Towards optimal use of antithrombotic therapy of people with cancer at the end of life: A research protocol for the development and implementation of the SERENITY shared decision support tool.

BACKGROUND: Even though antithrombotic therapy has probably little or even negative effects on the well-being of people with cancer during their last year of life, deprescribing antithrombotic therapy at the end of life is rare in practice. It is often continued until death, possibly resulting in excess bleeding, an increased disease burden and higher healthcare costs. METHODS: The SERENITY consortium comprises researchers and clinicians from eight European countries with specialties in different clinical fields, epidemiology and psychology. SERENITY will use a comprehensive approach combining a realist review, flash mob research, epidemiological studies, and qualitative interviews. The results of these studies will be used in a Delphi process to reach a consensus on the optimal design of the shared decision support tool. Next, the shared decision support tool will be tested in a randomised controlled trial. A targeted implementation and dissemination plan will be developed to enable the use of the SERENITY tool across Europe, as well as its incorporation in clinical guidelines and policies. The entire project is funded by Horizon Europe. RESULTS: SERENITY will develop an information-driven shared decision support tool that will facilitate treatment decisions regarding the appropriate use of antithrombotic therapy in people with cancer at the end of life. CONCLUSIONS: We aim to develop an intervention that guides the appropriate use of antithrombotic therapy, prevents bleeding complications, and saves healthcare costs. Hopefully, usage of the tool leads to enhanced empowerment and improved quality of life and treatment satisfaction of people with advanced cancer and their care givers.

HPV type-specific distribution among family members and linen in households of cutaneous wart patients.

BACKGROUND: Common and plantar warts are caused by human papillomaviruses (HPV). Mode of transmission of wart HPVs within families is largely unknown. OBJECTIVE: To demonstrate similarity of HPV type(s) among wart cases, family members and household linen. METHODS: In a cross-sectional study, swabs taken from 123 warts and foreheads of 62 index patients and 157 family members and from 58 kitchen towels and 59 bathroom mats were tested for DNA of 23 cutaneous wart-associated HPV types. Generalized estimating equations (GEE) were used to estimate the chance of detecting the same HPV type as was found in the index patients on the family contacts and on the kitchen towels and bathroom mats. RESULTS: HPV1, HPV2, HPV27 and HPV57 were the most prevalent types in the warts of the index patients. Altogether, 60 (42.3%) of the 142 family members without warts had HPV DNA on their foreheads. When HPV1 and HPV2 were found in the warts, these types were also frequently (>50%) found on the foreheads of index patients and their family members, as well as on the kitchen towels and the bathroom mats. HPV27 and HPV57 were less frequently found (<25%) on foreheads and linen. No associations were found for age, sex and site of HPV DNA presence. CONCLUSION: Dissemination of skin wart-causing HPV types, from wart cases to household contacts and linen, such as kitchen towels and bathroom mats, is more likely for HPV1 and HPV2 than for HPV27 and HPV57. The role of towels and bathroom mats in HPV transmission deserves further investigation.

Predictive value of traditional risk factors for cardiovascular disease in older people: A systematic review.

With increasing age, associations between traditional risk factors (TRFs) and cardiovascular disease (CVD) shift. It is unknown which mid-life risk factors remain relevant predictors for CVD in older people. We systematically searched PubMed and EMBASE on August 16th 2019 for studies assessing predictive ability of >1 of fourteen TRFs for fatal and non-fatal CVD, in the general population aged 60+. We included 12 studies, comprising 11 unique cohorts. TRF were evaluated in 2 to 11 cohorts, and retained in 0-70% of the cohorts: age (70%), diabetes (64%), male sex (57%), systolic blood pressure (SBP) (50%), smoking (36%), high-density lipoprotein cholesterol (HDL) (33%), left ventricular hypertrophy (LVH) (33%), total cholesterol (22%), diastolic blood pressure (20%), antihypertensive medication use (AHM) (20%), body mass index (BMI) (0%), hypertension (0%), low-density lipoprotein cholesterol (0%). In studies with low to moderate risk of bias, systolic blood pressure (SBP) (80%), smoking (80%) and HDL cholesterol (60%) were more often retained. Model performance was moderate with C-statistics ranging from 0.61 to 0.77. Compared to middle-aged adults, in people aged 60+ different risk factors predict CVD and current prediction models perform only moderate at best. According to most studies, age, sex and diabetes seem valuable predictors of CVD in old-age. SBP, HDL cholesterol and smoking may also have predictive value. Other blood pressure and cholesterol related variables, BMI, and LVH seem of very limited or no additional value. Without competing risk analysis, predictors are overestimated.

