Association Between NAD(P)H Quinone Oxidoreductase 1 (NQO1) Gene Methylation/Expression and Bleeding Incidence Among an Iranian Population Undergoing Warfarin Therapy.

Increased bleeding tendency is a common and challenging complication of warfarin therapy which results in extensive pharmacogenomic studies in order to develop a personalized dosing approach and minimize the risk of related side effects. Here we aimed to explore the potential role of NQO1 gene expression in warfarin response in a group of Iranian patients. We also evaluated the NQO1 promoter methylation and its association with mRNA expression. A total of 87 patients on warfarin therapy including 34 cases with drug-induced bleeding events and 53 matched controls without bleedings were included in the study. The expression of NQO1 was examined by real-time q-PCR and the methylation status of its promoter region was analyzed using methyQESD technique. There was a significant association between the reduced NQO1 gene expression and susceptibility to bleeding before (OR = 1.92, 95% CI = 1.23-3.00, p = 0.004) and following adjustment for hypertriglyceridemia (OR = 2.22, 95% CI = 1.33-3.69, p = 0.002). Furthermore, a medium negative correlation was observed between NQO1 expression and its promoter methylation (r = - 0.382, p = 0.001). The lower expression of NQO1 which partly arises from increased methylation of promoter region, may predispose warfarin treated patients to bleeding events.

The effectiveness of ruxolitinib and cyclophosphamide combination on T helper 17 and regulatory T cells in rat experimental membranous glomerulonephritis.

The progression and pathogenesis of membranous glomerulonephritis (MGN) are inextricably linked to chronic inflammation. Despite improving clinical remission rates due to the application of cyclophosphamide (CYC), treatment of MGN still requires further exploration. Ruxolitinib (Ruxo) negatively affects the signaling pathways participating in the production of pro-inflammatory cytokines. Hence, we investigated whether the combination of CYC and Ruxo can modulate inflammation through influencing T helper 17 (Th17) lineages and regulatory T cells (Tregs). Passive Heymann nephritis (PHN), an experimental model of MGN, was induced in a population of rats. Then, the animals were divided into five groups: PHN, CYC-receiving, Ruxo-receiving, CYC-Ruxo-receiving PHN rats, and healthy controls. After 28 days of treatment, biochemistry analysis was performed and splenocytes were isolated for flowcytometry investigation of Th17 cells and Tregs. The correlative transcription factors of the cells, alongside their downstream cytokine gene expressions, were also assessed using real-time PCR. Furthermore, serum cytokine signatures for the lymphocytes were determined through ELISA. The combination of CYC and Ruxo significantly reduced the serum values of urea in rats versus the PHN group (24.62 ± 7.970 vs. 40.60 ± 10.81 mg/dL). In contrast to Treg's activities, the functionality of Th17 cells noticeably increased not only in PHN rats but also in CYC or Ruxo-receiving PHN animals when compared with the control (10.60 ± 2.236, 8.800 ± 1.465, 8.680 ± 1.314 vs. 4.420 ± 1.551 %). However, in comparison to the PHN group, the incidence of Th17 cells notably fell in rats receiving CYC and Ruxo (10.60 ± 2.236 vs. 6.000 ± 1.373 %) in favor of the Treg's percentage (5.020 ± 1.761 vs. 8.980 ± 1.178 %), which was verified by the gene expressions and cytokine productions correlative to these lymphocytes. The combination of CYC and Ruxo was able to decline Th17 cells in favor of Tregs improvement in PHN rats, suggesting an innovative combination therapy in MGN treatment approaches.

The significance of stem cell-like memory T cells in viral and bacterial vaccines: A mini review.

Vaccination has become a widely used method to induce immune protection against microbial pathogens, including viral and bacterial microorganisms. Both humoral and cellular immunity serve a critical role in neutralizing and eliminating these pathogens. An effective vaccine should be able to induce a long-lasting immune memory response. Recent investigations on different subsets of T cells have identified a new subset of T cells using multi-parameter flow cytometry, which possess stem cell-like properties and the ability to mount a rapid immune response upon re-exposure to antigens known as stem cell-like memory T cells (TSCM). One of the major challenges with current vaccines is their limited ability to maintain long-term memory in the adaptive immune system. Recent evidence suggests that a specific subgroup of memory T cells has the unique ability to retain their longevity for up to 25 years, as observed in the case of the yellow fever vaccine. Therefore, in this study, we tried to explore and discuss the potential role of this new T cell memory subset in the development of viral and bacterial vaccines.

