Chronic Wasting Disease: Transmission Mechanisms and the Possibility of Harvest Management

We develop a model of CWD management by nonselective deer harvest, currently the most feasible approach available for managing CWD in wild populations. We use the model to explore the effects of 6 common harvest strategies on disease prevalence and to identify potential optimal harvest policies for reducing disease prevalence without population collapse. The model includes 4 deer categories (juveniles, adult females, younger adult males, older adult males) that may be harvested at different rates, a food-based carrying capacity, which influences juvenile survival but not adult reproduction or survival, and seasonal force of infection terms for each deer category under differing frequency-dependent transmission dynamics resulting from environmental and direct contact mechanisms. Numerical experiments show that the interval of transmission coefficients β where the disease can be controlled is generally narrow and efficiency of a harvest policy to reduce disease prevalence depends crucially on the details of the disease transmission mechanism, in particular on the intensity of disease transmission to juveniles and the potential differences in the behavior of older and younger males that influence contact rates. Optimal harvest policy to minimize disease prevalence for each of the assumed transmission mechanisms is shown to depend on harvest intensity. Across mechanisms, a harvest that focuses on antlered deer, without distinguishing between age classes reduces disease prevalence most consistently, whereas distinguishing between young and older antlered deer produces higher uncertainty in the harvest effects on disease prevalence. Our results show that, despite uncertainties, a modelling approach can determine classes of harvest strategy that are most likely to be effective in combatting CWD.     

Allele frequencies for candidate genes in atherosclerosis and diabetes among Trinidadian neonates

Trinidadians of South Asian origin have a high prevalence of cardiovascular disease and diabetes compared to Trinidadians of African origin. The degree to which these differences are related to genetic and/or environmental factors is unclear. To determine whether there might be a genetic basis for this difference in prevalence of deleterious phenotypes we examined allele frequencies for candidate genes in atherosclerosis and diabetes. We genotyped 81 consecutive neonates of African origin and 103 consecutive neonates of South Asian origin. We evaluated common polymorphisms in 11 candidate genes for atherosclerosis and diabetes. We found differences between the two subpopulations in the allele frequencies of several candidate genes, including APOE, LIPC, APOC3, PON1, PON2, and PPP1R3. However, the differences in the allele frequencies were not all consistent with the pattern of CHD expression between these two ethnic groups in adulthood. Thus, differences in genetic architecture alone may not explain the wide disparities in disease prevalence between these two subpopulations. It is very likely that environmental factors, or unmeasured genetic factors, influence the genetic susceptibility to disease in these subpopulations.     

Sex-Specific Prevalence of Diabetes and Cardiovascular Risk Factors in the Middle-Aged Population of China: A Subgroup Analysis of the 2007–2008 China National Diabetes and Metabolic Disorders Study

The sex difference in the prevalence rates of diabetes and cardiovascular diseases (CVDs) among the middle-aged population in China remain largely unknown. Therefore, we analyzed differences in the prevalence of diabetes, self-reported CVDs, and some CVD risk factors among men and women in the middle-aged population (30–49 years) and in individuals aged 50 years and older using data from the China National Diabetes and Metabolic Disorders Study of 2007–2008. Middle-aged men appeared to have significantly a higher prevalence of diabetes and self-reported CVDs than middle-aged women (8.07% vs 5.06% for diabetes, P < 0.001; 0.64% vs 0.22% for CVDs, P < 0.001). Men also showed higher rates of central obesity, hypertension, and dyslipidemia than women (all P < 0.01). Compared with women, men were more likely to drink alcohol and smoke cigarettes but less likely to be under diet control. The sex-specific differences in prediabetes, CVD, and CVD risk factors between men and women were diminished or even reversed in the population aged 50 years and older. No sex-specific differences were found in the prevalences of a family history of diabetes, coronary heart disease, and hypertension (P > 0.05) in middle-aged population. Specific strategies to reduce modifiable risk factors for the prevention and control of diabetes and CVD may be warranted in this population.     

Prevalence Studies of Dementia in Mainland China,Hong Kong and Taiwan: A Systematic Review and Meta-Analysis

Background

Many studies have considered the prevalence of dementia in mainland China, Hong Kong and Taiwan. However, area level estimates have not been produced. This study examines area differences across mainland China, Hong Kong and Taiwan adjusting for the effect of methodological factors with the aim of producing estimates of the numbers of people with dementia in these areas.

