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1.
J Am Heart Assoc ; 11(20): e023061, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36250666

RESUMO

Background A run-in period may increase adherence to intervention and reduce loss to follow-up. Whether use of a run-in period affects the magnitude of treatment effects is unknown. Methods and Results We conducted a meta-analysis comparing treatment effects from 11 systematic reviews of cardiovascular prevention trials using a run-in period with matched trials not using a run-in period. We matched run-in with non-run-in trials by population, intervention, control, and outcome. We calculated a ratio of relative risks (RRRs) using a random-effects meta-analysis. Our primary outcome was a composite of cardiovascular events, and the primary analysis was a matched comparison of clinical trials using a run-in period versus without a run-in period. We identified 66 run-in trials and 111 non-run-in trials (n=668 901). On meta-analysis there was no statistically significant difference in the magnitude of treatment effect between run-in trials (relative risk [RR], 0.83 [95% CI, 0.80-0.87]) compared with non-run-in trials (RR, 0.88 [95% CI, 0.84-0.91]; RRR, 0.95 [95% CI, 0.90-1.01]). There was no significant difference in the RRR for secondary outcomes of all-cause mortality (RRR, 0.97 [95% CI, 0.91-1.03]) or medication discontinuation because of adverse events (RRR, 1.05 [95% CI, 0.85-1.21]). Post hoc exploratory univariate meta-regression showed that on average a run-in period is associated with a statistically significant difference in treatment effect (RRR, 0.94 [95% CI, 0.90-0.99]) for cardiovascular composite outcome, but this was not statistically significant on multivariable meta-regression analysis (RRR, 0.95 [95% CI, 0.90-1.0]). Conclusions The use of a run-in period was not associated with a difference in the magnitude of treatment effect among cardiovascular prevention trials.


Assuntos
Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
Neurology ; 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36220600

RESUMO

BACKGROUND AND OBJECTIVES: There is uncertainty about the association between alcohol consumption and stroke, particularly for low-moderate intake. We explored these associations in a large international study. METHODS: INTERSTROKE, a case-control study, is the largest international study of risk factors for acute stroke. Alcohol consumption was self-reported and categorised by drinks/week as low (1-7), moderate (7-14 for females, 7-21 for males) or high (>14 for females, >21 for males). Heavy episodic drinking (HED) was defined as >5 drinks on ≥1 day per month. Multivariable conditional logistic regression was used to determine associations. RESULTS: We included 12,913 cases and 12,935 controls; 25.0% (n=6,449) were current drinkers, 16.7% (n=4,318) former and 58.3% (n=15,076) never drinkers. Current drinkers were younger, male, smokers, active and with higher-paid occupations. Current drinking was associated with all stroke (OR 1.14; 95% CI 1.04-1.26) and intracerebral hemorrhage (ICH) (OR 1.50, 95% CI 1.21-1.84) but not ischaemic stroke (OR 1.06; 95% CI 0.95-1.19). HED pattern was associated with all stroke (OR 1.39; 95% CI 1.21-1.59), ischaemic stroke (OR 1.29; 95% CI 1.10-1.51) and ICH (OR 1.76; 95% CI 1.31-2.36). High level of alcohol intake was consistently associated with all stroke, ischaemic stroke and ICH. Moderate intake was associated with all stroke and ICH, but not ischaemic stroke. Low alcohol intake was not associated with stroke overall but there were regional differences; low intake was associated with reduced odds of stroke in Western Europe/North America (OR 0.66; 95%CI 0.45-0.96) and increased odds in India (OR 2.18; 95%CI 1.42-3.36)(p-interaction 0.037). Wine consumption was associated with reduced odds of all stroke and ischaemic stroke but not ICH. The magnitudes of association were greatest in those without hypertension and current smokers. DISCUSSION: High and moderate intake were associated with increased odds of stroke, while low intake was not associated with stroke. However, there were important regional variations, which may relate to differences in population characteristics of alcohol consumers, types or patterns of consumption.

