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Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderate-to-severe atopic dermatitis: Results from two terminated phase II trials
Get PDFInterleukin-33 (IL-33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL-33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL-33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies—a dose-ranging itepekimab monotherapy study (NCT03738423) and a proof-of-concept study of itepekimab alone and in combination with dupilumab (NCT03736967)—were conducted in patients with moderate-to-severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof-of-concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose-proportional pharmacokinetics. Pharmacodynamics of total IL-33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration–time profiles of itepekimab and total IL-33 were similar for itepekimab with or without dupilumab, and between East Asian and non-East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL-33 may not be a key pathogenic driver in moderate-to-severe AD
A Randomized, Multi-Center, Open Label Study to Compare the Safety and Efficacy between Afatinib Monotherapy and Combination Therapy with HAD-B1 for the Locally Advanced or Metastatic NSCLC Patients with EGFR Mutations
Get PDFBackground: Lung cancer, especially non-small cell lung cancer (NSCLC), poses a significant health challenge globally due to its high mortality. Afatinib, a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has shown superior efficacy over traditional chemotherapy in NSCLC treatment. However, issues like secondary resistance and adverse effects call for alternative therapies. HAD-B1, comprising 4 herbal medicines, has shown promise in lung cancer treatment in both preclinical and clinical settings. This study assesses the combination of HAD-B1 and Afatinib in advanced NSCLC patients to potentially improve outcomes by addressing the limitations of current EGFR-TKI therapies. Method: A randomized, open-label trial evaluated the efficacy and safety of HAD-B1 with Afatinib in 90 EGFR-mutation-positive NSCLC patients. Participants were divided into treatment and control groups, receiving Afatinib with or without HAD-B1. The study focused on the initial dose maintenance rate and disease control rate (DCR) of Afatinib, alongside secondary outcomes like survival rates and quality of life, under continuous safety monitoring. Results: Among the 90 participants, no significant difference was found in initial dose maintenance (60.98% in the treatment group vs 52.50% in the control, P =.4414) or DCR (80.49% vs 90.00%, P =.2283). Secondary outcomes like PFS, TTP, and OS showed no notable differences. However, physical functioning significantly improved in the treatment group (P =.0475, PPS group). The control group experienced higher rates of adverse events of special interest and adverse drug reactions (P =.01), suggesting HAD-B1 with Afatinib might enhance physical function without increasing adverse effects. Conclusion: Combining HAD-B1 with Afatinib potentially improves quality of life and reduces adverse events in advanced NSCLC patients. Further research is necessary to confirm the long-term benefits of this combination therapy, aiming to advance NSCLC treatment outcomes. Trial registration: Clinical Research Information Service (CRIS) of the Republic of Korea, https://cris.nih.go.kr/ (ID: KCT0005414)
Global estimates on the number of people blind or visually impaired by age-related macular degeneration: a meta-analysis from 2000 to 2020
Get PDFBackground: We aimed to update estimates of global vision loss due to age-related macular degeneration (AMD). Methods: We did a systematic review and meta-analysis of population-based surveys of eye diseases from January, 1980, to October, 2018. We fitted hierarchical models to estimate the prevalence of moderate and severe vision impairment (MSVI; presenting visual acuity from <6/18 to 3/60) and blindness (< 3/60) caused by AMD, stratified by age, region, and year. Results: In 2020, 1.85 million (95%UI: 1.35 to 2.43 million) people were estimated to be blind due to AMD, and another 6.23 million (95%UI: 5.04 to 7.58) with MSVI globally. High-income countries had the highest number of individuals with AMD-related blindness (0.60 million people; 0.46 to 0.77). The crude prevalence of AMD-related blindness in 2020 (among those aged ≥ 50 years) was 0.10% (0.07 to 0.12) globally, and the region with the highest prevalence of AMD-related blindness was North Africa/Middle East (0.22%; 0.16 to 0.30). Age-standardized prevalence (using the GBD 2019 data) of AMD-related MSVI in people aged ≥ 50 years in 2020 was 0.34% (0.27 to 0.41) globally, and the region with the highest prevalence of AMD-related MSVI was also North Africa/Middle East (0.55%; 0.44 to 0.68). From 2000 to 2020, the estimated crude prevalence of AMD-related blindness decreased globally by 19.29%, while the prevalence of MSVI increased by 10.08%. Conclusions: The estimated increase in the number of individuals with AMD-related blindness and MSVI globally urges the creation of novel treatment modalities and the expansion of rehabilitation services
E-portfolio utilization in medical school clinical practice: assessing satisfaction and learning advantages