Method and Findings

A search of Chinese and English databases identified 76 dementia prevalence studies based on samples drawn from mainland China, Hong Kong and Taiwan between 1980 and 2012. A pattern of significantly decreasing prevalence was observed from northern, central, southern areas of mainland China, Hong Kong and Taiwan. Area variations in dementia prevalence were not explained by differences in methodological factors (diagnostic criteria, age range, study sample size and sampling method), socioeconomic level or life expectancy between areas. The results of meta-analysis were applied to current population data to provide best estimate. Based on the DSM-IV diagnostic criteria, the total number of people aged 60 and over with dementia in mainland China, Hong Kong and Taiwan is 8.4 million (4.6%, 95% CI: 3.4, 5.8) and in northern, central and southern areas are 3.8 (5.1%, 95% CI: 4.1, 6.1), 3.2 (4.4%, 95% CI: 3.2, 5.6) and 1.2 (3.9%, 95% CI: 2.3, 5.4) million respectively. These estimates were mainly based on the studies existing in highly developed areas and potentially affected by incomplete and insufficient data.

Conclusions

The findings of this review provide a robust estimate of area differences in dementia prevalence. Application of the estimated prevalence to population data reveals the number of people with dementia is expected to double every 20 years, areas in mainland China will be facing the greatest dementia challenge.     

Health and the avoidance of macroparasites: a preliminary cross-cultural study

Some evolutionary explanations of cross-cultural differences propose that human personality is caused by pathogen stress. Both xenophobia and ethnocentrism evolved under conditions with high parasite prevalence. Further, inter-individual variation in disgust or fear of parasites is expected to be influenced by human health, where healthy people should express lower disgust sensitivity to parasites. We examined inter-individual variation of children’s fear, disgust and self-perceived danger between two distinct cultures differing in overall pathogen prevalence. We found that children were able to distinguish between disease-relevant and disease-irrelevant groups of invertebrates and that children in regions with high pathogen prevalence expressed greater fear, disgust and self-perceived danger of all animals, irrespective of disease threat. After controlling for confounding factors, better health of children was associated with lower perceived danger of disease-relevant animals. Gender differences were found only in conditions with low pathogen stress. Our results support the idea that cross-cultural differences in human perception of animals are mediated by pathogen threat. Further research is necessary to investigate causal relationship between human health and avoidance of potentially hazardous animals.     

Quantification and Comparison of Soil Elements in the Tibetan Plateau Kaschin-Beck Disease Area

The prevalence rate of Kaschin-Beck disease (KBD) in most parts of China is currently decreasing, but the disease is still active and severe on the Tibetan Plateau. Soil samples including the surface layer (0–20 cm) and the subsurface layer (20–40 cm) in the cultivated and natural soil profiles were collected, and the mechanical composite and total concentration of arsenic, cobalt, copper, iron, mercury, manganese, molybdenum, selenium, and zinc were determined. Concentrations of arsenic, iron, manganese, copper, and selenium in the surface soil were lower than those in the subsurface soil. The same was true of physical clay in the soil profiles. However, there were no significant differences between the different soil layers. The concentrations of selenium, molybdenum, and mercury were somewhat lower compared with the average concentrations of soils in China. Deficiencies of molybdenum and selenium both play a critical role in occurrence of KBD, but whether or not soil mercury at a low level contributes to KBD is still unclear. A correlation analysis of soil elements showed that there is a positive correlation between iron, cobalt, and manganese due to their similar chemical characteristics. Selenium concentrations in soil as well as the physical clay and iron descend with the deterioration of KBD, but mercury concentrations in soil ascend with the aggravation of the disease. The results show that selenium deficiencies greatly influence the disease, and a deficiency of molybdenum is likely another important factor in inducing KBD. Moreover, determining whether low levels of soil mercury contribute to KBD should be investigated in the future.     