3.
J Evid Based Med ; 15(3): 263-271, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36123777

RESUMO

AIM: Whether or not use of intravenous alteplase in combination with endovascular thrombectomy (EVT) improves outcomes versus EVT alone, for acute stroke patients with large vessel occlusion presenting directly to a comprehensive stroke center, is uncertain. METHODS: Six randomized trials exploring this issue were published, and we synthesized this evidence to inform a rapid guideline based on the Guidelines International Network principles and guided by the GRADE approach. RESULTS: We enlisted an international panel that included 4 patient partners and 1 caregiver, individuals from 6 countries. The panel considered low certainty evidence that EVT alone, relative to EVT with intravenous alteplase, possibly results in a small decrease in the proportion of patients that achieve functional independence and possibly a small increase in mortality. Both effect estimates were downgraded twice due to very serious imprecision. The panel also considered moderate certainty evidence that EVT alone probably decreases symptomatic intracranial hemorrhage, versus EVT with alteplase, and combination therapy was more costly than EVT alone. As a result of the low certainty for improved recovery without impairment and mortality for combination therapy versus EVT alone, and moderate certainty for increased harm with combination therapy, the panel made a weak recommendation in favor of EVT alone for stroke patients eligible for both treatments, and initially presenting directly to a comprehensive stroke center that provides both treatments. CONCLUSIONS: Consistent with this weak recommendation, optimal patient management will likely often include co-treatment with intravenous alteplase, depending on local circumstances and patient presentation.


Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/terapia , Procedimentos Endovasculares/métodos , Fibrinolíticos/uso terapêutico , Humanos , Acidente Vascular Cerebral/terapia , Trombectomia/métodos , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento
5.
Neuroepidemiology ; 56(5): 355-364, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35817005

RESUMO

INTRODUCTION: Measuring patient-reported information in stroke research is challenging. To overcome this, use of proxy respondents is often a necessary strategy. In this study, we report on use and effect of proxy respondents on patient case-mix in a large international epidemiologic stroke study (INTERSTROKE). METHODS: This was a cross-sectional study of 13,458 cases of acute first stroke in 32 countries. A standardized study questionnaire recording behavioural cardiovascular risk factors was administered to the patient, and if unable to communicate adequately, a valid proxy, or both. We used logistic regression to evaluate the association of age, sex, education, occupation, stroke severity, and region with need for proxy respondent, and report odds ratio (OR) with 95% confidence interval (CI). RESULTS: Among 13,458 participants with acute stroke, questionnaires were completed by patients alone in 41.4% (n = 5,573), combination of patient and proxy together in 21.7% (n = 2,918), and proxy alone in 36.9% (n = 4,967). Use of proxy alone was greater in participants with severe stroke (4.7% with modified-Rankin score of 0 vs. 80.5% in those with score 5; OR 187.13; 95% CI: 119.61-308.22), older persons (43.8% of those aged 80 years and over vs. 33.2% of those aged less than 40 years; age per decade OR 1.09; 95% CI: 1.06-1.12), women (40.7% vs. 34.3% of men; OR 1.32 95% CI: 1.22-1.43), and those less educated (58.9% of those never educated vs. 25.7% of those who attended third level education; OR 7.84; 95% CI: 6.78-9.08). CONCLUSION: Use of proxy respondents enhances the generalizability of international research studies of stroke, by increasing representation of women, patients with severe stroke, older age, and lower education.


Assuntos
Acidente Vascular Cerebral , Masculino , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Procurador , Inquéritos e Questionários , Modelos Logísticos
6.
Eur J Neurol ; 29(9): 2864-2868, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35652757

