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Background and purpose: Testosterone is an essential sex hormone in maintaining masculine characteristics, which is prescribed for male hypogonadism as testosterone replacement treatment (TRT). Herein, we investigated long-standing controversies about the association between TRT and major adverse cardiovascular events (MACEs), based on real world adverse event (AE) reports, registered in the Food and Drug Administration Adverse Event Reporting System (FAERS).Methods: Publicly available FAERS data from 1 January 2004 to 31 December 2022 were retrieved from the Food and Drug Administration (FDA) website. The data mining protocol including the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network (BCPNN) was applied to analyze overreporting caused by risk factors and MACEs, including TRT, morbidities, and ages. The ROR and the BCPNN were also applied to investigate the annually developing trend of pharmacovigilance (PV) signals in the real world, retrospectively.Results: A total of 3,057 cases referring to MACEs, with a median age of 57 years old (yo), were identified from 28,921 cases of testosterone users. MACEs related to PV signals have emerged since 2014, including cardiac death, non-fatal myocardial infarction, and non-fatal stroke. Myocardial infarction (MI) (ROR: 9.46; IC025: 3.08), acute myocardial infarction (AMI) (ROR: 16.20; IC025: 3.72), ischemic cardiomyopathy (ROR: 11.63; IC025: 2.20), and cardiomyopathy (ROR: 5.98; IC025: 1.96) were the most significant signals generated, and weaker signals included cardiac failure acute (ROR: 4.01; IC025: 0.71), cardiac arrest (ROR: 1.88; IC025: 0.56), and ventricular fibrillation (VF) (ROR: 2.38; IC025: 0.38). The time-to-onset (TTO) of MACEs was calculated with a median of 246 days for AMI.Conclusion: For myocardial infarction and cardiomyopathy, TRT statistically tended to increase the risk of MACEs, while for cardiac arrhythmia, cardiac failure, and stroke, TRT demonstrated beneficial effects among the population with morbidities, such as testosterone deficiency (TD), diabetes mellitus (DM), and hypertension. MACEs were rare but led to serious outcomes including significant increase in death and disability. Since 2018, and before 2014, reports referring to TRT associated with MACEs were relatively scarce, which indicated that there might be a considerable number of cases that went unrecorded, due to neglection. Health workers and testosterone users might pay more attention to testosterone-induced MACEs.

Background and purpose: Several clinical trials have indicated that the use of canagliflozin increases the risk of lower extremity amputation. Although the US Food and Drug Administration (FDA) has withdrawn its black box warning about amputation risk for canagliflozin, the risk still exists. We sought to estimate the association between hypoglycemic medications, especially sodium-glucose co-transporter-2 inhibitors (SGLT2is), and adverse events (AEs) before the irreversible outcome of amputation as a promising early warning, based on the FDA Adverse Event Reporting System (FAERS) data.Methods: Publicly available FAERS data were analyzed using a reporting odds ratio (ROR) method and validated by a Bayesian confidence propagation neural network (BCPNN) method. The developing trend of the ROR was investigated by a series of calculations based on the accumulation of data in the FAERS database quarter by quarter.Results: Ketoacidosis, infection, peripheral ischemia, renal impairment, and inflammation including osteomyelitis might be more likely to occur among users of SGLT2is, especially canagliflozin. Osteomyelitis and cellulitis are AEs unique to canagliflozin. Among 2,888 osteomyelitis-related reports referring to hypoglycemic medications, 2,333 cases were associated with SGLT2is, with canagliflozin accounting for 2,283 of these cases and generating an ROR value of 360.89 and a lower limit of information component (IC025) of 7.79. No BCPNN-positive signal could be generated for drugs other than insulin and canagliflozin. Reports suggesting that insulin could generate BCPNN-positive signals span from 2004 to 2021, whereas reports with BCPNN-positive signals emerged only since the second quarter (Q2) of 2017, 4 years since the approval of SGLT2is in Q2 of 2013, for canagliflozin and drug groups containing canagliflozin.Conclusion: This data-mining investigation revealed a strong association between canagliflozin treatment and developing osteomyelitis that might be a crucial forewarning to lower extremity amputation. Further studies with updated data are needed to better characterize the risk of osteomyelitis associated with SGLT2is.

