Summary Background Although most cardiovascular disease occurs in low-income and middle-income countries, little is known about the use of effective secondary prevention medications in these ...communities. We aimed to assess use of proven effective secondary preventive drugs (antiplatelet drugs, β blockers, angiotensin-converting-enzyme ACE inhibitors or angiotensin-receptor blockers ARBs, and statins) in individuals with a history of coronary heart disease or stroke. Methods In the Prospective Urban Rural Epidemiological (PURE) study, we recruited individuals aged 35–70 years from rural and urban communities in countries at various stages of economic development. We assessed rates of previous cardiovascular disease (coronary heart disease or stroke) and use of proven effective secondary preventive drugs and blood-pressure-lowering drugs with standardised questionnaires, which were completed by telephone interviews, household visits, or on patient's presentation to clinics. We report estimates of drug use at national, community, and individual levels. Findings We enrolled 153 996 adults from 628 urban and rural communities in countries with incomes classified as high (three countries), upper-middle (seven), lower-middle (three), or low (four) between January, 2003, and December, 2009. 5650 participants had a self-reported coronary heart disease event (median 5·0 years previously IQR 2·0–10·0) and 2292 had stroke (4·0 years previously 2·0–8·0). Overall, few individuals with cardiovascular disease took antiplatelet drugs (25·3%), β blockers (17·4%), ACE inhibitors or ARBs (19·5%), or statins (14·6%). Use was highest in high-income countries (antiplatelet drugs 62·0%, β blockers 40·0%, ACE inhibitors or ARBs 49·8%, and statins 66·5%), lowest in low-income countries (8·8%, 9·7%, 5·2%, and 3·3%, respectively), and decreased in line with reduction of country economic status (ptrend <0·0001 for every drug type). Fewest patients received no drugs in high-income countries (11·2%), compared with 45·1% in upper middle-income countries, 69·3% in lower middle-income countries, and 80·2% in low-income countries. Drug use was higher in urban than rural areas (antiplatelet drugs 28·7% urban vs 21·3% rural, β blockers 23·5% vs 15·6%, ACE inhibitors or ARBs 22·8% vs 15·5%, and statins 19·9% vs 11·6%; all p<0·0001), with greatest variation in poorest countries (pinteraction <0·0001 for urban vs rural differences by country economic status). Country-level factors (eg, economic status) affected rates of drug use more than did individual-level factors (eg, age, sex, education, smoking status, body-mass index, and hypertension and diabetes statuses). Interpretation Because use of secondary prevention medications is low worldwide—especially in low-income countries and rural areas—systematic approaches are needed to improve the long-term use of basic, inexpensive, and effective drugs. Funding Full funding sources listed at end of paper (see Acknowledgments).
In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced ...mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up.
We invited surviving participants, who had previously been assigned to perindopril-indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events.
The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure-lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval CI, 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively.
The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286.).
The peridynamic stress formula proposed by Lehoucq and Silling (2008) is cumbersome to be implemented in numerical computations. In this paper, we show that the peridynamic stress tensor has the ...exact mathematical expression as that of the first Piola–Kirchhoff static Virial stress originated from the Irving–Kirkwood–Noll formalism (Irving and Kirkwood, 1905; Noll, 1955) through the Hardy–Murdoch procedure (Hardy, 1982; Murdoch, 1983), which offers a simple and clear expression for numerical calculations of peridynamic stress.
Several numerical verifications have been carried out to validate the accuracy of the proposed peridynamic stress formula in predicting the stress states in the vicinity of the crack tip and other sources of stress concentration. By evaluating the peridynamic stress in the prototype microelastic brittle (PMB) material model of bond-based peridynamics, it is found that the PMB material model may exhibit nonlinear constitutive behaviors at large deformations. The stress fields calculated through the proposed peridynamic stress formula show good agreements with these calculated by using finite element methods, analytical solutions, as well as experimental data, demonstrating the merit of the peridynamic stress formula in predicting stress states for material failure problems.
•Combined application of manure and chemical fertilizers increased sustainability yield index of rice crop more than chemical fertilization.•Combined application of manure and inorganic P fertilizer ...increased P balance above the environmental threshold level.•C sequestration rate was higher under combined application of manure and chemical fertilizer than chemical fertilization alone.