RESUMO

BACKGROUND AND PURPOSE: The purpose was to determine whether prior use of antiplatelet therapy modifies the effect of dual antiplatelet therapy in patients with acute minor ischaemic stroke or transient ischaemic attack. METHODS: A systematic review and meta-analysis of randomized controlled trials was performed comparing dual antiplatelet therapy to aspirin that reported subgroup analysis by prior antiplatelet use, adhering to the Cochrane Collaboration Guidelines. A fixed-effects meta-analysis was used to estimate a pooled treatment effect overall in subgroups with prior aspirin therapy and without prior aspirin therapy. Difference in treatment effect was assessed by testing p for interaction. The primary outcome measure was recurrent vascular events. RESULTS: Three eligible randomized controlled trials were identified, including 4831 participants with pre-existing antiplatelet use and 16,236 participants without pre-existing aspirin use. Recurrent vascular events occurred in 7.2% (95% confidence interval [CI] 4.3-10) of those without pre-existing aspirin use versus 7.3% (95% CI 4.1-10) of those receiving prior aspirin therapy. Effect of dual antiplatelet therapy on the primary outcome measure was consistent in participants with no prior aspirin use (odds ratio 0.75, 95% CI 0.66-0.84) compared to those taking aspirin before randomization (odds ratio 0.79, 95% CI 0.63-0.998) (p interaction = 0.66). The number needed to treat in the aspirin-naïve group was 55 (95% CI 37-107) compared to 66 (95% CI 32 to -746) in those on prior aspirin therapy. CONCLUSIONS: It was found that the effectiveness of dual antiplatelet therapy in patients with minor ischaemic stroke or high risk transient ischaemic attack does not significantly differ in patients with prior aspirin exposure; therefore there should be no influence on the decision to use dual antiplatelet therapy.


Assuntos
Isquemia Encefálica , Ataque Isquêmico Transitório , AVC Isquêmico , Acidente Vascular Cerebral , Aspirina/uso terapêutico , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Quimioterapia Combinada , Humanos , Ataque Isquêmico Transitório/tratamento farmacológico , Inibidores da Agregação Plaquetária , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/tratamento farmacológico
7.
J Stroke ; 24(2): 224-235, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35677977

RESUMO

BACKGROUND AND PURPOSE: The association of dyslipidemia with stroke has been inconsistent, which may be due to differing associations within etiological stroke subtypes. We sought to determine the association of lipoproteins and apolipoproteins within stroke subtypes. METHODS: Standardized incident case-control STROKE study in 32 countries. Cases were patients with acute hospitalized first stroke, and matched by age, sex and site to controls. Concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Non-HDL-C was calculated. We estimated multivariable odds ratio (OR) and population attributable risk percentage (PAR%). Outcome measures were all stroke, ischemic stroke (and subtypes), and intracerebral hemorrhage (ICH). RESULTS: Our analysis included 11,898 matched case-control pairs; 77.3% with ischemic stroke and 22.7% with ICH. Increasing apoB (OR, 1.10; 95% confidence interval [CI], 1.06 to 1.14 per standard deviation [SD]) and LDL-C (OR, 1.06; 95% CI, 1.02 to 1.10 per SD) were associated with an increase in risk of ischemic stroke, but a reduced risk of ICH. Increased apoB was significantly associated with large vessel stroke (PAR 13.4%; 95% CI, 5.6 to 28.4) and stroke of undetermined cause. Higher HDL-C (OR, 0.75; 95% CI, 0.72 to 0.78 per SD) and apoA1 (OR, 0.63; 95% CI, 0.61 to 0.66 per SD) were associated with ischemic stroke (and subtypes). While increasing HDL-C was associated with an increased risk of ICH (OR, 1.20; 95% CI, 1.14 to 1.27 per SD), apoA1 was associated with a reduced risk (OR, 0.80; 95% CI, 0.75 to 0.85 per SD). ApoB/A1 (OR, 1.38; 95% CI, 1.32 to 1.44 per SD) had a stronger magnitude of association than the ratio of LDL-C/HDL-C (OR, 1.26; 95% CI, 1.21 to 1.31 per SD) with ischemic stroke (P<0.0001). CONCLUSIONS: The pattern and magnitude of association of lipoproteins and apolipoproteins with stroke varies by etiological stroke subtype. While the directions of association for LDL, HDL, and apoB were opposing for ischemic stroke and ICH, apoA1 was associated with a reduction in both ischemic stroke and ICH. The ratio of apoB/A1 was the best lipid predictor of ischemic stroke risk.