Get PDFPurpose: This study aimed to investigate the difference in satisfaction and learning benefits between e-portfolios compared to paper portfolios during clinical practice in medical schools. Methods: Utilization of and satisfaction with e-portfolios among 40 third-year medical students in the medicine department of Ajou University School of Medicine was collected using an online survey in December 2020. The collected data were analyzed using descriptive statistics and an analysis of variance. Results: Students perceived that e-portfolios were highly beneficial for consistently documenting activities during clinical practice, when compared to paper-based portfolios (mean±standard deviation [SD]=2.60±1.22). However, the least rated aspect was that e-portfolios require less time than paper-based portfolios (mean±SD=1.80±1.14). Additionally, among the various clinical practice courses using e-portfolios, the highest satisfaction was observed with the fewest content items in the e-portfolio. Conclusion: To maximize the potential benefits of e-portfolios, improvements in implementation and usability are essential. Additionally, for effective utilization of e-portfolios in clinical practice, it is necessary to clearly define students’ required competencies and ultimate goals, and structure content accordingly
Treatment of a penetrating inferior vena cava injury using doctor-helicopter emergency medical service and direct-to-operating room resuscitation in Korea: a case report
Get PDFInferior vena cava (IVC) injuries can have fatal outcomes and are associated with high mortality rates. Patients with IVC injuries require multiple procedures, including prehospital care, surgical techniques, and postoperative care. We present the case of a 67-year-old woman who stabbed herself in the abdomen with a knife, resulting in an infrarenal IVC injury. We shortened the transfer time by transporting the patient using a helicopter and decided to perform direct-to-operating room resuscitation by a trauma physician in the helicopter. The patient underwent laparotomy with IVC ligation for damage control during the first operation. The second-and third-look operations, including previous suture removal, IVC reconstruction, and IVC thrombectomy, were performed by a trauma surgeon specializing in cardiovascular diseases. The patient was discharged without major complications on the 19th postoperative day with rivaroxaban as an anticoagulant medication. Computed tomography angiography at the outpatient clinic showed that thrombi in the IVC and both iliac veins had been completely removed. Patients with IVC injuries can be effectively treated using a trauma system that includes fast transportation by helicopter, damage control for rapid he-mostasis, and expert treatment of IVC injuries
Comparative diagnostic performance of rapid urease test with the sweeping method versus tissue sampling method after Helicobacter pylori eradication (with video)
No full textBackground and Aims: The rapid urease test (RUT) is widely used to detect Helicobacter pylori infection; however, it is not preferred as a monitoring strategy after eradication owing to its low sensitivity. In this study, we evaluated the diagnostic performance of RUT using the sweeping method, which overcomes the limitations of conventional tissue sampling methods after eradication. Methods: Patients who received H pylori eradication treatment were enrolled. Each of the sweeping and conventional methods was performed on the same patients to compare diagnostic performance. Urea breath test (UBT), histology, and polymerase chain reaction were performed to determine true infection. Logistic regression analysis was conducted to investigate reasons for discrepancies between the results of the 2 methods. Results: In 216 patients, the eradication success rate was 68.1%, and the sensitivity and specificity of the sweeping method were 0.812 and 0.912, respectively, whereas those of the conventional method were 0.391 and 0.993, respectively (P < .05 for all). The area under the receiver operating characteristic curve for the sweeping method was higher than that for the conventional method (0.862 vs 0.692, P < .001). The mean time to H pylori detection for the sweeping method was 4.7 ± 4.4 minutes and 12.3 ± 16.1 minutes for the conventional method (P < .001). The risk for inconsistent results between the 2 methods was the highest for UBT values of 1.4‰ to 2.4‰ (odds ratio, 3.8; P = .016). Conclusions: The RUT with the sweeping method could potentially replace the tissue sampling method as a test to confirm H pylori eradication and be an alternative option to UBT for patients requiring endoscopy
Deep learning-based analysis of EGFR mutation prevalence in lung adenocarcinoma H&E whole slide images
