Reporting System Research Articles

Large and small extracellular vesicles from Wharton’s jelly MSCs: Biophysics, function, and strategies to improve immunomodulation

Extracellular vesicles (EVs) have emerged as mediators of immunosuppression and pro-regenerative processes, particularly through mesenchymal stromal cells (MSCs) across various disease models. Despite significant progress, there is still a need for a deeper understanding of EV content and functionality to fully harness their biomedical potential. Moreover, strategies to enhance EV production for clinical scalability are still under development. This study aimed to characterize two distinct types of EV-large EV (lgEV) and small EV (smEV)-secreted by Wharton's jelly MSCs (WJ-MSCs). Strategies were explored to augment both EV production and their immunoregulatory effects. Both lgEV and smEV displayed typical EV markers and demonstrated inhibition of human lymphocyte proliferation. Furthermore, analysis of IsomiR content revealed a pronounced immunomodulating signature within MSC-derived EVs, validated by a dual-fluorescence reporter system. MSC primed with pro-inflammatory cytokines yielded increased production of lgEV and smEV, enhancing their immunomodulatory potency. Finally, genetically engineering WJ-MSC to express CD9 resulted in lgEV and smEV with heightened efficacy in suppressing lymphocyte proliferation. This study successfully isolated, characterized, and demonstrated the potent immunosuppressive effect of WJ-MSC-derived lgEV and smEV. We propose cytokine preconditioning and genetic manipulation as viable strategies to enhance the therapeutic potential of WJ-MSC-derived EV in inflammatory conditions.

Performance of CO-RADS in the diagnosis of COVID-19 in hemodialysis patients.

Different data systems have been used to reach a common decision in the interpretation of chest computed tomography (CT) scans for the detection of COVID-19 infection. The aim of our study was to determine the usefulness of the COVID-19 Reporting and Data System (CO-RADS) for COVID-19 in patients undergoing hemodialysis. We included 90 hemodialysis patients who underwent chest CT and had samples available for real-time reverse transcription-polymerase chain reaction (RT-PCR). The files of the patients were retrospectively reviewed and the data were recorded. Image interpretation and CO-RADS staging were performed retrospectively by two radiologists experienced in COVID-19 patients, blinded to the RT-PCR results. The RT-PCR results were then compared with the CO-RADS stages obtained. The success of CO-RADS in diagnosing COVID-19 was evaluated according to its prediction of a positive RT-PCR result. At the same time, the relationship between CO-RADS stages and prognosis was also evaluated. Patients were divided into two groups according to the RT-PCR results, of which 38 (42.2%) had positive results. Validity tests of CO-RADS were performed according to the RT-PCR test. While 71.1% of patients with CO-RADS ≥4 were RT-PCR (+), 13.2% of patients with CO-RADS ≤2 were RT-PCR (+) (p < 0.001). CO-RADS ≥4 detected COVID-19 with 71.1% sensitivity and 51.9% specificity. ROC analysis confirmed the diagnostic performance of CO-RADS for predicting RT-PCR positivity with AUC = 0.73 (95% CI: 0.63-0.84). The relationship between CO-RADS stages and mortality was not significant (p = 0.21). CO-RADS is moderately sensitive and poorly specific for the diagnosis of COVID-19 in hemodialysis patients. In these patients, CO-RADS would be more useful to exclude other infections than to diagnose COVID-19.

Enhancing radiologist's detection: an imaging-based grading system for differentiating Crohn's disease from ulcerative colitis

