Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case-control study.

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50). Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Factors associated with weight loss and health gains in a structured lifestyle modification programme for adults with severe obesity: a prospective cohort study.

Background: Individual responses to behavioural weight loss interventions can vary significantly, and a better understanding of the factors associated with successful treatment might help to target interventions for those who will benefit the most. We sought to identify demographic and clinical characteristics that predicted intervention "success" (defined as ≥5% weight loss) and other health gains in patients with severe obesity attending a ten-week structured lifestyle modification programme. Methods: We conducted a prospective cohort study of all 1122 patients (751 (66.9%) female, mean age 47.3 ± 11.9 years, mean body mass index (BMI) 46.7 ± 7.8 kgm-2) referred from our hospital-based obesity clinic, who started the structured lifestyle programme between 2012-2019. We compared routine clinical measures such as weight, fitness, blood pressure, lipids and HbA1c at baseline and follow-up. We also used validated questionnaires to quantify anxiety, depression and health-related quality of life. Results: Of 1122 patients who started, 877 (78.2%) completed the programme and attended for follow up. Of these, 12.8% lost ≥5% body weight. The amount of weight lost was a strong and consistent predictor of improvements in metabolic, cardiovascular, and mental health, even after adjusting for age, sex, programme attendance and baseline fitness. Older age, male sex, being physically active and having lower anxiety and depression scores at baseline predicted greater weight loss. Younger age, depression and longer wait time to start the intervention were associated with drop-out. Conclusions: In adults with severe obesity completing a structured lifestyle modification programme, older age and good mental health were associated with programme completion and attaining ≥5% weight loss. The magnitude of weight lost was a strong predictor of improvements in cardiovascular, metabolic and mental health associated with programme completion.

Effects of a Polypill, Aspirin, and the Combination of Both on Cognitive and Functional Outcomes: A Randomized Clinical Trial.

Importance: Vascular risk factors are associated with cognitive decline but studies addressing individual risk factors have not demonstrated an effect of risk factor management on the preservation of cognition. Few trials have examined the effect of vascular risk factor management on function. Objective: To determine if a polypill could reduce cognitive and functional decline in people with risk factors but without manifest cardiovascular disease. Design, Setting, and Participants: The International Polycap Study 3 (TIPS-3) was a 2 × 2 × 2 factorial randomized clinical trial. Hospital and community-based centers in 8 countries recruited and followed up participants between July 30, 2012, and September 30, 2020. A total of 5713 individuals were randomly assigned to treatment groups, and 2098 people 65 years or older at intermediate risk of cardiovascular disease completed a cognitive assessment and were included in the analyses. Interventions: Polypill (antihypertensives and a statin), aspirin, or a combination of both treatments. Main Outcomes and Measures: Cognitive and functional assessments completed at baseline, 2 years, and study end. The primary outcome was the effect of a polypill compared with placebo and a polypill plus aspirin compared with double placebo on the composite outcome of the proportion of participants in each group who experienced a substantive decrease (>1.5 SD change) in cognitive or functional abilities. Results: Of the 2389 study participants older than 65 years, a total of 2098 (88%; mean [SD] age, 70.1 [4.5] years; 1266 female individuals [60%]) completed the baseline and follow-up assessment. A total of 1796 participants (86%) had hypertension, and 680 participants (32%) had impaired fasting plasma glucose levels. Mean (SD) baseline systolic blood pressure was 146.1 (17.7) mm Hg, and mean (SD) low-density lipoprotein cholesterol (LDL-C) level was 124.3 (40.7) mg/dL and decreased by 5.7 mm Hg and 24 mg/dL, respectively, among those assigned to the polypill group. During a 5-year follow-up, there were no significant differences between treatment groups in the number of participants who experienced substantive cognitive decline (356 assigned polypill, 328 assigned placebo) or dementia (2 assigned polypill, 4 assigned placebo). Functional decline was reduced during follow-up for those assigned to polypill compared with placebo (mean [SD] country-standardized adjusted follow-up Standard Assessment of Global Everyday Activities [SAGEA] scores, 0.06 [0.03] vs 0.15 [0.03]; P = .01) and polypill plus aspirin compared with double placebo (mean [SD] country-standardized adjusted follow-up SAGEA scores, 0.01 [0.04] vs 0.14 [0.04]; P = .01). Conclusions and Relevance: In this randomized clinical trial of patients 65 years or older with vascular risk factors, a polypill, with or without aspirin, was not associated with reduced cognitive outcomes but was associated with reduced functional decline.