Organic and inorganic fertilization management in intensive cropping system is important to achieve long-term high crop yield sustainability. We quantitatively investigated crop yield sustainability through soil fertility and nutrients balance in 34-years long-term experiment under double rice cropping system in acidic paddy soil. Seven treatments were studied: CK (no fertilization); NPK (Chemical nitrogen, phosphorus and potassium fertilizer); NPM (Chemical N, P and manure); NKM (Chemical N, K and manure); PKM (Chemical P, K and manure); NPKM (Chemical N, P, K and manure) and M (Manure). Manure was applied at the rate of 45,000 kg ha−1. Results showed that crop yield and sustainability yield index under combined application of manure and chemical fertilizers was significantly higher than chemical fertilization and highest crop yield was under NPKM treatment. Long-term combined manure and chemical fertilization improved soil fertility as compared to CK and NPK treatments. Soil organic C sequestration rates under NPM, NKM, PKM and NPKM treatments were increased, while decreased under CK and NPK over the fertilization years. The uptake of N, P and K was increased over the fertilization years in all the treatments that received manure, compared with CK and NPK. Apparent K balance was negative in all the treatments. N balance (except CK and NPKM) and P balance (except CK) was positive in all fertilization treatments. P balance was exceeded the environmental risk threshold under combined application of chemical P fertilizer and manure. Boosted regression tree indicated that soil available N (AN), orgnaic carbon (OC) and total N (TN) were the most influencing factors of crop yield, accounted 36.5 %, 17.8 %, 13.4 % of variations of relative yield, respectively. Path analysis showed that long-term fertilizer inputs increased soil nutrient contents and C input directly affected soil OC. C input and soil pH indirectly influenced the relative crop yield. This study concluded that long-term combined application of manure and inorganic fertilizers increased crop yield sustainability, organic carbon sequestration rate compared to the inorganic fertilization. But long-term combined application of manure and inorganic phosphorus fertilizer increased the P balance. Therefore, rate of P inputs should be reduced under combined application of manure and inorganic P fertilizers in acidic paddy soil.
The present study aimed to understand the effect of venous valve lesion on the valve cycle. A modified immersed finite element method was used to model the blood-tissue interactions in the ...pathological vein. The contact process between leaflets or between leaflet and sinus was evaluated using an adhesive contact method. The venous valve modeling was validated by comparing the results of the healthy valve with those of experiments and other simulations. Four valve lesions induced by the abnormal elasticity variation were considered for the unhealthy valve: fibrosis, atrophy, incomplete fibrosis, and incomplete atrophy. The opening orifice area was inversely proportional to the structural stiffness of the valve, while the transvalvular flow velocity was proportional to the structural stiffness of the valve. The stiffening of the fibrotic leaflet led to a decrease in the orifice area and a stronger jet. The leaflet and blood wall shear stress (WSS) in fibrosis was the highest. The softening of the atrophic leaflet resulted in overly soft behavior. The venous incompetence and reflux were observed in atrophy. Also, the atrophic leaflet in incomplete atrophy exhibited weak resistance to the hemodynamic action, and the valve was reluctant to be closed owing to the large rotation of the healthy leaflet. Low blood WSS and maximum leaflet WSS existed in all the cases. A less biologically favorable condition was found especially in the fibrotic leaflet, involving a higher mechanical cost. This study provided an insight into the venous valve lesion, which might help understand the valve mechanism of the diseased vein. These findings will be more useful when the biology is also understood. Thus, more biological studies are needed.
The present study aimed to investigate the overall changes in exosomal proteomes in metastatic and non‐metastatic non‐small‐cell lung cancers (NSCLC) and healthy human serum samples, and evaluate the ...potential of serum exosomal biomarkers to predict NSCLC metastasis. Tandem mass tags combined with multidimensional liquid chromatography and mass spectrometry analysis were used for screening the proteomic profiles of serum samples. Quantitative proteome, significant pathway, and functional categories of patients with metastatic and non‐metastatic NSCLC and healthy donors were investigated. In total, 552 proteins of the 628 protein groups identified were quantified. Bioinformatics analysis indicated that quantifiable proteins were mainly involved in multiple biological functions, metastasis‐related pathways. Moreover, lipopolysaccharide‐binding proteins (LBP) in the exosomes were found to be well distinguished between patients with metastatic and patients with non‐metastatic NSCLC. Area under the curve (AUC) was 0.803 with a sensitivity of 83.1% and a specificity of 67% (P < .0001). Circulating LBP were also well distinguishable between metastatic and non‐metastatic NSCLC, the AUC was 0.683 with a sensitivity of 79.5% and a specificity of 47.2% (P = .005). This novel study provided a reference proteome map for metastatic NSCLC. Patients with metastatic and non‐metastatic NSCLC differed in exosome‐related proteins in the serum. LBP might be promising and effective candidates of metastatic NSCLC.
