Current obstetric outcomes in Jamaican women with sickle hemoglobinopathy - a balance of risks for aspirin?

OBJECTIVES: Sickle cell disease (SCD) occurs in 2.8 % of our Jamaican antenatal population with homozygous HbSS being most associated with adverse maternal and perinatal outcomes. METHODS: A retrospective comparative analysis of HbSS, HbSC and HbSßThal pregnancy outcomes at the University Hospital of the West Indies (UHWI) between January 2012 and December 2022 was conducted. RESULTS: Of 120 patients (138 pregnancies), obesity occurred in 36 % (20/56) of the 'non-HbSS' group, i.e. HbSßThal (55 %, 5/9) and HbSC (32 %, 15/47) combined vs. 9.7 % of the HbSS (8/82). HbSS patients had more crises requiring transfusions, acute chest syndrome (ACS), maternal 'near-misses' (OR=10.7, 95 % 3.5-32.3; p<0.001), hospitalizations (OR 7.6, 95 % CI 3.4-16.9; p<0.001), low birth weight (LBW) neonates (OR 3.1, 1.1-8.9; p=0.037) and preterm birth (OR=2.6, 1.2-5.8; p=0.018) compared to HbSC and HbSßThal. Low dose aspirin was prescribed in 43 %. Logistic regression showed those NOT on aspirin (n=76) had more miscarriages (22 v. 2 %), were LESS likely to have a live birth (75 v. 95 % (0.2, 0.04-0.57, p=0.005)), but surprisingly had fewer painful crises (28 v. 46 % (0.5, 0.03-0.9, p=0.03)). CONCLUSIONS: HbSS women had a 10-fold excess of maternal near-misses. Additional research may further clarify the effects of aspirin on pregnancy outcomes as related to SCD genotypes.

Dietary nitrate prevents progression of carotid subclinical atherosclerosis through blood pressure-independent mechanisms in patients with or at risk of type 2 diabetes mellitus.

AIMS: To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, vs. placebo/doxazosin, to control for blood pressure (BP). METHODS: A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial had carotid imaging. Patients with hypertension and with/at risk of type 2 diabetes were randomized to active nitrate-containing beetroot juice or placebo nitrate-depleted juice, and spironolactone or doxazosin. Vascular ultrasound for carotid diameter (CD, mm) and intima-media thickness (CIMT, mm) was performed at baseline, 3- and 6-months. Carotid local stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph) and carotid lumen area. Data were analysed by modified intention to treat and using mixed-model effect, adjusted for confounders. RESULTS: In total, 93 subjects had a baseline evaluation and 86% had follow-up data. No statistical interactions occurred between the juice and drug arms and BP was similar between the juices and between the drugs. Nitrate-containing vs. placebo juice significantly lowered CIMT (-0.06 [95% confidence interval -0.12, -0.01], P = .034), an overall difference of ~8% relative to baseline; but had no effect on CD or CS. Doxazosin appeared to reduce CS from baseline (-0.34 [-0.62, -0.06]) however, no difference was detected vs. spironolactone (-0.15 [-0.46, 0.16]). No differences were detected between spironolactone or doxazosin on CIMT and CD. CONCLUSIONS: Our results show that 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP-independent effect on carotid structure and function.

Ethnicity and Arterial Stiffness.

Early vascular aging reflects increased arterial stiffness of central blood vessels at young chronological ages and powerfully predicts cardiovascular events and mortality, independent of routine brachial blood pressure and other risk factors. Since ethnic disparities exist in routine blood pressure, in hypertension and cardiovascular outcomes, this review evaluates major studies comparing arterial stiffness through the life course between different ethnic groups or races (which have no biological definition)-in children, adolescents, young, and middle-aged adults and the very elderly. Most report that compared with white European-origin samples, populations of black African descent have increased central arterial stiffness throughout different life stages, as well as a more rapid increase in arterial stiffness at young ages. Exceptions may include African Caribbean origin people in Europe. Differences in vascular structure and function are clearest, where obesity, socioeconomic, and psychosocial factors are most marked. Few studies evaluate a wider spectrum of ethnic groups or factors contributing to these ethnic disparities. Genetic effects are not obvious; maternal risk and intergenerational studies are scarce. Nevertheless, across all ethnic groups, for given levels of blood pressure and age, some people have stiffer central arteries than others. These individuals are most at risk of vascular events and mortality and, therefore, may benefit from early, as yet untested, preventive action and treatment.

Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta cell dysfunction in type 2 diabetes.

AIMS/HYPOTHESIS: Progressive decline in functional beta cell mass is central to the development of type 2 diabetes. Elevated serum levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) are associated with beta cell failure in type 2 diabetes and eNAMPT immuno-neutralisation improves glucose tolerance in mouse models of diabetes. Despite this, the effects of eNAMPT on functional beta cell mass are poorly elucidated, with some studies having separately reported beta cell-protective effects of eNAMPT. eNAMPT exists in structurally and functionally distinct monomeric and dimeric forms. Dimerisation is essential for the NAD-biosynthetic capacity of NAMPT. Monomeric eNAMPT does not possess NAD-biosynthetic capacity and may exert distinct NAD-independent effects. This study aimed to fully characterise the structure-functional effects of eNAMPT on pancreatic beta cell functional mass and to relate these to beta cell failure in type 2 diabetes. METHODS: CD-1 mice and serum from obese humans who were without diabetes, with impaired fasting glucose (IFG) or with type 2 diabetes (from the Body Fat, Surgery and Hormone [BodyFatS&H] study) or with or at risk of developing type 2 diabetes (from the VaSera trial) were used in this study. We generated recombinant wild-type and monomeric eNAMPT to explore the effects of eNAMPT on functional beta cell mass in isolated mouse and human islets. Beta cell function was determined by static and dynamic insulin secretion and intracellular calcium microfluorimetry. NAD-biosynthetic capacity of eNAMPT was assessed by colorimetric and fluorescent assays and by native mass spectrometry. Islet cell number was determined by immunohistochemical staining for insulin, glucagon and somatostatin, with islet apoptosis determined by caspase 3/7 activity. Markers of inflammation and beta cell identity were determined by quantitative reverse transcription PCR. Total, monomeric and dimeric eNAMPT and nicotinamide mononucleotide (NMN) were evaluated by ELISA, western blot and fluorometric assay using serum from non-diabetic, glucose intolerant and type 2 diabetic individuals. RESULTS: eNAMPT exerts bimodal and concentration- and structure-functional-dependent effects on beta cell functional mass. At low physiological concentrations (~1 ng/ml), as seen in serum from humans without diabetes, eNAMPT enhances beta cell function through NAD-dependent mechanisms, consistent with eNAMPT being present as a dimer. However, as eNAMPT concentrations rise to ~5 ng/ml, as in type 2 diabetes, eNAMPT begins to adopt a monomeric form and mediates beta cell dysfunction, reduced beta cell identity and number, increased alpha cell number and increased apoptosis, through NAD-independent proinflammatory mechanisms. CONCLUSIONS/INTERPRETATION: We have characterised a novel mechanism of beta cell dysfunction in type 2 diabetes. At low physiological levels, eNAMPT exists in dimer form and maintains beta cell function and identity through NAD-dependent mechanisms. However, as eNAMPT levels rise, as in type 2 diabetes, structure-functional changes occur resulting in marked elevation of monomeric eNAMPT, which induces a diabetic phenotype in pancreatic islets. Strategies to selectively target monomeric eNAMPT could represent promising therapeutic strategies for the treatment of type 2 diabetes.

Association of macro-level determinants with adolescent overweight and suicidal ideation with planning: A cross-sectional study of 21 Latin American and Caribbean Countries.

