Concomitant Use of Multiple Nephrotoxins including Renal Hypoperfusion Medications Causes Vancomycin-Associated Nephrotoxicity: Combined Retrospective Analyses of Two Real-World Databases.

There is a growing concern about the relationship between vancomycin-associated nephrotoxicity (VAN) and concomitant use of nephrotoxins. We examined this relationship by combined retrospective analyses of two real-world databases. Initially, the FDA Adverse Event Reporting System (FAERS) was analyzed for the effects of concomitant use of one or more nephrotoxins on VAN and the types of combinations of nephrotoxins that exacerbate VAN. Next, electronic medical records (EMRs) of patients who received vancomycin (VCM) at Tokushima University Hospital between January 2006 and March 2019 were examined to confirm the FAERS analysis. An elevated reporting odds ratio (ROR) was observed with increases in the number of nephrotoxins administered (VCM + one nephrotoxin, adjusted ROR (95% confidence interval [CI]) 1.67 [1.51-1.85]; VCM + ≥2 nephrotoxins, adjusted ROR [95% CI] 1.54 [1.37-1.73]) in FAERS. EMRs analysis showed that the number of nephrotoxins was associated with higher incidences of VAN [odds ratio: 1.99; 95% CI: 1.42-2.78]. Overall, concomitant use of nephrotoxins was associated with an increased incidence of VAN, especially when at least one of those nephrotoxins was a renal hypoperfusion medication (furosemide, non-steroidal anti-inflammatory drugs, and vasopressors). The concomitant use of multiple nephrotoxins, especially including renal hypoperfusion medication, should be avoided to prevent VAN.

Angiogenesis inhibitor-specific hypertension increases the risk of developing aortic dissection.

Aortic dissection is an adverse event of angiogenesis inhibitors; however, the association between the drugs and aortic dissection is unclear. Therefore, we investigated if and how angiogenesis inhibitors increase the onset of aortic dissection using pharmacologically-induced aortic dissection-prone model (LAB) mice, cultured endothelial cells, and real-world databases, which is a novel integrated research approach. Disproportionality analysis was performed and calculated using the reporting odds ratio as a risk signal using a worldwide database of spontaneous adverse events to estimate the risk of adverse events. Angiogenesis inhibitors, but not other hypertension-inducing drugs, showed significant risk signals for aortic aneurysms and dissection. A retrospective cohort analysis using JMDC, a medical receipt database in Japan, showed that the history of atherosclerosis and dyslipidemia, but not hypertension, were significantly associated with the onset of aortic dissection during angiogenesis inhibitor medication administration. For in vivo studies, sunitinib (100 mg/kg/day) was administered to LAB mice. Sunitinib increased systolic blood pressure (182 mmHg vs. 288 mmHg with sunitinib; p＜0.01) and the incidence of aortic dissection (40% vs. 59% with sunitinib; p = 0.34) in mice. In vivo and in vitro studies revealed that sunitinib increased endothelin-1 expression and induced endothelial cell damage evaluated by intracellular- and vascular cell adhesion molecule-1 expressions. The increased risk of developing aortic dissection with angiogenesis inhibitors is associated with the development of drug-specific hypertension via endothelial cell damage and endothelin-1 expression. Our findings are invaluable in establishing safer anticancer therapies and strategies to prevent the development of vascular toxicity in high-risk patients.

Valproic acid treatment attenuates cisplatin-induced kidney injury by suppressing proximal tubular cell damage.

Cisplatin treatment is effective against several types of carcinomas. However, it frequently leads to kidney injury, which warrants effective prevention methods. Sodium valproic acid is a prophylactic drug candidate with a high potential for clinical application against cisplatin-induced kidney injury. Therefore, in this study, we aimed to elucidate the mechanism underlying the prophylactic effect of valproic acid on cisplatin-induced kidney injury in a mouse model and HK2 and PODO cells with cisplatin-induced toxicity. In the mouse model of cisplatin-induced kidney injury, various renal function parameters and tubular damage scores were worsened by cisplatin, but they were significantly improved upon combination with valproic acid. No difference was observed in cisplatin accumulation between the cisplatin-treated and valproic acid-treated groups in whole blood and the kidneys. The mRNA expression levels of proximal tubular damage markers, apoptosis markers, and inflammatory cytokines significantly increased in the cisplatin group 72 h after cisplatin administration but significantly decreased upon combination with valproic acid. In HK2 cells, a human proximal tubular cell line, the cisplatin-induced decrease in cell viability was significantly suppressed by co-treatment with valproic acid. Valproic acid may inhibit cisplatin-induced kidney injury by suppressing apoptosis, inflammatory responses, and glomerular damage throughout the kidneys by suppressing proximal tubular cell damage. However, prospective controlled trials need to evaluate these findings before their practical application.

Non-recovery of vancomycin-associated nephrotoxicity is related to worsening survival outcomes: Combined retrospective analyses of two real-world databases.

There has been growing concern in worsening survival and renal outcomes following vancomycin-associated nephrotoxicity (VAN) onset, but the factors associated with these phenomena remain unclear. To examine these factors, we performed a retrospective study combining the analysis of two real-world databases. Initially, the FDA Adverse Event Reporting System (FAERS) was used to evaluate the relationship between VAN and mortality using odds ratios (ORs) and 95% confidence intervals (CIs). Next, electronic medical records (EMRs) were examined in a more robust cohort for evaluation of the association between renal outcomes and worsening survival using Cox proportional hazards regression models. FAERS analysis revealed a significant correlation between VAN occurrence and increased mortality (OR: 1.30; 95% CI: 1.17-1.46). EMR analysis showed that non-recovery of VAN was associated with increased hospital mortality (hazard ratio [HR]: 4.05; 95% CI: 2.42-6.77) and 1-year mortality (HR: 3.03, 95% CI: 1.98-4.64). The HR for VAN recovery was lower for patients with acute kidney injury (AKI) stage ≥2 (HR: 0.09; 95% CI: 0.02-0.40). Thus, worsening survival outcomes were associated with non-recovery of VAN, whereby AKI stage ≥2 was a significant risk factor. Progression to severe VAN should be prevented for better survival outcomes.

A web-based survey of educational opportunities of medical professionals based on changes in conference design during the COVID-19 pandemic.

Owing to the coronavirus disease 2019 (COVID-19) pandemic, understanding how to hold future online academic conferences effectively is imperative. We assessed the impact of COVID-19 on academic conferences, including facilities and settings for attendance, participation status, cost burden, and preferences for future styles of holding conferences, through a web-based questionnaire survey of 2,739 Japanese medical professionals, from December 2020 to February 2021. Of the participants, 28% preferred web conferences, 60% preferred a mix of web and on-site conferences, and 12% preferred on-site conferences. Additionally, 27% of the presenters stopped presenting new findings at web conferences. The proportion of participants who audio-recorded or filmed the sessions, despite prohibition, was six times higher at web than face-to-face conferences. Since the COVID-19 outbreak, the percentage of participants attending general presentations decreased from 91 to 51%. While web conferencing offers advantages, these are offset by a decrease in presentations pertaining to novel findings and data. Supplementary Information: The online version contains supplementary material available at 10.1007/s10639-022-11032-5.

Discovery of preventive drugs for cisplatin-induced acute kidney injury using big data analysis.

Cisplatin is effective against many types of carcinoma. However, a high rate of renal damage is a clinical problem. Thus, there is a need to establish a method to prevent it. Although various compounds have been reported to be effective against cisplatin-induced renal injury, there are no examples of their clinical application. Therefore, we attempted to search for prophylactic agents with a high potential for clinical application. We used Cascade Eye to identify genes that are altered during cisplatin-induced renal injury, Library of Integrated Network-based Cellular Signatures (LINCS) to identify drugs that inhibit changes in gene expression, and a large database of spontaneous adverse drug reaction reports to identify drugs that could prevent cisplatin-induced kidney injury in clinical practice. In total, 10 candidate drugs were identified. Using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), we identified drugs that reduce cisplatin-induced kidney injury. Fenofibrate was selected as a candidate drug to prevent cisplatin-induced kidney injury based on the FAERS analysis. A model was used to evaluate the efficacy of fenofibrate against cisplatin-induced renal injury. Studies using HK2 cells and mouse models showed that fenofibrate significantly inhibited cisplatin-induced renal injury but did not inhibit the antitumor effect of cisplatin. Fenofibrate is a candidate prophylactic drug with high clinical applicability for cisplatin-induced renal injury. Analysis of data from multiple big databases will improve the search for novel prophylactic drugs with high clinical applicability. For the practical application of these findings, evaluation in prospective controlled trials is necessary.

Association Between Statin Use and Daptomycin-related Musculoskeletal Adverse Events: A Mixed Approach Combining a Meta-analysis and a Disproportionality Analysis.

BACKGROUND: There is a growing concern about the association between the combined use of daptomycin (DAP) and statins and the occurrence of musculoskeletal adverse events (MAEs), but this remains controversial. This study aimed to clarify the association between statin use and DAP-related MAEs. METHODS: We used a mixed approach that combines 2 methodologies. First, we conducted a meta-analysis to examine the effects of statin use on DAP-related MAEs. Second, we conducted a disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to further confirm the results of the meta-analysis and to examine the effect of each type of statin on DAP-related MAEs in a large population. RESULTS: In the meta-analysis, statin use significantly increased the incidence of DAP-related rhabdomyolysis (odds ratio [OR]: 3.83; 95% confidence interval [CI]: 1.43-10.26) but not DAP-related myopathy (OR: 1.72; 95% CI: .95-3.12). In the disproportionality analysis using the FAERS, the use of statin significantly increased the reporting OR (ROR) for DAP-related myopathy (ROR: 5.69; 95% CI: 4.31-7.51) and rhabdomyolysis (ROR: 5.77; 95% CI: 4.33-7.68). Atorvastatin, rosuvastatin, and simvastatin all increased the incidence of DAP-related myopathy and rhabdomyolysis. CONCLUSION: The mixed approach combining a meta-analysis and disproportionality analysis showed that statin use was associated with the occurrence of DAP-related rhabdomyolysis. The appropriate use of statins and DAP should be performed with careful consideration of its safety.

Effects of 5-HT3 receptor antagonists on cisplatin-induced kidney injury.

Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first-generation 5-HT3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT3 receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice.

Quantitative and Single-step Enzyme Immunosensing Based on an Electrochemical Detection Coupled with Lateral-flow System.

A single-step electrochemical immunochromatography has been developed: the device was based on two pieces of nitrocellulose membrane, a sample pad with anti-mouse IgG antibody labeled with glucose oxidase (GOx-labeled antibody), a conjugate pad with glucose, and a Pt working electrode. Either antibody or antigen was immobilized on the membrane. The addition of a solution containing mouse IgG, a model target, allows for the dissolution of GOx-labeled antibody in the sample pad to form an immunocomplex. The produced immunocomplex was automatically separated by capturing to the antibody immobilized on the membrane with the sandwich structure or by passing through the membrane modified with an antigen for the competitive reaction. The separated GOx label arrived at the conjugate pad with glucose to undergo the enzyme reaction. Hydrogen peroxide generated by this reaction was detected at the Pt electrode prepared on the second nitrocellulose membrane downstream from the conjugate pad. The results demonstrated that the designed immunochromatography can be applied to quantitative detection with a single-step procedure, because both the GOx-labeled antibody for revealing the immunoreactions and the substrate for the enzyme reaction were prepared in the device. Moreover, the initial concentration of the GOx-labeled antibody permitted control of the detectable concentration for mouse IgG.

Improvement of Electrochemical Response of Cocaine Sensors Based on DNA Aptamer by Heat Treatment.

We report on a biosensor for cocaine based on the conformation change of DNA aptamer by capturing the cocaine molecules. The oxidation current of ferrocene conjugated on the terminal end of aptamer immobilized on an Au electrode increased with increasing cocaine concentration. The sensor response has been improved by a simple heat treatment after immobilization, since the aggregates of DNA aptamer generated during the immobilization step could be dissociated and rearranged on the electrode.