This is the first study using the proteomics technique to find a diagnostic marker for metastatic NSCLC. It provides an objective basis for the early diagnosis, early treatment and prognosis of metastatic NSCLC, and provides a key point for the diagnosis of other cancerous solid tumors. It also provides a new idea for non‐invasive biomarkers for other metastatic cancers, and the clinical application of exosomes will have better prospects.
•A non-ordinary state-based peridynamic model for brittle fracture in ceramics or fracture in quasi-brittle materials is developed.•The modified Johnson Holmquist (JH-2) constitutive and damage model ...is implemented in peridynamics framework at finite strain with objectivity.•Numerical simulations have been performed to verify and demonstrate the proposed model, including validation cases, edge-on impact experiment, and drop ball test.
In this work, we have developed a non-ordinary state-based peridynamics model for brittle fracture in ceramics or fracture in quasi-brittle materials in general. The model is firstly validated by three numerical benchmark tests, and then it is applied to simulate the edge-on impact and drop ball test experiments. We have implemented the modified Johnson Holmquist (JH-2) constitutive damage model into the peridynamics framework at finite strain. Furthermore, the contact algorithm between the projectile and target is discussed. It is shown that the numerical results obtained from peridynamics simulations are in general agreement with those from the experiment. The comparison of experimental and numerical results indicates that the proposed peridynamics model has the ability to capture the damage propagation and other features of the brittle fracture.
Summary Background The contribution of various risk factors to the burden of stroke worldwide is unknown, particularly in countries of low and middle income. We aimed to establish the association of ...known and emerging risk factors with stroke and its primary subtypes, assess the contribution of these risk factors to the burden of stroke, and explore the differences between risk factors for stroke and myocardial infarction. Methods We undertook a standardised case-control study in 22 countries worldwide between March 1, 2007, and April 23, 2010. Cases were patients with acute first stroke (within 5 days of symptoms onset and 72 h of hospital admission). Controls had no history of stroke, and were matched with cases for age and sex. All participants completed a structured questionnaire and a physical examination, and most provided blood and urine samples. We calculated odds ratios (ORs) and population-attributable risks (PARs) for the association of all stroke, ischaemic stroke, and intracerebral haemorrhagic stroke with selected risk factors. Findings In the first 3000 cases (n=2337, 78%, with ischaemic stroke; n=663, 22%, with intracerebral haemorrhagic stroke) and 3000 controls, significant risk factors for all stroke were: history of hypertension (OR 2·64, 99% CI 2·26–3·08; PAR 34·6%, 99% CI 30·4–39·1); current smoking (2·09, 1·75–2·51; 18·9%, 15·3–23·1); waist-to-hip ratio (1·65, 1·36–1·99 for highest vs lowest tertile; 26·5%, 18·8–36·0); diet risk score (1·35, 1·11–1·64 for highest vs lowest tertile; 18·8%, 11·2–29·7); regular physical activity (0·69, 0·53–0·90; 28·5%, 14·5–48·5); diabetes mellitus (1·36, 1·10–1·68; 5·0%, 2·6–9·5); alcohol intake (1·51, 1·18–1·92 for more than 30 drinks per month or binge drinking; 3·8%, 0·9–14·4); psychosocial stress (1·30, 1·06–1·60; 4·6%, 2·1–9·6) and depression (1·35, 1·10–1·66; 5·2%, 2·7–9·8); cardiac causes (2·38, 1·77–3·20; 6·7%, 4·8–9·1); and ratio of apolipoproteins B to A1 (1·89, 1·49–2·40 for highest vs lowest tertile; 24·9%, 15·7–37·1). Collectively, these risk factors accounted for 88·1% (99% CI 82·3–92·2) of the PAR for all stroke. When an alternate definition of hypertension was used (history of hypertension or blood pressure >160/90 mm Hg), the combined PAR was 90·3% (85·3–93·7) for all stroke. These risk factors were all significant for ischaemic stroke, whereas hypertension, smoking, waist-to-hip ratio, diet, and alcohol intake were significant risk factors for intracerebral haemorrhagic stroke. Interpretation Our findings suggest that ten risk factors are associated with 90% of the risk of stroke. Targeted interventions that reduce blood pressure and smoking, and promote physical activity and a healthy diet, could substantially reduce the burden of stroke. Funding Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Pfizer Cardiovascular Award, Merck, AstraZeneca, and Boehringer Ingelheim.
