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At the 2019 International Aspirin Foundation Scientific Conference ‘Benefits and Risks of Antithrombotic Therapy for Cardiovascular Disease Prevention', held in Rome, Italy, international experts sought to discuss and debate the optimal antithrombotic strategy for the secondary prevention of cardiovascular disease (CVD) and to seek agreement around dosing and target populations for aspirin use in primary disease prevention. Getting the best evidence to support real-life decisions in the clinic can be complex, and individualising management in order to balance both the risks and benefits of different disease prevention strategies appears to be the best approach. It is hoped that future decision-making tools and biomarkers will help direct treatments at those most likely to benefit.

Background and Purpose: Breath-holding (BH) and hyperventilation (HV) are used to assess abnormal cerebrovascular reactivity (CVR), often in relation to severity of small vessel disease and risk of stroke with carotid stenosis, but responses may be confounded by blood pressure (BP) changes. We compared effects of BP and end-tidal CO2 (etCO2) on middle cerebral artery mean flow velocity (MFV) in consecutive TIA and minor stroke patients. Methods: In the population-based, prospective, Oxford Vascular Study (OXVASC) Phenotyped cohort, change in MFV on transcranial Doppler ultrasound (∆MFV, DWL-DopplerBox), beat-to-beat BP (Finometer) and etCO2 were measured during 30 seconds BH or HV. Two blinded reviewers independently assessed recording quality. Dependence of ∆MFV on ∆BP and ∆etCO2 were determined by general linear models, stratified by quartiles. Results: 488/602 (81%) patients with adequate bone windows had high quality recordings, more often in younger participants (64.6 vs 68.7 years, p Conclusions: In older patients with recent TIA or minor stroke, cerebral blood flow responses to breath-holding were confounded by BP changes, but reflected etCO2 change during hyperventilation. Correct interpretation of CVR responses to etCO2, including in small vessel disease and carotid stenosis, requires concurrent blood pressure measurement.

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10(-8); and LINC00539/ZDHHC20, p = 5.82 x 10(-9). Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 x 10(-25); p [SSBI] = 5.23 x 10(-14) for hypertension), smoking (p [BI] = 4.4 x 10(-10); p [SSBI] = 1.2 x 10(-4)), diabetes (p [BI] = 1.7 x 10(-8); p [SSBI] = 2.8 x 10(-3)), previous cardiovascular disease (p [BI] = 1.0 x 10(-18); p [SSBI] = 2.3 x 10(-7)), stroke (p [BI] = 3.9 x 10(-69); p [SSBI] = 3.2 x 10(-24)), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 x 10(-157); p [SSBI] = 3.16 x 10(-106)), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p

Summary Background Charts of size at birth are used to assess the postnatal growth of preterm babies on the assumption that extrauterine growth should mimic that in the uterus. Methods The INTERGROWTH-21 st Project assessed fetal, newborn, and postnatal growth in eight geographically defined populations, in which maternal health care and nutritional needs were met. From these populations, the Fetal Growth Longitudinal Study selected low-risk women starting antenatal care before 14 weeks' gestation and monitored fetal growth by ultrasonography. All preterm births from this cohort were eligible for the Preterm Postnatal Follow-up Study, which included standardised anthropometric measurements, feeding practices based on breastfeeding, and data on morbidity, treatments, and development. To construct the preterm postnatal growth standards, we selected all live singletons born between 26 and before 37 weeks' gestation without congenital malformations, fetal growth restriction, or severe postnatal morbidity. We did analyses with second-degree fractional polynomial regression models in a multilevel framework accounting for repeated measures. Fetal and neonatal data were pooled from study sites and stratified by postmenstrual age. For neonates, boys and girls were assessed separately. Findings From 4607 women enrolled in the study, there were 224 preterm singleton births, of which 201 (90%) were enrolled in the Preterm Postnatal Follow-up Study. Variance component analysis showed that only 0·2% and 4·0% of the total variability in postnatal length and head circumference, respectively, could be attributed to between-site differences, justifying pooling the data from all study sites. Preterm growth patterns differed from those for babies in the INTERGROWTH-21 st Newborn Size Standards. They overlapped with the WHO Child Growth Standards for term babies by 64 weeks' postmenstrual age. Interpretation Our data have yielded standards for postnatal growth in preterm infants. These standards should be used for the assessment of preterm infants until 64 weeks' postmenstrual age, after which the WHO Child Growth Standards are appropriate. Size-at-birth charts should not be used to measure postnatal growth of preterm infants. Funding Bill & Melinda Gates Foundation.

Objective/Background: There are few published data on the acute care or long-term costs after acute/critical limb or visceral ischaemia (ACLVI) events. Using data from patients with acute events in a population-based incidence study (Oxford Vascular Study), we aimed to determine the long-term costs after an ACLVI event. Methods: We studied all patients with first-ever incident ACLVI from 2002 to 2012. Analysis was based on follow-up until January 2017, with all patients having full 5-year follow-up. Multivariate regressions were used to assess baseline and subsequent predictors of total 5-year hospital care costs. Overall costs after an ACLVI event were benchmarked against those after stroke in the same population, during the same period. Results: Among 351 patients with an ACLVI event, mean 5-year total care costs were €35,211 (S.D. 50,500), of which €6,443 (18%) were due to long-term institutionalisation. Costs differed by type of event (acute visceral ischaemia €16,476; acute limb ischaemia €24,437; critical limb ischaemia €46,281; pConclusion: Long-term care costs after an ACLVI event are considerable, especially after critical limb ischaemia. Hospital care costs were significantly higher than for stroke over the long-term, and were similar after inclusion of costs of institutionalisation.