BACKGROUND: Adolescents and young people (10-24 years old) in the Latin America and the Caribbean (LAC) region represent approximately 25% of the region's population. Since the 2008 global economic crisis, the pace of reduction in poverty and income inequality in the LAC region has stalled. The region is characterised by high levels of inequities and is also vulnerable to many natural disasters. Food systems are changing with increased availability and marketing of packaged and fast foods and sugar-sweetened drinks. Adolescence is a formative phase of the life course with multiple physical, emotional and social changes which can make them vulnerable to health problems. We assess the potential impact of macro-determinants, human and economic development as well as income inequality, on 2 top-ranking regional priorities for adolescent nutrition and mental health, using measures of overweight and suicidal ideation and planning which some have shown to be associated. METHODS AND FINDINGS: The Global School-based Health Survey (GSHS) is a nationally representative self-administered, school-based survey. We examined overweight/obesity and suicidal ideation with planning by gross domestic product (GDP) per capita or human development index (HDI) in 10-19-year-old adolescents from 21 LAC countries between 2009 and 2013. Sample sizes varied from 943 in Anguilla to 27,988 in Argentina. A total of 55,295 adolescents had a measure of overweight/obesity status, and 59,061 adolescents reported about suicidal ideation with planning. There was equal representation by sex in the surveys (52% girls and 48% boys). A total of 28.8% of boys and 28.1% of girls had overweight/obesity, and 7.5% of boys and 17.5% of girls reported suicidal ideation with planning over the last 12 months. Adjusted for individual socioeconomic and risk behaviours, and relative to the highest GDP per capita tertile, the middle tertile was associated with 42% (95% confidence interval (CI) 59% to 17%, p = 0.003) and 32% (95% CI 60% to 5%, p = 0.023), and the lowest tertile with 40% (95% CI 55% to 19%, p = 0.001) and 46% (95% CI 59% to 29%, p < 0.001) lower chances of overweight/obesity for girls and boys, respectively. A similar positive effect was seen with HDI, with lowest chances of overweight in the lowest tertile compared with the highest tertile for both sexes. Overweight/obesity was positively related with suicidal ideation with planning for girls (odds ratio (OR) 1.12, 95% CI 1.02 to 1.22, p = 0.009) and weakly related for boys (OR 1.09, 95% CI 0.96 to 1.24, p = 0.182). In contrast to overweight/obesity status, suicidal ideation with planning was not related to macro-level indices despite both outcomes sharing common individual socioeconomic and risk behaviour correlates. Limitations include the dominance of Argentinians in the sample (40%), the exclusion of vulnerable adolescents who dropped out of school, and reporting bias due to stigma of mental health-related issues. CONCLUSIONS: This study shows that economic and human development were positively associated with adolescent overweight/obesity but not with suicidal ideation with planning. We also observed an interconnectedness between overweight/obesity and suicide ideation with planning among girls. These findings highlight the importance of strategies that engage with both upstream and downstream determinants to improve adolescent nutrition and mental health.

A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The VaSera trial testing dietary nitrate and spironolactone.

AIMS: To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure. METHODS: Daily spironolactone (≤50 mg) vs doxazosin (control ≤16 mg) and 70 mL beetroot juice (Beet-It ≤11 mmol nitrate) vs nitrate-depleted juice (placebo; 0 mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index (CAVI), a nominally pressure-independent stiffness measure (primary outcome), PWVart secondary, central systolic pressure and augmentation. Analysis was intention-to-treat, adjusted for systolic pressure differences between trial arms. RESULTS: Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95% confidence interval]; 0.25 [-0.3, 0.5] units, P = .080), firmer for PWVart (0.37 [0.01, 0.7] m/s, P = .045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7 [-4.8, 3.3] mmHg, P = .7). Circulating nitrate and nitrite increased on active vs placebo juice, with central systolic pressure lowered -2.6 [-4.5, - 0.8] mmHg, P = .007 more on the active juice, but did not reduce CAVI, PWVart or peripheral pressure. Change in nitrate and nitrite concentrations were 1.5-fold [1.1-2.2] and 2.2-fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both P < .05. CONCLUSION: Contrary to our hypothesis, in at-risk/type 2 diabetes patients, spironolactone did not reduce arterial stiffness, rather PWVart was lower on doxazosin. Dietary nitrate elevated plasma nitrite, selectively lowering central systolic pressure, observed previously for nitrite.

Weight misperception and psychological symptoms from adolescence to young adulthood: longitudinal study of an ethnically diverse UK cohort.

