Antihypertensive efficacy of single‐pill combinations (SPCs) consisting of a β1‐selective adrenergic blocker with vasodilatory properties via β3‐agonism (nebivolol) and an angiotensin II receptor ...blocker (valsartan) was demonstrated in an 8‐week phase 3 trial (NCT01508026). In this post hoc analysis, seated blood pressure, heart rate, 24‐hour ambulatory blood pressure monitoring, plasma aldosterone, estimated glomerular filtration rate, and safety measures were assessed in obese (body mass index >32 kg/m2; n=1823) and nonobese (body mass index <27 kg/m2; n=847) adults with hypertension (stage I or II) treated with nebivolol‐valsartan SPCs, nebivolol or valsartan monotherapy, or placebo. At week 8, reductions from baseline in blood pressure and ambulatory blood pressure monitoring were greater with SPCs and most nebivolol and valsartan monotherapy doses vs placebo regardless of obesity status. Aldosterone declined with all active treatments and estimated glomerular filtration rate remained steady. The nebivolol‐valsartan 5/80 mg/d SPC was efficacious regardless of degree of obesity.
This study sought to compare the estimation of central systolic blood pressure (cSBP) obtained by two different noninvasive devices, in addition to its comparisons with measured peripheral systolic ...blood pressure (pSBP), in a biracial (Black/White) community-based cohort.
Estimations of cSBP by applanation tonometry were obtained in 586 participants of the Bogalusa Heart Study (mean age: 43.5 years; 69% White, 54% women) using two different commonly used instruments: Omron HEM-9000AI and SphygmoCor CPV. pSBP was measured using a standard auscultatory technique.
The estimation of cSBP by the Omron device was higher than that of the SphygmoCor device (124.2±17.1 vs. 111.4±15.2 mmHg, P<0.001). Moreover, cSBP by Omron was significantly higher than peripheral blood pressure (124.2±17.1 vs. 119.4±15.6 mmHg, P<0.001), whereas cSBP by SphygmoCor was significantly lower than pSBP (111.4±15.2 vs. 119.4±15.6 mmHg, P<0.001). Similar results were observed in race-specific and sex-specific analyses.
These findings support the hypothesis that notable differences exist in the estimation of cSBP provided by the instruments utilized in this study. Further standardization studies are required to establish the most appropriate noninvasive estimation of cSBP before this parameter may be considered in the assessment, prediction, and prevention of cardio-metabolic risk and overt cardiovascular disease in clinical practice.
Long-term safety of a free-tablet combination of nebivolol and valsartan was assessed in a Phase III, open-label trial (NCT01415505). Adults with hypertension entered a 4-week placebo run-in phase, ...followed by a 52-week treatment phase. Initial dosage (Neb/Val 5/160 mg/d) was titrated up to 20/320 mg/d to achieve blood pressure (BP) goal (JNC7 criteria), with the addition of hydrochlorothiazide (up to 25 mg/d) if needed. Safety and tolerability parameters included adverse events. Efficacy assessments included baseline-to-endpoint change in diastolic BP and systolic BP and the percentage of patients who achieved BP goal. All analyses were performed using descriptive statistics. Study completion rate was 60.4% (489/810). The most frequent reason for discontinuation was insufficient therapeutic response (8.4%). Adverse events were experienced by 59.2% of patients, with the most common being headache (5.7%), nasopharyngitis (5.0%), and upper respiratory tract infection (4.6%). Three (0.4%) deaths occurred during the study; none was considered related to study medication. Mean ± standard deviation changes from baseline at week 52 (observed cases) were -25.5 ± 15.9 mm Hg (systolic BP) and -19.0 ± 8.7 mm Hg (diastolic BP). A total of 75.7% nebivolol/valsartan-treated and 57.8% nebivolol/valsartan/hydrochlorothiazide-treated completers achieved BP goal. Long-term treatment with nebivolol and valsartan in adults with hypertension was safe and well-tolerated.
