Risk of Hemorrhagic Stroke among Patients Treated with High-Intensity Statins versus Pitavastatin-Ezetimibe: A Population Based Study.

High-intensity statin (HIS) is recommended for high-risk patients in current guidelines. However, the risk of hemorrhagic stroke (HS) with HIS is a concern for Asians. Pitavastatin carries pharmacological differences compared with other statins. We compared the risk of HS in patients treated with pitavastatin-ezetimibe vs. HIS. We conducted a population-based, propensity score-matched cohort study using data from the Taiwan National Health Insurance Research Database. From January 2013 to December 2018, adults (≥ 18 years) who received pitavastatin 2-4 mg/day plus ezetimibe 10 mg/day (combination group, N = 3,767) and those who received atorvastatin 40 mg/day or rosuvastatin 20 mg/day (HIS group, N = 37,670) were enrolled. The primary endpoint was HS. We also assessed the difference of a composite safety endpoint of hepatitis or myopathy requiring hospitalization and new-onset diabetes mellitus. Multivariable Cox proportional hazards model was used to evaluate the relationship between study endpoints and different treatment. After a mean follow-up of 3.05 ± 1.66 years, less HS occurred in combination group (0.74%) than in HIS group (1.35%) [adjusted hazard ratio (aHR) 0.65, 95% confidence interval (CI) 0.44-0.95]. In subgroup analysis, the lower risk of HS in combination group was consistent among all pre-specified subgroups. There was no significant difference of the composite safety endpoint between the 2 groups (aHR 0.91, 95% CI 0.81-1.02). In conclusion, pitavastatin-ezetimibe combination treatment had less HS compared with high-intensity atorvastatin and rosuvastatin. Pitavastatin-ezetimibe may be a favorable choice for Asians who need strict lipid control but with concern of HS.

Pb(NO3 )2 induces cell apoptosis through triggering of reactive oxygen species accumulation and disruption of mitochondrial function via SIRT3/SOD2 pathways.

Lead (Pb) is nonbiodegradable and toxic to the lungs. To investigate the potential mechanisms of Pb-induced reactive oxygen species (ROS) accumulation and cell death in the lungs, human non-small lung carcinoma H460 cells were stimulated with Pb(NO3 )2 in this study. The results showed that Pb(NO3 )2 stimulation increased cell death by inducing cell apoptosis which showed a reduced Bcl-2 expression and an enhanced caspase 3 activation. Pb(NO3 )2 also caused the production of H2 O2 in H460 cells that triggering the buildup of ROS and mitochondrial membrane potential loss. We found that Pb(NO3 )2 modulates oxidoreductive activity through reduced the glutathione-disulfide reductase and glutathione levels in Pb(NO3 )2 -exposed H460 cells. Furthermore, the superoxide dismutase (SOD) upstream molecule sirtuin 3 (SIRT3) was increased with Pb(NO3 )2 dose. Collectively, these results demonstrate that Pb(NO3 )2 promotes lung cell death through SIRT3/SOD-mediated ROS accumulation and mitochondrial dysfunction.

Dunaliella salina Alga Protects against Myocardial Ischemia/Reperfusion Injury by Attenuating TLR4 Signaling.

Myocardial ischemia/reperfusion (I/R) injury is marked by rapid increase in inflammation and not only results in myocardial apoptosis but also compromises the myocardial function. Dunaliella salina (D. salina), a halophilic unicellular microalga, has been used as a provitamin A carotenoid supplement and color additive. Several studies have reported that D. salina extract could attenuate lipopolysaccharides-induced inflammatory effects and regulate the virus-induced inflammatory response in macrophages. However, the effects of D. salina on myocardial I/R injury remain unknown. Therefore, we aimed to investigate the cardioprotection of D. salina extract in rats subjected to myocardial I/R injury that was induced by occlusion of the left anterior descending coronary artery for 1 h followed by 3 h of reperfusion. Compared with the vehicle group, the myocardial infarct size significantly decreased in rats that were pre-treated with D. salina. D. salina significantly attenuated the expressions of TLR4, COX-2 and the activity of STAT1, JAK2, IκB, NF-κB. Furthermore, D. salina significantly inhibited the activation of caspase-3 and the levels of Beclin-1, p62, LC3-I/II. This study is the first to report that the cardioprotective effects of D. salina may mediate anti-inflammatory and anti-apoptotic activities and decrease autophagy through the TLR4-mediated signaling pathway to antagonize myocardial I/R injury.