Sperm epigenetics and male infertility: unraveling the molecular puzzle.

BACKGROUND: The prevalence of infertility among couples is estimated to range from 8 to 12%. A paradigm shift has occurred in understanding of infertility, challenging the notion that it predominantly affects women. It is now acknowledged that a significant proportion, if not the majority, of infertility cases can be attributed to male-related factors. Various elements contribute to male reproductive impairments, including aberrant sperm production caused by pituitary malfunction, testicular malignancies, aplastic germ cells, varicocele, and environmental factors. MAIN BODY: The epigenetic profile of mammalian sperm is distinctive and specialized. Various epigenetic factors regulate genes across different levels in sperm, thereby affecting its function. Changes in sperm epigenetics, potentially influenced by factors such as environmental exposures, could contribute to the development of male infertility. CONCLUSION: In conclusion, this review investigates the latest studies pertaining to the mechanisms of epigenetic changes that occur in sperm cells and their association with male reproductive issues.

Innovate and Validate: Design-Led Simulation Optimization to Test Centralized Registration Feasibility in a Multispecialty Clinic.

OBJECTIVE: This study utilizes a design-led simulation-optimization process (DLSO) to refine a hybrid registration model for a free-standing outpatient clinic. The goal is to assess the viability of employing DLSO for innovation support and highlight key factors influencing resource requirements. BACKGROUND: Manual registration in healthcare causes delays, impacting patient services and resource allocation. This study addresses these challenges by optimizing a hybrid centralized registration and adopting technology for efficiency. METHOD: An iterative methodology with simulation optimization was designed to test a proof of concept. Configurations of four and five registration options within a hybrid centralized system were explored under preregistration adoption rates of 30% and 50%. Three self-service kiosks served as a baseline during concept design and test fits. RESULTS: Centralized registration accommodated a daily throughput of 2,000 people with a 30% baseline preregistration rate. Assessing preregistration impact on seating capacity showed significant reductions in demand and floor census. For four check-in stations, a 30%-50% preregistration increase led to a 32% seating demand reduction and a 26% decrease in maximum floor census. With five stations, a 50% preregistration reduced seating demand by 23% and maximum floor census by 20%. CONCLUSION: Innovating introduces complexity and uncertainties requiring buy-in from diverse stakeholders. DLSO experimentation proves beneficial for validating novel concepts during design.

A novel scoring system for early prediction of massive transfusion requirement in trauma patients.

Early resuscitation using blood products is critical for patients with severe hemorrhagic shock. We aimed to develop and validate a new scoring system, hemorrhagic shock transfusion prediction (HSTP) score, to predict the need for massive transfusion (MT) in these patients, compared to the widely used Assessment of Blood Consumption (ABC) score. Trauma patients admitted to Emtiaz Hospital in Iran from 2017 to 2021 were retrospectively included. Patients assigned a code 1 or 2 according to the Emergency severity index (ESI) triage system have been divided into MT and non-MT groups. MT was defined as receiving ≥ 10 units of packed cells (PCs) in 24 h. Demographic information, admission vital signs, and lab results available within 15 min were compared between the groups. A new predictive score was developed using logistic regression of statistically significant parameters. Out of 1029 patients, 651 (63.3%) required MT. An arrival, diastolic blood pressure < 79.5 mm Hg, absolute lymphocyte count > 1850/µL, base excess < - 4.25, and blood glucose > 156 mg/dL were independent predictors included in the HSTP score. The sensitivity and specificity were 74.36% and 53.87% for the HSTP score, compared to 31.03% and 76.16% for the ABC score. Moreover, the positive and negative predictive values were 77.88% and 49.03% for the HSTP score, versus 74.15% and 33.66% for ABC. The new scoring system demonstrated higher sensitivity and improved positive and negative predictive values compared to the ABC score. This score can assist physicians in making accurate transfusion decisions quickly, but further prospective studies are warranted to validate its clinical utility.

