Simon G. Anderson

Complete mitochondrial genome sequences of two extinct moas clarify ratite evolution

The origin of the ratites, large flightless birds from the Southern Hemisphere, along with their flighted sister taxa, the South American tinamous, is central to understanding the role of plate tectonics in the distributions of modern birds and mammals. Defining the dates of ratite divergences is also critical for determining the age of modern avian orders. To resolve the ratite phylogeny and provide biogeographical data to examine these issues, we have here determined the first complete mitochondrial genome sequences of any extinct taxa— two New Zealand moa genera—along with a 1,000-base-pair sequence from an extinct Madagascan elephant-bird. For comparative data, we also generated 12u2009kilobases of contiguous sequence from the kiwi, cassowary, emu and two tinamou genera. This large dataset allows statistically precise estimates of molecular divergence dates and these support a Late Cretaceous vicariant speciation of ratite taxa, followed by the subsequent dispersal of the kiwi to New Zealand. This first molecular view of the break-up of Gondwana provides a new temporal framework for speciation events within other Gondwanan biota and can be used to evaluate competing biogeographical hypotheses.

Hypertension in four African-origin populations : current 'Rule of Halves', quality of blood pressure control and attributable risk of cardiovascular disease

Objective To assess the public health burden from high blood pressure and the current status of its detection and management in four African-origin populations at emerging or high cardiovascular risk. Design Cross-site comparison using standardized measurement and techniques. Setting Rural and urban Cameroon; Jamaica; Manchester, Britain. Subjects Representative population samples in each setting. African-Caribbeans (80% of Jamaican origin) and a local European sample in Manchester. Main outcome measures Cross-site age-adjusted prevalence; population attributable risk. Results Among 1587 men and 2087 women, age-adjusted rates of blood pressure ⩾ 160 or 95 mmHg or its treatment rose from 5% in rural to 17% in urban Cameroon, despite young mean ages, to 21% in Jamaica and 29% in Caribbeans in Britain. Treatment rates reached 34% in urban Cameroon, and 69% in Jamaican- and British- Caribbean-origin women. Sub-optimal blood pressure control (> 140 and 90 mmHg) on treatment reached 88% in European women. Population attributable risks (or fractions) indicated that up to 22% of premature all-cause, and 45% of stroke mortality could be reduced by appropriate detection and treatment. Additional benefit on just strokes occurring on treatment could be up to 47% (e.g. in both urban Cameroon men and European women) from tighter blood pressure control on therapy. Cheap, effective therapy is available. Conclusion With mortality risk now higher from non-communicable than communicable diseases in sub-Saharan Africa and elsewhere, systematic measurement, detection and genuine control of hypertension once treated can go hand-in-hand with other adult health programmes in primary care. Cost implications are not great. The data from this collaborative study suggest that such efforts should be well rewarded.

Circulating cellular adhesion molecules ICAM-1, VCAM-1, P- and E-selectin in the prediction of cardiovascular disease in diabetes mellitus

BACKGROUND: Macrovascular disease in diabetes mellitus is a multifactorial process resulting in part from accelerated atherosclerosis and increased thrombosis. The resultant cardiovascular mortality is up to five times that of an age-matched non-diabetic population. Recently, cell adhesion molecules (CAMs) have been demonstrated in atherosclerotic plaques and implicated in the initiation and development of atherosclerosis. METHODS: To assess circulating CAMs as potential predictors of the development of macrovascular disease in diabetes mellitus, we carried out a 5-year prospective study in 28 diabetic patients without manifest macrovascular disease at entry. Circulating CAMs [intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin and E-selectin] were measured at baseline and at follow-up. RESULTS: Except for neuropathy, no patient had other microvascular diabetic complications (retinopathy or nephropathy) or clinically manifest macrovascular disease. Eleven patients developed macrovascular disease at follow-up (seven coronary heart disease, two cerebrovascular disease, two peripheral vascular disease). At baseline, systolic blood pressure and serum creatinine were higher (but within normal range) in patients developing macrovascular disease. Baseline ICAM-1 was significantly higher in the patients who developed macrovascular disease than in those who did not, and it remained so even after adjusting for age, systolic blood pressure, creatinine and glycaemic control (P=0.0007). However, baseline VCAM-1, P-selectin and E-selectin were not found to be associated with macrovascular disease. The risk of developing macrovascular disease was associated with increasing baseline concentrations of ICAM-1 [odds ratios 1.04 (95% CI 1.01-1.07); P=0.01]. No correlation was seen between ICAM-1, HbA(1) and cholesterol. CONCLUSION: This study suggests that ICAM-1 may predict development of macrovascular disease in diabetes mellitus.