Current and Potential Applications of Atmospheric Cold Plasma in the Food Industry.

The cost-effectiveness and high efficiency of atmospheric cold plasma (ACP) incentivise researchers to explore its potentials within the food industry. Presently, the destructive nature of this nonthermal technology can be utilised to inactivate foodborne pathogens, enzymatic ripening, food allergens, and pesticides. However, by adjusting its parameters, ACP can also be employed in other novel applications including food modification, drying pre-treatment, nutrient extraction, active packaging, and food waste processing. Relevant studies were conducted to investigate the impacts of ACP and posit that reactive oxygen and nitrogen species (RONS) play the principal roles in achieving the set objectives. In this review article, operations of ACP to achieve desired results are discussed. Moreover, the recent progress of ACP in food processing and safety within the past decade is summarised while current challenges as well as its future outlook are proposed.

Particulate matter 2.5 exposure induces epithelial-mesenchymal transition via PI3K/AKT/mTOR pathway in human retinal pigment epithelial ARPE-19 cells.

Exposure to particulate matter 2.5 (PM2.5) has been linked to ocular surface diseases, yet knowledge of the molecular mechanism impacted on retina pathogenesis is limited. Therefore, the purpose of this study was to explore the effects and involved factors of PM2.5 exposure in human retinal pigment epithelial APRE-19 cells. Our data revealed a decreased cell viability and an increased migratory ability in APRE-19 cells after PM2.5 stimulation. The MMP-2 and MMP-9 protein levels were markedly increased while the MMPs regulators TIMP-1 and TIMP-2 were significantly reduced in PM2.5-exposed APRE-19 cells. PM2.5 also increased pro-MMP-2 expression in the cell culture supernatants. Additionally, PM2.5 promoted the EMT markers through the activation of PI3K/AKT/mTOR pathway. Moreover, the ICAM-1 production was also remarkably increased by PM2.5 but reduced by PI3K/AKT inhibitor LY294002 in APRE-19 cells. Taken together, these results suggest that PM2.5 promotes EMT in a PI3K/AKT/mTOR-dependent manner in the retinal pigment epithelium.

Osteoporosis increases the risk of rotator cuff tears: a population-based cohort study.

INTRODUCTION: Osteoporosis has been demonstrated to be a risk factor for rotator cuff retears after surgery; however, no studies have directly investigated the association between osteoporosis and the development of rotator cuff tears. To investigate whether osteoporosis is associated with an increased risk of rotator cuff tears. MATERIALS AND METHODS: We conducted a population-based, matched-cohort study with a 7-year follow-uTwo matched cohorts (n = 3511 with osteoporosis and 17,555 without osteoporosis) were recruited from Taiwan's Longitudinal Health Insurance Dataset. Person-year data and incidence rates were evaluated. A multivariable Cox model was used to derive an adjusted hazard ratio (aHR) after controlling for age, sex, and various prespecified comorbidities. Age and sex were added in the model to test for interaction with osteoporosis. RESULTS: Women constituted 88.5% of the cohorts. During follow-up of 17,067 and 100,501 person-years for the osteoporosis and nonosteoporosis cohorts, 166 and 89 rotator cuff tears occurred, respectively. The cumulative incidence of rotator cuff tears was significantly higher in the osteoporosis cohort than in the nonosteoporosis cohort (p < 0.001, log-rank). The Cox model revealed a 1.79-fold increase in rotator cuff tears in the osteoporosis cohort, with an aHR of 1.79 (95% confidence interval, 1.55-2.05). Effect modification of sex and age on rotator cuff tears was not found in patients with osteoporosis. CONCLUSION: This population-based study supports the hypothesis that compared with individuals without osteoporosis, those with osteoporosis have a higher risk of developing rotator cuff tears.

Luteolin Reduces Aqueous Extract PM2.5-induced Metastatic Activity in H460 Lung Cancer Cells.