Geographical Detector-based influence factors analysis for Echinococcosis prevalence in Tibet,China

Echinococcosis, caused by genus Echinococcus, is the most pathogenic zoonotic parasitic disease in the world. In Tibet of the People’s Republic of China, echinococcosis refers principally to two types of severe zoonosis, cystic echinococcosis (CE) and alveolar echinococcosis (AE), which place a serious burden on public health and economy in the local community. However, research on the spatial epidemiology of echinococcosis remains inadequate in Tibet, China. Based on the recorded human echinococcosis data, maps of the spatial distribution of human CE and AE prevalence in Tibet were produced at city level and county level respectively, which show that the prevalence of echinococcosis in northern and western Tibet was much higher than that in other regions. We employ a geographical detector to explore the influencing factors for causing CE and AE while sorting information on the maps of disease prevalence and environment factors (e.g. terrain, population, and yak population). The results of our analysis showed that biological factors have the most impact on the prevalence of echinococcosis, of which the yak population contributes the most for CE, while the dog population contributes the most for AE. In addition, the interaction between various factors, as we found out, might further explain the disease prevalence, which indicated that the echinococcosis prevalence is not simply affected by one single factor, but by multiple factors that are correlated with each other complicatedly. Our results will provide an important reference for the evaluation of the echinococcosis risk, control projects, and prevention programs in Tibet.     

Prevalence and spatial distribution characteristics of human echinococcosis in China

BackgroundEchinococcosis is a zoonotic parasitic disease caused by larval stages of cestodes belonging to the genus Echinococcus. The infection affects people’s health and safety as well as agropastoral sector. In China, human echinococcosis is a major public health burden, especially in western China. Echinococcosis affects people health as well as agricultural and pastoral economy. Therefore, it is important to understand the prevalence status and spatial distribution of human echinococcosis in order to advance our knowledge of basic information for prevention and control measures reinforcement.MethodsReport data on echinococcosis were collected in 370 counties in China in 2018 and were used to assess prevalence and spatial distribution. SPSS 21.0 was used to obtain the prevalence rate for CE and AE. For statistical analyses and mapping, all data were processed using SPSS 21.0 and ArcGIS 10.4, respectively. Chi-square test and Exact probability method were used to assess spatial autocorrelation and spatial clustering.ResultsA total of 47,278 cases of echinococcosis were recorded in 2018 in 370 endemic counties in China. The prevalence rate of human echinococcosis was 10.57 per 10,000. Analysis of the disease prevalence showed obvious spatial positive autocorrelation in globle spatial autocorrelation with two aggregation modes in local spatial autocorrelation, namely high-high and low-high aggregation areas. The high-high gathering areas were mainly concentrated in northern Tibet, western Qinghai, and Ganzi in the Tibetan Autonomous Region and in Sichuan. The low-high clusters were concentrated in Gamba, Kangma and Yadong counties of Tibet. In addition, spatial scanning analysis revealed two spatial clusters. One type of spatial clusters included 71 counties in Tibet Autonomous Region, 22 counties in Qinghai, 11 counties in Sichuan, three counties in Xinjiang Uygur Autonomous Region, two counties in Yunnan, and one county in Gansu. In the second category, six types of spatial clusters were observed in the counties of Xinjiang Uygur Autonomous Region, and the Qinghai, Gansu, and Sichuan Provinces.ConclusionThis study showed a serious prevalence of human echinococcosis with obvious spatial aggregation of the disease prevalence in China. The Qinghai-Tibet Plateau is the "hot spot" area of human echinococcosis in China. Findings from this study indicate that there is an urgent need of joint strategies to strengthen efforts for the prevention and control of echinococcosis in China, especially in the Qinghai-Tibet Plateau.     

Prevalence of coronary heart disease risk factors in a Cambridge, UK study

This paper examines the distribution and prevalence of risk factors for coronary heart disease in a sample of 165 men and 202 women over 40 years of age who had earlier participated in a coronary prevention trial from a general practice in Cambridge, UK. No significant differences were observed in total cholesterol levels between men and women, and a quarter of the sample had concentrations above 6.5 mmol/l which is 250 mg/dl. There were significant sex differences in a number of risk factors with males having significantly higher prevalence of low high density lipoprotein, systolic and diastolic blood pressures, obesity, and smoking than women. About 8% of men and women were obese (as defined by a body mass index > 30), while 47% of men and 35% of women were mildly overweight (body mass index > 25). Two or more risk factors for coronary heart disease (high total cholesterol and/or hypertension and/or obesity) were present in 4% and 9% of older men and women respectively. Furthermore, about half the subjects had more than one risk factor for coronary heart disease.     