BACKGROUND: To evaluate the association between weight misperception and psychological symptoms in the Determinants of young Adults Social well-being and Health (DASH) longitudinal study. METHODS: A longitudinal sample of 3227 adolescents, in 49 secondary schools in London, aged 11-16 years participated in 2002/2003 and were followed up in 2005/2006. A sub-sample (N = 595) was followed up again at ages 21-23 years in 2012/2013. An index of weight misperception was derived from weight perception and measured weight. Psychological well- being was measured using the Strengths and Difficulties Questionnaire at 11-16 years and the General Health Questionnaire at 21-23 years. Associations with weight misperception was assessed using regression models, adjusted for socio-economic and lifestyle factors. RESULTS: White British males and females were more likely than ethnic minority peers to report accurate perceptions of measured weight. At 11-13y, 46% females and 38% males did not have an accurate perception of their measured weight. The comparable figures at 14-16y were 42 and 40%. Compared with male adolescents, more females perceived themselves as overweight or were unsure of their weight but measured normal weight, and this was more pronounced among Indians, Pakistanis and Bangladeshis. At 14-16y, more males perceived themselves as underweight but measured normal weight, and this was more pronounced among Indians. Compared with those who had an accurate perception of their normal weight, a higher likelihood of probable clinically-relevant psychological symptoms was observed among those who measured normal weight but perceived themselves to be underweight (females Odds Ratio (OR) = 1.87 95% CI 1.03-3.40; males OR = 2.34 95% CI 1.47-3.71), overweight (females only OR = 2.06 95% CI 1.10-3.87), or unsure of their weight (males only OR = 1.61 95% CI 1.04-2.49). Among females, the association was driven by internalising rather than externalising symptoms. An accurate perception of overweight was associated with higher psychological symptoms in adolescence and early 20s. Ethnic specific effects were not evident. CONCLUSION: Weight misperception may be an important determinant of psychological symptoms in young people, with an accurate perception of normal weight status being protective. Culturally targeted interventions should be considered to promote healthy perceptions of body image.

[Optimizing observer performance of clinic blood Pressure measurement: a position statement from the Lancet Commission on Hypertension GroupOtimização do desempenho do observador na medição clínica da pressão arterial: posicionamento do Grupo da Lancet Commission on Hypertension]. / Optimización del desempeño del observador al medir la presión arterial en el consultorio: declaración de posición de la Comisión Lancet de Hipertensión.

High blood pressure (BP) is a highly prevalent modifiable cause of cardiovascular disease, stroke, and death. Accurate BP measurement is critical, given that a 5-mmHg measurement error may lead to incorrect hypertension status classification in 84 million individuals worldwide. This position statement summarizes procedures for optimizing observer performance in clinic BP measurement, with special attention given to low-tomiddle- income settings, where resource limitations, heavy workloads, time constraints, and lack of electrical power make measurement more challenging. Many measurement errors can be minimized by appropriate patient preparation and standardized techniques. Validated semi-automated/automated upper arm cuff devices should be used instead of auscultation to simplify measurement and prevent observer error. Task sharing, creating a dedicated measurement workstation, and using semi-automated or solar-charged devices may help. Ensuring observer training, and periodic re-training, is critical. Low-cost, easily accessible certification programs should be considered to facilitate best BP measurement practice.

A hipertensão é uma causa altamente prevalente de doença cardiovascular, acidente vascular cerebral e morte. A medição precisa da pressão arterial (PA) é um aspecto crítico, uma vez que erros de mensuração da ordem de 5 mmHg podem levar a uma classificação incorreta do status de hipertensão em 84 milhões de pessoas em todo o mundo. O presente posicionamento resume os procedimentos para otimizar o desempenho do observador (o indivíduo responsável pela mensuração da PA) na mensuração clínica da PA, com atenção especial para contextos de baixa a média renda, onde recursos limitados, cargas de trabalho pesadas, restrições de tempo e falta de energia elétrica tornam mais desafiadora a tarefa de medir a PA. Muitos erros de mensuração podem ser minimizados pela preparação adequada do paciente e pelo uso de técnicas padronizadas. Para simplificar a mensuração e evitar erros do observador, devem-se utilizar dispositivos semiautomatizados ou automatizados validados, com manguito para braço, ao invés de auscultação. O compartilhamento de tarefas, a criação de uma estação de trabalho dedicada à mensuração e o uso de dispositivos semiautomatizados ou com carga solar podem ajudar. É essencial que seja assegurado o treinamento e retreinamento periódico do observador. Programas de certificação de baixo custo e de fácil acesso devem ser considerados para facilitar a adoção das melhores práticas na mensuração da PA.

Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double-blind, randomized controlled VaSera trial.