Fine particulate matter (PM2.5) is the critical cause of lung cancer and can further promote tumor cell migration and invasion. This study investigated the effects of luteolin, an antiangiogenic flavonoid agent, on blocking aqueous extract PM2.5-prompted cancer progression. We observed that luteolin reduced cell migration and the expression of pro-metastatic factors pro-matrix metalloproteinase (MMP)-2 and intercellular adhesion molecule (ICAM)-1 in PM2.5-exposed H460 lung cancer cells. Luteolin treatment also reduced the transduction of PM2.5-induced epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) cascade signaling. Furthermore, the reduction of MMP-2 expression and ICAM-1 production by luteolin in PM2.5-stimulated H460 cells is EGFR-PI3K-AKT pathway dependent. These results suggest that luteolin exhibits antitumor progression by inhibiting EGFR-PI3K-AKT pathway.

Production of Siamenoside I and Mogroside IV from Siraitia grosvenorii Using Immobilized ß-Glucosidase.

Siraitia grosvenorii is a type of fruit used in traditional Chinese medicine. Previous studies have shown that the conversion of saponins was often carried out by chemical hydrolysis, which can be problematic because of the environmental hazards it may cause and the low yield it produces. Therefore, the purpose of this study is to establish a continuous bioreactor with immobilized enzymes to produce siamenoside I and mogroside IV. The results show that the immobilization process of ß-glucosidase exhibited the best relative activity with a glutaraldehyde (GA) concentration of 1.5%, carrier activation time of 1 h and binding enzyme time of 12 h. After the immobilization through GA linkage, the highest relative activity of ß-glucosidase was recorded through the reaction with the substrate at 60 °C and pH 5. Subsequently, the glass microspheres with immobilized ß-glucosidase were filled into the reactor to maintain the optimal active environment, and the aqueous solution of Siraitia grosvenorii extract was introduced by controlling the flow rate. The highest concentration of siamenoside I and mogroside IV were obtained at a flow rate of 0.3 and 0.2 mL/min, respectively. By developing this immobilized enzyme system, siamenoside I and mogroside IV can be prepared in large quantities for industrial applications.

Anti-inflammatory effects of Flos Lonicerae Japonicae Water Extract are regulated by the STAT/NF-κB pathway and HO-1 expression in Virus-infected RAW264.7 cells.

This study examined the effect of the Flos Lonicerae Japonicae water extract (FLJWE), chlorogenic acid, and luteolin on pseudorabies virus (PRV)-induced inflammation in RAW264.7 cells and elucidated related molecular mechanisms. The results revealed that FLJWE and luteolin, but not chlorogenic acid, inhibited the production of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inflammatory cytokines in PRV-infected RAW 264.7 cells. We found that the FLJWE and luteolin suppressed nuclear factor (NF)-κB activation by inhibiting the phosphorylation of signal transducer and activator of transcription 1 and 3 (STAT1 and STAT3, respectively). Moreover, the FLJWE significantly upregulated the expression of pNrf2 and its downstream target gene heme oxygenase-1 (HO-1). Our data indicated that FLJWE and luteolin reduced the expression of proinflammatory mediators and inflammatory cytokines, such as COX-2 and iNOS, through the suppression of the JAK/STAT1/3-dependent NF-κB pathway and the induction of HO-1 expression in PRV-infected RAW264.7 cells. The findings indicate that the FLJWE can be used as a potential antiviral agent.

Ganoderma formosanum Exopolysaccharides Inhibit Tumor Growth via Immunomodulation.

Ganoderma formosanum (GF) is a medicinal mushroom endemic to Taiwan. Previous research established the optimal culture conditions to produce exopolysaccharide rich in ß-glucan (GF-EPS) from submerged fermentation of GF. The present study investigated the antitumor effects of GF-EPS in a Lewis lung carcinoma cell (LLC1) tumor-bearing mice model. In the preventive model, GF-EPS was orally administered to mice before LLC1 injection. In the therapeutic model, GF-EPS oral administration was initiated five days after tumor cell injection. The tumor size and body weight of the mice were recorded. After sacrifice, the lymphocyte subpopulation was analyzed using flow cytometry. Spleen tissues were used to analyze cytokine mRNA expression. The results showed that GF-EPS (80 mg/kg) effectively suppressed LLC1 tumor growth in both the preventive and therapeutic models. GF-EPS administration increased the proportion of natural killer cells in the spleen and activated gene expression of several cytokines. Our results provide evidence that GF-EPS promotes tumor inhibition through immunomodulation in tumor-bearing mice.

Protective Effect of Quercetin on Sodium Iodate-Induced Retinal Apoptosis through the Reactive Oxygen Species-Mediated Mitochondrion-Dependent Pathway.

Age-related macular degeneration (AMD) leads to gradual central vision loss and is the third leading cause of irreversible blindness worldwide. The underlying mechanisms for this progressive neurodegenerative disease remain unclear and there is currently no preventive treatment for dry AMD. Sodium iodate (NaIO3) has been reported to induce AMD-like retinal pathology in mice. We established a mouse model for AMD to evaluate the effects of quercetin on NaIO3-induced retinal apoptosis, and to investigate the pertinent underlying mechanisms. Our in vitro results indicated that quercetin protected human retinal pigment epithelium (ARPE-19) cells from NaIO3-induced apoptosis by inhibiting reactive oxygen species production and loss of mitochondrial membrane potential as detected by Annexin V-FITC/PI flow cytometry. We also evaluated the relative expression of proteins in the apoptosis pathway. Quercetin downregulated the protein expressions of Bax, cleaved caspase-3, and cleaved PARP and upregulated the expression of Bcl-2 through reduced PI3K and pAKT expressions. Furthermore, our in vivo results indicated that quercetin improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer, whereas the expression of caspase-3 was inhibited. Taken together, these results demonstrate that quercetin could protect retinal pigment epithelium and the retina from NaIO3-induced cell apoptosis via reactive oxygen species-mediated mitochondrial dysfunction, involving the PI3K/AKT signaling pathway. This suggests that quercetin has the potential to prevent and delay AMD and other retinal diseases involving NaIO3-mediated apoptosis.

Changing Treatment Patterns in Patients With Venous Thromboembolism in Taiwan.

BACKGROUND: In Asia, little information is available about contemporary real-world treatment patterns for venous thromboembolism (VTE).Methods and Results:Consecutive patients (n=11,414) from the Taiwan National Health Insurance Research Database with initial VTE and taking oral anticoagulants between May 1, 2014 and June 30, 2016 were included. The temporal trends of using oral anticoagulants and pharmacomechanical therapy during the study period were evaluated. The efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) vs. warfarin were compared. Propensity score analysis (NOACs n=3,647 vs. warfarin n=3,647) was used to balance covariates between groups, and Cox proportional hazards models with adjustment were used to estimate the risks of clinical outcomes. The use of NOACs increased from 0.3% to 60.2% for VTE treatment during the study period. Pharmacomechanical therapy was used in 9.60%, 8.22%, and 5.63% from 2014 through 2016. NOACs were associated with a 16% risk reduction (adjusted hazard ratio [aHR] 0.84, 95% confidence interval [CI] 0.77-0.93) in all-cause mortality and a 21% risk reduction (aHR 0.79, 95% CI 0.65-0.96) in recurrent VTE vs. warfarin. Overall, NOACs were associated with a lower risk of major bleeding compared with warfarin (aHR 0.804, 95% CI 0.648-0.998). CONCLUSIONS: In real-world practice, NOACs have become the major anticoagulant used for Asians with VTE. Although NOACs had a lower risk of recurrent VTE and major bleeding compared with warfarin in Taiwan, we still need a large-scale randomized controlled trial to confirm the findings.

Indium Uptake and Accumulation by Rice and Wheat and Health Risk Associated with Their Consumption.

The increasing use of indium in high-tech industries has inevitably caused its release into the environment. However, knowledge of its environmental fate has been very limited so far. This study investigates the indium uptake and accumulation by two staple crops, rice (Oryza sativa L.) and wheat (Triticum aestivum L.), and evaluates potential risks associated with their consumption. Rice and wheat were grown on three kinds of soil, including acidic soils spiked with a high indium concentration (1.0 mmol kg-1), which is considered the worst-case scenario, because high soil acidity promotes indium bioavailability. The results revealed that a large portion of soil indium was associated with iron hydroxides, even in acidic soils. Indium precipitates in soils resulted in relatively low availability at the plant root site. Most absorbed indium accumulated at the roots, with only a tiny portion reaching the grains. The corresponding Hazard Quotient indicated no adverse effects on human health. Due to the low translocation of indium from soil to grain, the consumption of rice and wheat grains harvested from indium-contaminated soils may pose an insignificant risk to human health. Further field studies are necessary to better elucidate the risks associated with consuming crops grown in indium-contaminated soils.