Comparison of programmed death-ligand 1 expression in adenocarcinoma and squamous cell carcinoma of the cervix in paraffin blocks of patients with cervical cancer.

AIMS: Cervical cancer (CC) is a common malignancy in women, predominantly caused by human papillomavirus. The most subtypes are adenocarcinomas (AC) and squamous cell carcinomas (SCC), which show various features and treatment responses. Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) as Immune checkpoint molecules, play a role in immune evasion. We investigated PD-L1 expression in AC and SCC of the cervix and explored its link to clinical characteristics. METHODS AND RESULTS: The present cross-sectional research was done between 2016 and 2022 on samples in Shahid Beheshti University of Medical Sciences-affiliated hospitals in Iran. Histological tissue samples of CCs (16 AC and 48 SCC) were assessed, and clinical information was obtained by reviewing their medical documents. PD-L1 expression was evaluated by immunohistochemistry and we used the combined positive score. SCC cases showed a higher (not significant) PD-L1 expression. The PD-L1 expression and clinical characteristics were not significantly correlated in both subgroups. CONCLUSION: Although SCC cases exhibited higher PD-L1 expression, this difference was non-significant. More investigations should highlight the role of PD-L1 in CC and the potential benefits of immunotherapy.

Evaluation of the Cutoff Point and Diagnostic Value of the Neutrophil-to-Lymphocyte Ratio in Predicting Ovarian Cancer Compared to Pathological Findings.

PURPOSE: This research aims to establish a neutrophil-to-lymphocyte ratio (NLR) threshold and evaluate its diagnostic accuracy compared to pathological criteria for diagnosing Epithelial Ovarian Cancer (EOC). METHODS: We conducted a cross-sectional study at Imam Hossein Hospital involving 204 women aged 18 and older with confirmed ovarian mass based on pathology. We recorded clinical, pathological, and preoperative blood count data, including neutrophil-to-lymphocyte ratio (NLR). Patients were categorized into malignant and benign ovarian mass groups based on postoperative pathology. The power of NLR to diagnosis of EOC was evaluated using ROC curve. RESULTS: At total, 204 patients (Benign 75.5% vs. Malignant 24.5%) were included in the analysis with mean age of 54.26 ±12.04 yrs in malignant and 46.31±13.21 in benign. In all cases, the proportion of patients with the following tumor markers HE4 (>140 Pm), CA 125 (> 35U/Ml) and CEA (>5 ng/Ml) were 52.45%, 41.67% and 3.43%, respectively, and proportion of abnormal tumor markers was statistically higher in malignant group compared to benign mass (p <0.05).  Odds of having higher NLR levels in the malignancy group was higher than benign group (e.g., OR of 4.45 for NLR in quartile 4 vs. quartile 1).  According to model selection criteria, the full model with including NLR level and age, BMI and tumor markers has best performance for diagnosis of malignancy (AUC =0.87). CONCLUSION: High NLR in combination with tumor markers including CA125, HE4 and CEA were associated with malignancy in patients with ovarian mass. More attention and further examinations should be devoted for patients with ovarian mass having high NLR and abnormal tumor markers levels to detect the probable malignancy as soon as possible.

Concurrent rectal perforation and obstruction following neoadjuvant chemoradiation for locally advanced rectal cancer: A case report.