Variations in risks from smoking between high-income, middle-income, and low-income countries: an analysis of data from 179 000 participants from 63 countries.

BACKGROUND: Separate studies suggest that the risks from smoking might vary between high-income (HICs), middle-income (MICs), and low-income (LICs) countries, but this has not yet been systematically examined within a single study using standardised approaches. We examined the variations in risks from smoking across different country income groups and some of their potential reasons. METHODS: We analysed data from 134 909 participants from 21 countries followed up for a median of 11·3 years in the Prospective Urban Rural Epidemiology (PURE) cohort study; 9711 participants with myocardial infarction and 11 362 controls from 52 countries in the INTERHEART case-control study; and 11 580 participants with stroke and 11 331 controls from 32 countries in the INTERSTROKE case-control study. In PURE, all-cause mortality, major cardiovascular disease, cancers, respiratory diseases, and their composite were the primary outcomes for this analysis. Biochemical verification of urinary total nicotine equivalent was done in a substudy of 1000 participants in PURE. FINDINGS: In PURE, the adjusted hazard ratio (HR) for the composite outcome in current smokers (vs never smokers) was higher in HICs (HR 1·87, 95% CI 1·65-2·12) than in MICs (1·41, 1·34-1·49) and LICs (1·35, 1·25-1·46; interaction p<0·0001). Similar patterns were observed for each component of the composite outcome in PURE, myocardial infarction in INTERHEART, and stroke in INTERSTROKE. The median levels of tar, nicotine, and carbon monoxide displayed on the cigarette packs from PURE HICs were higher than those on the packs from MICs. In PURE, the proportion of never smokers reporting high second-hand smoke exposure (≥1 times/day) was 6·3% in HICs, 23·2% in MICs, and 14·0% in LICs. The adjusted geometric mean total nicotine equivalent was higher among current smokers in HICs (47·2 µM) than in MICs (31·1 µM) and LICs (25·2 µM; ANCOVA p<0·0001). By contrast, it was higher among never smokers in LICs (18·8 µM) and MICs (11·3 µM) than in HICs (5·0 µM; ANCOVA p=0·0001). INTERPRETATION: The variations in risks from smoking between country income groups are probably related to the higher exposure of tobacco-derived toxicants among smokers in HICs and higher rates of high second-hand smoke exposure among never smokers in MICs and LICs. FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).

Household-level lifestyle interventions for the prevention of cognitive decline; A Systematic review.

BACKGROUND: Lifestyle interventions targeting households may be an effective means of promoting healthier cognitive function in later life, with extended benefit to other household members. In this systematic review and meta-analysis, we sought to assess the effect of targeting lifestyle behaviours of households on cognitive outcomes METHODS: An electronic search strategy was designed to identify randomised controlled trials (RCTs) where households were randomised to receive a lifestyle intervention for the prevention of cognitive decline, from database inception until April 2020. Our initial search identified no eligible studies, so we revised our search strategy to include trials enroling dyads. We reported the cognitive outcomes, functional outcomes, caregiver outcomes and long-term care (LTC) admissions for eligible studies. FINDINGS: We identified no RCTs which randomised households to receive a lifestyle intervention for preventing cognitive decline. We identified five RCTs (n = 1721, with mean follow-up of 9.6 months) which randomised dyads, which evaluated diet (two trials) and physical activity (three trials). CONCLUSION: Trials evaluating dietary and exercise interventions in dyads were identified. No trial demonstrated a significant association of interventions with change in cognitive testing, functional outcomes or long-term care admissions, although trials were small with short-term follow-up. Future studies should consider targeting lifestyle behaviours of households for prevention of dementia.

Virtual geriatric clinics and the COVID-19 catalyst: a rapid review.

