Intramolecular locking and coumarin insertion: a stepwise approach for TADF design.

Three novel TADF (thermally activated delayed fluorescence) emitters based on the well-studied Qx-Ph-DMAC fluorophore are designed and synthesized. The photophysical properties of these materials are studied from a theoretical and experimental point of view, demonstrating the cumulative effects of multiple small modifications that combine to afford significantly improved TADF performance. First, an extra phenyl ring is added to the acceptor part of Qx-Ph-DMAC to increase the conjugation length, resulting in BQx-Ph-DMAC, which acts as an intermediate molecular structure. Next, an electron-deficient coumarin unit is incorporated to fortify the electron accepting ability, affording ChromPy-Ph-DMAC with red-shifted emission. Finally, the conjugated system is further enlarged by 'locking' the molecular structure, generating DBChromQx-DMAC with further red-shifted emission. The addition of the coumarin unit significantly impacts the charge-transfer excited state energy levels with little effect on the locally excited states, resulting in a decrease of the singlet-triplet energy gap. As a result, the two coumarin-based emitters show considerably improved TADF performance in 1 w/w% zeonex films when compared to the initial Qx-Ph-DMAC structure. 'Locking' the molecular structure further lowers the singlet-triplet energy gap, resulting in more efficient reverse intersystem crossing and increasing the contribution of TADF to the total emission.

Injectable alginate hydrogels for synergistic tumor combination therapy through repolarization of tumor-associated macrophages.

Locally administered drug delivery systems are promising as they allow to circumvent the side effects associated with systematic administration. In this study, we constructed multifunctional hydrogels by simply mixing commercial alginate (ALG) sols with glucose oxidase (GOx)-conjugated polyacrylic acid-stabilized iron oxide nanoparticles (GPI NPs) and Toll-like receptor 7/8 agonist resiquimod (R848). The injectable sols were able to transform into hydrogels (GPI/R848@ALG) by the ionic cross-linking between ALG and physiological Ca2+ to trap the therapeutic components within the hydrogel framework. Upon intratumoral injection, the hydrogels were employed for starvation therapy, promoted chemodynamic therapy and tumor-associated macrophages (TAMs) repolarization. The energy supply was blocked by consuming the intratumoral glucose via the GOx-catalyzed conversion of glucose into gluconic acid and hydrogen peroxide (H2O2).In vitro results showed that the generated H2O2 could be further converted into highly cytotoxic hydroxyl radicals (·HO) by the Fenton reaction to induce enhanced chemodynamic therapy. The TAMs repolarization studies in vitro exhibited that the GPI/R848@ALG hydrogels up-regulated the expression of CD86 by 63% and down-regulated the proportion of CD206 by 14% with a synergistic effect of the presence of Fe3O4 and R848, suggesting that the multifunctional hydrogels exert functions to direct the remodeling of TAMs from the tumor supportive M2-like phenotype to the tumor destructive M1-like phenotype to further contribute to the antitumor effect. Moreover, both in vitro and in vivo experiments demonstrate that the multifunctional hydrogels exhibit admirable antitumor performance towards 4T1 tumors. This work thereby provides a promising multifunctional nanoplatform for synergistic cancer starvation therapy, chemodynamic therapy and TAMs repolarization.

Implementation of the 2015 European Society of Cardiology guidelines for the management of infective endocarditis in the Netherlands.

Because the occurrence of infective endocarditis (IE) continues to be associated with high mortality, a working group was created by the Dutch Society of Cardiology to examine how the most recent European Society of Cardiology (ESC) guidelines for IE management could be implemented most effectively in the Netherlands. In order to investigate current Dutch IE practices, the working group conducted a country-wide survey. Based on the results obtained, it was concluded that most ESC recommendations could be endorsed, albeit with some adjustments. For instance, the suggested pre-operative screening and treatment of nasal carriers of Staphylococcus aureus as formulated in the ESC guideline was found to be dissimilar to current Dutch practice, and was therefore made less restrictive. The recently adapted ESC diagnostic criteria for IE were endorsed, while the practical employment of the relevant diagnostic techniques was simplified in an adapted flowchart. In addition, the presence of a multidisciplinary, so-called 'endocarditis team' in tertiary centres was proposed as a quality indicator. An adapted flowchart specifically tailored to Dutch practice for microbiological diagnostic purposes was constructed. Lastly, the working group recommended the Stichting Werkgroep Antibioticabeleid (SWAB; Dutch Working Party on Antibiotic Policy) guidelines for IE treatment instead of the antibiotic regimens proposed by the ESC.