8.
Harm Reduct J ; 19(1): 56, 2022 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-35643528

RESUMO

BACKGROUND: Global commitment to achieving hepatitis C virus (HCV) elimination has enhanced efforts in improving access to direct-acting antiviral (DAA) treatments for people who inject drugs (PWID). Scale-up of efforts to engage hard-to-reach groups of PWID in HCV testing and treatment is crucial to success. Automatic needle/syringe dispensing machines (ADMs) have been used internationally to distribute sterile injecting equipment. ADMs are a unique harm reduction service, affording maximum anonymity to service users. This paper explores the feasibility and acceptability of extending the HCV cascade of care to sites where ADMs are located. METHODS: The ADM users into Treatment (ADMiT) study was undertaken in a metropolitan region in Sydney, Australia. This mixed methods study involved analysis of closed-circuit television footage, ethnographic methods (fieldwork observation and in-depth interviews) and structured surveys. Researchers and peers conducted fieldwork and data collection over 10 weeks at one ADM site, including offering access to HCV testing and treatment. RESULTS: Findings from 10 weeks of fieldwork observations, 70 survey participants and 15 interviews highlighted that there is scope for engaging with this population at the time they use the ADM, and enhanced linkage to HCV testing and treatment may be warranted. Most survey participants reported prior HCV testing, 61% in the last 12 months and 38% had received HCV treatment. However, fieldwork revealed that most people observed using the ADM were not willing to engage with the researchers. Field work data and interviews suggested that extending the HCV cascade of care to ADMs may encroach on what is a private space for many PWID, utilized specifically to avoid engagement. DISCUSSION: Enhanced linkage to HCV testing and treatment for people who use ADMs may be warranted. However, data suggested that extending the HCV cascade of care to ADMs may encroach on what is a private space for many PWID, utilized specifically to avoid engagement. The current study raises important public health questions about the need to ensure interventions reflect the needs of affected communities, including their right to remain anonymous.


Assuntos
Hepatite C Crônica , Hepatite C , Abuso de Substâncias por Via Intravenosa , Antivirais/uso terapêutico , Hepacivirus , Hepatite C/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Humanos , Abuso de Substâncias por Via Intravenosa/epidemiologia , Seringas
9.
Artigo em Inglês | MEDLINE | ID: mdl-35679052

RESUMO

OBJECTIVE: Automatic syringe dispensing machines (ADM) have become an important adjunct to Australia's needle and syringe programs (NSP). However, concerns that they reduce face-to-face contact with health staff and other health interventions remain. We examined changes in the number of needle/syringes dispensed at an ADM and occasions of service at a co-located face-to-face NSP and targeted primary healthcare clinic during the first wave of COVID-19 restrictions. METHODS: We reviewed data from an inner-city harm reduction program during the study period of April 2020 to March 2021 compared to the previous year. Multivariable linear regression models were used to estimate the association between occasions of service and equipment distribution. RESULTS: ADM-dispensed equipment increased significantly by 41.1%, while face-to-face NSP occasions decreased by 16.2%. Occasions provided by the targeted primary healthcare clinic increased by 59.7% per month. CONCLUSION: We have shown that 24-hour ADM access did not adversely affect the number of people using targeted primary healthcare when provided within close proximity. Implication for public health: These findings reinforce the demand for 24-hour needle/syringe access and can be used to support the expanded access to ADMs, especially where people who inject drugs (PWID) have access to appropriate healthcare.

10.
Artigo em Inglês | MEDLINE | ID: mdl-35383832

RESUMO

AIMS: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long term open label extension (LTOLE). METHODS AND RESULTS: Of 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1 191 days). During LTOLE, the incident events per 100 patient years were: for the primary outcome (cardiovascular [CV] death, stroke, or myocardial infarction [MI]) 2.35 (95% CI 2.11-2.61), mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76) and MI 1.02 (0.86-1.19), with confidence intervals that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major bleeding were 1.01 (0.86-1.19) and for minor bleeding 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination. CONCLUSION: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals.