Drug-related problems identified during medication review before and after the introduction of a clinical decision support system.

WHAT IS KNOWN AND OBJECTIVE: To facilitate the identification of drug-related problems (DRPs) during medication review, several tools have been developed. Explicit criteria, like Beers criteria or STOPP (Screening Tool of Older Peoples' Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment) criteria, can easily be integrated into a clinical decision support system (CDSS). The aim of this study was to investigate the effect of adding a CDSS to medication review software on identifying and solving DRPs in daily pharmacy practice. METHODS: Pre- to post-analysis of clinical medication reviews (CMRs) performed by 121 pharmacies in 2012 and 2013, before and after the introduction of CDSS into medication review software. Mean number of DRPs per patient, type of DRPs and their resolution rates were compared in the pharmacies pre- and post-CDSS using paired t tests. RESULTS AND DISCUSSION: In total, 9151 DRPs were identified in 3100 patients pre-CDSS and 15 268 DRPs were identified in 4303 patients post-CDSS. The mean number of identified DRPs per patient (aggregated per pharmacy) was higher after the introduction of CDSS (3.2 vs 3.6 P < .01). The resolution rate was lower post-CDSS (50% vs 44%; P < .01), which overall resulted in 1.6 resolved DRPs per patient in both groups (P = .93). After the introduction of CDSS, 41% of DRPs were detected by the CDSS. The resolution rate of DRPs generated by CDSS was lower than of DRPs identified without the help of CDSS (29% vs 55%; P < .01). The two most prevalent DRP types were "Overtreatment" and "Suboptimal therapy" in both groups. The prevalence of "Overtreatment" was equal in both groups (mean DRPs per patient: 0.84 vs 0.77; P = .22), and "Suboptimal therapy" was more frequently identified post-CDSS (mean DRPs per patient: 0.54 vs 1.1; P < .01). WHAT IS NEW AND CONCLUSION: The introduction of CDSS to medication review software generated additional DRPs with a lower resolution rate. Structural assessment including a patient interview elicited the most relevant DRPs. Further development of CDSS with more specific alerts is needed to be clinical relevant.

Evidence-based medicine in older patients: how can we do better?

Evidence-based medicine (EBM) aims to integrate three elements in patient care: the patient situation, scientific evidence, and the doctors' expertise. This review aims 1) to assess how these elements are systematically different in older patients and 2) to propose strategies how to improve EBM in older patients. The ageing process systematically affects all three elements that constitute EBM. First, ageing changes the physiology of the older body, makes the patient more vulnerable with more multimorbidity and polypharmacy and affects somatic, psychological and social function. The heterogeneity of older patients may lead to overtreatment of vulnerable and undertreatment of fit older patients. Second, representative older patients are underrepresented in clinical studies and endpoints studied may not reflect the specific needs of older patients. Third, adequate clinical tools and schooling are lacking to aid physicians in clinical decision-making. Strategies to improve elements of EBM include: first systematically acknowledging that physical, mental and social function may reveal patients vulnerability and specific treatment goals. Second, clinical studies specifically targeting more representative older patients and studying endpoints relevant to older patients are warranted. Finally, teaching of physicians may increase their experience and expertise in treating older patients. In conclusion, in older patients the same elements constitute EBM, but the elements need tailoring to the older patient. In the clinic, a thorough assessment of individual patient preferences and physical, mental and social functioning in combination with increased level of experience of the doctor can increase the quality of EBM in older patients.