INTRODUCTION: Locally advanced rectal cancer (LARC) is commonly managed with neoadjuvant chemoradiation (neoCRT) followed by surgery, though not without complications. The anatomical exposure of the colon and rectum and pelvic radiotherapy poses risk, with rectal perforation and bowel obstruction, though rare, carrying life-threatening potential. PRESENTATION OF CASE: This case highlights an exceptionally rare occurrence of concurrent rectal perforation and rectal obstruction in a 77-year-old male with LARC, just two months post neoCRT. Initial symptoms included rectal bleeding, and diagnostic procedures confirmed rectal T1N3adenocarcinoma with no metastasis. Emergency admission, prompted by complete bowel obstruction symptoms, led to discovery of rectal perforation during laparotomy, sealed by the bladder. Pathological analysis attributed the cause to radiation proctitis, reporting complete response to neoCRT with no residual tumor. DISCUSSION: The rarity of both bowel obstruction and perforation as neoCRT complications, particularly in the acute phase of radiation proctitis, is noteworthy in this case. The absence of tumoral cells at the affected sites emphasizes the exceptional nature of this case. CONCLUSION: This case underscores the importance of recognizing acute post neoCRT injuries as potentially life-threatening complications, emphasizing the need for heightened awareness and consideration in clinical management.

Harnessing the therapeutic potential of mesenchymal stem/stromal cell-derived extracellular vesicles as a novel cell-free therapy for animal models of multiple sclerosis.

Multiple sclerosis (MS) is a chronic, neuroinflammatory, and demyelinating disease of the central nervous system (CNS). Current treatments offer only limited relief from symptoms, and there is no cure. Mesenchymal stem/stromal cells (MSCs) have demonstrated therapeutic potential for MS. However, their clinical application faces challenges, including immune rejection and the potential for tumor formation. Recent studies suggest that MSCs exert their effects through extracellular vesicles (EVs) released from the cells, rather than direct cellular engraftment or differentiation. This discovery has sparked interest in the potential of MSC-derived EVs as a cell-free therapy for MS. This review explores the existing literature on the effects of MSC-EVs in animal models of MS. Administration of MSC-EVs from various tissue sources, such as bone marrow, adipose tissue, and umbilical cord, was found to reduce clinical scores and slow down disease progression in experimental autoimmune encephalomyelitis (EAE), the primary mouse model of MS. The mechanisms involved immunomodulation through effects on T cells, cytokines, CNS inflammation, and demyelination. Although the impact on CNS repair markers remained unclear, MSC-EVs exhibited the potential to modulate neuroinflammation and suppress harmful immune responses in EAE. Further studies are still required, but MSC-EVs demonstrate promising therapeutic effects for MS and warrant further exploration as a novel treatment approach.

The Urban Toolkit: A Grammar-Based Framework for Urban Visual Analytics.

While cities around the world are looking for smart ways to use new advances in data collection, management, and analysis to address their problems, the complex nature of urban issues and the overwhelming amount of available data have posed significant challenges in translating these efforts into actionable insights. In the past few years, urban visual analytics tools have significantly helped tackle these challenges. When analyzing a feature of interest, an urban expert must transform, integrate, and visualize different thematic (e.g., sunlight access, demographic) and physical (e.g., buildings, street networks) data layers, oftentimes across multiple spatial and temporal scales. However, integrating and analyzing these layers require expertise in different fields, increasing development time and effort. This makes the entire visual data exploration and system implementation difficult for programmers and also sets a high entry barrier for urban experts outside of computer science. With this in mind, in this paper, we present the Urban Toolkit (UTK), a flexible and extensible visualization framework that enables the easy authoring of web-based visualizations through a new high-level grammar specifically built with common urban use cases in mind. In order to facilitate the integration and visualization of different urban data, we also propose the concept of knots to merge thematic and physical urban layers. We evaluate our approach through use cases and a series of interviews with experts and practitioners from different domains, including urban accessibility, urban planning, architecture, and climate science. UTK is available at urbantk.org.

Clinico-Pathological and Prognostic Significance of a Combination of Tumor Biomarkers in Iranian Patients With Breast Cancer.