11.
BMC Geriatr ; 22(1): 322, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35418013

RESUMO

INTRODUCTION: While lifestyle risk factors are implicated in the development and progression of cognitive impairment, interventional trials of individual participants have yielded unconvincing evidence. We sought to explore the development of lifestyle interventions targeting the household-unit. METHODS: Semi-structured interviews were carried out among eight households affected by cognitive impairment (i.e. member of the household had cognitive impairment). Interviews took place online using a secure, web-based video platform recommended for patient clinician interaction. Interview content was analysed, and important themes identified. RESULTS: Eighteen participants were interviewed within households, of which eight (one per household) had cognitive impairment and others were spouses or first-degree relatives living in the same home. Several themes emerged; 1) household members without cognitive impairment were more likely to report poor sleep habits, and sleep was perceived to be the hardest behaviour to change; 2) diet generated most interest as a potential lifestyle intervention target as most participants believed there is a strong link with nutrition and cognition; 3) physical activity is challenging to adapt due to lack of motivation and focus when individuals are cognitively impaired. Barriers to study participation, including risk of harm, complexity of intervention and deviation from routine emerged during discussions. CONCLUSIONS: This study identified beliefs and preferences of households towards lifestyle intervention trials. Findings from this study may be used to inform future clinical trial protocols and future qualitative studies should explore acceptability and feasibility of digital intervention applications.


Assuntos
Ensaios Clínicos como Assunto , Disfunção Cognitiva , Demência , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/prevenção & controle , Demência/epidemiologia , Demência/prevenção & controle , Exercício Físico , Humanos , Estilo de Vida , Projetos Piloto
12.
J Stroke Cerebrovasc Dis ; 31(5): 106404, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35292423

RESUMO

BACKGROUND: The effect of interventions on functional impairment is an important outcome in stroke prevention trials and should be considered as an adjunct to counting discrete events. In the NAVIGATE-ESUS trial, 7213 patients with recent embolic strokes of undetermined source were randomized to rivaroxaban (15 mg once daily) or aspirin (100 mg daily). After 11 months there was no effect on the prevention of recurrent stroke. AIMS: To determine the effect of rivaroxaban compared to aspirin on functional and cognitive outcomes. METHODS: Function and cognition were measured at baseline, 1 year, and study end using the Standard Assessment of Global Everyday Activities (SAGEA), a 15-item scale assessing cognitive, instrumental, and basic activities of daily living as well as mobility, and the Montreal Cognitive Assessment (MoCA). Changes in scores were calculated by subtracting either study end or 1-year scores from baseline, and differences in distributions were compared using the Mann-Whitney U test. SAGEA and MoCA scores were also correlated with recurrent stroke. RESULTS: Follow-up SAGEA scores were available in 6378 (88%) participants. There was no difference in change in function for those allocated to rivaroxaban compared to aspirin (Mann-Whitney U test, p = 0.8), with both distributions having a median (25p,75p) change of 0 (-2,1). Overall, more of those who experienced a recurrent stroke (n=247; mostly minor ischemic), reported functional difficulty at study end versus entry, compared with those who did not (51% versus 30%, chi-square test, p< 0.001), and this was consistent across global regions. There was no difference in the change in cognition by treatment group, nor were recurrent strokes associated with a change in cognition. CONCLUSIONS: Rivaroxaban, compared to aspirin, was not associated with changes in functional or cognitive status in patients with recent ESUS. The SAGEA scale detected changes in functional status associated with recurrent strokes in an international stroke population.


Assuntos
AVC Embólico , Embolia Intracraniana , Acidente Vascular Cerebral , Atividades Cotidianas , Aspirina/efeitos adversos , Cognição , Método Duplo-Cego , Inibidores do Fator Xa/efeitos adversos , Humanos , Embolia Intracraniana/diagnóstico , Embolia Intracraniana/tratamento farmacológico , Embolia Intracraniana/etiologia , Inibidores da Agregação Plaquetária , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia
13.
J Stroke Cerebrovasc Dis ; 31(4): 106329, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35124321