BackgroundDelayed diagnosis of inflammatory bowel disease (IBD) is common, there is still no effective imaging system to distinguish Crohn's Disease (CD) and Ulcerative Colitis (UC) patients.MethodsThis multicenter retrospective study included IBD patients at three centers between January 2012 and May 2022. The intestinal and perianal imaging signs were evaluated. Visceral fat information from CT images was extracted, including the ratio of visceral to subcutaneous fat volume (VSR), fat distribution, and attenuation values. The valuable indicators were screened out in the derivation cohort by binary logistic regression and receiver working curve (ROC) analysis to construct an imaging report and data system for IBD (IBD-RADS), which was tested in the validation cohort.ResultsThe derivation cohort included 606 patients (365 CD, 241 UC), and the validation cohort included 155 patients (97 CD, 58 UC). Asymmetric enhancement (AE) (OR = 87.75 [28.69, 268.4]; P < 0.001), perianal fistula (OR = 4.968 [1.807, 13.66]; P = 0.002) and VSR (OR = 1.571 [1.087, 2.280]; P = 0.04) were independent predictors of CD. VSR improved the efficiency of imaging signs (AUC: 0.929 vs. 0.901; P < 0.001), with a threshold greater than 0.97 defined as visceral fat predominance (VFP). In IBD-RADS, AE was the major criterion, VFP and perianal fistula were auxiliary criteria, and intestinal fistula, limited small bowel disease, and skip distribution were special favoring items as their 100% specificity. Grade 3 to 5 correctly classified most CD patients (derivation: 96.5% (352/365), validation: 98.0% (95/97)), and 98% of those were eventually diagnosed with CD (derivation: 97.8% (352/360), validation: 98.0% (95/97)).ConclusionsIBD-RADS can help radiologists distinguish between CD and UC in patients with suspected IBD.

ProstateZones – Segmentations of the prostatic zones and urethra for the PROSTATEx dataset

Manual segmentations are considered the gold standard for ground truth in machine learning applications. Such tasks are tedious and time-consuming, albeit necessary to train reliable models. In this work, we present a dataset with expert segmentations of the prostatic zones and urethra for 200 randomly selected patients from the PROSTATEx dataset. Notably, independent duplicate segmentations were performed for 40 patients, providing inter-reader variability data. This results in a total of 240 segmentations. This dataset can be used to train machine learning models or serve as an external test set for evaluating models trained on private data, thereby addressing a current gap in the field. The delineated structures and terminology adhere to the latest Prostate Imaging Reporting and Data Systems v2.1 guidelines, ensuring consistency.

Host-Graft Synapses Form Functional Microstructures and Shape the Host Light Responses After Stem Cell-Derived Retinal Sheet Transplantation.

Retinitis pigmentosa represents a leading cause of blindness in developed countries, yet effective treatments for the disease remain unestablished. Previous studies have demonstrated the potential of stem cell-derived retinal organoid (SC-RO) sheet transplantation to form host-graft synapses and to improve light responsiveness in animal models of retinal degeneration. However, the detailed microstructures of these de novo synapses and their functional contribution have not been well elucidated. This study aims to (1) elucidate the microstructures of the host-graft synapse, and (2) investigate the overall distribution and contribution of these synapses to host retinal light responses. We identified host-graft synapses using a reporter system in mouse SC-RO and rd1 mice, a well-established model of end-stage retinal degeneration. Correlative array tomography was used to reveal the microstructure of host-graft synapses. Furthermore, we developed a semi-automated algorithm that robustly detects the host-graft photoreceptor synapses in the overall grafted area using the same reporter system in flat-mount retinas. We then integrated the spatial distribution of the host-graft synapses with light responses detected by multi-electrode array recording. Correlative array tomography revealed that host-graft synapses recapitulate the developmental process of photoreceptor synapse formation involving horizontal cells first and then rod bipolar cells. By integrating the spatial distribution of host-graft synapse and multi-electrode array recording, we showed that the number of light-responsive host retinal ganglion cells is positively correlated with the local density of host-graft synapses. De novo host-graft synapses recapitulate the developmental microstructure of the photoreceptor synapse, and their formation contributes to the light responsiveness after SC-RO transplantation.

Diagnosis and management of Rosai–Dorfman disease of the breast: Case report and literature review

AbstractRosai–Dorfman disease (RDD) is a rare subtype of non–Langerhans cell histiocytosis. It is a benign disease with variable presentations, with breast involvement being an uncommon manifestation. In this paper, we present a case of breast RDD in a 59‐year‐old Chinese woman who presented with a painless, enlarging mass in her right breast, accompanied by skin changes and no palpable axillary lymph node. A mammogram and breast ultrasonography revealed a progressively enlarging lesion with a suspicious axillary lymph node, leading to an upgrade from Breast Imaging Reporting and Data System (BIRADS) score of 3 to 4A on interval imaging. Core biopsy of the breast mass and cytology of the right axillary lymph node confirmed extranodal RDD. After a 5‐year period of observation, excision was performed due to persistent symptoms. Local recurrence of RDD, with skin discolouration and thickening, was confirmed by skin biopsy 1 year and 9 months after the operation. To the best of our knowledge, this is the first reported case of breast RDD in Hong Kong.