No full textEGFR mutations are a major prognostic factor in lung adenocarcinoma. However, current detection methods require sufficient samples and are costly. Deep learning is promising for mutation prediction in histopathological image analysis but has limitations in that it does not sufficiently reflect tumor heterogeneity and lacks interpretability. In this study, we developed a deep learning model to predict the presence of EGFR mutations by analyzing histopathological patterns in whole slide images (WSIs). We also introduced the EGFR mutation prevalence (EMP) score, which quantifies EGFR prevalence in WSIs based on patch-level predictions, and evaluated its interpretability and utility. Our model estimates the probability of EGFR prevalence in each patch by partitioning the WSI based on multiple-instance learning and predicts the presence of EGFR mutations at the slide level. We utilized a patch-masking scheduler training strategy to enable the model to learn various histopathological patterns of EGFR. This study included 868 WSI samples from lung adenocarcinoma patients collected from three medical institutions: Hallym University Medical Center, Inha University Hospital, and Chungnam National University Hospital. For the test dataset, 197 WSIs were collected from Ajou University Medical Center to evaluate the presence of EGFR mutations. Our model demonstrated prediction performance with an area under the receiver operating characteristic curve of 0.7680 (0.7607–0.7720) and an area under the precision-recall curve of 0.8391 (0.8326–0.8430). The EMP score showed Spearman correlation coefficients of 0.4705 (p = 0.0087) for p.L858R and 0.5918 (p = 0.0037) for exon 19 deletions in 64 samples subjected to next-generation sequencing analysis. Additionally, high EMP scores were associated with papillary and acinar patterns (p = 0.0038 and p = 0.0255, respectively), whereas low EMP scores were associated with solid patterns (p = 0.0001). These results validate the reliability of our model and suggest that it can provide crucial information for rapid screening and treatment plans
Rosmarinic acid promotes cartilage regeneration through Sox9 induction via NF-κB pathway inhibition in mouse osteoarthritis progression
Get PDFBackground: The natural polyphenolic compound known as Rosmarinic acid (RosA) can be found in various plants. Although its potential health benefits have been extensively studied, its effect on osteoarthritis (OA) progression and cartilage regeneration function still needs to be fully elucidated in OA animal models. This study elucidated the effect of RosA on OA progression and cartilage regeneration. Methods: In vitro assessments were conducted using RT-PCR, qRT-PCR, Western blotting, and ELISA to measure the effects of RosA. The molecular mechanisms of RosA were determined by analyzing the translocation of p65 into the nucleus using immunocytochemistry (ICC). Histological analysis of cartilage explant was performed using alcian blue staining and immunohistochemistry (IHC). For in vivo analysis, the destabilization of the medial meniscus (DMM)-induced OA mouse model was utilized to evaluate cartilage destruction through Safranin-O staining. The expression of catabolic and anabolic factors in mice knee joints was quantified by immunohistochemistry. Results: The expression of catabolic factors in chondrocytes was significantly impeded by RosA. It also suppressed the NF-κB signaling pathway by decreasing phosphorylation of p65 and reducing degradation of IκB protein. In ex vivo experiments, RosA protected sulfated proteoglycan erosion triggered by IL-1β and suppressed the catabolic factors in cartilage explant. RosA treatment in animal models resulted in preventing cartilage destruction and reducing catabolic factors in the cartilage. RosA was also found to promote the expression of Sox9, Col2a1, and Acan in vitro, ex vivo, and in vivo analyses. Conclusions: RosA attenuated the OA progression by suppressing the catabolic factors expression. These effects were facilitated through the suppression of the NF-κB signaling pathway. Additionally, it promotes cartilage regeneration by inducing anabolic factors. Therefore, RosA shows potential as an effective therapeutic agent for treating OA
Diagnostic and Prognostic Utilities of Pancreatic Stone Protein in Patients with Suspected Sepsis
Get PDFBackground/Objectives: Pancreatic stone protein (PSP) is an emerging biomarker of sepsis that is secreted from pancreas sensing remote organ damages. We explored the diagnostic and prognostic utilities of PSP in patients with suspected sepsis. Methods: In a total of 285 patients (suspected sepsis, n = 148; sepsis, n = 137), we compared PSP with procalcitonin (PCT) and sequential organ failure assessment (SOFA) score. Sepsis diagnoses were explored using receiver operating characteristic curve analyses with area under the curves (AUCs). Clinical outcomes (in-hospital mortality, 30-day mortality, and kidney replacement therapy [KRT]) were explored using the Kaplan–Meier method and a multivariate analysis with hazard ratio (HR). Results: PCT and PSP were comparable for sepsis diagnosis (AUC = 0.71–0.72, p < 0.001). The sepsis proportion was significantly higher when both biomarkers increased than when either one or both biomarkers did not increase (89.0% vs. 21.3–47.7%, p < 0.001). Each biomarker quartile (Q1–Q4) differed significantly according to their SOFA score (all p < 0.001). Compared with Q1, the Q2–Q4 groups showed worse clinical outcomes (p = 0.002–0.041). Both biomarkers added to the SOFA score showed higher HRs than the SOFA score alone (3.3–9.6 vs. 2.8–4.2, p < 0.001–0.011), with nearly 2.5-fold higher HR (9.6 vs. 4.2) for predicting KRT. Conclusions: Although PCT and PSP did not independently predict clinical outcomes in the multivariate analysis, PSP demonstrated diagnostic and prognostic utilities in patients with suspected sepsis, especially for predicting kidney dysfunction. PSP, alone or in combination with PCT, would be a valuable tool that can be added to clinical assessments