Brief communication: physiological stress in the Florida Archaic-enamel hypoplasia and patterns of developmental insult in early North American hunter-gatherers

We examined the prevalence and developmental timing of linear enamel hypoplasias (LEHs) in an early Archaic Floridian population from Windover (8,120-6,980 (14)C years B.P. uncorrected). Using digital images, mandibular and maxillary canines were analyzed for defect prevalence and timing of insults. Although overall prevalence was very weakly correlated with earlier defect timing, there were significant differences in defect prevalence that varied by sex and tooth type. The mean LEH count in male mandibular canines was far higher than in male maxillary canines or in female mandibular or maxillary canines. We examined defect timing as a possible predictor of the sex differences in LEH prevalence. There were no significant sex differences in the developmental timing of the earliest defects in either tooth class. Developmental timing is not responsible for the sex differences seen in defect prevalence in mandibular canines.     

Racialized genetics and the study of complex diseases: the thrifty genotype revisited

Current debate on the use of population genetic data for complex disease research is driven by the laudable goals of disease prevention and harm reduction for all, especially dispossessed, formerly enslaved, or colonized populations. This article examines one of the oldest gene-based theories of complex disease causation: the thrifty genotype hypothesis (THG). This hypothesis is emblematic of the way in which genetic research into complex disease attracts a high investment of scientific resources while contributing little to our capacity to understand these diseases and perpetuating problematic conceptions of human variation. Although there are compelling reasons to regard the high prevalence of type 2 diabetes mellitus as a by-product of our biological incapacity to cope with modern affluent and sedentary lifestyles, there is at present no consistent evidence to suggest that minority populations are especially genetically susceptible. Nor is it clear why such genetic differences would be expected, given the original pan-species orientation of the TGH. The limitations inherent in current applications of the TGH demonstrate that genetic research into complex disease demands careful attention to key environmental, social, and genetic risk factors operating within and between groups, not the simplistic attribution of between-group differences to racialized genetics. A robust interdisciplinary approach to genetic epidemiological research is proposed.     

On the Genetic Interpretation of Disease Data

Background

The understanding of host genetic variation in disease resistance increasingly requires the use of field data to obtain sufficient numbers of phenotypes. We introduce concepts necessary for a genetic interpretation of field disease data, for diseases caused by microparasites such as bacteria or viruses. Our focus is on variance component estimation and we introduce epidemiological concepts to quantitative genetics.

Methodology/Principal Findings

We have derived simple deterministic formulae to predict the impacts of incomplete exposure to infection, or imperfect diagnostic test sensitivity and specificity on heritabilities for disease resistance. We show that these factors all reduce the estimable heritabilities. The impacts of incomplete exposure depend on disease prevalence but are relatively linear with the exposure probability. For prevalences less than 0.5, imperfect diagnostic test sensitivity results in a small underestimation of heritability, whereas imperfect specificity leads to a much greater underestimation, with the impact increasing as prevalence declines. These impacts are reversed for prevalences greater than 0.5. Incomplete data recording in which infected or diseased individuals are not observed, e.g. data recording for too short a period, has impacts analogous to imperfect sensitivity.

Conclusions/Significance

These results help to explain the often low disease resistance heritabilities observed under field conditions. They also demonstrate that incomplete exposure to infection, or suboptimal diagnoses, are not fatal flaws for demonstrating host genetic differences in resistance, they merely reduce the power of datasets. Lastly, they provide a tool for inferring the true extent of genetic variation in disease resistance given knowledge of the disease biology.     

Temporal changes and rural-urban differences in cardiovascular disease risk factors and mortality in China.

We summarize several studies, from the last 10 years, of temporal changes and rural-urban differences in the risk factors of cardiovascular disease (CVD) in China to indicate the influences of economic modernization. Two national blood pressure surveys have shown that the prevalence of hypertension increased from 5.1% to 7.7% between 1958-1959 and 1979-1980. Throughout China hypertension is more prevalent in urban areas than in rural areas. Within the Shanghai region body mass index, blood pressure, and total serum cholesterol were higher in urban districts than in rural areas. Rural-urban differences in lipid levels were also found in the Beijing and Guangzhou regions. A related four-year followup study showed that total serum cholesterol and triglycerides increased markedly in both urban and rural areas of Guangzhou. In Shanghai part-time farmers who worked in factories had a higher age-adjusted prevalence of definite hypertension than farmers who worked full-time in the fields (5.0% versus 2.3%). In a prospective study in Wuhan a new productivity-based salary system was associated with increased serum cholesterol and blood pressure. Age-adjusted CVD mortality increased from 1973 to 1982 in a rapidly industrializing county in the Shanghai metropolitan region. The results from several studies indicate that China is undergoing the expected increase in modernization-related CVD risk factors and mortality, especially in urban metropolitan regions.     