Background and purpose: Serious adverse events following immunization (AEFI) associated with the COVID-19 vaccines, including BNT162b2 (Pfizer-BioNTech), Ad26.COV2.S (Janssen), and mRNA-1273 (Moderna), have not yet been fully investigated. This study was designed to evaluate the serious AEFI associated with these three vaccines.Methods: A disproportionality study was performed to analyze data acquired from the Vaccine Adverse Event-Reporting System (VAERS) between 1 January 2010 and 30 April 2021. The reporting odds ratio (ROR) method was used to identify the association between the COVID-19 vaccines BNT162b2, Ad26.COV2.S, and mRNA-1273 and each adverse event reported. Moreover, the ratio of the ROR value to the 95% CI span was applied to improve the credibility of the ROR. The median values of time from vaccination to onset (TTO) for the three vaccines were analyzed.Results: Compared with BNT162b2 and mRNA-1273, Ad26.COV2.S vaccination was associated with a lower death frequency (p < 0.05). Ad26.COV2.S vaccination was associated with a lower birth defect and emergency room visit frequency than BNT162b2 (p < 0.05). There were 6,605, 830, and 2,292 vaccine recipients who suffered from COVID-19-related symptoms after vaccination with BNT162b2, Ad26.COV2.S, and mRNA-1273, respectively, including people who were infected by COVID-19, demonstrated a positive SARS-CoV-2 test, and were asymptomatic. Serious AEFI, including thromboembolism, hemorrhage, thrombocytopenia, cardiac arrhythmia, hypertension, and hepatotoxicity, were associated with all three vaccines. Cardiac failure and acute renal impairment events were associated with BNT162b2 and mRNA-1273, while seizure events were associated with BNT162b2 and Ad26.COV2.S. The median values of TTO associated with the three vaccinations were similar.Conclusion: These findings may be useful for health workers and the general public prior to inoculation, especially for patients with underlying diseases; however, the risk/benefit profile of these vaccines remains unchanged. The exact mechanism of SARS-CoV-2 vaccine-induced AEFI remains unknown, and further studies are required to explore these phenomena.

Introduction Pharmacotherapy is one of the main treatments for patients with young-onset Parkinson’s disease (YOPD). Although numerous studies on the treatment of YOPD have been published, the real-world prescription patterns of these populations remain unclear in China.Methods A national comprehensive evaluation was performed to reveal the pharmacological treatment patterns in Chinese patients with Parkinson’s disease from 1 January 2014 to 31 December 2019, with patients aged 21–50 years classified as having YOPD for the subgroup analysis. Information on patients and drugs was extracted to analyse the demographic characteristics, prescription patterns, and levodopa equivalent daily dose (LED) during disease progression.Results A total of 1,134 patients with YOPD were included, and the majority were aged 41–50 years. Prescription of L-DOPA/benserazide and pramipexole accounted for more than 30 and 20%, respectively, in each year from 2014 to 2019. There was no difference in prescription patterns in terms of age, sex and geographical areas. Half of the patients with YOPD were on monotherapy, but the proportion decreased from 2016. Correspondingly, the proportion of patients receiving polytherapy increased, especially those who were prescribed more than two anti-Parkinson’s disease drugs. During the disease course, LED showed high variability, which increased over time.Conclusion L-DOPA/benserazide and pramipexole were the most frequently prescribed anti-PD drugs for patients with YOPD in China. There was a slight trend in the transition from monotherapy to polytherapy. LED increased with disease duration. Thus, we provided an overview of the prescription patterns for patients with YOPD in China.