High prevalence of cutaneous warts in elementary school children and the ubiquitous presence of wart-associated human papillomavirus on clinically normal skin.

BACKGROUND: One-third of Dutch primary school children have cutaneous warts; each year around 20% of them seek medical treatment. However, little is known about the epidemiology of the types of human papillomavirus (HPV) causing these warts. OBJECTIVES: To investigate the distribution of cutaneous wart-associated HPV types in three primary school classes by analysing skin swabs taken from warts, and the forehead, hand dorsum and sole of the foot of included children. METHODS: Using the hyperkeratotic skin lesion polymerase chain reaction/multiplex genotyping assay, each swab sample was used to genotype for 23 cutaneous wart-associated HPV types. RESULTS: Thirty-one (44%) of the 71 children had a total of 69 warts, with a maximum of six warts per child. In the wart swabs, HPV2, HPV27 and HPV57, members of Alphapapillomavirus species 4, were most frequently detected (27%, 32% and 14%, respectively), whereas HPV1 was only found in two plantar warts. The prevalence of HPV carriage, detected in swabs of clinically normal skin of the forehead, left hand and left sole was 80%, with the most prevalent types being HPV1 (59%), HPV2 (42%), HPV63 (25%) and HPV27 (21%). CONCLUSIONS: Cutaneous wart-associated HPV types were highly prevalent in primary school children, but did not correlate with the HPV types in warts. In contrast to the existing literature, HPV1 was frequently detected on clinically normal skin but was much less frequent in warts.

Completeness of medication reviews provided by community pharmacists.

WHAT IS KNOWN AND OBJECTIVES: Little is known about the ability of community pharmacists who are inexperienced in medication review to identify drug-related problems (DRPs). The objective of our study was to investigate the completeness of DRPs in terms of number, type and clinical relevance identified by community pharmacists when performing home medication reviews (HMRs). METHODS: This is a cross-sectional study within the intervention arm of a randomized controlled trial among community-dwelling patients (≥65 years, ≥5 drugs) in ten Dutch community pharmacies. Community pharmacists, who were inexperienced in medication review, received 2-day training in medication review. These pharmacists interviewed patients at home about their medicines, identified potential DRPs and made recommendations in combination with medication and clinical records. Expert reviewers completed the number of potential DRPs and recommendations by reviewing all available information, including patient interview reports. RESULTS AND DISCUSSION: In 155 patients, community pharmacists identified a mean of 3·6 (SD 2·8) potential DRPs per patient and expert reviewers added 6·5 (SD 3·2) DRPs. Community pharmacists formulated 2·6 (SD 2·3) recommendations per patient and reviewers added 7·5 (SD 3·3) recommendations. Community pharmacists identified a higher proportion of clinically relevant DRPs compared with expert reviewers, as assessed by DRPs with high priority [OR = 1·8 (95% CI 1·4-2·2)], DRPs associated with recommendations for drug change [OR = 1·9 (95% CI 1·5-2·3)] and implemented recommendations for drug change [OR = 2·1 (95% CI 1·6-2·7)]. WHAT IS NEW AND CONCLUSION: This study shows that the completeness of medication reviews by inexperienced community pharmacists with limited training could be improved, although they identified a higher proportion of potentially clinically relevant DRPs compared with expert reviewers. The results suggest that community pharmacists with limited experience in medication review may need more intensive post-graduate training.

The contribution of patient interviews to the identification of drug-related problems in home medication review.