RESUMO

BACKGROUND AND OBJECTIVES: Function is an important outcome after stroke; traditional assessments may not capture functional deficits important to patients. We examined the validity of the Standard Assessment of Global Everyday Activities (SAGEA), a patient-reported outcome that assesses activities important to patients and for use in international clinical trials. METHODS: The NAVIGATE-ESUS trial evaluated rivaroxaban compared to aspirin in preventing recurrent stroke in 7213 participants. The Modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), and the SAGEA were collected at entry. Chi square tests were used to compare proportions and Spearman rank correlations were used to compare between measures. SAGEA was compared to the Modified Frailty Index (MFI) and the occurrence of infarct to examine criterion validity RESULTS: Participants were 67 years, 2/3 were male, and at baseline 30% had no disability and 58% had slight disability according to mRS scores. SAGEA was weakly correlated with the mRS (r=0.37), the NIHSS (r=0.29) and the MFI (r=0.30). Of the 2154 with an mRS score of 0, 61% reported difficulty on the SAGEA. The largest discrepancies between SAGEA and other measures were because of cognitive functional deficits detected by the SAGEA that were not identified on other assessments. A larger number of MRI identified infarcts (acute and covert) were associated with a higher SAGEA score (p=0.007). CONCLUSIONS: The SAGEA is a simple, globally applicable measure of cognitive and functional abilities that identifies issues that other commonly used assessments of disability and function do not capture.


Assuntos
Acidente Vascular Cerebral , Atividades Cotidianas , Idoso , Aspirina/uso terapêutico , Feminino , Humanos , Masculino , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/terapia
14.
Front Neurol ; 13: 821135, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35185772

RESUMO

Cognitive impairment, and dementia, are major contributors to global burden of death and disability, with projected increases in prevalence in all regions of the world, but most marked increases in low and middle-income countries. Hypertension is a risk factor for both Vascular Cognitive Impairment and Alzheimer's disease, the two most common causes of dementia, collectively accounting for 85% of cases. Key end-organ pathological mechanisms, for which hypertension is proposed to be causative, include acute and covert cerebral ischemia and hemorrhage, accelerated brain atrophy, cerebral microvascular rarefaction and endothelial dysfunction, disruption of blood-brain barrier and neuroinflammation that affects amyloid pathologies. In addition to the direct-effect of hypertension on brain structure and microvasculature, hypertension is a risk factor for other diseases associated with an increased risk of dementia, most notably chronic kidney disease and heart failure. Population-level targets to reduce the incidence of dementia are a public health priority. Meta-analyses of blood pressure lowering trials report a significant reduction in the risk of dementia, but the relative (7-11%) and absolute risk reductions (0.4% over 4 years) are modest. However, given the high lifetime prevalence of both conditions, such relative risk reduction would translate into important population-level reductions in dementia globally with effective screening and control of hypertension. Optimal blood pressure target, especially in older adults with orthostatic hypotension, and antihypertensive agent(s) are uncertain. In this review article, we will detail the observational and interventional evidence linking hypertension with cognitive impairment, summarizing the mechanisms through which hypertension causes cognitive decline.

15.
Lancet Glob Health ; 10(2): e216-e226, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35063112

RESUMO

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).


Assuntos
Países Desenvolvidos/estatística & dados numéricos , Países em Desenvolvimento/estatística & dados numéricos , Infarto do Miocárdio/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Fumar Tabaco/epidemiologia , Adulto , Idoso , Monóxido de Carbono/análise , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Neoplasias/epidemiologia , Nicotina/análise , Estudos Prospectivos , Doenças Respiratórias/epidemiologia , Acidente Vascular Cerebral/mortalidade , Fumar Tabaco/efeitos adversos
16.
Elife ; 112022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35023831

RESUMO

Background: Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial (MT) function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation. Methods: We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called 'automatic mitochondrial copy (AutoMitoC).' We applied AutoMitoC to 395,781 UKBiobank study participants and performed genome- and exome-wide association studies, identifying novel common and rare genetic determinants. Finally, we performed two-sample Mendelian randomization to assess whether genetically low mtDNA-CN influenced select MT phenotypes. Results: Overall, genetic analyses identified 71 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, deoxynucleoside triphosphate (dNTP) metabolism, and the MT central dogma. Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta = 0.23 SDs; 95% CI, 0.18-0.29; p=2.6 × 10-19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR = 1.91; 95% CI, 1.52-2.40; p=2.7 × 10-8). Finally, Mendelian randomization analyses suggest a causal effect of low mtDNA-CN on dementia risk (OR = 1.94 per 1 SD decrease in mtDNA-CN; 95% CI, 1.55-2.32; p=7.5 × 10-4). Conclusions: Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific MT processes related to mtDNA regulation, and that these processes are causally related to human diseases. Funding: No funds supported this specific investigation. Awards and positions supporting authors include: Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award (MC, PM); CIHR Post-Doctoral Fellowship Award (RM); Wellcome Trust Grant number: 099313/B/12/A; Crasnow Travel Scholarship; Bongani Mayosi UCT-PHRI Scholarship 2019/2020 (TM); Wellcome Trust Health Research Board Irish Clinical Academic Training (ICAT) Programme Grant Number: 203930/B/16/Z (CJ); European Research Council COSIP Grant Number: 640580 (MO); E.J. Moran Campbell Internal Career Research Award (MP); CISCO Professorship in Integrated Health Systems and Canada Research Chair in Genetic and Molecular Epidemiology (GP).