8414 Utilization of Cell Free DNA Integrity Index to Differentiate Benign from Malignant Thyroid Nodules

Abstract Disclosure: S. Tarafdar: None. S. Dutta: None. P. Mukhopadhyay: None. N.P. Bhattacharya: None. S. Ghosh: None. Introduction: Recent advances in molecular genetics have evaluated a potential role for plasma cell-free DNA (cfDNA) integrity index as a non-invasive cancer marker. Data on cfDNA integrity in differentiated thyroid cancer is sparse and needs to be investigated further. Aim of the study: The purpose of this study is to investigate the hypothesis that longer DNA strands in plasma may serve as a marker for thyroid cancer. Methods: Patients presenting with thyroid nodules underwent ultrasonography with Thyroid Image Reporting and Data Systems (TIRADS) scoring and FNAC (Bethesda classification).Patients with Bethesda 3, 4, 5, and 6 had surgery and confirmation by histopathology. Patients with Bethesda 2 presenting with compressive symptoms and cosmetic concerns underwent surgery; the remaining patients were considered benign based on clinical follow-up, USG, and FNAC characteristics. Blood sample collected prior to FNAC was used to extract and quantify cfDNA. To assess the integrity index 180/67, 306/67, and 476/67 for the APP gene, we used a quantitative real-time PCR (qPCR) method based on the quantification of four amplicons of varying lengths (67, 180, 306, and 476 bp, respectively). Because culture cells had extremely intact genomic DNA, the genomic DNA obtained from the MDA-T32 papillary thyroid cancer cell line was utilised as a reference to estimate the relative DNA strand integrity in plasma DNA. To determine the (ΔCt) value for 67,180, 306, and 476 bp, the Ct value of the sample was subtracted from that of the MDA-T32 control. Results: A total of 161 subjects were recruited, of these 92 were benign and 69 had differentiated thyroid cancer(confirmed by histopathology). Using the 180/67 bp integrity index benign thyroid nodule patients had significant lower value (median 0.39, 95% CI: 0.33-0.46) compared to patients with differentiated thyroid cancer (median 0.62, 95% CI: 0.56-0.68). A cfDNA integrity index of 180/67 bp could significantly differentiate between benign and malignant thyroid nodules (P&amp;lt;0.001). However, there was no significant difference between malignant and benign thyroid nodules based on the cell free DNA integrity indexes of 306/67 and 476/67. Conclusions: The cfDNA integrity score of 180/67 exhibits potential as a circulating marker for the detection of thyroid nodules and as a means of monitoring cfDNA fragmentation in patients with thyroid cancer. However, further confirmation through prospective trials is necessary. Presentation: 6/3/2024