Baseline Bleeding Risk and Arterial Access Site Practice in Relation to Procedural Outcomes After Percutaneous Coronary Intervention

BACKGROUNDnTransradial access (TRA) has been associated with reduced access site-related bleeding complications and mortality after percutaneous coronary intervention (PCI). It is unclear, however, whether these observed benefits are influenced by baseline bleeding risk.nnnOBJECTIVESnThis study investigated the relationship between baseline bleeding risk, TRA utilization, and procedure-related outcomes in patients undergoing PCI enrolled in the British Cardiovascular Intervention Society database.nnnMETHODSnBaseline bleeding risk was calculated by using modified Mehran bleeding risk scores in 348,689 PCI procedures performed between 2006 and 2011. Four categories for bleeding risk were defined for the modified Mehran risk score (MMRS): low (<10), moderate (10 to 14), high (15 to 19), and very high (≥20). The impact of baseline bleeding risk on 30-day mortality and its relationship with access site were studied.nnnRESULTSnTRA was independently associated with a 35% reduction in 30-day mortality risk (odds ratio [OR]: 0.65 [95% confidence interval (CI): 0.59 to 0.72]; p < 0.0001), with the magnitude of mortality reduction related to baseline bleeding risk (MMRS <10, OR: 0.73 [95% CI: 0.62 to 0.86]; MMRS ≥20, OR: 0.53 [95% CI: 0.47 to 0.61]). In patients with an MMRS <10, TRA was used in 71,771 (43.2%) of 166,083 PCI procedures; TRA was used in 8,655 (40.1%) of 21,559 PCI procedures in patients with an MMRS ≥20, illustrating that TRA was used less in those at highest risk from bleeding complications (p < 0.0001).nnnCONCLUSIONSnTRA was independently associated with reduced 30-day mortality, and the magnitude of this effect was related to baseline bleeding risk; those at highest risk of bleeding complications gained the greatest benefit from adoption of TRA during PCI.

Angiotensin I-converting enzyme polymorphisms, ACE level and blood pressure among Nigerians, Jamaicans and African-Americans

The genes in the renin–angiotensin system are important physiologic candidates in studies of the genetic susceptibility to hypertension. Limited information has been available in most studies on the extent of variation in the candidate loci or the modifying effects of different environmental settings. We consequently genotyped 13 polymorphisms at the angiotensin I-converting enzyme (ACE) locus at an average distance of 2u2009kb in 2776 family members from Nigeria, Jamaica and an African-American community in the US. Allele and haplotype frequencies were similar in the three populations, with modest evidence of European admixture in the US. Two markers were consistently associated with ACE level in the three samples and the proportion of variance accounted for by ACE8 was similar in the three groups. No evidence of consistent association of single markers was noted with blood pressure across the three population samples, however. Likewise, in a haplotype-based analysis, despite significant associations within each population, the findings were not replicated consistently across all three samples. We did observe, however, that the overtransmitted haplotypes among hypertensives were drawn from a single clade, suggesting that susceptibility may cluster in patterns not captured directly by our markers.

Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults

Objectives To determine the subgroup specific associations between usual blood pressure and risk of peripheral arterial disease, and to examine the relation between peripheral arterial disease and a range of other types of vascular disease in a large contemporary cohort. Design Cohort study. Setting Linked electronic health records from 1990 to 2013 in the United Kingdom. Participants 4u2009222u2009459 people aged 30-90 years, registered at a primary care practice for at least one year and with a blood pressure measurement. Main outcome measures Time to first diagnosis of new onset peripheral arterial disease and time to first diagnosis of 12 different vascular events. Results A 20 mm Hg higher than usual systolic blood pressure was associated with a 63% higher risk of peripheral arterial disease (hazard ratio 1.63, 95% confidence interval 1.59 to 1.66). The strength of the association declined with increasing age and body mass index (P<0.001 for interaction) but was not modified by sex or smoking status. Peripheral arterial disease was associated with an increased risk of 11 different vascular events, including ischaemic heart disease (1.68, 1.58 to 1.79), heart failure (1.63, 1.52 to 1.75), aortic aneurysm (2.10, 1.79 to 2.45), and chronic kidney disease (1.31, 1.25 to 1.38), but not haemorrhagic stroke. The most common initial vascular event among those with peripheral arterial disease was chronic kidney disease (24.4% of initial events), followed by ischaemic heart disease (18.5% of initial events), heart failure (14.7%), and atrial fibrillation (13.2%). Overall estimates from this cohort were consistent with those derived from traditional studies when we pooled the findings in two meta-analyses. Conclusions Raised blood pressure is a strong risk factor for peripheral arterial disease in a range of patient subgroups. Furthermore, clinicians should be aware that those with established peripheral arterial disease are at an increased risk of a range of other vascular events, including chronic kidney disease, ischaemic heart disease, heart failure, atrial fibrillation, and stroke.

Bivalirudin, glycoprotein inhibitor, and heparin use and association with outcomes of primary percutaneous coronary intervention in the United Kingdom.

AIMSnThe HORIZONS trial reported a survival advantage for bivalirudin over heparin-with-glycoprotein inhibitors (GPIs) in primary PCI for ST elevation myocardial infarction. This drove an international shift in clinical practice. Subsequent studies have produced divergent findings on mortality benefits with bivalirudin. We investigated this issue in a larger population than studied in any of these trials, using the United Kingdom national PCI registry.nnnMETHODS AND RESULTSn61 136 primary PCI procedures were performed between January 2008 and January 2012. Demographic and procedural data were obtained from the registry. Mortality information was obtained through the UK Office of National Statistics. Multivariable logistic regression and propensity analysis modelling were utilized to study the association of different anti-thrombotic strategies with outcomes. Unadjusted data demonstrated near-identical survival curves for bivalirudin and heparin-plus-GPI groups. Significantly higher early and late mortality was found in patients treated with heparin alone ( ITALIC! P < 0.0001) but this group had a markedly higher baseline risk. After propensity matching, the bivalirudin vs. heparin-plus-GPI groups still demonstrated very similar adjusted mortality (odds ratio 1.00 at 30 days, and 0.96 at 1 year). Patients treated with heparin alone continued to show higher mortality after adjustment, although effect size was considerably diminished (odds ratio vs. other groups 1.17-1.24 at 30 days).nnnCONCLUSIONSnAnalysis of recent UK data showed no significant difference in short- or medium-term mortality between ST elevation myocardial infarction patients treated with bivalirudin vs. heparin-plus-GPI at primary PCI.

Blood Pressure and Risk of Vascular Dementia: Evidence From a Primary Care Registry and a Cohort Study of Transient Ischemic Attack and Stroke.