Kaempferol suppresses cell migration through the activation of the ERK signaling pathways in ARPE-19 cells.

Kaempferol is a flavonoid with anticancer and anti-metastasis activity in different cancer-cell lines. However, the underlying mechanisms by which kaempferol acts on human retinal pigment epithelial (ARPE-19) cells remain unclear. In this study, we demonstrated that kaempferol inhibited migration and invasion in ARPE-19 cells at non-toxic dosages. We discovered that kaempferol obviously reduced the enzyme activity and protein expression of matrix metalloproteinase-2 by increasing the phosphorylated levels of extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathways. Additionally, ERK1/2-specific inhibitor PD98059 significantly reversed kaempferol's inhibitory effects on migration and expression of MMP-2 in ARPE-19 cells. Overall, our results are the first to demonstrate that kaempferol is capable of inhibiting cell migration by targeting ERK1/2 signaling in human retinal pigment epithelial cells.

Nickel-induced VEGF expression via regulation of Akt, ERK1/2, NFκB, and AMPK pathways in H460 cells.

Prospective cohort studies have indicated that a highly nickel-polluted environment may severely affect human health, resulting in such conditions as respiratory tract cancers. Such exposure can trigger vascular endothelial growth factor (VEGF) expression. However, the signal transduction pathways leading to VEGF induction by nickel compounds are not well understood. This study revealed the occurrence of VEGF induction in human non-small-cell lung cancer H460 cells exposed to NiCl2 . Moreover, exposing H460 cells to NiCl2 activated extracellular signal-regulated protein kinase (ERK), nuclear factor kappa B (NFκB), and protein kinase B (Akt) as well as downregulated AMP activated protein kinase (AMPK) expression. The mitogen-activated protein kinase (MAPK) and ERK inhibitor significantly blocked NiCl2 -induced ERK activation and VEGF production. Pretreating H460 cells with a PI3K/Akt inhibitor substantially inhibited NiCl2 -induced VEGF expression and reduced Akt, ERK, and NFκB phosphorylation. Furthermore, 5-aminoimidazole-4-carboxamide ribonucleoside-induced AMPK activation improved VEGF expression in NiCl2 -treated H460 cells significantly. These results indicate that NiCl2 induces VEGF production through Akt, ERK, NFκB activation and AMPK suppression and mediates various types of pathophysiological angiogenesis.

Effects of dihydromyricetin on ARPE-19 cell migration through regulating matrix metalloproteinase-2 expression.

Dihydromyricetin (DHM), a flavanonol compound in Ampelopsis grossedentata, possesses several biological activities. However, the molecular mechanism underlying the effects of DHM on human proliferative vitreoretinopathy (PVR) remains unclear. We explored the effects of DHM on cell migration and the metastasis-promoting proteins in human retinal pigment epithelial (RPE) cells (ARPE-19 cells). Our results revealed that DHM attenuated ARPE-19 cell invasion and migration by reducing matrix metalloproteinase-2 (MMP-2) expression. Furthermore, a Western blot analysis revealed that DHM significantly reduced levels of phosphorylated c-Jun N-terminal kinase 1/2, but not those of extracellular signal-regulated kinase 1/2 and p38. In conclusion, our findings shown that DHM inhibits human RPE cell migration through the inhibition of MMP-2 expression; therefore, DHM may have potential therapeutic value in treating PVR as adjuvant therapy.

Coronarin D induces apoptotic cell death through the JNK pathway in human hepatocellular carcinoma.

Coronarin D, a diterpene derived from the rhizomes of Hedychium coronarium, has been used to treat inflammatory diseases. Coronarin D can exert strong anticancer effects through cell growth prevention and cell cycle arrest in many cancer cells. In this study, we investigated the molecular mechanism through which coronarin D suppresses cell proliferation and triggers cell death in human hepatocellular carcinoma (HCC) cells. Treatment of Huh7 and Sk-hep-1 cells with coronarin D resulted in a significantly increased loss of mitochondrial membrane potential, leading to the cleavage and activation of caspase-9, caspase-8, and caspase-3 and changes in Bax, Bcl-2, and Bcl-xL protein levels. Coronarin D significantly induced autophagy by increasing the expression of Beclin-1 and LC3-II and reducing the expression of p62. Moreover, Huh7 and Sk-hep-1 cells exposed to coronarin D had decreased expression of phosphorylated AKT, p38, and ERK and increased expression of phosphorylated JNK. Exposure of cells to the JNK-specific inhibitor SP600125 attenuated the apoptotic effects of coronarin D. Taken together, this is the first study to report that coronarin D may effectively inhibit cell growth through apoptosis. We have provided evidence indicating that coronarin D induces cell death through the upregulation of JNK mitogen-activated protein kinases in human HCC cells.