Summary Background Percutaneous closure of patent foramen ovale (PFO) has been shown to be superior to medical treatment alone for prevention of recurrent stroke after cryptogenic transient ischaemic attack or non-disabling stroke in patients aged 60 years or younger. The justification for trials in older patients with transient ischaemic attack or stroke depends on whether PFO is shown to be associated with cryptogenic events at older ages, for which existing evidence is conflicting, and on the population burden of PFO-associated events. Therefore, we did a population-based screening study using contrast-enhanced transcranial Doppler (bubble-TCD) to detect probable PFO as indicated by a right-to-left shunt (RLS); we also did a systematic review and meta-analysis to compare our results with previous studies. Methods In this population-based study, nested in the Oxford Vascular Study (OXVASC), we established the prevalence of any RLS, and of large RLS (>20 microbubbles), in consecutive patients attending a rapid-access transient ischaemic attack and stroke clinic, or at 1-month follow-up after stroke unit admission, with transient ischaemic attack or non-disabling ischaemic stroke, comparing cryptogenic events with those of known cause (according to Trial of Org 10172 in Acute Stroke Treatment [TOAST] criteria). We stratified participants by age, and extrapolated data to the UK population. We also did a systematic review of published studies of PFO prevalence (using transthoracic or transoesophageal echocardiography or bubble-TCD) according to stroke subtype, which included older patients and reported age-specific results, and determined by meta-analysis (including the OXVASC data) the pooled odds ratio (95% CI) of finding PFO of any size in cryptogenic events compared with events of known cause, stratified by screening modality (transthoracic or transoesophageal echocardiography or bubble-TCD). The study protocol is registered with PROSPERO, number CRD42018087074. Findings Among 572 consecutive patients with transient ischaemic attack or non-disabling stroke between Sept 1, 2014, and Oct 9, 2017 (439 [77%] patients aged >60 years, mean age 70·0 years [SD 13·7]), bubble-TCD was feasible in 523 patients (91%) of whom 397 were aged older than 60 years. Compared with those with transient ischaemic attack or stroke of known cause, patients with cryptogenic events had a higher prevalence of RLS overall (odds ratio [OR] 1·93, 95% CI 1·32–2·82; p=0·001), and in those aged older than 60 years (2·06, 1·32–3·23; p=0·001). When we pooled the OXVASC data with that from two previous smaller studies of bubble-TCD in patients aged 50 years or older, we found an association between RLS and cryptogenic events (OR 2·35, 95% CI 1·42–3·90; p=0·0009; pheterogeneity=0·15), which was consistent with the equivalent estimate from transoesophageal echocardiography studies (2·20, 1·15–4·22; p=0·02; pheterogeneity=0·02). No data on large RLS in patients with TOAST-defined cryptogenic events compared with other events were available from previous studies, but we found no evidence that the association was diminished in such cases. Of 41 patients with large RLS and cryptogenic transient ischaemic attack or non-disabling stroke in our study, 25 (61%) were aged older than 60 years, which extrapolates to 5951 patients per year in the UK (data from mid-2016). Interpretation Bubble-TCD was feasible in most older patients with transient ischaemic attack or non-disabling stroke, the association of RLS with cryptogenic events remained at older ages, and the population burden of PFO-associated events is substantial. Randomised trials of PFO closure at older ages are required and should be feasible. Funding National Institute for Health Research, Oxford Biomedical Research Centre, Wellcome Trust, and Wolfson Foundation.

Supplemental Digital Content is available in the text., Background and Purpose— It has been hypothesized that cerebral small vessel disease (SVD) and chronic renal impairment may be part of a multisystem small-vessel disorder, but their association may simply be as a result of shared risk factors (eg, hypertension) rather than to a systemic susceptibility to premature SVD. However, most previous studies were hospital based, most had inadequate adjustment for hypertension, many were confined to patients with lacunar stroke, and none stratified by age. Methods— In a population-based study of transient ischemic attack and ischemic stroke (OXVASC [Oxford Vascular Study]), we evaluated the magnetic resonance imaging markers of cerebral SVD, including lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular space. We studied the age-specific associations of renal impairment (estimated glomerular filtration rate

Background and purpose Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin−protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. Methods Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15–49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age Results Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. Conclusion PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.

Background and Purpose Among screening tools for cognitive impairment in large cohorts, the Montreal Cognitive assessment (MoCA) appears to be more sensitive to early cognitive impairment than the Mini-Mental State Examination (MMSE), particularly after transient ischemic attack (TIA) or minor stroke. We reasoned that if MoCA-detected early cognitive impairment is pathologically significant, then it should be specifically associated with the presence of white matter hyperintensities (WMH) and reduced fractional anisotropy (FA) on MRI. Methods Consecutive eligible patients with TIA or minor stroke (Oxford Vascular Study) underwent MRI and cognitive assessment. We correlated MoCA and MMSE scores with WMH and FA, then specifically studied patients with low MoCA and normal MMSE. Results Among 400 patients, MoCA and MMSE scores were significantly correlated (all p Conclusions In patients with TIA or minor stroke, early cognitive impairment detected with the MoCA but not with the MMSE was independently associated with white matter damage on MRI, particularly reduced FA.

In the four decades since the independence of Portugal’s African colonies, the world has changed in ways that in the 1970s could scarcely have been imagined. The Cold War politics that lurked in the background of the 1960s struggles for independence took center stage in the 1970s and 1980s as Mozambique and Angola stumbled into civil wars that fused with proxy-conflicts between the USA and USSR. Cabo Verde and Guinea-Bissau’s improbable joint statehood ruptured in 1980, and the two political entities took very different paths that reflected very different experiences of colonialism. For its part, São Tomé e Príncipe initially followed a socialist trajectory, nationalizing the plantations, before a post-Cold War constitution heralded multiparty politics underpinned by capitalism.