The spatial distribution of plant populations, disease dynamics and evolution of resistance

Empirical studies of the interaction between the anther smut fungus Microbotryum violaceum and its host plant Lychnis alpina were combined with modelling approaches to investigate how variation in the spatial distribution of host populations influences disease dynamics and variation in resistance. Patterns of disease incidence and prevalence were surveyed in three contrasting systems of natural L . alpina populations where there is substantial variation in spatial structure, ranging from large continuous populations through to small isolated patches. Disease incidence (fraction of populations where disease was present) was highest in the continuous situation, and lowest in the most isolated populations. The reverse was true for prevalence (fraction of individuals diseased). To better understand the long-term ecological and evolutionary consequences of differences in among population spatial structure, we developed a two-dimensional spatially explicit simulation model in which host-population spacing was modelled by varying the percentage of sites suitable for the host. The general patterns of disease incidence and prevalence generated in the simulations corresponded well with the patterns observed in natural populations of L. alpina and M. violaceum ; i.e. the fraction of sites with disease increased while the average disease prevalence in diseased populations decreased when host populations became more connected. One likely explanation for the differences in disease incidence and prevalence seen in natural populations is that the evolution of host resistance varies as a function of the degree of fragmentation. This is supported by simulation results that were qualitatively similar to the survey data when resistance was allowed to vary, but not when hosts were assumed to be uniformly susceptible. In the former, the frequency of resistance increased markedly as host populations became more connected.     

Case-control association studies in mixed populations: correcting using genomic control

OBJECTIVE: Case-control association studies in mixed populations can result in spurious disease-marker associations if subpopulation disease prevalence and marker frequencies both differ. Genomic control (GC) uses neutral loci to correct for spurious association (due to population stratification), but how well this works remains undetermined. METHODS: We simulated and mixed populations with different disease and marker frequencies but without marker-disease association. We generated case-control datasets, calculated the chi2 for disease association with each marker, and applied two GC procedures, dividing by the mean chi2 or median-chi2/0.456. RESULTS: Corrections became conservative (false positive rate [FPR] <5%) with increasing subpopulation prevalence and marker differences. The mean correction resulted in FPRs close to 5% at average subpopulation allele frequency differences <0.26, but inclusion of just a few markers with large frequency differences resulted in conservative FPRs. FPRs from the median correction were mostly conservative but became anticonservative when a few markers with large frequency differences were included. CONCLUSION: GC can both lead to a notable loss of power to detect a true association (conservative) in many circumstances or may fail to eliminate the spurious associations (anticonservative). The mean correction factor is useful in certain situations to correct population stratification, but it is difficult to know when those situations exist.     

Global drivers of human pathogen richness and prevalence

The differences in the richness and prevalence of human pathogens among different geographical locations have ramifying consequences for societies and individuals. The relative contributions of different factors to these patterns, however, have not been fully resolved. We conduct a global analysis of the relative influence of climate, alternative host diversity and spending on disease prevention on modern patterns in the richness and prevalence of human pathogens. Pathogen richness (number of kinds) is largely explained by the number of birds and mammal species in a region. The most diverse countries with respect to birds and mammals are also the most diverse with respect to pathogens. Importantly, for human health, the prevalence of key human pathogens (number of cases) is strongly influenced by disease control efforts. As a consequence, even where disease richness is high, we might still control prevalence, particularly if we spend money in those regions where current spending is low, prevalence is high and populations are large.     