Angiotensin II type 1 receptor antagonists (ARBs) have become an important drug class in the treatment of hypertension and heart failure and the protection from diabetic nephropathy. Eight ARBs are ...clinically available azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan. Azilsartan (in some countries), candesartan, and olmesartan are orally administered as prodrugs, whereas the blocking action of some is mediated through active metabolites. On the basis of their chemical structures, ARBs use different binding pockets in the receptor, which are associated with differences in dissociation times and, in most cases, apparently insurmountable antagonism. The physicochemical differences between ARBs also manifest in different tissue penetration, including passage through the blood-brain barrier. Differences in binding mode and tissue penetration are also associated with differences in pharmacokinetic profile, particularly duration of action. Although generally highly specific for angiotensin II type 1 receptors, some ARBs, particularly telmisartan, are partial agonists at peroxisome proliferator-activated receptor-γ. All of these properties are comprehensively reviewed in this article. Although there is general consensus that a continuous receptor blockade over a 24-hour period is desirable, the clinical relevance of other pharmacological differences between individual ARBs remains to be assessed.
Hypertension is the most important preventable cause of morbidity and mortality globally, yet there are relatively few data collected using standardized methods.
To examine hypertension prevalence, ...awareness, treatment, and control in participants at baseline in the Prospective Urban Rural Epidemiology (PURE) study.
A cross-sectional study of 153,996 adults (complete data for this analysis on 142,042) aged 35 to 70 years, recruited between January 2003 and December 2009. Participants were from 628 communities in 3 high-income countries (HIC), 10 upper-middle-income and low-middle-income countries (UMIC and LMIC), and 4 low-income countries (LIC).
Hypertension was defined as individuals with self-reported treated hypertension or with an average of 2 blood pressure measurements of at least 140/90 mm Hg using an automated digital device. Awareness was based on self-reports, treatment was based on the regular use of blood pressure-lowering medications, and control was defined as individuals with blood pressure lower than 140/90 mm Hg.
Among the 142,042 participants, 57,840 (40.8%; 95% CI, 40.5%-41.0%) had hypertension and 26,877 (46.5%; 95% CI, 46.1%-46.9%) were aware of the diagnosis. Of those who were aware of the diagnosis, the majority (23,510 87.5%; 95% CI, 87.1%-87.9% of those who were aware) were receiving pharmacological treatments, but only a minority of those receiving treatment were controlled (7634 32.5%; 95% CI, 31.9%-33.1%). Overall, 30.8%, 95% CI, 30.2%-31.4% of treated patients were taking 2 or more types of blood pressure-lowering medications. The percentages aware (49.0% 95% CI, 47.8%-50.3% in HICs, 52.5% 95% CI, 51.8%-53.2% in UMICs, 43.6% 95% CI, 42.9%-44.2% in LMICs, and 40.8% 95% CI, 39.9%-41.8% in LICs) and treated (46.7% 95% CI, 45.5%-47.9% in HICs, 48.3%, 95% CI, 47.6%-49.1% in UMICs, 36.9%, 95% CI, 36.3%-37.6% in LMICs, and 31.7% 95% CI, 30.8%-32.6% in LICs) were lower in LICs compared with all other countries for awareness (P <.001) and treatment (P <.001). Awareness, treatment, and control of hypertension were higher in urban communities compared with rural ones in LICs (urban vs rural, P <.001) and LMICs (urban vs rural, P <.001), but similar for other countries. Low education was associated with lower rates of awareness, treatment, and control in LICs, but not in other countries.
Among a multinational study population, 46.5% of participants with hypertension were aware of the diagnosis, with blood pressure control among 32.5% of those being treated. These findings suggest substantial room for improvement in hypertension diagnosis and treatment.
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