PURPOSE: Breast cancer is one of the most common cancers in the world. It is a multifaceted malignancy with different histopathological and biological features. Molecular biomarkers play an essential role in accurate diagnosis, classification, prognosis, prediction of treatment response, and cancer surveillance. This study investigated the clinico-pathological and prognostic significance of HER3 and ROR1 in breast cancer samples. METHODS: Tissue microarrays (TMA) were constructed using tissue blocks of 444 Iranian breast cancer patients diagnosed with breast cancer. Overall survival (OS) and disease-free survival (DFS) were assessed after 5 years follow-up. TMA slides were stained with monoclonal antibodies against ROR1, HER3, ER, PR, Ki67, P53, HER2 and CK5/6 using IHC and correlation between the investigated tumor markers and the clinico-pathological parameters of patients were analyzed. RESULTS: Our results showed a significant correlation between ROR1 and ER, PR, HER3, and CK5/6 expression. Additionally, there was a significant correlation between HER3 and ER, PR, HER2, and Ki67 expression. Ki67 was also correlated with HER2 and P53 expression. HER3 expression was significantly correlated with tumor stage, lymph node metastasis, perineural invasion, and multifocal tumors. Furthermore, ROR1 expression was significantly associated with tumor metastasis, lympho-vascular invasion, and perineural invasion. While HER2-HER3 coexpression was significantly associated with poor OS, HER3-ROR1 coexpression was associated with lymph node invasion, lymph node metastasis, and distant metastasis. CONCLUSION: ROR1 and HER3 displayed significant association with different clinic-pathological features and in addition to the other tumor biomarkers could be considered as diagnostic and prognostic biomarkers in breast cancer patients.

Myrtenol Inhalation Mitigates Asthma-Induced Cognitive Impairments: an Electrophysiological, Behavioral, Histological, and Molecular Study.

Asthma is an inflammatory disorder with significant health problems. It generally affects the lungs but can also impact brain performance via several mechanisms. Some investigations have proposed that asthma impairs cognition. This study assessed the impacts of myrtenol as a monoterpene on cognitive disorders following asthma at behavioral, molecular, and synaptic levels. Asthma was induced by injection and inhalation of ovalbumin (OVA). Male Wistar rats were allocated to five groups: control, asthma, asthma/vehicle, asthma/myrtenol, and asthma/budesonide. Myrtenol (8 mg/kg) or budesonide (160 µg/kg) was administered through inhalation once a day for 1 week, and at the end of the inhalation period, behavioral tests (MWM and Open Field), field potential recording, hippocampal brain-derived neurotrophic factor (BDNF), IL1ß (ELISA), and NFκB measurement (Western blot) were performed to evaluate cognitive performance. Moreover, H&E (hematoxylin and eosin) staining was used for hippocampus histological evaluation. Myrtenol improved spatial learning, memory, LTP (long-term potentiation) impairments, and anxiety-like behaviors following asthma. Myrtenol inhalation increased the BDNF level and decreased the IL1ß level and NFκB expression in the hippocampus of the asthmatic rats. The neuronal damage in the hippocampus following allergic asthma was alleviated via myrtenol administration. Myrtenol, as an herbal extract, protects the hippocampus from asthma consequences. Our observations revealed that myrtenol can improve spatial learning, memory, synaptic plasticity impairments, and anxiety-like behaviors following asthma. We believe that these ameliorating effects of myrtenol can be attributed to inflammation suppression and increased BDNF in the hippocampus.

Validity and Reliability of The Persian Version of Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire: A Psychometric Study.

BACKGROUND: Women with uterine fibroids (UFs) experience many clinical manifestations that affect their quality of life (QOL). The Uterine Fibroid Symptom and Health-related Quality of Life (UFS-QOL) questionnaire is an English instrument specifically designed to assess fibroid-related symptoms and their impact on QOL. This study aims to investigate the reliability and validity of the Persian version of the UFS-QOL questionnaire in Iranian women with UF. MATERIALS AND METHODS: In this psychometric study, women with UFs who presented to Imam Hossein Hospital (Tehran, Iran) between August 2022 and January 2023 were enrolled in this study. A forward-backward approach was applied to translate the UFS-QOL questionnaire into Persian. The reliability of the UFS-QOL questionnaire was assessed by internal consistency and test-retest correlation. Confirmatory factor analysis (CFA) was used to assess convergent validity between items and subscales of the UFS-QOL questionnaire. Pearson's correlation coefficient was used to assess convergence validity between subscales of the UFS-QOL and the World Health Organization Quality of Life Brief Version 26 questionnaire (WHOQOL-BREF-26). RESULTS: Overall, we assessed 226 women with UFs. All subscales of the UFS-QOL questionnaire had acceptable internal consistency (Cronbach's alpha>0.7). Test-retest analysis indicated significant positive correlations between two measurements of all subscales of the UFS-QOL questionnaire: symptom severity (P<0.001), concern (P<0.001), activities (P<0.001), energy/mood (P<0.001), control (P<0.001), self-consciousness (P=0.002), and sexual function (P<0.001). The Kaiser-Meyer-Olkin (KMO) measure value was 0.920, and the result of Bartlett's test of sphericity was significant (P<0.001). CFA identified six factors for the health-related QOL (HRQL) questionnaire, which explained 73.827% of the total variation. Most subscales of the UFS-QOL questionnaire correlated with domains of the WHOQOL-BREF-26 questionnaire (P<0.05). CONCLUSION: The Persian version of the UFS-QOL questionnaire is a valid and reliable instrument to evaluate UFrelated symptoms and QOL among Iranian women.

