Objectives: Statins are essential in the prevention of cardiovascular disease; however, their association with type 2 diabetes mellitus (T2DM) risk is concerning. We examined whether genetic susceptibility to T2DM modifies the association between regular statin use and T2DM risk. Methods: This study included 447 176 individuals from the UK Biobank without baseline diabetes or major cardiovascular disease. Statin use was recorded at baseline, and T2DM incidence was determined using clinical records. Polygenic risk scores (PRS) for T2DM risk were provided by the UK Biobank. Using propensity scores adjusted for age, sex, body mass index, and comorbidities, 14 831 statin users were matched with 37 060 non-users. Cox proportional hazards models were used to estimate the interaction effect of statin use and PRS on T2DM incidence, adjusting for key confounders. Results: In the propensity-matched cohort, 3675 of 51 891 participants developed T2DM over a mean follow-up period of 13.7 years. Within the top 5% of the PRS distribution, per 1000 person-years, the incidence of T2DM was 15.42 for statin users versus 12.18 for non-users. Among the lowest 5%, the incidence was 1.90 for statin users and 1.65 for non-users. Based on the Cox proportional hazards model, regular statin use was associated with a 1.24-fold increased T2DM risk (95% confidence interval [CI], 1.15 to 1.33). Furthermore, PRS exhibited a significant multiplicative interaction with regular statin use (odds ratio, 1.10; 95% CI, 1.02 to 1.19). Conclusions PRS may help identify individuals particularly susceptible to the diabetogenic effects of statins, providing a potential path for personalized cardiovascular disease management.

Objectives: Statins are essential in the prevention of cardiovascular disease; however, their association with type 2 diabetes mellitus (T2DM) risk is concerning. We examined whether genetic susceptibility to T2DM modifies the association between regular statin use and T2DM risk. Methods: This study included 447 176 individuals from the UK Biobank without baseline diabetes or major cardiovascular disease. Statin use was recorded at baseline, and T2DM incidence was determined using clinical records. Polygenic risk scores (PRS) for T2DM risk were provided by the UK Biobank. Using propensity scores adjusted for age, sex, body mass index, and comorbidities, 14 831 statin users were matched with 37 060 non-users. Cox proportional hazards models were used to estimate the interaction effect of statin use and PRS on T2DM incidence, adjusting for key confounders. Results: In the propensity-matched cohort, 3675 of 51 891 participants developed T2DM over a mean follow-up period of 13.7 years. Within the top 5% of the PRS distribution, per 1000 person-years, the incidence of T2DM was 15.42 for statin users versus 12.18 for non-users. Among the lowest 5%, the incidence was 1.90 for statin users and 1.65 for non-users. Based on the Cox proportional hazards model, regular statin use was associated with a 1.24-fold increased T2DM risk (95% confidence interval [CI], 1.15 to 1.33). Furthermore, PRS exhibited a significant multiplicative interaction with regular statin use (odds ratio, 1.10; 95% CI, 1.02 to 1.19). Conclusions PRS may help identify individuals particularly susceptible to the diabetogenic effects of statins, providing a potential path for personalized cardiovascular disease management.

Objectives: Statins are essential in the prevention of cardiovascular disease; however, their association with type 2 diabetes mellitus (T2DM) risk is concerning. We examined whether genetic susceptibility to T2DM modifies the association between regular statin use and T2DM risk. Methods: This study included 447 176 individuals from the UK Biobank without baseline diabetes or major cardiovascular disease. Statin use was recorded at baseline, and T2DM incidence was determined using clinical records. Polygenic risk scores (PRS) for T2DM risk were provided by the UK Biobank. Using propensity scores adjusted for age, sex, body mass index, and comorbidities, 14 831 statin users were matched with 37 060 non-users. Cox proportional hazards models were used to estimate the interaction effect of statin use and PRS on T2DM incidence, adjusting for key confounders. Results: In the propensity-matched cohort, 3675 of 51 891 participants developed T2DM over a mean follow-up period of 13.7 years. Within the top 5% of the PRS distribution, per 1000 person-years, the incidence of T2DM was 15.42 for statin users versus 12.18 for non-users. Among the lowest 5%, the incidence was 1.90 for statin users and 1.65 for non-users. Based on the Cox proportional hazards model, regular statin use was associated with a 1.24-fold increased T2DM risk (95% confidence interval [CI], 1.15 to 1.33). Furthermore, PRS exhibited a significant multiplicative interaction with regular statin use (odds ratio, 1.10; 95% CI, 1.02 to 1.19). Conclusions PRS may help identify individuals particularly susceptible to the diabetogenic effects of statins, providing a potential path for personalized cardiovascular disease management.

Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019.In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virusinfected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

Osteoarthritis (OA) involves cartilage degeneration, thereby causing inflammation and pain. Cardiovascular diseases, such as dyslipidemia, are risk factors for OA; however, the mechanism is unclear. We investigated the effect of dyslipidemia on the development of OA. Treatment of cartilage cells with low-density lipoprotein (LDL) enhanced abnormal autophagy but suppressed normal autophagy and reduced the activity of transcription factor EB (TFEB), which is important for the function of lysosomes. Treatment of LDL-exposed chondrocytes with rapamycin, which activates TFEB, restored normal autophagy. Also, LDL enhanced the inflammatory death of chondrocytes, an effect reversed by rapamycin. In an animal model of hyperlipidemia-associated OA, dyslipidemia accelerated the development of OA, an effect reversed by treatment with a statin, an anti-dyslipidemia drug, or rapamycin, which activates TFEB. Dyslipidemia reduced the autophagic flux and induced necroptosis in the cartilage tissue of patients with OA. The levels of triglycerides, LDL, and total cholesterol were increased in patients with OA compared to those without OA. The C-reactive protein level of patients with dyslipidemia was higher than that of those without dyslipidemia after total knee replacement arthroplasty. In conclusion, oxidized LDL, an important risk factor of dyslipidemia, inhibited the activity of TFEB and reduced the autophagic flux, thereby inducing necroptosis in chondrocytes.

We analyzed the manner and cause of death in 1,193 forensic autopsies from the Jungbu province (central part of South Korea) conducted by the National Forensic Service Daejeon Institute in 2022. Analysis of the manner of deaths revealed that 43.1% (514/1,193 cases) were natural deaths; 42.8% (511/1,193 cases) were unnatural deaths; and 14.1% (168/1,193 cases) were unknown. Among the unnatural deaths, the major manner of death was 44.6% (228/511 cases) by accidents, 34.1% (174/511 cases) by suicide, 13.5% (69/511 cases) undetermined, and 7.8% (40/511 cases) by homicide. Among the unnatural deaths, the major causes of death was 38.4% (196/511 cases) by trauma, 20.4% (104/511 cases) by poisoning, and 17.6% (90/511 cases) by asphyxia. Falling was the major cause of death by trauma (58.7%, 115/196 cases), and strangulation was the major cause of death by asphyxia (75.6%, 68/90 cases). Among the natural deaths, heart disease was the major cause (46.7%, 240/514 cases), followed by endocrine, nutritional and metabolic diseases (14.0%, 72/514 cases). A time-series statistical analysis and comparison of the manner and cause of deaths in this province may facilitate more advanced interpretations relating to both public safety and healthcare in the future.

We analyzed the manner and cause of death in 1,193 forensic autopsies from the Jungbu province (central part of South Korea) conducted by the National Forensic Service Daejeon Institute in 2022. Analysis of the manner of deaths revealed that 43.1% (514/1,193 cases) were natural deaths; 42.8% (511/1,193 cases) were unnatural deaths; and 14.1% (168/1,193 cases) were unknown. Among the unnatural deaths, the major manner of death was 44.6% (228/511 cases) by accidents, 34.1% (174/511 cases) by suicide, 13.5% (69/511 cases) undetermined, and 7.8% (40/511 cases) by homicide. Among the unnatural deaths, the major causes of death was 38.4% (196/511 cases) by trauma, 20.4% (104/511 cases) by poisoning, and 17.6% (90/511 cases) by asphyxia. Falling was the major cause of death by trauma (58.7%, 115/196 cases), and strangulation was the major cause of death by asphyxia (75.6%, 68/90 cases). Among the natural deaths, heart disease was the major cause (46.7%, 240/514 cases), followed by endocrine, nutritional and metabolic diseases (14.0%, 72/514 cases). A time-series statistical analysis and comparison of the manner and cause of deaths in this province may facilitate more advanced interpretations relating to both public safety and healthcare in the future.