BACKGROUND: During the current COVID-19 health crisis virtual geriatric clinics have become increasingly utilised to complete outpatient consultations, although concerns exist about feasibility of such virtual consultations for older people. The aim of this rapid review is to describe the satisfaction, clinic productivity, clinical benefit, and costs associated with the virtual geriatric clinic model of care. METHODS: A rapid review of PubMed, MEDLINE and CINAHL databases was conducted up to April 2020. Two independent reviewers extracted the information. Four subdomains were focused on: satisfaction with the virtual geriatric clinic, clinic productivity, clinical benefit to patients, costs and any challenges associated with the virtual clinic process. RESULTS: Nine studies with 975 patients met our inclusion criteria. All were observational studies. Seven studies reported patients were satisfied with the virtual geriatric clinic model of care. Productivity outcomes included reports of cost-effectiveness, savings on transport, and improved waiting list metrics. Clinical benefits included successful polypharmacy reviews, and reductions in acute hospitalisation rates. Varying challenges were reported for both clinicians and patients in eight of the nine studies. Hearing impairments and difficulty with technology added to anxieties experienced by patients. Physicians missed the added value of a thorough physical examination and had concerns about confidentiality. CONCLUSION: Virtual geriatric clinics demonstrate evidence of productivity, benefit to patients, cost effectiveness and patient satisfaction with the treatment provided. In the current suboptimal pandemic climate, virtual geriatric clinics may allow Geriatricians to continue to provide an outpatient service, despite the encountered inherent challenges.

Preparation and Use of a General Solid-Phase Intermediate to Biomimetic Scaffolds and Peptide Condensations.

The Distributed Drug Discovery (D3) program develops simple, powerful, and reproducible procedures to enable the distributed synthesis of large numbers of potential drugs for neglected diseases. The synthetic protocols are solid-phase based and inspired by published work. One promising article reported that many biomimetic molecules based on diverse scaffolds with three or more sites of variable substitution can be synthesized in one or two steps from a common key aldehyde intermediate. This intermediate was prepared by the ozonolysis of a precursor functionalized at two variable sites, restricting their presence in the subsequently formed scaffolds to ozone compatible functional groups. To broaden the scope of the groups available at one of these variable sites, we developed a synthetic route to an alternative, orthogonally protected key intermediate that allows the incorporation of ozone sensitive groups after the ozonolysis step. The utility of this orthogonally protected intermediate is demonstrated in the synthesis of several representative biomimetic scaffolds containing ozonolytically labile functional groups. It is compatible with traditional Fmoc peptide chemistry, permitting it to incorporate peptide fragments for use in fragment condensations with peptides containing cysteine at the N-terminus. Overall yields for its synthesis and utilization (as many as 13 steps) indicate good conversions at each step.

Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study.

BACKGROUND: Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke. METHODS: We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals. FINDINGS: Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases [10 388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72-3·28; PAR 47·9%, 99% CI 45·1-50·6), regular physical activity (0·60, 0·52-0·70; 35·8%, 27·7-44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65-2·06 for highest vs lowest tertile; 26·8%, 22·2-31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53-0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2-28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27-1·64 for highest vs lowest tertile; 18·6%, 13·3-25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78-2·72; 17·4%, 13·1-22·6), current smoking (1·67, 1·49-1·87; 12·4%, 10·2-14·9), cardiac causes (3·17, 2·68-3·75; 9·1%, 8·0-10·2), alcohol consumption (2·09, 1·64-2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4-9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05-1·30; 3·9%, 1·9-7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001). INTERPRETATION: Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network.

Methotrexate use and risk of lung disease in psoriasis, psoriatic arthritis, and inflammatory bowel disease: systematic literature review and meta-analysis of randomised controlled trials.

OBJECTIVE: To evaluate the relative risk of pulmonary disease among patients with psoriasis, psoriatic arthritis, and inflammatory bowel disease treated with methotrexate. DATA SOURCES: PubMed, Cochrane central register of controlled trials, and Embase to 9 January 2014. STUDY SELECTION: Double blind randomised controlled trials of methotrexate versus placebo or active comparator agents in adults with psoriatic arthritis, psoriasis, or inflammatory bowel disease. Studies with fewer than 50 participants or of less than 12 weeks' duration were excluded. DATA SYNTHESIS: Two investigators independently searched both databases. All authors reviewed selected studies. We compared relative risk differences using the Mantel-Haenszel random effects method to assess total respiratory adverse events, infectious respiratory adverse events, non-infectious respiratory adverse events, interstitial lung disease, and death. RESULTS: Seven studies met our inclusion criteria, six with placebo as the comparator. Heterogeneity across the studies was not significant (I(2)=0%), allowing combination of trial results. 504 respiratory adverse events were documented in 1630 participants. Methotrexate was not associated with an increased risk of adverse respiratory events (relative risk 1.03, 95% confidence interval 0.90 to 1.17), respiratory infections (1.02, 0.88 to 1.19), or non-infectious respiratory events (1.07, 0.58 to 1.96). No pulmonary deaths occurred. CONCLUSIONS: Findings suggested that there was no increased risk of lung disease in methotrexate treated patients with non-malignant inflammatory diseases. Given the limitations of the study, however, we cannot exclude a small but clinically important risk.