Prognostic value of the coronary artery calcium score in suspected coronary artery disease: a study of 644 symptomatic patients.

AIM: The long-term value of coronary artery calcium (CAC) scanning has not been studied extensively in symptomatic patients, but was evaluated by us in 644 consecutive patients referred for stable chest pain. METHODS: We excluded patients with a history of cardiovascular disease and with a CAC score of zero. CAC scanning was done with a 16-row MDCT scanner. Endpoints were: (a) overall mortality, (b) mortality or non-fatal myocardial infarction and (c) the composite of mortality, myocardial infarction or coronary revascularisation. Revascularisations within 1 year following CAC scanning were not considered. RESULTS: The mean age of the 320 women and 324 men was 63 years. Follow-up was over 8 years. There were 58 mortalities, while 22 patients suffered non-fatal myocardial infarction and 24 underwent coronary revascularisation, providing 104 combined endpoints. Cumulative 8­year survival was 95% with CAC score <100, 90% in patients with CAC score >100 and <400, and 82% with CAC score ≥400 Agatston units. Risk of mortality with a CAC score >100 and ≥400 units was 2.6 [95% confidence interval (CI) 1.23-5.54], and 4.6 (95% CI 2.1-9.47) respectively. After correction for clinical risk factors, CAC score remained independently associated with increased risk of cardiac events. CONCLUSIONS: Risk increased with increasing CAC score. Patients with CAC >100 or ≥400 Agatston units were at increased risk of major adverse cardiac events and are eligible for preventive measures. CAC scanning provided incremental prognostic information to guide the choice of diagnostic and therapeutic options in many subjects evaluated for chest pain.

Diagnostic re-classification and prognostic risk stratification of patients with acute chest pain.

Unstable angina and myocardial infarction are prevalent manifestations of acute coronary artery disease, combined in the term 'acute coronary syndromes'. The introduction of sensitive markers for myocardial necrosis has led to confusion regarding the distinction between small myocardial infarctions and 'true' unstable angina, and the application of ever more sensitive markers has accelerated the pace at which patients with unstable angina are being re-classified to non-ST-segment elevation myocardial infarction. But in how many patients with acute chest pain is myocardial ischaemia really the cause of their symptoms? Numerous studies have shown that most have <5 ng/l high-sensitivity cardiac troponin, and that their prognosis is excellent (event rate <0.5% per year), incompatible with 'impending infarction'. This marginalisation of patients with unstable angina pectoris should lead to the demise of this diagnosis. Without unstable angina, the usefulness of the term acute coronary syndromes may be questioned next. It is better to abandon the term altogether and revert to the original diagnosis of thrombus-related acute coronary artery disease, myocardial infarction. A national register should be the next logical step to monitor and guide the application of effective therapeutic measures and clinical outcomes in patients with myocardial infarction.

A novel experimental setup for evaluating the stiffness of ankle foot orthoses.

OBJECTIVE: The purpose of this study was the construction of a new semi-automated experimental setup for the evaluation of the stiffness of ankle foot orthoses (AFOs) around an axis aligned to the anatomical ankle joint during the second rocker of the gait. The setup, developed in close collaboration with the orthopedic device company V!GO NV (Wetteren, Belgium), allows measurement of plantarflexion and dorsiflexion in the sagittal plane for a maximal range of motion of 50° (- 25° plantarflexion up to 25° dorsiflexion) in a non-destructive way. RESULTS: The mechanical properties of four 3D printed AFOs are investigated, based on the ranges of motion derived from the gait assessment of the patients when they walked with their AFO. The reliability of the stiffness measures was studied by the evaluation of the test-retest repeatability and the intra-tester and inter-tester variability. These studies revealed that the ankle stiffness can be measured with high reliability (ICC = 0.94-1.00). The obtained outcomes indicate that the experimental setup could be applied to measure the ankle stiffness of any topology of AFOs and, in the future, help finding the correlation with the information coming from the gait assessment of the patients.