AIMS: The aims of the present study were to explore whether a long-term intervention with dietary nitrate [(NO3- ), a potential tolerance-free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). METHODS: A subsample of participants in our double-blind, randomized, factorial-design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent-to-treat. RESULTS: Nitrate-containing juice (n = 40) decreased left ventricular (LV) end-diastolic volume {-6.3 [95% confidence interval (CI) -11.1, -1.6] ml} and end-systolic volume [-3.2 (95% CI -5.9, -0.5) ml], and increased end-diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [-0.01 (95% CI -0.02, -0.00)]. Although spironolactone reduced LV mass index relative to baseline [-1.48 (95% CI -2.08, -0.88) g m-2.7 ], there was no difference vs. doxazosin [-0.85 (95% CI -1.76, 0.05) g m-2.7 ]. Spironolactone also decreased the E/A ratio [-0.12 (95% CI -0.19, -0.04)] and increased S' (a tissue-Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s-1 . BP did not differ between the juices, or between the drugs. CONCLUSIONS: Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP-independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic-diastolic function, although confirmatory, were independent of BP.

Fruit and vegetable consumption and mental health across adolescence: evidence from a diverse urban British cohort study.

BACKGROUND: Evidence on the relationship between fruit and vegetable consumption (FV) and mental health in adolescence is sparse and inconsistent. Social determinants of FV include ethnicity, family environments and economic disadvantage. We investigated the relationship between FV and mental health in the British multi-ethnic Determinants of Adolescents (now young Adult) Social well-being and Health (DASH) longitudinal study. METHODS: A longitudinal study of 4683 adolescents living in London at age 11-13 years and followed up at 14-16 years. FV was measured using validated questions on the number of portions consumed daily. Mental health was measured by the Strengths and Difficulties Questionnaire as mean Total Difficulties Score (TDS) and by classification as a 'probable clinical case' (TDS > 17). Social measures included ethnicity, parenting and socioeconomic circumstances. Multilevel modelling was used to investigate the association between FV and mental health throughout adolescence. RESULTS: Low FV was common among adolescents, with approximately 60-70% of adolescents reporting < 5 portions/day and 20-30% reporting < 1 portion/day. In late adolescence, most ethnic minority groups reported lower FV than their White peers. In fully adjusted models, < 1 portion/day remained a significant correlate with mean TDS (Coef: 0.55, 0.29-0.81, P < 0.001) and TDS > 17 (Odds Ratio: 1.43, 1.11-1.85, P = 0.007). Gender- or ethnic-specific effects were not observed. Low parental care partly attenuated the association between FV and mental health. CONCLUSIONS: Low FV is a longitudinal correlate of poor mental health across adolescence. A focus on FV in parenting interventions could yield interrelated benefits across developmental outcomes given its importance to both physical and socioemotional health.

Blood Pressure and Arterial Stiffness in Kenyan Adolescents With the Sickle Cell Trait.

The potential association between sickle cell trait (SCT) and increased arterial stiffness/blood pressure (BP) has not been evaluated in detail despite its association with stroke, sudden death, and renal disease. We performed 24-hour ambulatory BP monitoring and arterial stiffness measurements in adolescents raised in a malaria-free environment in Kenya. Between December 2015 and June 2016, 938 randomly selected adolescents (ages 11-17 years) who had been continuous residents of Nairobi from birth were invited to participate in the study. Standard clinic BP measurement was performed, followed by 24-hour ambulatory BP monitoring and arterial stiffness measurement using an Arteriograph24 (TensioMed Ltd., Budapest, Hungary) device. SCT status was determined using DNA genotyping in contemporaneously collected blood samples. Of the 938 adolescents invited to participate, 609 (65%) provided complete data for analysis. SCT was present in 103 (15%). Mean 24-hour systolic and diastolic BPs were 116 (standard deviation (SD), 11.5) mm Hg and 64 (SD, 7) mm Hg, respectively, in children with SCT and 117 (SD, 11.4) mm Hg and 64 (SD, 6.8) mm Hg, respectively, in non-SCT children. Mean pulse wave velocity (PWV) was 7.1 (SD, 0.8) m/second and 7.0 (SD, 0.8) m/second in SCT and non-SCT children, respectively. We observed no differences in PWV or in any clinic or ambulatory BP-derived measures between adolescents with and without SCT. These data suggest that SCT does not independently influence BP or PWV.