Unexpected hydrolytic instability of N-acylated amino acid amides and peptides.

Remote amide bonds in simple N-acyl amino acid amide or peptide derivatives 1 can be surprisingly unstable hydrolytically, affording, in solution, variable amounts of 3 under mild acidic conditions, such as trifluoroacetic acid/water mixtures at room temperature. This observation has important implications for the synthesis of this class of compounds, which includes N-terminal-acylated peptides. We describe the factors contributing to this instability and how to predict and control it. The instability is a function of the remote acyl group, R(2)CO, four bonds away from the site of hydrolysis. Electron-rich acyl R(2) groups accelerate this reaction. In the case of acyl groups derived from substituted aromatic carboxylic acids, the acceleration is predictable from the substituent's Hammett σ value. N-Acyl dipeptides are also hydrolyzed under typical cleavage conditions. This suggests that unwanted peptide truncation may occur during synthesis or prolonged standing in solution when dipeptides or longer peptides are acylated on the N-terminus with electron-rich aromatic groups. When amide hydrolysis is an undesired secondary reaction, as can be the case in the trifluoroacetic acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize that hydrolysis.

Vascular risk factors, cardiovascular disease and functional impairment in community-dwelling adults.

BACKGROUND: Older adults report preservation of functional independence as one of the most important constructs of successful ageing. Vascular risk factors may increase the risk of functional impairment due to clinical and subclinical vascular disease. OBJECTIVE: To describe the association between vascular risk factors and impaired ability to perform daily living activities, independent of established cardiovascular disease. METHODS: We conducted an analysis of the Clarity Cohort, which is a cross-sectional study of 9,816 community-dwelling Irish adults. Of the total cohort, 3,499 completed standardized self-reported health questionnaires, which included questions on activities of daily living. Functional impairment was defined as self-reported impairment in self-care, mobility or household tasks. Using logistic regression analyses, we determined the association between vascular risk factors and functional impairment, independent of demographics, prior coronary artery disease, stroke, congestive heart failure, and peripheral vascular disease. RESULTS: Functional impairment was reported in 40.4% (n = 1,413) of the cohort overall and in 23% of those with established cardiovascular disease. The mean age was 66.2 ± 10.3 years, 52% of the cohort were aged over 65 and 45.6% were male. Some difficulty with instrumental activities of daily living was reported by 35.4% (n = 1,240) while 29.4% (n = 1,029) reported some difficulty with basic activities of daily living. On multivariable analysis, older age [OR 1.03 (1.02, 1.04) per year], current smoking [OR 1.43 (1.08, 1.89)], atrial fibrillation [OR 1.68 (1.07, 2.65)], former alcohol use [OR 1.87 (1.36, 2.57)] and prior stroke [OR 1.91 (1.24, 2.93)] were associated with an increased risk of functional impairment. Older age leaving education [OR 0.96 (0.94, 0.99)], non-use of alcohol [OR 0.76 (0.61, 0.93)] and increased high-density lipoprotein levels [OR 0.70 (0.56, 0.88)] were associated with reduced risk of functional impairment. CONCLUSIONS: Independent of established cardiovascular disease, some vascular risk factors are associated with functional impairment. Modification of these risk factors is expected to have a large impact on preservation of functional independence through prevention of overt and covert vascular disease.

The PLAN score: a bedside prediction rule for death and severe disability following acute ischemic stroke.

