-04152-8. Online ahead of print.

ABSTRACT

OBJECTIVES: The aim of this study was to evaluate the in vitro effect of enamel matrix derivative (EMD) and hyaluronic acid (HA) and their synergistic combination on lipopolysaccharides (LPS)-induced inflammation in human keratinocytes and osteoblasts.

MATERIAL AND METHODS: Cells were challenged with LPS (1 μg/ml) and cultured in the following treatment groups with EMD (30 mg/ml) and HA (30 mg/ml): LPS, EMD, HA, EMD + HA, EMD + LPS, HA + LPS, and EMD + HA + LPS. Cell viability, inflammatory cytokine expression, and cell migration were determined using colorimetric assay, quantitative real-time polymerase chain reaction (qPCR), and scratch wound healing assay, respectively.

RESULTS: Cell viability was decreased when exposed to LPS compared to the controls. Overall, LPS treatment expressed upregulation on inflammatory cytokine tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6). EMD and HA reduced up to 3.0-fold the cytokine expression caused by LPS (p < 0.05). EMD and HA statistically induced higher migration in osteoblasts and keratinocytes, respectively. Migration was impaired by LPS, whereas it significantly increased after addition of EMD and HA.

CONCLUSIONS: EMD and HA are advantageous biomaterials that individually generate strong directional migratory keratinocyte and osteoblast response. Their combination also enhances cell viability, and anti-inflammatory and migratory abilities to promote healing specially under LPS inflammatory stimulus. Future in vivo and animal research is necessary to further characterize the effect of EMD and HA on periodontal regeneration.

CLINICAL RELEVANCE: The use of EMD in conjunction with HA resulted in a reduction of inflammation and improvement of tissue healing at wound sites. Both biomaterials combined may potentially improve the effectiveness of bone regeneration in periodontal bone defects, pointing to the potential clinical relevance of both materials in regenerative periodontal surgery.

PMID:34460002 | DOI:10.1007/s00784-021-04152-8

J Anesth. 2021 Aug 28. doi: 10.1007/s00540-021-02993-x. Online ahead of print.

ABSTRACT

PURPOSE: Angiogenesis, one of regenerative medicine, is essential in the process of wound healing. The detailed effects of intravenous anesthetics and sedatives used during perioperative period have not yet been clarified. We investigated the effects of benzodiazepines and propofol on in vitro capillary tube formation.

METHODS: The effects of midazolam, diazepam and propofol (1, 10, 50 µM each) on proliferation of human umbilical vein endothelial cells (HUVEC) and normal human diploid fibroblasts (NHDF) were determined. Quantitation of migration was achieved by measuring the fluorescence of migrating HUVEC using angiogenesis system. The effects of midazolam, diazepam and propofol on in vitro angiogenesis were investigated in co-cultured HUVEC and NHDF incubated. The effects of midazolam on activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases were examined by Western blot analysis using phospho-specific antibodies. Parametric data were analyzed with one-way repeated measures analysis of variance followed by the Scheffé test. A value of P < 0.05 was considered statistically significant.

RESULTS: Fifty µM of midazolam significantly impaired endothelial cell proliferation, migration, and in vitro capillary tube formation. Propofol, diazepam or lower dose midazolam did not show any enhancing or suppressive effects on in vitro angiogenesis. Fifty µM of midazolam remarkably activated ERK, but not p38 MAPK in HUVEC.

CONCLUSION: Propofol and benzodiazepines except high-dose midazolam did not affect in vitro angiogenesis. High-dose midazolam may impair in vitro capillary tube formation due to by suppressing proliferation and migration of endothelial cells via activation of ERK.

PMID:34460008 | DOI:10.1007/s00540-021-02993-x