WHAT IS KNOWN AND OBJECTIVE: To determine to what extent patient interviews contribute to the identification of drug-related problems (DRPs) in home medication reviews, in terms of number, type and clinical relevance. METHODS: We performed a cross-sectional study within the intervention arm of a randomized controlled trial. Patients were recruited from 10 Dutch community pharmacies. Patients were eligible if they were home-dwelling, aged 65 years and over and used five or more different drugs, including at least one cardiovascular or antidiabetic drug. The community pharmacist interviewed the patient at home about the medicines and identified potential DRPs in combination with medication and clinical records. This medication review was assessed and modified by an independent pharmacist reviewers' panel. Outcomes were the number and type of DRPs and recommendations and percentage of clinical relevant DRPs. Clinical relevance of DRPs was assessed by DRPs assigned a high priority, DRPs followed by recommendations for drug change and DRPs followed by implemented recommendations for drug change. RESULTS: A total of 1565 potential DRPs and recommendations (10 per patient).were identified for 155 patients (median age, 76 years; 54% women). Fifty-eight per cent of all recommendations involved a drug change; 27% of all DRPs were identified during patient interviews and 74% from medication and clinical records. Compared to DRPs identified from patient medication and clinical records, DRPs identified during patient interviews were more frequently assigned a high priority (OR = 1.8 [1.4-2.2]), were more frequently associated with recommendations for drug change (OR = 2.4 [1.9-3.1]) and were implemented recommendations for drug change (OR = 2.8 [2.1-3.7]). WHAT IS NEW AND CONCLUSION: This study shows that more than a quarter of all DRPs were identified during patient interviews. DRPs identified during patient interviews were more frequently assigned a higher clinical relevance.

Diabetic retinopathy screening in patients with diabetes mellitus in primary care: Incentives and barriers to screening attendance.

AIM: Although diabetic retinopathy (DR) screening is a basic component of diabetes care, uptake of screening programs is less than optimal. Because attendance rates and reasons for non-attendance in an unselected diabetes population are unknown, this study examines incentives and barriers to attend DR-screening. METHOD: Four focus groups provided patient-related themes concerning individual decision-making regarding attendance at DR-screening. A questionnaire measuring attendance rates and the influence of several factors was sent to 3236 diabetes patients (>18 years) in 20 Dutch general practices, of which 2363 (73%) responded. RESULTS: In the past 3 years, 81% of the patients had attended DR-screening. Patients not attending had lower levels of education, a more recent diagnosis of diabetes, and less frequently used insulin. There was no difference in DM types 1 and 2 patients regarding attendance. Patients attending more often visited health-care providers. Patients reported 'knowledge of detrimental effects of DR on visual acuity', 'sense of duty' and 'fear of impaired vision' as main incentives. The main barrier was the absence of a recommendation by the health-care provider. CONCLUSION: Knowledge about detrimental effects of DR on visual acuity and recommendation by health-care providers are important, possibly modifiable, factors in the attendance to DR screening.

Lesional HPV types of cutaneous warts can be reliably identified by surface swabs.

BACKGROUND: Large numbers of HPV types infect the human skin and members from the HPV genera alpha, gamma and mu are associated with cutaneous warts. OBJECTIVES: The aim of this study was to test if the HPV genotypes in swabs of the overlying skin are identical to the types present within these warts. STUDY DESIGN: To this purpose, 25 persons being treated for persistent cutaneous warts were enrolled. Swabs of the overlying skin of the wart were collected from each participant. Additionally, scabs of the wart and deeper portions of the warts were surgically removed. HPV genotyping was performed on all samples using the novel HSL-PCR/MPG assay and the HPV genotyping results were compared. RESULTS: From the 25 wart biopsies one was HPV negative. 15 were positive for HPV27, 3 for HPV57, 2 for HPV2, 2 for HPV1, 1 for HPV3 and 1wart biopsy was positive for both HPV41 and HPV65. Scabs and swabs of the warts both showed identical typing results as the biopsies in 24 of the 25 cases (sensitivity: 96%). CONCLUSIONS: There was an excellent agreement between HPV types in the swabs of the skin that overlies the warts and the biopsies of these warts validating the use of wart swabs for future studies of wart-associated HPV types. HPV27 was highly prevalent (70%) in the in adults of the investigated population of patients with persistent cutaneous warts.

Low innate production of interleukin-1beta and interleukin-6 is associated with the absence of osteoarthritis in old age.