BACKGROUND: We sought to develop and validate a simple clinical prediction rule for death and severe disability after acute ischemic stroke that can be used by general clinicians at the time of hospital admission. METHODS: We analyzed data from a registry of 9847 patients (4943 in the derivation cohort and 4904 in the validation cohort) hospitalized with acute ischemic stroke and included in the Registry of the Canadian Stroke Network (July 1, 2003, to March 31, 2008; 11 regional stroke centers in Ontario, Canada). Outcome measures were 30-day and 1-year mortality and a modified Rankin score of 5 to 6 at discharge. RESULTS: Overall 30-day mortality was 11.5% (derivation cohort) and 13.5% (validation cohort). In the final multivariate model, we included 9 clinical variables that could be categorized as preadmission comorbidities (5 points for preadmission dependence [1.5], cancer [1.5], congestive heart failure [1.0], and atrial fibrillation [1.0]), level of consciousness (5 points for reduced level of consciousness), age (10 points, 1 point/decade), and neurologic focal deficit (5 points for significant/total weakness of the leg [2], weakness of the arm [2], and aphasia or neglect [1]). Maximum score is 25. In the validation cohort, the PLAN score (derived from preadmission comorbidities, level of consciousness, age, and neurologic deficit) predicted 30-day mortality (C statistic, 0.87), death or severe dependence at discharge (0.88), and 1-year mortality (0.84). The PLAN score also predicted favorable outcome (modified Rankin score, 0-2) at discharge (C statistic, 0.80). CONCLUSIONS: The PLAN clinical prediction rule identifies patients who will have a poor outcome after hospitalization for acute ischemic stroke. The score comprises clinical data available at the time of admission and may be determined by nonspecialist clinicians. Additional studies to independently validate the PLAN rule in different populations and settings are required.

Solid-phase synthetic route to multiple derivatives of a fundamental peptide unit.

Amino acids are Nature's combinatorial building blocks. When substituted on both the amino and carboxyl sides they become the basic scaffold present in all peptides and proteins. We report a solid-phase synthetic route to large combinatorial variations of this fundamental scaffold, extending the variety of substituted biomimetic molecules available to successfully implement the Distributed Drug Discovery (D3) project. In a single solid-phase sequence, compatible with basic amine substituents, three-point variation is performed at the amino acid a-carbon and the amino and carboxyl functionalities.

Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study.

BACKGROUND: The contribution of various risk factors to the burden of stroke worldwide is unknown, particularly in countries of low and middle income. We aimed to establish the association of known and emerging risk factors with stroke and its primary subtypes, assess the contribution of these risk factors to the burden of stroke, and explore the differences between risk factors for stroke and myocardial infarction. METHODS: We undertook a standardised case-control study in 22 countries worldwide between March 1, 2007, and April 23, 2010. Cases were patients with acute first stroke (within 5 days of symptoms onset and 72 h of hospital admission). Controls had no history of stroke, and were matched with cases for age and sex. All participants completed a structured questionnaire and a physical examination, and most provided blood and urine samples. We calculated odds ratios (ORs) and population-attributable risks (PARs) for the association of all stroke, ischaemic stroke, and intracerebral haemorrhagic stroke with selected risk factors. FINDINGS: In the first 3000 cases (n=2337, 78%, with ischaemic stroke; n=663, 22%, with intracerebral haemorrhagic stroke) and 3000 controls, significant risk factors for all stroke were: history of hypertension (OR 2.64, 99% CI 2.26-3.08; PAR 34.6%, 99% CI 30.4-39.1); current smoking (2.09, 1.75-2.51; 18.9%, 15.3-23.1); waist-to-hip ratio (1.65, 1.36-1.99 for highest vs lowest tertile; 26.5%, 18.8-36.0); diet risk score (1.35, 1.11-1.64 for highest vs lowest tertile; 18.8%, 11.2-29.7); regular physical activity (0.69, 0.53-0.90; 28.5%, 14.5-48.5); diabetes mellitus (1.36, 1.10-1.68; 5.0%, 2.6-9.5); alcohol intake (1.51, 1.18-1.92 for more than 30 drinks per month or binge drinking; 3.8%, 0.9-14.4); psychosocial stress (1.30, 1.06-1.60; 4.6%, 2.1-9.6) and depression (1.35, 1.10-1.66; 5.2%, 2.7-9.8); cardiac causes (2.38, 1.77-3.20; 6.7%, 4.8-9.1); and ratio of apolipoproteins B to A1 (1.89, 1.49-2.40 for highest vs lowest tertile; 24.9%, 15.7-37.1). Collectively, these risk factors accounted for 88.1% (99% CI 82.3-92.2) of the PAR for all stroke. When an alternate definition of hypertension was used (history of hypertension or blood pressure >160/90 mm Hg), the combined PAR was 90.3% (85.3-93.7) for all stroke. These risk factors were all significant for ischaemic stroke, whereas hypertension, smoking, waist-to-hip ratio, diet, and alcohol intake were significant risk factors for intracerebral haemorrhagic stroke. INTERPRETATION: Our findings suggest that ten risk factors are associated with 90% of the risk of stroke. Targeted interventions that reduce blood pressure and smoking, and promote physical activity and a healthy diet, could substantially reduce the burden of stroke. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Pfizer Cardiovascular Award, Merck, AstraZeneca, and Boehringer Ingelheim.