Our cells are powered by small internal compartments known as mitochondria, which host several copies of their own 'mitochondrial' genome. Defects in these semi-autonomous structures are associated with a range of severe, and sometimes fatal conditions: easily checking the health of mitochondria through cheap, quick and non-invasive methods can therefore help to improve human health. Measuring the concentration of mitochondrial DNA molecules in our blood cells can help to estimate the number of mitochondrial genome copies per cell, which in turn act as a proxy for the health of the compartment. In fact, having lower or higher concentration of mitochondrial DNA molecules is associated with diseases such as cancer, stroke, or cardiac conditions. However, current approaches to assess this biomarker are time and resource-intensive; they also do not work well across people with different ancestries, who have slightly different versions of mitochondrial genomes. In response, Chong et al. developed a new method for estimating mitochondrial DNA concentration in blood samples. Called AutoMitoC, the automated pipeline is fast, easy to use, and can be used across ethnicities. Applying this method to nearly 400,000 individuals highlighted 71 genetic regions for which slight sequence differences were associated with changes in mitochondrial DNA concentration. Further investigation revealed that these regions contained genes that help to build, maintain, and organize mitochondrial DNA. In addition, the analyses yield preliminary evidence showing that lower concentration of mitochondrial DNA may be linked to a higher risk of dementia. Overall, the work by Chong et al. demonstrates that AutoMitoC can be used to investigate how mitochondria are linked to health and disease in populations across the world, potentially paving the way for new therapeutic approaches.


Assuntos
DNA Mitocondrial/sangue , Demência/genética , Estudo de Associação Genômica Ampla/métodos , Mitocôndrias/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Idoso , Biomarcadores , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Feminino , Dosagem de Genes , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Reino Unido
17.
Neurology ; 98(5): e470-e482, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34880091

RESUMO

BACKGROUND AND OBJECTIVES: Low buffy coat mitochondrial DNA copy number (mtDNA-CN) is associated with incident risk of stroke and poststroke mortality; however, its prognostic utility has not been extensively explored. Our goal was to investigate whether low buffy coat mtDNA-CN is a marker and causal determinant of poststroke outcomes using epidemiologic and genetic studies. METHODS: First, we performed association testing between baseline buffy coat mtDNA-CN measurements and 1-month poststroke outcomes in 3,498 cases of acute, first stroke from 25 countries from the international, multicenter case-control study Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World (INTERSTROKE). Then, we performed 2-sample mendelian randomization analyses to evaluate potential causative effects of low mtDNA-CN on 3-month modified Rankin Scale (mRS) score. Genetic variants associated with mtDNA-CN levels were derived from the UK Biobank study (N = 383,476), and corresponding effects on 3-month mRS score were ascertained from the Genetics of Ischemic Stroke Functional Outcome (GISCOME; N = 6,021) study. RESULTS: A 1-SD lower mtDNA-CN at baseline was associated with stroke severity (baseline mRS score: odds ratio [OR] 1.27, 95% confidence interval [CI] 1.19-1.36; p = 4.7 × 10-12). Independently of baseline stroke severity, lower mtDNA-CN was associated with increased odds of greater 1-month disability (ordinal mRS score: OR 1.16, 95% CI 1.08-1.24; p = 4.4 × 10-5), poor functional outcome status (mRS score 3-6 vs 0-2: OR 1.21, 95% CI 1.08-1.34; p = 6.9 × 10-4), and mortality (OR 1.35, 95% CI 1.14-1.59; p = 3.9 × 10-4). Subgroup analyses demonstrated consistent effects across stroke type, sex, age, country income level, and education level. In addition, mtDNA-CN significantly improved reclassification of poor functional outcome status (net reclassification index [NRI] score 0.16, 95% CI 0.08-0.23; p = 3.6 × 10-5) and mortality (NRI score 0.31, 95% CI 0.19-0.43; p = 1.7 × 10-7) beyond known prognosticators. With the use of independent datasets, mendelian randomization revealed that a 1-SD decrease in genetically determined mtDNA-CN was associated with increased odds of greater 3-month disability quantified by ordinal mRS score (OR 2.35, 95% CI 1.13-4.90; p = 0.02) and poor functional outcome status (OR 2.68, 95% CI 1.05-6.86; p = 0.04). DISCUSSION: Buffy coat mtDNA-CN is a novel and robust marker of poststroke prognosis that may also be a causal determinant of poststroke outcomes. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that low buffy coat mtDNA-CN (>1 SD) was associated with worse baseline severity and 1-month outcomes in patients with ischemic or hemorrhagic stroke.