Detection of a second mesiobuccal canal in maxillary molars by swept-source optical coherence tomography.

INTRODUCTION: The purpose of this study was to investigate the ability of swept-source optical coherence tomographic (SS-OCT) imaging to detect a second mesiobuccal canal (MB2) in maxillary molars compared with visual inspection (VI) and dental operating microscopy (DOM). METHODS: Forty extracted human maxillary molars were examined. After the removal of half the crown and access cavity preparation, the existence of MB2 canals was confirmed based on cross-sectional images of each tooth obtained by micro-computed tomographic scanning as the reference standard. Then, the pulp chamber floor was scanned by SS-OCT imaging. Three dentists independently evaluated the SS-OCT images and the pulp chamber floor under VI and DOM for the presence of MB2 canals. The detection rate of MB2 canals for SS-OCT imaging, VI, and DOM was calculated, and statistical analysis was performed. RESULTS: MB2 canals existed in 19 of 40 teeth (47.5%) using micro-CT imaging. Sensitivity of DOM (0.947) was significantly higher than that of SS-OCT imaging (0.632). Specificity of SS-OCT imaging (0.714) was significantly higher than that of DOM (0.333). No statistically significant differences were found for accuracy among the 3 methods. Kappa values of SS-OCT, VI, and DOM were 0.526, 0.417, and 0.326, respectively. CONCLUSIONS: SS-OCT imaging is noninvasive, involves no ionizing radiation, and is accurate for the detection of MB2 canals.

Evaluation of coronal leakage and pathway of dye leakage after obturation with various materials for open apical foramina.

The aim of this study was to investigate coronal leakage after obturation with mineral trioxide aggregate (MTA), resin-based sealer, and silicon-based sealer for open apical foramina and to evaluate pathway of leakage. Twenty-eight maxillary premolars were used, and instrumented to ISO size #80. Teeth were randomly divided into four groups as follows: Group A filled with MTA, Group B with gutta-percha and resin-based sealer, Group C with polymer-based material and resin-based sealer, and Group D with gutta-percha and silicon-based sealer. All samples were evaluated for coronal leakage with methylene blue solution and spectrophotometry. After leakage testing, samples were cut, and sections were observed. Dye leakage of Group A was significantly lowest among all groups at 15 days and 30 days. Defects which induced coronal leakage in resin-based sealer were observed at 7 mm from the apex. Coronal leakage after obturation with MTA for open apical foramina was significantly lower than resin-based sealer and silicon-based sealer.

Detection of root surface fractures with swept-source optical coherence tomography (SS-OCT).

OBJECTIVE: The purpose of this study was to compare optical coherence tomography (OCT) with the existing technologies, to assess its accuracy and utility in detecting vertical root fractures of extracted human teeth. BACKGROUND DATA: The detection of root fractures in teeth that have undergone root canal treatment is challenging because of the great difficulty in differentiating these fractures from morphologic or radiographic anomalies. OCT methods are based on depth-resolved optical reflectivity and have been developed to reduce the invasiveness and radiation exposure inherent to other techniques. METHODS: Twelve extracted human mandibular teeth (totaling 25 roots) that were free of caries, calculus, and root treatment were used, and assessed by microfocus computed tomography, the current gold standard for fracture detection. The ability of appropriately trained observers to detect root fractures using visual, microscopic, and swept-source OCT (SS-OCT) techniques were compared. micro-CT and SS-OCT produce three-dimensional images of the tooth from which to diagnose fractures, but CT scanning involves radiation exposure that is not required in SS-OCT. RESULTS: Seventeen of the 25 roots were found to have fractures by microfocus CT. These findings were replicated by SS-OCT, which revealed fractures exhibiting identical origin, size, and angulation within the root. We found that SS-OCT gave results compatible to the gold standard technique, and that SS-OCT and microscopy were more effective for identifying root fractures than was visual observation alone. CONCLUSIONS: SS-OCT may represent a novel, noninvasive, noncontact and nonexposure alternative to the conventional methods used for assessing root fractures in teeth.