Distributed Drug Discovery, Part 3: using D(3) methodology to synthesize analogs of an anti-melanoma compound.

For the successful implementation of Distributed Drug Discovery (D(3)) (outlined in the accompanying Perspective), students, in the course of their educational laboratories, must be able to reproducibly make new, high quality, molecules with potential for biological activity. This article reports the successful achievement of this goal. Using previously rehearsed alkylating agents, students in a second semester organic chemistry laboratory performed a solid-phase combinatorial chemistry experiment in which they made 38 new analogs of the most potent member of a class of antimelanoma compounds. All compounds were made in duplicate, purified by silica gel chromatography, and characterized by NMR and LC/MS. As a continuing part of the Distributed Drug Discovery program, a virtual D(3) catalog based on this work was then enumerated and is made freely available to the global scientific community.

Distributed Drug Discovery, Part 2: global rehearsal of alkylating agents for the synthesis of resin-bound unnatural amino acids and virtual D(3) catalog construction.

Distributed Drug Discovery (D(3)) proposes solving large drug discovery problems by breaking them into smaller units for processing at multiple sites. A key component of the synthetic and computational stages of D(3) is the global rehearsal of prospective reagents and their subsequent use in the creation of virtual catalogs of molecules accessible by simple, inexpensive combinatorial chemistry. The first section of this article documents the feasibility of the synthetic component of Distributed Drug Discovery. Twenty-four alkylating agents were rehearsed in the United States, Poland, Russia, and Spain, for their utility in the synthesis of resin-bound unnatural amino acids 1, key intermediates in many combinatorial chemistry procedures. This global reagent rehearsal, coupled to virtual library generation, increases the likelihood that any member of that virtual library can be made. It facilitates the realistic integration of worldwide virtual D(3) catalog computational analysis with synthesis. The second part of this article describes the creation of the first virtual D(3) catalog. It reports the enumeration of 24,416 acylated unnatural amino acids 5, assembled from lists of either rehearsed or well-precedented alkylating and acylating reagents, and describes how the resulting catalog can be freely accessed, searched, and downloaded by the scientific community.

Solid-phase synthesis of multiple classes of peptidomimetics from versatile resin-bound aldehyde intermediates.

A wide variety of highly substituted lactam containing peptidomimetic scaffolds are prepared by solid-phase synthesis from a single, versatile class of resin-bound aldehyde intermediates (1). These include monocyclics 3, bicyclics 4, tricyclics 5, and tetracyclics 6. The key intermediate 1 is readily synthesized from resin-bound natural or unnatural alpha-amino acids. The synthetic procedures permit the construction of a large diversity of substitution patterns for ready use in combinatorial chemistry. In every case, the release of final products from resin is by a cyclitive cleavage process. Since this depends on successful completion of multiple intermediate synthetic steps, the products are often quite pure, even though previous steps involve only a filtration workup. The mild conditions for many of these synthetic procedures offer the promise of using this chemistry in peptide fragment condensations to produce modified peptides, at either the N-terminus or C-terminus, or as individually assembled peptide segments with a wide variety of conformationally restricted peptidomimetic linkers at the point of juncture.

Brief communication: Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin.

BACKGROUND: Preoperative low-molecular-weight heparin (LMWH) is often used when warfarin therapy is interrupted for surgery. OBJECTIVE: To determine the preoperative anticoagulant activity of LMWH following a standardized "bridging" regimen. DESIGN: Prospective cohort study. SETTING: Single university hospital. PATIENTS: Consecutive patients who had warfarin therapy interrupted before an invasive procedure. INTERVENTION: Enoxaparin, 1 mg/kg of body weight, twice daily. The last dose was administered the evening before surgery. MEASUREMENTS: Blood anti-factor Xa heparin levels measured shortly before surgery. RESULTS: Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels. LIMITATIONS: The small sample size limits accurate estimates of the frequency of the clinical outcomes. A single regimen of LMWH was evaluated. CONCLUSIONS: Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.