Fisetin induces apoptosis through mitochondrial apoptosis pathway in human uveal melanoma cells.

Fisetin, a diatery flavonoid, been reported that possess anticancer effects in various cancers. The purpose of the study was to investigate the antitumor effects of fisetin in cultured uveal melanoma cell lines and compared with normal retinal pigment epithelial (RPE) cells. MTT assay was used for evaluating cytotoxic effects of fisetin. Flow cytometry study was used for the determination of apoptosis. JC-1 fluorescent reader was used to determine mitochondrial transmembrane potential changes. The results shown that fisetin dose-dependently decreased the cell viability of uveal melanoma cells but not influenced the cell viability of RPE cells. Apoptosis of uveal melanoma cells was induced by fisetin efficiently. Fisetin inhibited antiapoptotic Bcl-2 family proteins and damaged the mitochondrial transmembrane potential. The levels of proapoptotic Bcl-2 proteins, cytochrome c, and various caspase activities were increased by fisetin. In conclusion, fisetin induces apoptosis of uveal melanoma cells selectively and may be a promising agent to be explored for the treatment of uveal melanoma.

Electrochemical Production of Magnetite Nanoparticles for Sulfide Control in Sewers.

Recently, naturally occurring magnetite (Fe3O4) has emerged as a new material for sulfide control in sewers. However, unrefined magnetite could have high heavy metal contents (e.g., Cr, Zn, Ni, Sn, etc.) and the capacity to remove dissolved sulfide is reasonably limited due to relatively large particle sizes. To overcome the drawbacks of unrefined magnetite we used an electrochemical system with mild steel as sacrificial electrodes to in-situ generate high strength solutions of plate-like magnetite nanoparticles (MNP). MNP with a size range between 120 and 160 nm were electrochemically generated at 9.35 ± 0.28 g Fe3O4-Fe/L, resulting in a Coulombic efficiency (CE) for iron oxidation of 93.5 ± 2.8%. The produced MNP were found to effectively reduce sulfide levels in sewage from 12.7 ± 0.3 to 0.2 ± 0.0 mg S/L at a sulfide-to-MNP ratio of 0.26 g S/g Fe3O4-Fe. Subsequently, MNP were continuously generated with polarity switching at stable cell voltage for 31 days at 4.53 ± 0.35 g Fe3O4-Fe/L with a CE for iron oxidation of 92.4 ± 7.2%. The continuously produced MNP reduced sulfide at similar levels to around 0.2 mg S/L at a ratio of 0.28 g S/g Fe3O4-Fe.

Risk of stroke among patients with cerebral palsy: a population-based cohort study.

AIM: The aim of the study was to investigate the risk of stroke in patients with cerebral palsy (CP), based on nationwide data in Taiwan. METHOD: This prospective cohort study was comprised of patients recorded on the Taiwan Longitudinal Health Insurance Database 2005 (LHID2005) who had a diagnosis of CP (n=1975) in records between 1 January 2004 and 31 December 2007. A comparison group (1:5) drawn from the same database was matched for age and sex (n=9875). Each patient was tracked by data until the development of stroke or the end of 2008. Cox proportional-hazards regression analysis was used to evaluate the hazard ratios after adjusting for potential confounding factors. RESULTS: Patients with CP were more likely to suffer stroke than the comparison population, after adjusting for potential confounding factors (adjusted hazard ratio: 2.17; 95% confidence interval [CI]: 1.74-2.69). The hazard ratio of stroke was 4.78 (95% CI: 3.18-7.17) and 1.57 (95% CI: 1.20-2.05) for patients with CP aged 50 years and under, and over 50 years respectively. INTERPRETATION: Cerebral palsy is a risk factor or marker for stroke that is independent of traditional stroke risk factors. Further research in this area is warranted.