OBJECTIVE: We investigated whether innate differences in cytokine response were associated with the absence of osteoarthritis (OA) in old age. DESIGN: In 82 participants from a cross-sectional birth cohort, radiographs of hands, hips and knees were taken at the age of 90 years. OA was defined as a Kellgren-Lawrence score of at least two. "Free from OA" was defined at patient level as absence of hip and knee OA, and presence of OA in maximally two hand joints. The innate cytokine response was determined in whole-blood samples upon stimulation with lipopolysaccharide. Logistic regression analyses were used to investigate associations between absence of OA in relation to tertiles of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, IL-1 receptor antagonist (RA) and IL-10. Adjustments were made for gender and body mass index. RESULTS: Sixteen percent of the participants were "free from OA". Subjects in the lowest tertile of Il-1beta production had a 11-fold increased chance to be free of OA [odds ratio (OR) 11.3, confidence intervals (CI) 95% 1.1-115.9], subjects in the lowest tertile of IL-6 production had an almost 7-fold increased chance to be free of OA (OR 6.7, 95% CI 1.1-41.2). Absence of hand OA was associated with low innate production of IL-6 and IL-1RA, absence of hip OA was associated with low innate IL-1beta production. No associations were found for TNF-alpha and IL-10. CONCLUSIONS: Low innate capacity to produce the pro-inflammatory cytokines IL-1beta and IL-6 is associated with the absence of OA in old age.

Incidence and predictive factors of lower respiratory tract infections among the very elderly in the general population. The Leiden 85-plus Study.

OBJECTIVES: To target preventive strategies in old age, which of the very elderly are predisposed to developing lower respiratory tract infections was investigated. DESIGN: Prospective observational follow-up study. SETTING: General population. PARTICIPANTS: Unselected cohort of 587 participants aged 85 years in Leiden, The Netherlands. MEASUREMENTS: As reported in the literature, predictive factors were selected and assessed at baseline. During a 5 year follow-up period, information on the development of lower respiratory tract infections was obtained from general practitioners or nursing home physicians. Associations between predictive factors were analysed with Cox regression, and population attributable risks were calculated. RESULTS: The incidence of lower respiratory tract infections among persons aged 85-90 years was 94 (95% CI 80-108) per 1000 person years. After multivariate analysis, history of chronic obstructive pulmonary disease (COPD), smoking, oral glucocorticosteroid use, severe cognitive impairment, history of stroke and declined functional status remained independently associated with the occurrence of lower respiratory tract infections. Smoking was the greatest contributor with a population attributable risk of 32%. CONCLUSION: In the very old, smoking, COPD, stroke and declined functional status were associated with the occurrence of lower respiratory tract infections and provide a means of targeting patients at risk of severe health complications.

Vascular disease and apathy in old age. The Leiden 85-Plus Study.

BACKGROUND: Apathy is defined as an important loss of motivation in all domains of daily functioning. Especially in old age, apathy might be a specific neuropsychiatric syndrome separate from depression. There are indications that apathy in elderly subjects is related to vascular disease. OBJECTIVE: To assess the relation between vascular disease and apathy in subjects aged 85 years and older. METHODS: The Leiden 85-plus Study is a prospective, population-based study of 500 elderly subjects. Vascular disease including myocardial infarction, angina pectoris or myocardial ischemia, claudicatio intermittens, and arterial surgery was determined at baseline. Symptoms of apathy were assessed annually from age 85 through 90 years using the apathy questions of the 15-item Geriatric Depression Rating Scale (GDS). Diagnostic accuracy of the apathy questions was validated using the Apathy Scale at age 90 years. The association between vascular disease and apathy was estimated both at baseline and longitudinally. RESULTS: The apathy items of the GDS showed a sensitivity of 69% and a specificity of 85%. At baseline, 69 subjects with apathy but free of depression had significantly more cardiovascular pathologies compared to 287 subjects without apathy. In the 287 subjects who were free of apathy and depression, increase of apathy but not depression during follow-up was significantly higher for each additional cardiovascular pathology at baseline. CONCLUSION: In community dwelling elderly, those with vascular disease were at higher risk of developing apathy but not depression. This suggests that apathy and depression in old age have different etiologies.

Generalized atherosclerosis, cognitive decline, and depressive symptoms in old age.