Pathological Features of Localized Prostate Cancer in China: A Contemporary Analysis of Radical Prostatectomy Specimens

There has been a rapid increase in the incidence of prostate cancer in China, especially in areas with boosted economic development. In this study, we analyzed the pathological features of a contemporary series of radical prostatectomy cases. A total of 230 consecutive, whole-mounted radical prostatectomy specimens collected from 2012 to 2014 were reviewed. The median age of the patients was 68 years, and 64.3% of patients presented with prostate specific antigen alone. Pathological examination indicated that a high proportion (77.4%) of patients had intermediate- or high-risk disease according to the Cancer of the Prostate Risk Assessment Post-Surgical score. After surgery, only 28 patients met the criteria for active surveillance (organ-confined Gleason ≥6 disease). The Prostate Cancer Research International Active Surveillance criteria achieved a sensitivity of 57.1% and a specificity of 98.0% for identifying candidates. The probability of Gleason score upgrading was 24.8% in the entire group and 59.0% in biopsy-confirmed Gleason ≥6 disease. The predominant tumor was located in the transition zone in 14.8% of cases, while only three patients (1.3%) had a predominant tumor located in the anterior region. Patients with transition zone-predominant tumor were likely to have been referred with urinary symptoms and high prostate specific antigen levels. The results of this study highlight the contemporary pathological features of localized prostate cancer in urban China. There was an increased trend towards asymptomatic cases, though most patients had intermediate- or high-risk disease and were suitable for definitive treatment. The low prevalence of dominant cancer in the anterior region may reflect race-based pathological differences.     

The Prevalence and Incidence of Latent Tuberculosis Infection and Its Associated Factors among Village Doctors in China

BackgroundChina is a high tuberculosis (TB) burden country. More than half of acute TB cases first seek medical care in village doctors’ clinics or community health centers. Despite being responsible for patient referral and management, village doctors are not systematically evaluated for TB infection or disease. We assessed prevalence and incidence of latent TB infection (LTBI) among village doctors in China.ConclusionsPrevalence and incidence of LTBI among Chinese village doctors is high. TB infection control measures should be strengthened among village doctors and at village healthcare settings.     

Sex hormones and coronary disease: a review of the clinical studies

A male to female ration of coronary disease of 2:1 has been a consistent finding. This differential persists event when the classic risk factors for coronary disease--hypertension, smoking, obesity, diabetes, and hyperlipidemia--are controlled for gender. The most likely ultimate cause of this phenomenon is male-female differences in sex hormone patterns. Clinical studies in this area have either compared the sex hormone profiles of men and women with and without coronary disease or computed the relative prevalence of disease in populations that differ in their sex hormone patterns. In general, research findings have disputed the hypothesis that persons with coronary disease have low levels of a protective factor such as estrogen or progesterone and high levels of testosterone. Coronary disease patients actually have elevated estrogen levels and low testosterone levels; endogenous progesterone levels are normal before infarction but show a stress-mediated increase in the immediate postinfarction period. Findings of a low prevalence of coronary disease in premenopausal women, a loss of protection after menopause, and a low prevalence of coronary disease in men with cirrhosis-related hyperestrogenemia suggest that natural estrogens are antiatherogenic. The protective effect of pregnancy against myocardial infarction, despite concomitant potentially thrombogenic levels of estrogen at the time, seems to indicate that progesterone, whose levels are also extremely high during pregnancy, plays a major anti-infarction protective effect distinct from that of estrogen. Studies of women oral contraceptive (OC) users and men taking estrogens for brief periods have found that these exogenous hormones produce coronary thrombosis but not atherosclerosis. Finally, the finding of increased coronary disease risk in long-term OC users indicates that synthetic estrogens favor coronary atherosclerosis by suppressing natural estrogen and progesterone production.     

Chlorpropamide-alcohol flushing and large-vessel disease in non-insulin-dependent diabetes.

A total of 220 non-insulin-dependent diabetics aged over 45 (139 with a history of chlorpropamide-alcohol flushing and 81 without such a history) were examined for the prevalence of large-vessel disease. Large-vessel disease was significantly more common in the group without a history of flushing (41% v 24% of the two groups respectively; p < 0.05). A history of myocardial infarction was found in 14 (17%) of the patients without flushing but in only 10 (7%) patients with flushing. Similar differences were detected in the prevalences of angina, intermittent claudication, and absent foot pulses. There were, however, no significant differences in the prevalence of cerebrovascular disease or hypertension between the two groups. These results suggest that patients with non-insulin-dependent diabetes who flush in response to chlorpropamide and alcohol are significantly less likely to develop large-vessel disease than those who do not. Hence such flushing is probably related to the pathogenesis not only of small-vessel but also of large-vessel disease.