Smoking cessation in European patients with coronary heart disease. Results from the EUROASPIRE IV survey: A registry from the European Society of Cardiology.

OBJECTIVE: We investigated smoking cessation rates in coronary heart disease (CHD) patients throughout Europe; current and as compared to earlier EUROASPIRE surveys, and we studied characteristics of successful quitters. METHODS: Analyses were done on 7998 patients from the EUROASPIRE-IV survey admitted for myocardial infarction, unstable angina and coronary revascularisation. Self-reported smoking status was validated by measuring carbon monoxide in exhaled air. RESULTS: Thirty-one percent of the patients reported being a smoker in the month preceding hospital admission for the recruiting event, varying from 15% in centres from Finland to 57% from centres in Cyprus. Smoking rates at the interview were also highly variable, ranging from 7% to 28%. The proportion of successful quitters was relatively low in centres with a low number of pre- event smokers. Overall, successful smoking cessation was associated with increasing age (OR 1.50; 95% CI 1.09-2.06) and higher levels of education (OR 1.38; 95% CI 1.08-1.75). Successful quitters more frequently reported that they had been advised (56% vs. 47%, p < .001) and to attend (81% vs. 75%, p < .01) a cardiac rehabilitation programme. CONCLUSION: Our study shows wide variation in cessation rates in a large contemporary European survey of CHD patients. Therefore, smoking cessation rates in patients with a CHD event should be interpreted in the light of pre-event smoking prevalence, and caution is needed when comparing cessation rates across Europe. Furthermore, we found that successful quitters reported more actions to make healthy lifestyle changes, including participating in a cardiac rehabilitation programme, as compared with persistent smokers.

[Secondary prevention of coronary heart disease: results of Euroaspire IV]. / Secundaire preventie van coronaire hartziekte.

OBJECTIVE: Secondary prevention is an important part of cardiovascular risk management. Since 1996, an inventory of cardiovascular risk factors and their treatment has been carried out periodically among patients with coronary heart disease within the framework of the European Action on Secondary Prevention by Intervention to Reduce Events (Euroaspire) project. DESIGN: Retrospective investigation of consecutively hospitalised patients with coronary heart disease. METHOD: Major cardiovascular risk factors and their treatment were investigated using standardised methods in patients who were hospitalised following a first heart infarction or with coronary revascularisation in the Amsterdam and Rijnmond regions of the Netherlands from 2012 to 2013. The investigations were carried out at an average of 18 months after admission. In addition, an oral glucose-tolerance test was carried out in patients without known diabetes. RESULTS: We studied 498 patients. The average BMI was 28 kg/m2, almost 75% had a BMI ≥ 25 kg/m2and 29% had a BMI ≥ 30 kg/m2. The mean cholesterol level was 4.4 mmol/l. Among those included, 16% smoked and 20% had diabetes mellitus; the oral glucose-tolerance test led to a new diabetes-mellitus diagnosis in 1% of the patients without known diabetes. A large majority of those included used antihypertensive agents, and slightly more than half used two or more medications. Despite this, half of the patients were hypertensive. CONCLUSION: As far as cardiovascular risk factors are concerned, smoking has almost halved in the past 20 years. Secondary preventative medication has increased to a stable high level. Blood pressure and overweight continue to be serious points for attention. Treatment of hypertension, in particular, should be improved, for instance by dose increases or combination of hypertensive medications. Routine oral glucose-tolerance tests are not useful in cardiac patients.

Impact of papyrus wetland encroachment on spatial and temporal variabilities of stream flow and sediment export from wet tropical catchments.