There is a need for coatings for biomedical devices and implants that can prevent the attachment of fungal pathogens while allowing human cells and tissue to appose without cytotoxicity. Here, the ...authors study whether a poly(2-hydroxyethylmethacrylate) (PHEMA) coating can suppress attachment and biofilm formation by Candida albicans and whether caspofungin terminally attached to surface-tethered polymeric linkers can provide additional benefits. The multistep coating scheme first involved the plasma polymerization of ethanol, followed by the attachment of α-bromoisobutyryl bromide (BiBB) onto surface hydroxyl groups of the plasma polymer layer. Polymer chains were grafted using surface initiated activators regenerated by electron transfer atom transfer radical polymerization with 2-hydroxyethylmethacrylate, yielding PHEMA layers with a dry thickness of up to 89 nm in 2 h. Hydroxyl groups of PHEMA were oxidized to aldehydes using the Albright-Goldman reaction, and caspofungin was covalently immobilized onto them using reductive amination. While the PHEMA layer by itself reduced the growth of C. albicans biofilms by log 1.4, the addition of caspofungin resulted in a marked further reduction by >4 log units to below the threshold of the test. The authors have confirmed that the predominant mechanism of action is caused by antifungal drug molecules that are covalently attached to the surface, rather than out-diffusing from the coating. The authors confirm the selectivity of surface-attached caspofungin in eliminating fungal, not mammalian cells by showing no measurable toxicity toward the myeloid leukaemia suspension cell line KG-1a.
An Acid Test: Facile SI‐ARGET‐ATRP of Methacrylic Acid Michl, Thomas D.; Jung, Dimitri; Pertoldi, Andrea ...
Macromolecular chemistry and physics,
August 2018, 2018-08-00, 20180801, Letnik:
219, Številka:
15
Journal Article
Recenzirano
Odprti dostop
Atom transfer radical polymerization (ATRP) of methacrylic acid (MAA) is challenging. Herein is reported a study of conditions for facile surface‐initiated ATRP by activator regenerated electron ...transfer (SI‐ARGET‐ATRP) growth of poly‐methacrylic acid (PMAA) chains from a plasma polymer surface bearing surface‐immobilized α‐bromoisobutyryl bromide, with no deoxygenation required. Factors that affect PMAA polymer growth off the surface under ARGET‐ATRP conditions are systematically investigated, such as monomer/catalyst ratio, solvent, and, most importantly, addition of salts and change of pH. While the concentrations of the copper catalyst and acid affect grafting, the most pronounced effect arises from the concentration of chloride ions. Adding 0.1 m NaCl and acidifying the reaction solution to pH 3 offers the best trade‐off between reaction rate and reproducibility; yielding ≈60 nm thick PMAA graft polymers in 1 h under ambient conditions. Using this easily scalable recipe and surface analysis, the grafted polymers are verified to be pure PMAA and the graft coatings to be homogenous across a substrate of 100 mm diameter.
Homogenous, ≈60 nm thick poly‐methacrylic acid (PMAA) polymers are surface‐grafted within 1 h under ambient conditions. While the concentrations of the copper catalyst and acid affect grafting, the most pronounced effect arises from the concentration of chloride ions. Adding 0.1 m NaCl and acidifying the reaction solution to pH 3 offers the best trade‐off between reaction rate and reproducibility.
Microvascular and/or vasospastic anginas are relevant causes of ischemia with no obstructive coronary artery disease (INOCA) in patients after computed tomography coronary angiography (CTCA).
Our ...research has 2 objectives. The first is to undertake a diagnostic study, and the second is to undertake a nested, clinical trial of stratified medicine.
A prospective, multicenter, randomized, blinded, sham-controlled trial of stratified medicine (NCT03477890) will be performed. All-comers referred for clinically indicated CTCA for investigation of suspected coronary artery disease (CAD) will be screened in 3 regional centers. Following informed consent, eligible patients with angina symptoms are enrolled before CTCA and remain eligible if CTCA excludes obstructive CAD.