BACKGROUND: Atherosclerosis may be linked to cognitive decline and depression in old age. METHODS: The Leiden 85-Plus Study is a prospective population-based study of 599 subjects from age 85 onward. The generalized atherosclerotic burden was rated by the number of cardiovascular pathologies at baseline, as assessed by history taking from treating physicians and EKG. Cardiovascular pathologies included myocardial infarction, angina pectoris or myocardial ischemia, claudicatio intermittens, and arterial surgery. Global cognitive function (Mini-Mental State Examination), attention (Stroop Test), processing speed (Letter Digit Coding Test), immediate recall memory (Word Learning Test-Immediate Recall), delayed recall memory (Word Learning Test-Delayed Recall), and depressive symptoms (15-item Geriatric Depression Scale) were assessed each year from ages 85 through 90. The prospective associations between both the generalized atherosclerosis rating and stroke with cognitive function and depressive symptoms were analyzed by linear mixed models adjusted for sex and level of education. RESULTS: During follow-up, there was a significant cognitive decline and a significant increase of depressive symptoms. At baseline, a history of stroke was correlated with lower global cognitive function, slower processing speed, impaired immediate and delayed recall memory, and more depressive symptoms. In addition, a higher generalized atherosclerosis rating was correlated with impaired global cognitive function, lower attention, and a slower processing speed at baseline. During follow-up, a higher generalized atherosclerosis rating was associated with an accelerated decline of immediate recall memory and delayed recall memory. In contrast, there was no relation between the generalized atherosclerosis rating and depressive symptoms, either in the cross-sectional analysis or in the prospective analysis. CONCLUSION: In the population at large, generalized atherosclerosis contributes to cognitive decline in old age but not to depression.

Interaction of atherosclerosis and inflammation in elderly subjects with poor cognitive function.

OBJECTIVE: To test the hypothesis that a pro-inflammatory response is associated with cognitive impairment among individuals with cardiovascular disease. METHOD: All 85-year-old inhabitants of Leiden (n = 599) were visited at their place of residence. A history of cardiovascular disease and an EKG were used as indicators of atherosclerosis. Production of the pro-inflammatory cytokine tumor necrosis factor-alpha and the anti-inflammatory cytokine interleukin-10 was assessed in a whole-blood assay using lipopolysaccharide as a stimulus. Global cognitive functioning was determined with the Mini-Mental State Examination (MMSE); attention, cognitive speed, and memory were determined with four neuropsychological tests; and a history of dementia was obtained. RESULTS: In subjects with cardiovascular disease, median MMSE scores were lower in those with a pro-inflammatory response when compared with those with an anti-inflammatory response (p = 0.02). Similar associations were found for the Stroop Test, measuring attention (p < 0.01), the Coding Test measuring cognitive speed (p = 0.02), the Word Learning Test measuring memory (p < 0.01), and the presence of dementia (p = 0.04). The associations remained unaltered after adjustments for possible confounders such as gender, level of education, use of nonsteroidal anti-inflammatory drugs, use of cardiovascular drugs, and cardiovascular risk factors. In contrast, outcomes of the cognitive tests and presence of dementia were not dependent on the inflammatory response when cardiovascular disease was absent. CONCLUSION: The combination of cardiovascular disease and a pro-inflammatory cytokine response may be associated with cognitive impairment and dementia.

Inflammation and stroke: the Leiden 85-Plus Study .