During the past decades, land use change in the Lake Victoria basin has significantly increased the sediment fluxes to the lake. These sediments as well as their associated nutrients and pollutants affect the food and water security of millions of people in one of Africa's most densely populated regions. Adequate catchment management strategies, based on a thorough understanding of the factors controlling runoff and sediment discharge are therefore crucial. Nonetheless, studies on the magnitude and dynamics of runoff and sediment discharge are very scarce for the Lake Victoria basin and the African Rift region. We therefore conducted runoff discharge and sediment export measurements in the Upper Rwizi, a catchment in Southwest Uganda, which is representative for the Lake Victoria basin. Land use in this catchment is characterized by grazing area on the high plateaus, banana cropping on the slopes and Cyperus papyrus L. wetlands in the valley bottoms. Due to an increasing population pressure, these papyrus wetlands are currently encroached and transformed into pasture and cropland. Seven subcatchments (358 km2-2120 km2), with different degrees of wetland encroachment, were monitored during the hydrological year June 2009-May 2010. Our results indicate that, due to their strong buffering capacity, papyrus wetlands have a first-order control on runoff and sediment discharge. Subcatchments with intact wetlands have a slower rainfall-runoff response, smaller peak runoff discharges, lower rainfall-runoff ratios and significantly smaller suspended sediment concentrations. This is also reflected in the measured annual area-specific suspended sediment yields (SYs): subcatchments with encroached papyrus swamps have SY values that are about three times larger compared to catchments with intact papyrus vegetation (respectively 106-137 ton km(-2) y(-1) versus 34-37 ton km(-2) y(-1)). We therefore argue that protecting and (where possible) rehabilitating these papyrus wetlands should be a corner stone of catchment management strategies in the Lake Victoria basin.

Is it cost-effective to use a test to decide which individuals with an intermediate cardiovascular disease risk would benefit from statin treatment?

BACKGROUND: The 2012 European guidelines recommend statins for intermediate-risk individuals with elevated cholesterol levels. Improved discrimination of intermediate-risk individuals is needed to prevent both cardiovascular disease (CVD) and statin side-effects (e.g. myopathy) efficiently since only 3-15 in every 100 individuals actually experience a cardiovascular event in the next 10 years. We estimated the potential cost-effectiveness of a hypothetical test which helps to determine which individuals will benefit from statins. METHODS AND RESULTS: Prognosis of different age- and gender-specific cohorts with an intermediate risk was simulated with a Markov model to estimate the potential costs and quality-adjusted life-years for four strategies: treat all with statins, treat none with statins, treat according to the European guidelines, or use a test to select individuals for statin treatment. The test-first strategy dominated the other strategies if the hypothetical test was 100% accurate and cost no more than €237. This strategy and the treat-all strategy were equally effective but the test generated lower costs by reducing statin usage and side-effects. The treat-none strategy was the least effective strategy. Threshold analyses show that the test must be highly accurate (especially sensitive) and inexpensive to be the most cost-effective strategy, since myopathy has a negligible impact on cost-effectiveness and statin costs are low. CONCLUSION: Use of a highly accurate prognostic test could reduce overall CVD risk, frequency of drug side-effects and lifetime costs. However, no additional test would add usefully to risk prediction over SCORE when it does not satisfy the costs and accuracy requirements.

Heart disease in the Netherlands: a quantitative update.

In this review we discuss cardiovascular mortality, incidence and prevalence of heart disease, and cardiac interventions and surgery in the Netherlands. We combined most recently available data from various Dutch cardiovascular registries, Dutch Hospital Data (LMR), Statistics Netherlands (CBS), and population-based cohort studies, to provide a broad quantitative update. The absolute number of people dying from cardiovascular diseases is declining and cardiovascular conditions are no longer the leading cause of death in the Netherlands. However, a substantial burden of morbidity persists with 400,000 hospitalisations for cardiovascular disease involving over 80,000 cardiac interventions annually. In the Netherlands alone, an estimated 730,000 persons are currently diagnosed with coronary heart disease, 120,000 with heart failure, and 260,000 with atrial fibrillation. These numbers emphasise the continuous need for dedicated research on prevention, diagnosis, and treatment of heart disease in our country.