D-dimer, Fibrinogen and Tumor Marker Levels in Patients with benign and Malignant Ovarian Tumors.

Limited studies have investigated the differences between the levels of plasma coagulants and tumor markers in ovarian cancer. Therefore, we conducted this study to determine and compare the level of coagulation, fibrinolysis and tumor markers in patients with benign and malignant ovarian tumors. This cross-sectional study was conducted between January 2022 and February 2023 in Imam Hossein Hospital on patients with ovarian mass. Laboratory tests included platelet count, PT, INR, PTT, fibrinogen and D-dimer were sent to the pathology laboratory to be examined by a pathologist. Based on histopathology, patients were divided into benign, borderline and malignant groups. Logistic regression was used for determine predictors of malignancy. Receiver operating characteristics (ROC) curves and their corresponding 95% CI were determined for the predictor value of the full model. From 141 investigated patients, tumor type in 124 (87.94%) patients were benign, in 12 (8.51%) was malignant and in 5 (3.55%) was borderline. D-dimer, Ca-125 and HE4 were significantly higher in the patients with malignant tumor type (P<0.001), whereas AFP was significantly higher in patients with borderline tumor type (P<0.001). With one-unit increase in D-dimer odds of borderline/malignant tumor 0.3% increases (OR=1.003, 95% CI: 1.001, 1.006) and with one-unit increase in Ca-125 odds of borderline/malignant tumor 1% increases (OR=1.01, 95% CI: 1.003, 1.02). We found that plasma fibrinogen, D-dimer and Ca-125 levels are independently associated with malignant ovarian tumors and combined use of these markers has the high discriminant power for distinction of benign and malignant ovarian masses.
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Associations between exposure to common technology devices and reported neck pain among Iranian school-age adolescents: a cross sectional study.

BACKGROUND: The advancement of technology has contributed to a more sedentary lifestyle, and the extensive use of handheld devices among adolescents may potentially result in neck pain. This study aimed to assess the association between exposure to common technology devices and self-reported neck pain in Iranian school-age adolescents. METHODS: This cross-sectional study was conducted between June and October 2021, employing a randomized multi-stage cluster sampling approach. We enrolled 808 adolescent students aged 11 to 19 years old. We asked participants about any neck pain they experienced in the week leading up to the study. Additionally, we gathered demographic information and assessed participants' use of electronic devices using a questionnaire. RESULTS: Our study comprised 73.5% female participants with an average age of 15.1 ± 1.7 years and 26.5% male participants with an average age of 14.5 ± 1.5 years. In the regression model, the female gender (p = 0.038), using mobile for more than 6 h (p = 0.04), and using electronic devices while sitting on the floor (p = 0.02) were associated with a higher prevalence of neck pain among participants. CONCLUSION: In our study, we observed a relatively high prevalence of neck pain, which was linked to extended daily mobile phone usage and body posture during electronic device use. Policymakers may consider interventions aimed at reducing mobile phone usage and promoting proper body posture while using electronic devices as potential strategies to alleviate the burden of neck pain among Iranian adolescents.