BACKGROUND: Experimental evidence indicates that interleukin-10 (IL-10) deficiency is associated with the development of cardiovascular and cerebrovascular disease. We analyzed the relation between low IL-10 production levels, history of stroke, and incident fatal stroke. SUMMARY OF REPORT: All 85-year-old inhabitants of Leiden, Netherlands (n=599) were visited at their place of residence (response rate, 87%). Production levels of the anti-inflammatory cytokine IL-10 were assessed in a whole blood assay whereby lipopolysaccharide was used as a stimulus. Plasma concentrations of C-reactive protein (CRP) were also used as a marker of inflammation. A history of stroke was obtained at baseline (prevalence, 10%). The number of fatal strokes was prospectively obtained for a median follow-up of 2.6 years (incidence, 1.82 per 100 person-years at risk). Subjects with a history of stroke had significantly lower median IL-10 production levels at baseline than subjects without stroke (558 versus 764 pg/mL; P<0.05). They also had significantly higher median CRP concentrations (6 versus 3 mg/L; P<0.05). The odds ratio for a history of stroke increased to 2.30 (95% CI, 1.12 to 4.72) over strata representing decreasing production levels of IL-10. The relative risk for incident fatal stroke was 2.94 (95% CI, 1.01 to 8.53) when we compared subjects with low or intermediate baseline IL-10 production levels to those with high production levels of IL-10. CONCLUSIONS: Our data support the hypothesis that subjects with low IL-10 production levels have an increased risk of stroke.

C-reactive protein is a strong but nonspecific risk factor of fatal stroke in elderly persons.

An elevated level of C-reactive protein is a strong predictor of cardiovascular events in elderly persons. Whether C-reactive protein has direct adverse vascular effects or is a marker of aspecific systemic inflammation remains to be determined. The aim of this study was to investigate the relation between C-reactive protein and the occurrence of fatal strokes in elderly persons. In the Leiden 85-Plus Study, a population-based prospective follow-up study, we studied the levels of C-reactive protein in 80 participants who died from stroke within the first 5 years of follow-up. Levels of C-reactive protein were determined in serum samples at baseline. Levels of C-reactive protein were also determined in 82 control subjects who survived for the first 5 years of follow-up and in 83 participants who died from noncardiovascular causes. Mortality risks were estimated with logistic regression and adjusted for differences in age, sex, smoking, medication, total cholesterol, history of diabetes or hypertension, and previous cardiovascular events. Levels of C-reactive protein at baseline were 2-fold higher in subjects who died from stroke than in control subjects (median 5.7 versus 2.7 mg/L, P<0.005). The levels of C-reactive protein in subjects who died from stroke or from noncardiovascular causes were similar (median 5.7 versus 4.9 mg/L, P=0.7). The risk of death from stroke as well as from noncardiovascular causes increased linearly up to 10-fold in subjects with the highest levels of C-reactive protein at baseline (P<0.001). The levels of C-reactive protein were lower when more time had elapsed between blood sampling and time of death during follow-up (P=0.01). C-reactive protein is a strong but nonspecific risk factor of fatal stroke in old persons. The data do not support the idea that C-reactive protein has direct vascular effects that underlie fatal cerebrovascular disease.

Mortality risk in men is associated with a common mutation in the methylene-tetrahydrofolate reductase gene (MTHFR).

An elevated level of homocysteine in plasma is associated with the occurrence of cardiovascular disease. A common ala-to-val mutation in the methylenetetrahydrofolate reductase gene (MTHFR) is associated with an elevated level of plasma homocysteine. We studied the possible detrimental effects of the MTHFR mutation on mortality. Within a population-based study in the city of Leiden, the Netherlands, we first compared the MTHFR genotype distribution among 365 elderly subjects aged 85 years and over born in Leiden, and 250 young subjects aged 18 to 40 years whose families originated from the same geographical region. Second, the complete cohort of 666 subjects aged 85 years and over was followed over a period of 10 years for all-cause and cause-specific mortality and stratified according to MTHFR genotype. The frequency of the MTHFR mutation was significantly lower in the elderly than in the young (0.30 and 0.36, respectively; P = 0.03). The difference in genotype distribution was only present in men. The estimated mortality risk up to 85 years in men carrying the vallval genotype was 3.7 (95% confidence interval (CI), 1.3-10.9). Over the age of 85, mortality in men with the vallval genotype was increased 2.0-fold (95% CI, 1.1-3.9) and appeared to be attributable to cancer rather than cardiovascular causes of death. Among women aged 85 years and over, no deleterious effect of the MTHFR mutation was observed. In conclusion, the MTHFR mutation is associated with increased mortality in men in middle and old age, but not in women.