The Malaria-High Blood Pressure Hypothesis.

RATIONALE: Several studies have demonstrated links between infectious diseases and cardiovascular conditions. Malaria and hypertension are widespread in many low- and middle-income countries, but the possible link between them has not been considered. OBJECTIVE: In this article, we outline the basis for a possible link between malaria and hypertension and discuss how the hypothesis could be confirmed or refuted. METHODS AND RESULTS: We reviewed published literature on factors associated with hypertension and checked whether any of these were also associated with malaria. We then considered various study designs that could be used to test the hypothesis. Malaria causes low birth weight, malnutrition, and inflammation, all of which are associated with hypertension in high-income countries. The hypothetical link between malaria and hypertension can be tested through the use of ecological, cohort, or Mendelian randomization studies, each of which poses specific challenges. CONCLUSIONS: Confirmation of the existence of a causative link with malaria would be a paradigm shift in efforts to prevent and control hypertension and would stimulate wider research on the links between infectious and noncommunicable disease.

Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.

BACKGROUND: Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure. METHODS: In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. FINDINGS: Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4·26 [-5·13 to -3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (-4·03 [-5·04 to -3·02]; p<0·0001) and versus bisoprolol (-4·48 [-5·50 to -3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion. INTERPRETATION: Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. FUNDING: The British Heart Foundation and National Institute for Health Research.

Arterial stiffness in hypertensive and type 2 diabetes patients in Ghana: comparison of the cardio-ankle vascular index and central aortic techniques.

BACKGROUND: Diabetes and hypertension increase arterial stiffness and cardiovascular events in all societies studied so far; sub-Saharan African studies are sparse. We investigated factors affecting arterial function in Ghanaians with diabetes, hypertension, both or neither. METHOD: Testing the hypothesis that arterial stiffness would progressively increase from controls to multiply affected patients, 270 participants were stratified into those with diabetes or hypertension only, with both, or without either. Cardio-ankle vascular index (CAVI), heart-ankle pulse wave velocity (haPWV), aortic PWV (PWVao) by Arteriograph, aortic and brachial blood pressures (BP), were measured. RESULTS: In patients with both diabetes and hypertension compared with either alone, values were higher of CAVI (mean ± SD, 8.3 ± 1.2 vs 7.5 ± 1.1 and 7.4 ± 1.1 units; p < 0.05), PWVao (9.1 ± 1.4 vs 8.7 ± 1.9 and 8.1 ± 0.9 m/s; p < 0.05) and haPWV (8.5 ± 1 vs 7.9 ± 1 and 7.2 ± 0.7 m/s; p < 0.05) respectively. In multivariate analysis, age, having diabetes or hypertension and BMI were independently associated with CAVI in all participants (ß = 0.49, 0.2, 0.17 and -0.2 units; p < 0.01, respectively). Independent determinants of PWVao were heart rate, systolic BP and age (ß = 0.42, 0.27 and 0.22; p < 0.01), and for haPWV were systolic BP, age, BMI, diabetes and hypertension status (ß = 0.46, 0.32, -0.2, 0.2 and 0.11; p < 0.01). CONCLUSION: In this sub-Saharan setting with lesser atherosclerosis than the western world, arterial stiffness is significantly greater in patients with coexistent diabetes and hypertension but did not differ between those with either diabetes or hypertension only. Simple, reproducibly measured PWV/CAVI may offer effective and efficient targets for intervention.

Future Treatment of Hypertension: Shifting the Focus from Blood Pressure Lowering to Arterial Stiffness Modulation?

Isolated systolic hypertension is the commonest form of hypertension from middle age onwards. Achieving target systolic blood pressure (BP) control remains difficult in everyday clinical practice and even under clinical trial conditions. Most antihypertensive medicines were designed to lower peripheral vascular resistance, which was considered the haemodynamic determinant of hypertension; most are effective in reducing steady but not pulsatile components of BP. Arterial stiffness, defined via aortic length-specific pulse wave velocity (PWV), is thought to be an important determinant of pulse pressure widening through its effects on the timing and amplitude of pressure wave reflection, and/or the aorta's Windkessel function, or its excess 'reservoir' pressure. Whereas pulse pressure is neither an independent nor consistent cardiovascular risk factor, particularly below the age of about 60 years, PWV has become the most powerful predictor of cardiovascular outcomes including mortality, independent of systolic, pulse, mean or other BP components. PWV is therefore a more direct target for treatment. This review addresses the potential therapeutic options for targeting arterial stiffness and the role of pulse pressure.

