PD-1/PD-L1 inhibitors-associated cardiac adverse events: a retrospective and real-world study based on the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors have reformed the treatment landscape for various malignancies and improved prognosis of patients. However, they also lead to events that although rare may prove to be fatal. RESEARCH DESIGN AND METHODS: Data from July 2014 to June 2022 based on FDA Adverse Event Reporting System (FAERS) were analyzed. The signal index reporting odds ratio (ROR) was used to evaluate the correlation between cardiac AEs and given medications. The indications and the median time to onset (TTO) of different PD-1/PD-L1 inhibitors were compared. RESULTS: Cardiac AEs are rare but may be fatal with particular profiles in primary tumor, onset time, and especially gender. We identified 11,538 reports that were related to cardiotoxicity of PD-1/PD-L1 inhibitors, in which 178 different preferred terms (PTs) were distinguished, and nivolumab reported the most PTs with signal. All targeted medications showed signals in myocardial disorders and pericardial disorders, which tend to occur in the first 1-2 months. Non-small cell neoplasm was the top and common indication during anti-PD-1 or anti-PD-L1 therapy with cardiotoxicity. CONCLUSIONS: This study could help early diagnosis and surveillance of ICIs-related cardiotoxicity.

Cardiovascular and Cerebrovascular Safety of Ranibizumab, Bevacizumab, and Aflibercept in Ocular Diseases: An Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

The cardiovascular and cerebrovascular safety of ranibizumab, bevacizumab, and aflibercept for ocular diseases is unclear. This study aimed to evaluate and compare the cardiovascular and cerebrovascular safety in patients receiving ranibizumab, bevacizumab, and aflibercept for ocular disease. A cross-sectional study was conducted from 2017 (Q1) to 2021 (Q4) in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. The outcomes of interest were central nervous system vascular disorders, ischemic heart disease, hypertension, pulmonary hypertension, torsade de pointes/QT prolongation, embolic and thrombotic events, cardiac arrhythmias, cardiac failure, and cardiomyopathy. Data mining was performed by a disproportional method with a compression, using compressed reporting odds ratios (sRORs) with 95% confidence intervals (CIs) to measure signals. The results showed 1462 cardiovascular and cerebrovascular events associated with aflibercept, 834 with ranibizumab, and 150 with bevacizumab. Ranibizumab, bevacizumab, and aflibercept were linked to central nervous system vascular disorders (sROR, 5.57[95%CI, 4.95-6.26] vs sROR, 2.23 [95%CI, 1.75-2.85] vs sROR, 2.73[95%CI, 2.43-3.06]), ischemic heart disease (sROR, 3.31[95%CI, 2.65-4.13] vs sROR, 1.98 [95%CI, 1.24-3.16] vs sROR, 3.00 [95%CI, 2.46-3.65]), embolic and thrombotic (sROR, 3.36 [95%CI, 3.04-3.72] vs sROR, 2.16 [95%CI, 1.70-2.74] vs sROR, 5.25 [95%CI, 4.82-5.72]). Both ranibizumab and bevacizumab produced hypertension (sROR, 1.73 [95%CI, 1.41-2.12] vs sROR, 1.46 [95%CI, 1.03-2.06]) and arrhythmias (sROR, 2.82 [95%CI, 1.99-3.99] vs sROR, 2.13 [95%CI, 1.08-4.22]) signals. The signals of heart failure were detected in ranibizumab (sROR, 5.64 [95%CI, 4.08-7.79]) and aflibercept (sROR, 2.80 [95%CI, 2.03-3.86]). Ranibizumab, bevacizumab, and aflibercept for ocular disease have different safety profiles in cardiovascular and cerebrovascular. The overall cardiovascular and cerebrovascular risk of the patient should be thoroughly assessed in order to select the safest drug for treatment.

Mechanistic views and computational studies on transition-metal-catalyzed reductive coupling reactions.

Transition-metal-catalyzed reductive coupling reactions have been considered as a powerful tool to convert two electrophiles into value-added products. Numerous related reports have shown the fascinating potential. Mechanistic studies, especially theoretical studies, can provide important implications for the design of novel reductive coupling reactions. In this review, we summarize the representative advancements in theoretical studies on transition-metal-catalyzed reductive coupling reactions and systematically elaborate the mechanisms for the key steps of reductive coupling reactions. The activation modes of electrophiles and the deep insights of selectivity generation are mechanistically discussed. In addition, the mechanism of the reduction of high-oxidation-state catalysts and further construction of new chemical bonds are also described in detail.

The fate of diclofenac in anaerobic fermentation of waste activated sludge.

Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, is one of the most commonly detected pharmaceuticals in wastewater treatment plants. However, the fate of DCF in waste activated sludge (WAS) anaerobic fermentation has not been well-understood so far. This work therefore aims to comprehensively reveal whether and how DCF is transformed in WAS mesophilic anaerobic fermentation through both experimental investigation and density functional theory (DFT) calculation. Experimental results showed that ∼28.8% and 45.8% of DCF were respectively degraded during the batch and long-term fermentation processes. Based on the detected intermediates and DFT-predicted active sites, three metabolic pathways, i.e., chlorination, hydroxylation, and dichlorination, responsible for DCF transformation were proposed. DFT calculation also showed that the Gibbs free energy (ΔG) of the three transformation pathways was respectively 19.0, -4.3, and -19.3 kcal/mol, suggesting that the latter two reactions (i.e., hydroxylation and dichlorination) were thermodynamically favorable. Illumina MiSeq sequencing analyses revealed that DCF improved the populations of complex organic degradation microbes such as Proteiniclasticum and Tissierellales, which was in accord with the chemical analyses above. This work updates the fundamental understanding of the degradation of DCF in WAS anaerobic fermentation process and enlightens engineers to apply theoretical calculation to the field of sludge treatment or other complex microbial ecosystems.