8414 Utilization Of Cell Free DNA Integrity Index To Differentiate Benign From Malignant Thyroid Nodules

Abstract Disclosure: S. Tarafdar: None. S. Dutta: None. P. Mukhopadhyay: None. N.P. Bhattacharya: None. S. Ghosh: None. Introduction: Recent advances in molecular genetics have evaluated a potential role for plasma cell-free DNA (cfDNA) integrity index as a non-invasive cancer marker. Data on cfDNA integrity in differentiated thyroid cancer is sparse and needs to be investigated further. Aim of the study: The purpose of this study is to investigate the hypothesis that longer DNA strands in plasma may serve as a marker for thyroid cancer. Methods: Patients presenting with thyroid nodules underwent ultrasonography with Thyroid Image Reporting and Data Systems (TIRADS) scoring and FNAC (Bethesda classification).Patients with Bethesda 3, 4, 5, and 6 had surgery and confirmation by histopathology. Patients with Bethesda 2 presenting with compressive symptoms and cosmetic concerns underwent surgery; the remaining patients were considered benign based on clinical follow-up, USG, and FNAC characteristics. Blood sample collected prior to FNAC was used to extract and quantify cfDNA. To assess the integrity index 180/67, 306/67, and 476/67 for the APP gene, we used a quantitative real-time PCR (qPCR) method based on the quantification of four amplicons of varying lengths (67, 180, 306, and 476 bp, respectively). Because culture cells had extremely intact genomic DNA, the genomic DNA obtained from the MDA-T32 papillary thyroid cancer cell line was utilised as a reference to estimate the relative DNA strand integrity in plasma DNA. To determine the (ΔCt) value for 67,180, 306, and 476 bp, the Ct value of the sample was subtracted from that of the MDA-T32 control. Results: A total of 161 subjects were recruited, of these 92 were benign and 69 had differentiated thyroid cancer(confirmed by histopathology). Using the 180/67 bp integrity index benign thyroid nodule patients had significant lower value (median 0.39, 95% CI: 0.33-0.46) compared to patients with differentiated thyroid cancer (median 0.62, 95% CI: 0.56-0.68). A cfDNA integrity index of 180/67 bp could significantly differentiate between benign and malignant thyroid nodules (P&amp;lt;0.001). However, there was no significant difference between malignant and benign thyroid nodules based on the cell free DNA integrity indexes of 306/67 and 476/67. Conclusions: The cfDNA integrity score of 180/67 exhibits potential as a circulating marker for the detection of thyroid nodules and as a means of monitoring cfDNA fragmentation in patients with thyroid cancer. However, further confirmation through prospective trials is necessary. Presentation: 6/3/2024

7626 Endocrine Adverse Reactions Of Tyrosine Kinase Inhibitors In Combination With Immune Checkpoint Inhibitors: A Retrospective Analysis Using The US FDA Adverse Event Reporting System

Abstract Disclosure: W. Shao: None. D. Lu: None. K. Yang: None. Y. Gao: None. J. Zhang: None. Y. Zhang: None. Background: Tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) have been recognized to cause multiple endocrine adverse reactions (EARs). However, the combination therapy-associated EARs is still unclear. We aimed to evaluate the clinical characteristics and prognosis of EARs induced by TKI, ICI and TKI+ICI therapy. Methods: Using the US FDA Adverse Event Reporting System, 938464 cases of all adverse events, adult patients, related to the three types of treatments from January 2001 to September 2023 were identified. A total of 22275 cases were EARs and divided into TKI (n=9181), ICI (n=11363) and TKI+ICI group (n=1731). Results: The incidence of EARs was the highest in TKI+ICI group (9.1%), followed by ICI (7.7%), and TKI group (1.2%) (P &amp;lt; 0.05). Among patients with EARs, the proportions of female and Asian patients were significantly greater in TKI+ICI group than in the other groups (P&amp;lt;0.05 for all). TKI+ICI group had a larger proportion of elderly patients compared with TKI group. The most common type of EARs in TKI+ICI group was thyroid dysfunction (TD) (67.5%), followed by glucose metabolism disorder (GMD) (14.0%). Compared with TKI group, TKI+ICI group displayed a higher risk of TD (OR 3.247, 95% CI [2.849-3.701]), pituitary dysfunction (PD) (OR 6.199, 95% CI [4.534-8.474]), and primary adrenal insufficiency (PAI) (OR 4.178, 95% CI [3.470-5.031]), while the risk of GMD was lower (OR 0.136, 95% CI [0.115-0.161]). Compared with ICI group, an increasing trend of TD (OR 2.640, 95% CI [2.328-2.995]) was found in TKI+ICI group, while a lower risk of GMD (OR 0.388, 95% CI [0.328-0.459]) and PD (OR 0.312, 95% CI [0.255-0.383]) was observed in TKI+ICI group. Hypothyroidism and diabetes mellitus were the main types of TD and GMD in all three groups. Patients with polyendocrine glands involvement accounted for the largest proportion in ICI group (11.4%), followed by TKI +ICI (7.9%), and TKI group (2.3%) (P&amp;lt;0.05). In TKI+ICI group, elderly patients, Asians, melanoma patients were more likely to experience multi-glandular EARs. In terms of prognosis, TKI+ICI group presented a higher risk of hospitalization compared to TKI (OR 2.201, 95% CI [1.943-2.492]) and ICI group (OR 1.282, 95%CI [1.139-1.442]). However, the mortality risk of TKI+ICI group was significantly lower (OR 0.717, 95% CI [0.588-0.874]) than TKI group, and there was no significant difference compared to ICI group. Moreover, there was no difference in mortality between patients with polyendocrine and single endocrine gland involvement. Conclusions: EARs were more common in TKI+ICI therapy. The distribution of EARs in different glands varied among combination therapy and monotherapy. Combination therapy associated EARs did not increase the risk of mortality. Key words: Tyrosine kinase inhibitors, Immune checkpoint inhibitors, Combination therapy, Endocrine adverse reactions, Prognosis Presentation: 6/3/2024

Adverse Event Profile of First-line Drugs for Treating Patent Ductus Arteriosus in Neonates: A Disproportionality Analysis Study of USFDA Adverse Event Reporting System.

Acetaminophen, ibuprofen, and indomethacin are widely used as first-line drugs for patent ductus arteriosus (PDA) closure in preterm neonates. However, their relative safety profiles remain unclear. Adverse event reports related to the first-line drugs used in PDA and neonates in general were retrieved from the US Food and Drug Authority (FDA) Adverse Event Reporting System. Deduplicated reports were analyzed using proportional reporting ratios and reporting odds ratios to identify disproportionality safety signals between drugs. A total of 969 unique reports related to the first-line drugs used in PDA and 499 reports in the neonatal period were included. Acetaminophen signals primarily involved the liver, while ibuprofen and indomethacin signals pertained to gastrointestinal, renal, vascular, and mortality outcomes. Higher occurrences of death were reported with indomethacin and ibuprofen compared with acetaminophen. This first comparison of PDA drug safety profiles from spontaneous reports highlights some differences, with acetaminophen potentially conferring a safer adverse effect profile overall. While limitations include missing data and reporting biases, the signals warrant further validation. Given its comparable efficacy to ibuprofen, as demonstrated in other studies, acetaminophen has the potential to be preferred as an initial medical therapy for PDA.

A real-world pharmacovigilance study using disproportionality analysis of United States Food and Drug Administration Adverse Event Reporting System events for vinca alkaloids: comparing vinorelbine and Vincristine

ABSTRACT Background Vinca alkaloids are widely used in cancer treatment for their ability to target microtubule dynamics. While their efficacy in treating certain cancers is well-established, the full spectrum of their adverse event profiles remains an area of ongoing research. Methods We analyzed AEs related to vinorelbine and vincristine using a retrospective case/non-case approach with data from the FDA Adverse Event Reporting System (FAERS). We applied various algorithms to detect AE signals: the reporting odds ratio (ROR) and proportional reporting ratio (PRR) measured disproportionality and association strength; the Bayesian confidence propagation neural network (BCPNN) calculated the Information Component (IC) for associations against background rates; and the multi-item gamma Poisson shrinker (MGPS) yielded empirical Bayes geometric mean (EBGM) values, accounting for reporting variability. Results Both medications significantly involve the blood and lymphatic systems, with vinorelbine reporting 401 cases in this System Organ Class (SOC), exhibiting a ROR of 17.4, PRR of 12.4, IC of 3.63, and EBGM of 12.38. An intersection analysis of Preferred Terms (PTs) has uncovered previously unreported AEs shared by both drugs, including posterior reversible encephalopathy syndrome and inappropriate antidiuretic hormone secretion. Conclusions This analysis highlights the need for ongoing research of the risks associated with vinorelbine and vincristine.

Assessment of thyroid nodule risk stratification knowledge and utilization among Polish physicians: a pilot study.