Readiness of primary care centres for a community-based intervention to prevent and control noncommunicable diseases in the Caribbean: A participatory, mixed-methods study.

INTRODUCTION: Epidemiological transition to NCDs is a challenge for fragile health systems in the Caribbean. The Congregations Taking Action against NCDs (CONTACT) Study intervention proposes that trained health advocates (HAs) from places of worship (PoWs), supervised by nurses at nearby primary healthcare centres (PHCs), could facilitate access to primary care among vulnerable communities. Drawing on participatory and systems thinking, we explored the capacity of local PHCs in three Caribbean countries to support this intervention. METHODS: Communities in Jamaica (rural, urban), Guyana (rural) and Dominica (Indigenous Kalinago Territory) were selected for CONTACT because of their differing socio-economic, cultural, religious and health system contexts. Through mixed-method concept mapping, we co-developed a list of perceived actionable priorities (possible intervention points ranked highly for feasibility and importance) with 48 policy actors, healthcare practitioners and civic society representatives. Guided in part by the concept mapping findings, we assessed the readiness of 12 purposefully selected PHCs for the intervention, using a staff questionnaire and an observation checklist to identify enablers and constrainers. RESULTS: Concept mapping illustrated stakeholder optimism for the intervention, but revealed perceptions of inadequate primary healthcare service capacity, resources and staff training to support implementation. Readiness assessments of PHCs identified potential enablers and constrainers that were consistent with concept mapping results. Staff support was evident. Constraints included under-staffing, which could hinder supervision of HAs; and inadequate essential NCD medicines, training in NCDs and financial and policy support for embedding community interventions. Despite a history of socio-political disadvantage, the most enabling context was found in the Kalinago Territory, where ongoing community engagement activities could support joint development of programmes between churches and PHCs. CONCLUSION: Multi-sectoral stakeholder consultation and direct PHC assessments revealed viability of the proposed POW-PHC partnership for NCD prevention and control. However, structural and policy support will be key for implementing change.

Impact of diet on mortality from stroke: results from the U.S. multiethnic cohort study.

OBJECTIVES: Stroke is the fourth leading cause of death in the United States and stroke mortality rates vary by ethnicity. The purpose of this study was to examine the associations between food group consumption and risk of death from stroke among 5 ethnic groups in the United States. METHODS: The Multiethnic Cohort includes >215,000 participants, the majority of whom are African American, Native Hawaiian, Japanese American, Latino, and Caucasian men and women recruited by mail survey in Hawaii and Los Angeles in 1993-1996. Deaths from stroke were identified by linkage to the state death files and the U.S. National Death Index. Diet was assessed using a validated food frequency questionnaire. Associations were examined using multivariable Cox proportional hazards models, stratified by ethnicity and gender. RESULTS: A total of 860 deaths from stroke were identified among the cohort participants. Vegetable intake was associated with a significant reduction in risk for fatal stroke among African American women (relative risk [RR]=0.60; 95% CI: 0.36-0.99). Among Japanese American women only, high fruit intake was significantly associated with a risk reduction for stroke mortality (RR=0.43; 95% confidence interval [CI]: 0.22-0.85), whereas meat intake increased risk (RR=2.36; 95% CI: 1.31-4.26). Among men, a significant reduction in stroke mortality was observed among Native Hawaiians (RR=0.26; 95% CI: 0.07-0.95). After pooling the data for the ethnic groups, the findings support an elevated risk for high meat intake among women overall (RR=1.56; 95% CI: 1.12-2.16); no significant effects of dietary intake on risk for fatal stroke were observed among men. CONCLUSIONS: Although some variations were observed for the associations between diet and stroke mortality among ethnic groups, the findings suggest that these differences are not substantial and may be due to dietary intake of specific food subgroups. Additional investigations including dietary subgroups and nutrients sources are needed to clarify these findings.

[11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial.

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [11C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = -6.5 to 24.1%) and 3.8% (95% confidence interval = -11.9 to 9.4) lay within the pre-specified -17% margin for non-inferiority (P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA.