Objective: We aimed to evaluate alirocumab- and evolocumab-related adverse events (AEs) in real-world compared with all other drugs, overall and by gender and age subgroups; we also aimed to compare their risks of cognitive impairment, musculoskeletal disorders and diabetes with various statins and ezetimibe.Methods: We retrospectively extracted AE reports from the FDA Adverse Event Reporting System (FAERS) database during July 2015-June 2021. Disproportionality analyses were performed using reporting odds ratios (RORs) to detect AE signals of alirocumab and evolocumab in the overall population and in different age and gender subgroups, respectively.Results: Compared with all other drugs, both alirocumab and evolocumab had a significant signal in “musculoskeletal and connective tissue disorders” (ROR₁ = 2.626, 95% CI 2.552–2.702; ROR2 = 2.575, 95% CI 2.538–2.613). The highest ROR value of 2.311 (95% CI 2.272–2.351) was for “injury, poisoning and procedural complications” and was found in patients aged ≥65 years on evolocumab. The most frequent AEs were “general disorders and administration site conditions” and “musculoskeletal and connective tissue disorders” for all subpopulations. At the preferred term level, the most frequent AE signal was myalgia for alirocumab and injection site pain for evolocumab, overall and by subgroups. Compared with statins/ezetimibe, PCSK9 inhibitors exhibited lower ROR values for adverse events associated with SOC “nervous system disorders”, “psychiatric disorders” and “metabolism and nutrition disorders” (all RORs < 1), but mixed results for musculoskeletal disorders. Compared with all other drugs, undocumented AEs, such as acute cardiac event (ROR = 30.0, 95% CI 9.4–95.3) and xanthoma (ROR = 9.3, 95% CI 3.4–25.5), were also reported.Conclusion: Real-world evidence showed that PCSK9 inhibitors were associated with an increased risk of musculoskeletal and connective tissue disorders and general disorders and administration site conditions, overall and by subgroups. Muscle toxicity, injection site reactions, and influenza-like illness were significant AE signals. Compared with various statins and ezetimibe, PCSK9 inhibitors have shown a favorable safety profile in muscle-related events, cognitive impairment and diabetes. Some undocumented AE signals were also reported. Due to the limitations of spontaneous reporting databases, further studies are still needed to establish causality and validate our results.

Metastasis accounts for the vast majority of cancer deaths. To minimize metastasis‐associated mortality, it is crucially important to evaluate the metastatic potential (M.P.), that is, defined as a tendency of a primary tumor to colonize a distant organ. Dysregulated pH in solid tumors, especially the acidification of extracellular pH (pH_e) promotes dormant metastasis by driving protease‐mediated digestion, disrupting cell‐matrix interaction and increasing migration of cancer cells. Therefore, imaging intratumoral acidosis creates a unique opportunity to evaluate the M.P. In this work, a novel pH activatable probe was developed, in which two near‐infrared (NIR) fluorophores were conjugated via a flexible and acid liable linkage. While the fluorescence of this probe is quenched due to intramolecular dimeric aggregate under neutral environment, the cleavage of pH liable linkage with the concomitant disruption of aggregates in acidic tumor microenvironment results in a remarkable fluorescence enhancement. This probe not only visualized the primary tumors with high target to background (T/B) signal ratio in vivo, but also revealed the correlation between the M.P. and acidosis distribution pattern in tumor. While the acidosis locate dispersedly at tumor periphery in highly metastatic tumor, it distribute more widely in lowly metastatic tumor and the acidification degree increases substantially from the margin to core areas. This pH activatable NIR fluorescent probe holds the potential to evaluate the M.P., monitor the therapeutic response and predict the prognosis by delineating acidosis in tumors.

Background: Individuals with diabetes have increased risk of depression, but there are limited nationally representative studies on this topic. We aimed to investigate the prevalence and predictors of depression, as well as its impact on all-cause and cardiovascular mortality in adults with type 2 diabetes (T2DM) using a prospective cohort study and a representative sample of the U.S. population. Methods: We analyzed National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018 and linked it with the most recent publicly available National Death Index (NDI) data. Individuals aged 20 years or old who had depression measurements were included. Depression was defined as a Patient Health Questionnaire (PHQ-9) score ≥ 10, and categorized into moderate (10–14 points) and moderately severe to severe (≥ 15 points). Cox proportional hazard models were used to estimate the association between depression and mortality. Results: Among 5695 participants with T2DM, 11.6% had depression. Depression was associated with female gender, younger age, overweight, lower education, being unmarried, smoking, and a history of coronary heart disease and stroke. During a mean follow-up period of 78.2 months, 1161 all-cause deaths occurred. Total depression and moderately severe to severe depression significantly increased all-cause mortality (adjusted hazard ratio [aHR] 1.36, 95% CI [1.09–1.70]; 1.67 [1.19–2.34]) and non-cardiovascular mortality (aHR 1.36, 95% CI [1.04–1.78]; 1.78, 95% CI [1.20–2.64]), but not cardiovascular mortality. Subgroup analysis showed a significant association between total depression and all-cause mortality in males (aHR 1.46, 95% CI [1.08–1.98]) and those aged 60 years or older (aHR 1.35, 95% CI [1.02–1.78]). Any severity of depression was not significantly associated with cardiovascular mortality in age- or gender- stratified subgroups. Conclusions: In a nationally representative sample of U.S. adults with T2DM, approximately 10% experienced depression. Depression did not significantly associate with cardiovascular mortality. However, comorbid depression in T2DM patients increased the risk of all-cause and non-cardiovascular mortality. The impact of depression on mortality varied across subgroups. Therefore, healthcare providers should consider incorporating depression screening and management into routine care, especially for subgroups with specific risk factors, due to the increased risk of all-cause mortality in T2DM patients with depression.

Methimazole (MMI) has been used for the treatment of Graves' Disease (GD) for more than half a century. The MMI treatment has been reported to be associated with hepatotoxicity. Previous studies have demonstrated that human leukocyte antigen (HLA) genetic polymorphisms were associated with many drugs-induced liver injuries. To investigate HLA genetic susceptibility to MMI-induced liver injury (MMI-DILI), we characterized both HLA class I and class Ⅱ in a well-characterized phenotypic cohort with 40 MMI-DILI cases and 118 MMI-tolerant controls. Among the 40 MMI-DILI cases, 57.5% were women and 50% were cholestatic liver damage with occurring time from days to months after MMI dosing. The frequency of HLA-C*03:02 was 6.7% (5/75) in the MMI-DILI case patients and 6.4% (4/62) in MMI-induced cholestatic/mixed liver damage, which were significantly different from the percentage of 0.4% (1/231) in the MMI-tolerant patients (odds ratio (OR) = 15.4, 95% confidence interval (CI) = 1.77-133.9, adjusted P = 0.0292; OR=14.9, 95% CI=2.38-182.9, adjusted P = 0.0323; respectively). HLA-A*02:01 was also found to be associated with MMI-induced cholestatic/mixed liver injury (OR = 3.13, 95%CI=1.45-6.91, adjusted P = 0.0464). The present study demonstrated that individuals carrying HLA-C*03:02 allele are at increased risk of developing MMI-induced DILI. These results may assist doctors to prevent the occurrence of hepatotoxicity in GD patients receiving MMI.

Drug-induced liver injury (DILI) is a major cause of the withdrawal of pre-marketed drugs, typically attributed to oxidative stress, mitochondrial damage, disrupted bile acid homeostasis, and innate immune-related inflammation. DILI can be divided into intrinsic and idiosyncratic DILI with cholestatic liver injury as an important manifestation. The diagnosis of DILI remains a challenge today and relies on clinical judgment and knowledge of the insulting agent. Early prediction of hepatotoxicity is an important but still unfulfilled component of drug development. In response, in silico modeling has shown good potential to fill the missing puzzle. Computer algorithms, with machine learning and artificial intelligence as a representative, can be established to initiate a reaction on the given condition to predict DILI. DILIsym is a mechanistic approach that integrates physiologically based pharmacokinetic modeling with the mechanisms of hepatoxicity and has gained increasing popularity for DILI prediction. This article reviews existing in silico approaches utilized to predict DILI risks in clinical medication and provides an overview of the underlying principles and related practical applications.