Aims: Long-term salt diet induces the oxidative stress in the paraventricular nucleus (PVN) and increases the blood pressure. Extracellular superoxide dismutase (Ec-SOD) is a unique antioxidant enzyme that exists in extracellular space and plays an essential role in scavenging excessive reactive oxygen species (ROS). However, the underlying mechanism of Ec-SOD in the PVN remains unclear.Methods: Sprague–Dawley rats (150–200 g) were fed either a high salt diet (8% NaCl, HS) or normal salt diet (0.9% NaCl, NS) for 6 weeks. Each group of rats was administered with bilateral PVN microinjection of AAV-Ec-SOD (Ec-SOD overexpression) or AAV-Ctrl for the next 6 weeks.Results: High salt intake not only increased mean arterial blood pressure (MAP) and the plasma noradrenaline (NE) but also elevated the NAD(P)H oxidase activity, the NAD(P)H oxidase components (NOX2 and NOX4) expression, and ROS production in the PVN. Meanwhile, the NOD-like receptor protein 3 (NLRP3)–dependent inflammatory proteins (ASC, pro-cas-1, IL-β, CXCR, CCL2) expression and the tyrosine hydroxylase (TH) expression in the PVN with high salt diet were higher, but the GSH level, Ec-SOD activity, GAD67 expression, and GABA level were lower than the NS group. Bilateral PVN microinjection of AAV-Ec-SOD decreased MAP and the plasma NE, reduced NAD(P)H oxidase activity, the NOX2 and NOX4 expression, and ROS production, attenuated NLRP3-dependent inflammatory expression and TH, but increased GSH level, Ec-SOD activity, GAD67 expression, and GABA level in the PVN compared with the high salt group.Conclusion: Excessive salt intake not only activates oxidative stress but also induces the NLRP3-depensent inflammation and breaks the balance between inhibitory and excitability neurotransmitters in the PVN. Ec-SOD, as an essential anti-oxidative enzyme, eliminates the ROS in the PVN and decreases the blood pressure, probably through inhibiting the NLRP3-dependent inflammation and improving the excitatory neurotransmitter release in the PVN in the salt-induced hypertension.

Background and purpose: Testosterone is an essential sex hormone in maintaining masculine characteristics, which is prescribed for male hypogonadism as testosterone replacement treatment (TRT). Herein, we investigated long-standing controversies about the association between TRT and major adverse cardiovascular events (MACEs), based on real world adverse event (AE) reports, registered in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Publicly available FAERS data from 1 January 2004 to 31 December 2022 were retrieved from the Food and Drug Administration (FDA) website. The data mining protocol including the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network (BCPNN) was applied to analyze overreporting caused by risk factors and MACEs, including TRT, morbidities, and ages. The ROR and the BCPNN were also applied to investigate the annually developing trend of pharmacovigilance (PV) signals in the real world, retrospectively. Results: A total of 3,057 cases referring to MACEs, with a median age of 57 years old (yo), were identified from 28,921 cases of testosterone users. MACEs related to PV signals have emerged since 2014, including cardiac death, non-fatal myocardial infarction, and non-fatal stroke. Myocardial infarction (MI) (ROR: 9.46; IC 025 : 3.08), acute myocardial infarction (AMI) (ROR: 16.20; IC 025 : 3.72), ischemic cardiomyopathy (ROR: 11.63; IC 025 : 2.20), and cardiomyopathy (ROR: 5.98; IC 025 : 1.96) were the most significant signals generated, and weaker signals included cardiac failure acute (ROR: 4.01; IC 025 : 0.71), cardiac arrest (ROR: 1.88; IC 025 : 0.56), and ventricular fibrillation (VF) (ROR: 2.38; IC 025 : 0.38). The time-to-onset (TTO) of MACEs was calculated with a median of 246 days for AMI. Conclusion: For myocardial infarction and cardiomyopathy, TRT statistically tended to increase the risk of MACEs, while for cardiac arrhythmia, cardiac failure, and stroke, TRT demonstrated beneficial effects among the population with morbidities, such as testosterone deficiency (TD), diabetes mellitus (DM), and hypertension. MACEs were rare but led to serious outcomes including significant increase in death and disability. Since 2018, and before 2014, reports referring to TRT associated with MACEs were relatively scarce, which indicated that there might be a considerable number of cases that went unrecorded, due to neglection. Health workers and testosterone users might pay more attention to testosterone-induced MACEs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Li, Li, Zhang, Zhong, Yan and Qiu.)