Levels and trends in cardiovascular risk factors and drug treatment in 4837 elderly Dutch myocardial infarction patients between 2002 and 2006.

BACKGROUND: It is important to gain insight into opportunities for secondary prevention of cardiovascular disease. Our aim was to investigate levels and trends in cardiovascular risk factors and drug treatment in Dutch post-myocardial infarction (MI) patients between 2002 and 2006 and to make comparisons with the EUROASPIRE surveys (1999-2007). METHODS: We analysed data from 4837 post-MI patients (aged 69 years, 78% men) from 32 Dutch hospitals, using baseline cross-sectional data from the Alpha Omega Trial. RESULTS: Between 2002 and 2006, significant declines were found in the prevalence of smoking (23% to 16%, p < 0.001), hypercholesterolaemia (≥5 mmol/l; 54% to 27%, p < 0.0001) and hypertension (≥140/90 mmHg; 58% to 48%, p < 0.001). The prevalence of antithrombotic drugs was high (97%). The prevalence of lipid-modifying drugs and antihypertensives was high, and increased (74% to 90%, p < 0.0001 and 82% to 93%, p < 0.001, respectively). The prevalence of obesity (27%) was high in 2002 and decreased to 24% in 2006, albeit not significantly. Diabetes prevalence was high and increased between 2002 and 2006 (18% to 22%, p = 0.02). In comparison with EUROASPIRE patients, who were on average 8-10 years younger, our study in 2006 included patients with lower levels of obesity, hypertension, hypercholesterolaemia, diabetes and lower use of antiplatelets and ß-blockers, but similar levels of lipid-modifying drugs. CONCLUSIONS: This study showed that older Dutch post-MI patients were adequately treated with drugs, and that risk factors reached lower levels than in the younger EUROASPIRE patients. However, there is room for improvement in diet and lifestyle, given the high prevalence of smoking, obesity, and diabetes.

Measures of body composition and risk of heart failure in the elderly: the Rotterdam study.

OBJECTIVES: The incidence of heart failure increases with aging. Aim of the present study was to determine whether measures body composition predict incident heart failure in older adults. SETTING: Prospective community-based cohort study. 5, 868 men and women aged 55 years and older participating the Rotterdam study. Measures of body mass index and waist circumference were obtained at baseline. Information on incident heart failure was obtained during follow-up. Cox regression analyses were performed to investigate the possible association between measure of body composition and incident heart failure. RESULTS: During a mean follow up of 10.9 (SD ±4.4) years, 765 participants had heart failure. After adjustment for age and gender, 1-standard deviation of body mass index, waist circumference and the waist-hip ratio predicted heart failure (HR 1.25; 95% CI 1.17-1.34; HR 1.26; 95% CI 1.18-1.36; and HR 1.17; 95% CI 1.08-1.27), respectively. In age-stratified analyses, 1-standard deviation of body mass index (1.17; 95% CI 1.06- 1.29) and waist circumference (1.16; 95% CI 1.05- 1.29) were still associated with the risk of heart failure in the oldest participants, whereas the waist-hip ratio was not (1.06; 95% CI 0.945-1.18). CONCLUSION: Although estimates decrease with age, measures of overall and central adiposity predict incident heart failure among community dwelling older adults.

The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials.

OBJECTIVES: To investigate whether statins reduce all cause mortality and major coronary and cerebrovascular events in people without established cardiovascular disease but with cardiovascular risk factors, and whether these effects are similar in men and women, in young and older (>65 years) people, and in people with diabetes mellitus. DESIGN: Meta-analysis of randomised trials. DATA SOURCES: Cochrane controlled trials register, Embase, and Medline. Data abstraction Two independent investigators identified studies on the clinical effects of statins compared with a placebo or control group and with follow-up of at least one year, at least 80% or more participants without established cardiovascular disease, and outcome data on mortality and major cardiovascular disease events. Heterogeneity was assessed using the Q and I(2) statistics. Publication bias was assessed by visual examination of funnel plots and the Egger regression test. RESULTS: 10 trials enrolled a total of 70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetes mellitus. Mean follow-up was 4.1 years. Treatment with statins significantly reduced the risk of all cause mortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to 0.81), and major cerebrovascular events (0.81, 0.71 to 0.93). No evidence of an increased risk of cancer was observed. There was no significant heterogeneity of the treatment effect in clinical subgroups. CONCLUSION: In patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events.