Assuntos
DNA Mitocondrial , Acidente Vascular Cerebral , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Humanos , Análise da Randomização Mendeliana , Prognóstico , Fatores de Risco , Acidente Vascular Cerebral/genética
18.
Int J Stroke ; 17(7): 799-805, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34791941

RESUMO

BACKGROUND: Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown. AIMS: To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies. METHODS: At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression. RESULTS: Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52-1.7). CONCLUSIONS: Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide.Registration: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.


Assuntos
AVC Embólico , Embolia Intracraniana , Acidente Vascular Cerebral , Idoso , Aspirina/uso terapêutico , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/etiologia , Hemorragia Cerebral/tratamento farmacológico , Método Duplo-Cego , Inibidores do Fator Xa/uso terapêutico , Feminino , Humanos , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/tratamento farmacológico , Embolia Intracraniana/epidemiologia , Imageamento por Ressonância Magnética , Masculino , Estudos Prospectivos , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle
19.
Eur Heart J ; 43(3): 202-209, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-34850877

RESUMO

AIMS: In INTERSTROKE, we explored the association of anger or emotional upset and heavy physical exertion with acute stroke, to determine the importance of triggers in a large, international population. METHODS AND RESULTS: INTERSTROKE was a case-control study of first stroke in 32 countries. Using 13 462 cases of acute stroke we adopted a case-crossover approach to determine whether a trigger within 1 hour of symptom onset (case period), vs. the same time on the previous day (control period), was associated with acute stroke. A total of 9.2% (n = 1233) were angry or emotional upset and 5.3% (n = 708) engaged in heavy physical exertion during the case period. Anger or emotional upset in the case period was associated with increased odds of all stroke [odds ratio (OR) 1.37, 99% confidence interval (CI), 1.15-1.64], ischaemic stroke (OR 1.22, 99% CI, 1.00-1.49), and intracerebral haemorrhage (ICH) (OR 2.05, 99% CI 1.40-2.99). Heavy physical exertion in the case period was associated with increased odds of ICH (OR 1.62, 99% CI 1.03-2.55) but not with all stroke or ischaemic stroke. There was no modifying effect by region, prior cardiovascular disease, risk factors, cardiovascular medications, time, or day of symptom onset. Compared with exposure to neither trigger during the control period, the odds of stroke associated with exposure to both triggers were not additive. CONCLUSION: Acute anger or emotional upset was associated with the onset of all stroke, ischaemic stroke, and ICH, while acute heavy physical exertion was associated with ICH only.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Ira , Isquemia Encefálica/epidemiologia , Estudos de Casos e Controles , Humanos , Esforço Físico , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/etiologia
20.
Arch Gerontol Geriatr ; 98: 104565, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34823126

RESUMO

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.


Assuntos
Disfunção Cognitiva , Estilo de Vida , Cognição , Disfunção Cognitiva/prevenção & controle , Dieta , Exercício Físico , Humanos
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