Background and Purpose— Vascular dementia is the second most common form of dementia but reliable evidence on age-specific associations between blood pressure (BP) and risk of vascular dementia is limited and some studies have reported negative associations at older ages. Methods— In a cohort of 4.28 million individuals, free of known vascular disease and dementia and identified from linked electronic primary care health records in the United Kingdom (Clinical Practice Research Datalink), we related BP to time to physician-diagnosed vascular dementia. We further determined associations between BP and dementia in a prospective population-based cohort of incident transient ischemic attack and stroke (Oxford Vascular Study). Results— For a median follow-up of 7.0 years, 11u2009114 initial presentations of vascular dementia were observed in the primary care cohort after exclusion of the first 4 years of follow-up. The association between usual systolic BP and risk of vascular dementia decreased with age (hazard ratio per 20 mmu2009Hg higher systolic BP, 1.62; 95% confidence interval, 1.13–2.35 at 30–50 years; 1.26, 1.18–1.35 at 51–70 years; 0.97, 0.92–1.03 at 71–90 years; P trend=0.006). Usual systolic BP remained predictive of vascular dementia after accounting for effect mediation by stroke and transient ischemic attack. In the population-based cohort, prior systolic BP was predictive of 5-year risk of dementia with no evidence of negative association at older ages. Conclusions— BP is positively associated with risk of vascular dementia, irrespective of preceding transient ischemic attack or stroke. Previous reports of inverse associations in old age could not be confirmed.

Usual blood pressure, atrial fibrillation and vascular risk: evidence from 4.3 million adults

Abstract Background: Although elevated blood pressure is associated with an increased risk of atrial fibrillation (AF), it is unclear if this association varies by individual characteristics. Furthermore, the associations between AF and a range of different vascular events are yet to be reliably quantified. Methods: Using linked electronic health records, we examined the time to first diagnosis of AF and time to first diagnosis of nine vascular events in a cohort of 4.3 million adults, aged 30 to 90 years, in the UK. Results: A 20-mmHg higher usual systolic blood pressure was associated with a higher risk of AF [hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.19, 1.22]. The strength of the association declined with increasing age, from an HR of 1.91 (CI 1.75, 2.09) at age 30-40 to an HR of 1.01 (CI 0.97, 1.04) at age 80-90 years. AF without antithrombotic use at baseline was associated with a greater risk of any vascular event than AF with antithrombotic usage (P interaction < 0.0001). AF without baseline antithrombotic usage was associated with an increased risk of ischaemic heart disease (HR 2.52, CI 2.23, 2.84), heart failure (HR 3.80, CI 3.50, 4.12), ischaemic stroke (HR 2.72, CI 2.19, 3.38), unspecified stroke (HR 2.59, CI 2.25, 2.99), haemorrhagic stroke, chronic kidney disease, peripheral arterial disease and vascular dementia, but not aortic aneurysm. Conclusions: The association between elevated blood pressure and AF attenuates with increasing age. AF without antithrombotic usage is associated with an increased risk of eight vascular events.

Variation in hospital performance for heart failure management in the National Heart Failure Audit for England and Wales

Objective Investigation of variations in provider performance and its determinants may help inform strategies for improving patient outcomes. Methods We used the National Heart Failure Audit comprising 68u2005772 patients with heart failure with reduced left ventricular ejection fraction (HFREF), admitted to 185 hospitals in England and Wales (2007–2013). We investigated hospital adherence to three recommended key performance measures (KPMs) for inhospital care (ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) on discharge, β-blockers on discharge and referral to specialist follow-up) individually and as a composite performance score. Hierarchical regression models were used to investigate hospital-level variation. Results Hospital-level variation in adherence to composite KPM ranged from 50% to 97% (median 79%), but after adjustments for patient characteristics and year of admission, only 8% (95% CI 7% to 10%) of this variation was attributable to variations in hospital features. Similarly, hospital prescription rates for ACE-I/ARB and β-blocker showed low adjusted hospital-attributable variations (7% CI 6% to 9% and 6% CI 5% to 8%, for ACE-I/ARB and β-blocker, respectively). Referral to specialist follow-up, however, showed larger variations (median 81%; range; 20%, 100%) with 26% of this being attributable to hospital-level differences (CI 22% to 31%). Conclusion Only a small proportion of hospital variation in medication prescription after discharge was attributable to hospital-level features. This suggests that differences in hospital practices are not a major determinant of observed variations in prescription of investigated medications and outcomes. Future healthcare delivery efforts should consider evaluation and improvement of more ambitious KPMs.