Diagnostic study: Invasive coronary angiography involving an interventional diagnostic procedure (IDP) to assess for disease endotypes: (1) angina due to obstructive CAD (fractional flow reserve ≤0.80); (2) microvascular angina (coronary flow reserve <2.0 and/or index of microvascular resistance >25); (3) microvascular angina due to small vessel spasm (acetylcholine); (4) vasospastic angina due to epicardial coronary spasm (acetylcholine); and (5) noncoronary etiology (normal coronary function). The IDP involves direct invasive measurements using a diagnostic coronary guidewire followed by provocation testing with intracoronary acetylcholine. The primary outcome of the diagnostic study is the reclassification of the initial CTCA diagnosis based on the IDP.
Stratified medicine trial: Participants are immediately randomized 1:1 in the catheter laboratory to therapy stratified by endotype (intervention group) or not (control group). The primary outcome of the trial is the mean within-subject change in Seattle Angina Questionnaire score at 6 months.
Secondary outcomes include safety, feasibility, diagnostic utility (impact on diagnosis and certainty), and clinical utility (impact on treatment and investigations). Health status assessments include quality of life, illness perception, anxiety-depression score, treatment satisfaction, and physical activity. Participants who are not randomized will enter a follow-up registry. Health and economic outcomes in the longer term will be assessed using electronic patient record linkage.
CorCTCA will prospectively characterize the prevalence of disease endotypes in INOCA and determine the clinical value of stratified medicine in this population.
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Risk factors for stroke are well-established in general populations but sparsely studied in individuals with impaired glucose tolerance.
We identified predictors of stroke among participants with ...impaired glucose tolerance in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Cox proportional-hazard regression models were constructed using baseline variables, including the 2 medications studied, valsartan and nateglinide.
Among 9306 participants, 237 experienced a stroke over 6.4 years. Predictors of stroke included classical risk factors such as existing cerebrovascular and coronary heart disease, higher pulse pressure, higher low-density lipoprotein cholesterol, older age, and atrial fibrillation. Other factors, including previous venous thromboembolism, higher waist circumference, lower estimated glomerular filtration rate, lower heart rate, and lower body mass index, provided additional important predictive information, yielding a C-index of 0.72. Glycemic measures were not predictive of stroke. Variables associated with stroke were similar in participants with no prior history of cerebrovascular disease at baseline.
The most powerful predictors of stroke in patients with impaired glucose tolerance included a combination of established risk factors and novel variables, such as previous venous thromboembolism and elevated waist circumference, allowing moderately effective identification of high-risk individuals.
We perform a joint analysis of the counts and weak lensing signal of redMaPPer clusters selected from the Dark Energy Survey (DES) Year 1 dataset. Our analysis uses the same shear and source ...photometric redshifts estimates as were used in the DES combined probes analysis. Our analysis results in surprisingly low values for S8 = σ8 (Ωm/0.3)0.5 = 0.65 ± 0.04, driven by a low matter density parameter, Ωm = 0.179+0.031−0.038, with σ8 − Ωm posteriors in 2.4σ tension with the DES Y1 3x2pt results, and in 5.6σ with the Planck CMB analysis. These results include the impact of post-unblinding changes to the analysis, which did not improve the level of consistency with other data sets compared to the results obtained at the unblinding. The fact that multiple cosmological probes (supernovae, baryon acoustic oscillations, cosmic shear, galaxy clustering and CMB anisotropies), and other galaxy cluster analyses all favor significantly higher matter densities suggests the presence of systematic errors in the data or an incomplete modeling of the relevant physics. Cross checks with x-ray and microwave data, as well as independent constraints on the observable-mass relation from Sunyaev-Zeldovich selected clusters, suggest that the discrepancy resides in our modeling of the weak lensing signal rather than the cluster abundance. Repeating our analysis using a higher richness threshold (λ ≥ 30) significantly reduces the tension with other probes, and points to one or more richness-dependent effects not captured by our model.
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