Ultrasonography is the primary diagnostic tool for evaluating thyroid nodules. The Thyroid Imaging Reporting & Data System (TIRADS) aims to standardise assessment and reduce fine-needle aspiration biopsies through risk stratification. This pilot study examined knowledge and utilisation of TIRADS among Polish physicians, their perception of the usefulness of TIRADS application and the extent of knowledge of individual nodule features included. An internet-based questionnaire about TIRADS use in clinical practice was sent out to Polish Ultrasound Society members. Information on the responder's experience with thyroid ultrasound and knowledge and use of TIRADS was assessed and analysed. Out of 159 physicians, 66.6% did not use TIRADS despite 43.4% being aware of its existence. EU-TIRADS was the most commonly adopted classification (50.9%). Participants who adopted TIRADS were younger (p = 0.047) and more likely to be radiologists (p < 0.01). TIRADS use was more prevalent in university clinical hospitals (p = 0.02), among physicians doing thyroid ultrasound as their primary professional activity (p < 0.01), those performing > 100 thyroid ultrasound examinations per year (p < 0.01) and those involved with thyroid fine-needle aspiration biopsy (p < 0.01). The purposes of TIRADS adoption (p < 0.01) and included imaging features (p < 0.01) were more accurately recognized by TIRADS users. TIRADS utilization among Polish clinicians is limited, despite awareness of the classification's existence. Knowledge of TIRADS components and the purpose of its application among users is satisfactory. Further training and TIRADS adoption should be encouraged, especially in the light of the recent EU-TIRADS-PL guidelines recommended by the Polish Scientific Societies.

Investigating the characteristics of mumps outbreaks in Fujian Province, China

ObjectivesIdentifying the specifics and potential causes of mumps outbreaks in the Fujian Province during the period of 2017 to 2022. MethodsMumps cases reported by the National Notifiable Communicable Disease Report System (NNCDRS) in China during the observation period of the 5 years were investigated annually and by age to detect homogeneity of the spread of the disease over time. If specific age-peaks may appear, we investigated those figures by analysing group characteristics in mumps cases presented as outbreaks. Those characteristics include demography (age and sex), clinical symptoms, place and time identification, and vaccination status. Regarding the latter, it was hypothesized that cases manifesting an outbreaks and appearing in young adults should have a low vaccination coverage, and a long-lasting period since they received their vaccine. ResultsThe total number of mumps cases reported during the observation period was 15,294, leading to incidence rates ranging from 3.2/100,000 to 8.0/100,000 per year. In the older age-group the disease spread by year and age (9 to 15y old) manifested 20 outbreaks accounting for 710 cases, all happening during 2017 to 2019. Thereafter those outbreaks disappeared in that age-group. The group characteristics specified that all the outbreaks happened in school settings, with a median age of 13y (range 6 to 19y). Parotid gland enlargement was observed in 82.7 %. The median duration of the outbreaks was 28 days, varying from 14 to 74 days. Only 27.6 % of the cases received at least one dose of the MuCV vaccine, and among these vaccinated individuals, 94.9 % developed mumps more than 5 years after vaccination. The dramatic reduction in outbreaks after 2019 could be explained by the public health measures taken during the COVID period and/or the new vaccination policy implemented in 2008 (free vaccination, 1 dose) and 2020 (2 doses) of young children causing therefore a lower rate of circulation of the virus. ConclusionMumps outbreaks observed in young adults during 2017–2019 causing a disease peak, indicated a potential link to unsatisfactory vaccination coverage with prolonged interval since receiving the vaccine. As those disease peaks disappeared since 2020, close monitoring for new outbreaks in young adults is recommended that may initiate a new vaccination strategy for that age-group.

Highly sensitive reporter cell line for detection of interferon types I-III and their neutralization by antibodies.

Interferons (IFNs) are a critical component of innate immune defenses and limit viral disease severity. To advance studies on IFNs and their neutralization by pathogenic autoantibodies, we generated a Renilla luciferase-based reporter cell line capable of detecting the activities of IFN-Is, IFN-II, and IFN-IIIs. The reporter cell line exhibits a 125- to 2000-fold higher sensitivity to IFNs than a commonly used alternative biological reporter system and allows for a rapid and simple live-cell workflow for detecting low titer amounts of neutralizing anti-IFN antibodies.

