## 4 Discussion

Table 5: Sensitivity Analysis of Adjusted HRs of Vaccination in the Risk Reduction of All Strokes in All Seasons. metabolic demands due to changes in sympathetic activity and hyperdynamic cardiovascular response increase the risk of strokes. The findings of this study support the protective effect of the influenza vaccination on the incidence of stroke in older individuals with hypertension. A 42% risk reduction was observed for the entire cohort throughout all seasons with stronger effects seen in the 55-64-year-old group and in male subjects (Tables 2-5). The protective effect of the influenza vaccination could stem mainly from the prevention of infection and inflammation-induced sequelae. Various neurological complications besides stroke may occur in patients with pandemic H1N1 influenza A infection [6; 7; 32]. There have been reports of increased risk for hospital admissions and a high rate of mortality in elderly men during the influenza season [33; 34; 35]. As high mortality during the influenza season could mask the incidence of strokes, individuals with various diseases and health conditions (e.g., AF, hypertension) may die before encountering a stroke [17]. However, during the non-influenza season, the mortality rate usually decreases and the actual effect of the influenza vaccination can be observed. This likely explains why the influenza vaccination exerted marked protective effects against stroke during the non-influenza season (Tables 2-5). A similar phenomenon was reported in a previous study [23]. Men and women may have competing risk factors during the influenza and non-influenza seasons [17; 23]. Epidemiological evidence from influenza outbreaks and pandemics reveals that morbidity and mortality are often higher for women than men. Females generate higher proinflammatory cytokine and chemokine responses and experience greater morbidity and mortality than males. Males and females also respond differently to influenza vaccines, with women initiating higher humoral immune responses but experiencing more adverse reactions to seasonal influenza vaccines than men. Sex-hormones, including estradiol and testosterone, as well as genetic differences between the sexes may play roles in modulating sex differences in immune responses to influenza virus infection and vaccination [36]. The present study demonstrated the consistent neuroprotective effect of influenza among male and female patients. This study found that more unvaccinated subjects live in the urban areas and have a higher income. Urban habitats with a higher income are supposed to have better living standards, educational background, healthcare support and consequently a reduced risk of major complications (e.g., stroke) from chronic diseases such as hypertension. However, that was in contrast to the finding of the current study. Our results showed that individuals who receive the influenza vaccination, despite living in a rural area with lower income, have a reduced risk of stroke. Nevertheless, stroke prevention in elderly individuals remains challenging and a growing health concern as the elderly population is rapidly increasing worldwide [3]. Our study indicates the importance of the influenza vaccination in elderly individuals, particularly males with hypertension in the 55-64-year-old group, and the overall relatively high risk of stroke. Hypertension is known to increase the risk of hemorrhagic stroke [37], whereas diabetes increases the risk of ischemic stroke but not hemorrhagic stroke [38]. Additionally, the protective effects of the influenza vaccination are likely to be related to the prevention of acute infection, which can elicit both systemic and local vascular inflammatory responses [23]. The influenza vaccination exerted protective effects in patients with AF who were receiving statins (Tables 4 and 5). Furthermore, studies show that prevention of vascular remodeling by metformin can reduce hemorrhage and improve functional outcomes, emphasizing the importance of vascular protection in cases of hemorrhage stroke [39].