Adverse events of nivolumab plus ipilimumab versus nivolumab plus cabozantinib: a real-world pharmacovigilance study.

BACKGROUND: No head-to-head clinical trials have compared the differences in adverse events (AEs) between nivolumab plus ipilimumab (NIVO-IPI) and nivolumab plus cabozantinib (NIVO-CABO) in the treatment of metastatic renal cell carcinoma (mRCC). AIM: We analysed the two largest real-world databases, the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the World Health Organization's VigiBase, to elucidate the differences in AEs between NIVO-IPI and NIVO-CABO. METHOD: In total, 40,376 and 38,022 records were extracted from FAERS and VigiBase, and 193 AEs were analysed. The reporting odds ratios (ROR) with 95% confidence interval were calculated using a disproportionality analysis (NIVO-CABO/NIVO-IPI). RESULTS: The reported numbers of immune-related AEs, including myocarditis, colitis, and hepatitis, were significantly higher with NIVO-IPI (ROR = 0.18 for FAERS and 0.13 for VigiBase). Contrarily, the reported numbers of other AEs, including gastrointestinal disorders (ROR = 2.68 and 2.92) and skin and subcutaneous tissue disorders (ROR = 2.94 and 3.55), considered to be potentiated by the combination of NIVO and CABO, were higher with NIVO-CABO. CONCLUSION: Our findings contribute to the selection and clinical management of NIVO-IPI and NIVO-CABO, which minimizes the risk of AEs for individual patients with mRCC by considering distinctive differences in the AE profiles.

Synthesis of 2-Iodoazulenes by the Iododeboronation of Azulen-2-ylboronic Acid Pinacol Esters with Copper(I) Iodide.

Azulen-2-ylboronic acid pinacol ester, prepared by iridium-catalyzed C-H borylation of azulene, efficiently underwent iododeboronation with a stoichiometric amount of copper(I) iodide. This reaction allowed the synthesis of 2-iodoazulene in only two steps starting from azulene. This methodology was successfully applied to analogous azulenes.

Interhemispheric Resting-State Functional Connectivity Predicts Severity of Idiopathic Normal Pressure Hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by a clinical triad (gait disturbance, dementia, and urinary incontinence), and by radiological findings of enlarged ventricles reflecting disturbance of central spinal fluid circulation. A diagnosis of iNPH is sometimes challenging, and the pathophysiological mechanisms underlying the clinical symptoms of iNPH remain largely unknown. Here, we used an emerging MRI technique, resting-state functional connectivity MRI (rsfcMRI), to develop a subsidiary diagnostic technique and to explore the underlying pathophysiological mechanisms of iNPH. rsfcMRI data were obtained from 11 patients with iNPH and 11 age-matched healthy volunteers, yielding rsfcMRI-derived functional connectivity (FC) from both groups. A linear support vector machine classifier was trained to distinguish the patterns of FCs of the patients with iNPH from those of the healthy volunteers. After dimensional reduction, the support vector machine successfully classified the two groups with an accuracy of 80%. Moreover, we found that rsfcMRI-derived FC carried information to predict the severity of the triad in iNPH. FCs relevant to the classification of severity were mainly based on interhemispheric connectivity, suggesting that disruption of the corpus callosum fibers due to ventricular enlargement may explain the triad of iNPH. The present results support the usefulness of rsfcMRI as a tool to understand pathophysiology of iNPH, and also to help with its clinical diagnosis.

Roles of dynamical symmetry breaking in driving oblate-prolate transitions of atomic clusters.

This paper explores the driving mechanisms for structural transitions of atomic clusters between oblate and prolate isomers. We employ the hyperspherical coordinates to investigate structural dynamics of a seven-atom cluster at a coarse-grained level in terms of the dynamics of three gyration radii and three principal axes, which characterize overall mass distributions of the cluster. Dynamics of gyration radii is governed by two kinds of forces. One is the potential force originating from the interactions between atoms. The other is the dynamical forces called the internal centrifugal forces, which originate from twisting and shearing motions of the system. The internal centrifugal force arising from twisting motions has an effect of breaking the symmetry between two gyration radii. As a result, in an oblate isomer, activation of the internal centrifugal force that has the effect of breaking the symmetry between the two largest gyration radii is crucial in triggering structural transitions into prolate isomers. In a prolate isomer, on the other hand, activation of the internal centrifugal force that has the effect of breaking the symmetry between the two smallest gyration radii is crucial in triggering structural transitions into oblate isomers. Activation of a twisting motion that switches the movement patterns of three principal axes is also important for the onset of structural transitions between oblate and prolate isomers. Based on these trigger mechanisms, we finally show that selective activations of specific gyration radii and twisting motions, depending on the isomer of the cluster, can effectively induce structural transitions of the cluster. The results presented here could provide further insights into the control of molecular reactions.