Lower levels of ADAMTS13 are associated with cardiovascular disease in young patients.

ADAMTS13 may play a role in arterial thrombosis by cleaving the highly active and thrombogenic ultralarge Von Willebrand Factor (VWF) multimers into less active VWF multimers. The aim was to investigate the relationship between plasma levels of ADAMTS13, VWF and genetic variation in the ADAMTS13 gene with cardiovascular disease. We performed a case-control study in 374 patients with a first-ever arterial thrombosis before the age of 45 years in males and 55 years in women. We included 218 patients with coronary heart disease (CHD), 109 patients with ischemic stroke (IS) and 47 patients with peripheral arterial disease (PAD) and 332 healthy population-based controls. ADAMTS13 and VWF levels were measured 1-3 months after the event. ADAMTS13 levels were associated with cardiovascular disease (OR antigen 5.1 (95% CI 3.1-8.5, p<0.001) and OR activity 4.4 (95% CI 2.5-7.5, p<0.001), in the lowest quartiles). VWF levels were associated with cardiovascular disease (OR antigen 2.1 (95% CI 1.3-3.3, p=0.001) and OR activity 2.0 (95% CI 1.3-3.1, p=0.003), in the highest quartile). Patients with combined low ADAMTS13 levels and high VWF levels had an odds ratio of 7.7 (95% CI 3.3-17.7) (p for trend <0.0001). No association was found between genetic variation in the ADAMTS13 gene with levels of ADAMTS13 or with risk of cardiovascular disease. In conclusion, levels of ADAMTS13 and VWF are strongly associated with the risk of cardiovascular disease.

The role of thrombin activatable fibrinolysis inhibitor in arterial thrombosis at a young age: the ATTAC study.

BACKGROUND AND OBJECTIVES: Thrombin activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis and may therefore contribute to the pathophysiology of arterial thrombosis. The aim of the present study was to elucidate the pathogenetic role of TAFI levels and genotypes in young patients with arterial thrombosis. PATIENTS AND METHODS: In a case-control study, 327 young patients with a recent first-ever event of coronary heart disease (CHD subgroup) or cerebrovascular disease (ischemic stroke subgroup) and 332 healthy young controls were included. TAFI levels [intact TAFI, activation peptide (TAFI-AP) and (in)activated TAFI (TAFIa(i)] and TAFI activity were measured and genetic variations in the TAFI gene (-438G/A, 505G/A and 1040C/T) were determined. RESULTS: In the total group of patients, TAFIa(i) levels were higher (145.1 +/- 37.5%) than in controls (137.5 +/- 31.3%, P = 0.02). Plasma levels of intact TAFI, TAFI-AP and TAFI activity were similar in patients and controls. In the CHD subgroup (n = 218), intact TAFI levels were higher (109.4 +/- 23.0%) than in controls (102.8 +/- 20.7%, P = 0.02). In 325Ile/Ile homozygotes, lower TAFI levels and a decreased risk of arterial thrombosis were observed (OR 0.58, 95% CI 0.34-0.99) compared with patients with the common 325Thr/Thr genotype. This association was most evident in CHD patients (OR 0.48, 95% CI 0.26-0.90). Haplotype analyses supported a role for the Thr325Ile polymorphism. CONCLUSIONS: TAFIa(i) levels were higher in patients with cardiovascular disease. Furthermore, the TAFI 325Thr/Ile polymorphism was associated with lower TAFI levels and with the risk of cardiovascular disease in young patients, especially in CHD.