SIRS (Student Involvement Report System) Case Study – Studies on QOS (Quality of Service) Perimeters, Daily Error Types and Activities Within the Server

Relational Database Management System (RDBMS) is commonly applied in Small, Medium, and Enterprise businesses. In this research, we investigated Quality of Service (QoS) perimeters over day-to-day operations in RDBMS and how the running process able to be expedited with the adaptation and combination of autonomic computing approach using MAPE-K (Monitor, Analyse, Plan, Execute, and Knowledge Base) and Fuzzy rules. The core function of the system is to monitor student attendance, assessment, and lastly escalation of identified student issues to the department of academic. In a nutshell, it is called the Student Involvement Report (Sir). Two segments have been analysed and focused on errors in request time out, bandwidth, hits, and user activities. The outcomes of this are significant on activities that related to the peak of academic activity, due to the submission of student reports and escalation among departments. The MAPE-K and Fuzzy rules can capture the scenarios and identify rules that are significantly important to reduce and enhance the Request Time Out and Hits activities.

Assessment of safety profile of ivabradine in real-world scenario using FDA adverse event reporting system database

ABSTRACT Background Ivabradine is primarily indicated for patients with sinus rhythm and a heart rate ≥ 75 beats/min, who have NYHA class II-IV chronic heart failure with systolic dysfunction. There is currently a lack of large-scale, real-world studies concerning its drug adverse reactions. Research design & methods This research assesses the side effects of ivabradine by analyzing reports of adverse events (AEs) from the FDA’s Adverse Event Reporting System (FAERS) database. To evaluate the importance of these AEs, four sequential analytic strategies were utilized. Results In total, 2,701 ivabradine-related AE reports were identified in the FAERS database. We identified 26 ivabradine-induced AEs, each with more than 20 reports, including some significant AEs not mentioned on the product label. The timing of AEs was also analyzed, with the majority of AEs occurring within the first month of ivabradine use. Gender-specific analysis indicates that female have a higher risk of AEs, such as off-label use, tachycardia, drug effectiveness for unapproved indications, and rash compared to male. Conclusion This study provides important information for maximizing the usage of ivabradine, increasing its efficacy, and reducing any possible negative effects. The actual clinical use of the medication will be greatly aided by this knowledge.

A20 intrinsically influences human effector T-cell survival and function by regulating both NF-κB and JNK signaling.

A20 is a dual-function ubiquitin-editing enzyme that maintains immune homeostasis by restraining inflammation. Although A20 serves a similar negative feedback function for T-cell receptor (TCR) signaling, the molecular mechanisms utilized and their ultimate impact on human T-cell function remain unclear. TCR engagement triggers the assembly of the CARD11-BCL10-MALT1 (CBM) protein complex, a signaling platform that governs the activation of downstream transcription factors including NF-κB and c-Jun/AP-1. Utilizing WT and A20 knockout Jurkat T cells, we found that A20 is required to negatively regulate NF-κB and JNK. Utilizing a novel set of A20 mutants in NF-κB and AP-1-driven reporter systems, we discovered the ZnF7 domain is crucial for negative regulatory capacity, while deubiquitinase activity is dispensable. Successful inactivation of A20 in human primary effector T cells congruently conferred sustained NF-κB and JNK signaling, including enhanced upregulation of activation markers, and increased secretion of several cytokines including IL-9. Finally, loss of A20 in primary human T cells resulted in decreased sensitivity to restimulation-induced cell death and increased sensitivity to cytokine withdrawal-induced death. These findings demonstrate the importance of A20 in maintaining T-cell homeostasis via negative regulation of both NF-κB and JNK signaling.

Clinicopathological and Radiological Correlation Among the Spectrum of Nodular Thyroid Lesions.

Objective The primary objective of this study is to comprehensively evaluate nodular thyroid lesions. By analyzing the morphological characteristics of surgically resected specimens and biopsies, the aim is to establish correlations between the patterns, corresponding clinical diagnoses and radiological findings. Furthermore, the study will investigate cases where there is a discrepancy between imaging and pathological assessments, with the goal of understanding the contributing factors to this discordance and improving diagnostic accuracy. Methodology This retrospective observational study utilized convenience sampling to recruit participants. Sample size was determined using GPower software (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany).Statistical analysis was performed using Jamovi 2.3.28 (Jamovi Research, Vienna, Austria).The Chi-square test was employed to assess the association between the Thyroid Imaging Reporting and Data System (TIRADS) score and histopathological diagnosis.Receiver operating characteristic (ROC) analysis was conducted to identify the optimal TIRADS cut-off point for classifying nodules as malignant and to evaluate the diagnostic accuracy of TIRADS.Discordant cases between histopathological and radiological findings were analyzed to investigate potential discrepancies. Result Taking into consideration histopathology report as a gold standard, correlation of TIRADS with histopathology findings, TIRADS showed 73.08% sensitivity and 81.08% specificity, showing the strongest balance between sensitivity and specificity, as demonstrated by the Youden's Index and Metric Score. The area under the curve (AUC) remains constant at 0.805, suggesting a consistent overall discriminative ability of the TIRADS scale. Conclusion A primary advantage of this study is its exclusive focus on surgically resected nodules, which allows for definitive histological confirmation and thereby ensures the most accurate diagnostic assessment.

Nitrogen-doped carbon quantum dot regulates cell proliferation and differentiation by endoplasmic reticulum stress

ABSTRACT Quantum dots have diverse biomedical applications, from constructing biological infrastructures like medical imaging to advancing pharmaceutical research. However, concerns about human health arise due to the toxic potential of quantum dots based on heavy metals. Therefore, research on quantum dots has predominantly focused on oxidative stress, cell death, and other broader bodily toxicities. This study investigated the toxicity and cellular responses of mouse embryonic stem cells (mESCs) and mouse adult stem cells (mASCs) to nitrogen-doped carbon quantum dots (NCQDs) made of non-metallic materials. Cells were exposed to NCQDs, and we utilized a fluorescent ubiquitination-based cell system to verify whether NCQDs induce cytotoxicity. Furthermore, we validated the differentiation-inducing impact of NCQDs by utilizing embryonic stem cells equipped with the Oct4 enhancer-GFP reporter system. By analyzing gene expression including Crebzf, Chop, and ATF6, we also observed that NCQDs robustly elicited endoplasmic reticulum (ER) stress. We confirmed that NCQDs induced cytotoxicity and abnormal differentiation. Interestingly, we also confirmed that low concentrations of NCQDs stimulated cell proliferation in both mESCs and mASCs. In conclusion, NCQDs modulate cell death, proliferation, and differentiation in a concentration-dependent manner. Indiscriminate biological applications of NCQDs have the potential to cause cancer development by affecting normal cell division or to fail to induce normal differentiation by affecting embryonic development during pregnancy. Therefore, we propose that future biomedical applications of NCQDs necessitate comprehensive and diverse biological studies.

Diagnostic Performance of European and American College of Radiology Thyroid Imaging Reporting and Data System Classification Systems in Thyroid Nodules Over 20 mm in Diameter

ObjectiveThe challenge of selecting thyroid nodules for fine needle aspiration (FNA) cytology has led to the development of the Thyroid Imaging Reporting and Data System, primarily in 2 formats: European Thyroid Imaging Reporting and Data System (EU-TIRADS) and American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS). Clinical observations suggest imperfect risk assessment for TIRADS 3 nodules ≥20 mm. This study aimed to evaluate the efficacy of TIRADS systems in distinguishing benign from malignant nodules in this subgroup. MethodsFrom May 2023 to March 2024, 1094 patients with thyroid nodules were referred for ultrasound at a University Hospital. Data on clinical, ultrasound, cytological, and histopathological parameters were collected. Nodules ≥20 mm were categorized by EU-TIRADS and ACR-TIRADS, and their predictive performance for malignancy was assessed through postthyroidectomy histopathology or FNA cytology (Bethesda classification). ResultsTwo hundred sixty-seven patients (mean age 60.3 ± 14.3 years; 46 men, 221 women) with 308 nodules were analyzed. Twenty-two malignancies and 286 benign nodules were recorded. Recalculating European Thyroid Imaging Reporting and Data System 3 performance using 25-mm and 30-mm thresholds (ACR-modified EU-TIRADS) avoided 24% and 41% of FNAs, respectively, while ACR-TIRADS would prevent 26.6% (P > .05). Two malignancies were missed. ConclusionEU-TIRADS and ACR-TIRADS show similar efficacy when using a 25 mm FNA threshold. Raising the cutoff for FNA in European Thyroid Imaging Reporting and Data System 3 nodules could reduce unnecessary procedures but may increase the risk of missed malignancies, impacting patient outcomes.