Assessing Adherence to Antihypertensive Medication by Means of Dose-Dependent Reference Plasma Concentration Ranges and Ultra-High Performance Liquid Chromatography-Ion Trap Mass Spectrometry Analysis

Poor adherence to antihypertensive drug therapy is a well-recognized problem and can be assessed by mass spectrometry-based analyses of body fluids. However, contrary statements exist whether drug quantification in blood or qualitative screening in urine is more suitable. The present pilot study aimed to further elucidate the power of blood plasma drug concentrations for adherence monitoring by developing and validating a quantification procedure for nine antihypertensive drugs (amlodipine, bisoprolol, candesartan, canrenone, carvedilol, metoprolol, olmesartan, torasemide, and valsartan) in blood plasma using liquid–liquid extraction and an ultra-high-performance liquid chromatography-ion trap mass spectrometry analysis. The procedure should then be used for an adherence assessment and compared with the results of an established qualitative urine screening. Selectivity, carryover, matrix effect, accuracy, precision, dilution integrity, and stability were successfully validated, except for amlodipine. The applicability was demonstrated by analyzing 19 plasma samples containing 28 antihypertensive drugs and comparing the measured concentrations with calculated dose-dependent reference plasma concentration ranges. The interpretation of plasma concentrations was found to be more sophisticated and time-consuming than that of urine screening results, and adherence could not be assessed in two cases (10%) due to measured plasma concentrations below the lower limit of quantification. However, 14 out of 19 subjects were classified as adherent (75%) and three as nonadherent (15%), in contrast to 19 (100%) that were claimed to be adherent based on the results of the qualitative urine screening. Nevertheless, further data is needed to estimate whether plasma quantification is superior in terms of assessing adherence to antihypertensive medication

Effect of vitamin D replacement on maternal and neonatal outcomes: a randomised controlled trial in pregnant women with hypovitaminosis D. A protocol

Introduction: The vitamin D recommended doses during pregnancy differ between societies. The WHO guidelines do not recommend routine prenatal supplementation, but they underscore the fact that women with the lowest levels may benefit most. The effects of routine supplementation during pregnancy on maternal and neonatal clinical outcomes have not been investigated in the Middle East, where hypovitaminosis D is prevalent. Our hypothesis is that in Middle Eastern pregnant women, a vitamin D dose of 3000?IU/day is required to reach a desirable maternal 25-hydroxyvitamin D [25(OH)D] level, and to positively impact infant bone mineral content (BMC).Methods and analysis: This is a multicentre blinded randomised controlled trial. Pregnant women presenting to the Obstetrics and Gynaecology clinics will be approached. Eligible women will be randomised to daily equivalent doses of cholecalciferol, 600?IU or 3000?IU, from 15 to 18?weeks gestation until delivery. Maternal 25(OH)D and chemistries will be assessed at study entry, during the third trimester and at delivery. Neonatal anthropometric variables and 25(OH)D level will be measured at birth, and bone and fat mass assessment by dual-energy X-ray absorptiometry scan at 1?month. A sample size of 280 pregnant women is needed to demonstrate a statistically significant difference in the proportion of women reaching a 25(OH)D level ?50?nmol/L at delivery, and a difference in infant BMC of 6 (10)g, for a 90% power and a 2.5% level of significance. The proportions of women achieving a target 25(OH)D level will be compared between the two arms, using ?2. An independent t test will be used to compare mean infant BMC between the two arms. The primary analysis is an intention-to-treat analysis of unadjusted results.Ethics and dissemination: The protocol has been approved by the Institutional Review Board at the American University of Beirut-Lebanon (IM.GEHF.22). The trial results will be published in peer-reviewed medical journals and presented at scientific conferences.Trial registration number: NCT02434380.<br/

The evolution of the Aristolochia pallida complex (Aristolochiaceae) challenges traditional taxonomy and reflects large-scale glacial refugia in the Mediterranean

The taxonomy of the Mediterranean Aristolochia pallida complex has been under debate since several decades with the following species currently recognized: A. pallida, A. lutea, A. nardiana, A. microstoma, A. merxmuelleri, A. croatica, and A. castellana. These taxa are distributed from Iberia to Turkey. To reconstruct phylogenetic and biogeographic patterns, we employed cpDNA sequence variation using both noncoding (intron and spacer) and protein-coding regions (i.e., trnK intron, matK gene, and trnK-psbA spacer). Our results show that the morphology-based traditional taxonomy was not corroborated by our phylogenetic analyses. Aristolochia pallida, A. lutea, A. nardiana, and A. microstoma were not monophyletic. Instead, strong geographic signals were detected. Two major clades, one exclusively occurring in Greece and a second one of pan-Mediterranean distribution, were found. Several subclades distributed in Greece, NW Turkey, Italy, as well as amphi-Adriatic subclades, and a subgroup of southern France and Spain, were revealed. The distribution areas of these groups are in close vicinity to hypothesized glacial refugia areas in the Mediterranean. According to molecular clock analyses the diversification of this complex started around 3–3.3 my, before the onset of glaciation cycles, and the further evolution of and within major lineages falls into the Pleistocene. Based on these data, we conclude that the Aristolochia pallida alliance survived in different Mediterranean refugia rarely with low, but often with a high potential for range extension, and a high degree of morphological diversity.Turkish Science Foundatio

Side effects and treatment initiation barriers of sodium-glucose cotransporter 2 inhibitors in heart failure: a systematic review and meta-analysis

Aims Physicians are sometimes reluctant to initiate guideline-directed therapy in patients with heart failure and reduced ejection fraction (HFrEF) due to concerns of adverse events. We explored the risk of hypotension, volume depletion, and acute kidney injury (AKI) on sodium–glucose cotransporter 2 (SGLT2) inhibitors in HFrEF populations. Methods and results We determined summary risk ratios (RRs) by conducting a meta-analysis on reported aforementioned adverse events on SGLT2 inhibitors from randomized controlled trials. We explored robustness of meta-analyses by computing fragility and/or reverse fragility index (FI or RFI) and its corresponding fragility quotient (FQ or RFQ) for each outcome. A total of 10 050 patients with HFrEF entered the final meta-analysis. Hypotension was reported in 4.5% (219/4836) on SGLT2 inhibitors and in 4.1% (202/4846) on placebo (RR 1.09, 95% confidence interval [CI] 0.91–1.31, p = 0.36). An RFI of 21 and RFQ of 0.002 suggest robust findings for hypotension. Volume depletion occurred in 9.4% (473/5019) on SGLT2 inhibitors and in 8.7% (438/5031) on placebo (RR 1.07, 95% CI 0.95–1.21, p = 0.25), respectively. RFI of 19 and RFQ of 0.001 suggest moderately robust findings for volume depletion. AKI was reported in fewer patients (1.9% [95/4888]) on SGLT2 inhibitors than on placebo (2.8% [140/4899]) providing lower incidence of AKI (RR 0.69, 95% CI 0.51–0.93, p = 0.02). FI of 14 and RFQ of 0.001 suggest moderately robust findings for AKI. Conclusion Sodium–glucose cotransporter 2 inhibitor therapy is not associated with a clinically relevant risk of hypotension and volume depletion. Its use reduces the risk of AKI. This analysis supports current guideline recommendations on early use of SGLT2 inhibitors

Parametric analysis of a rigid rotor drop onto touchdown bearings

Touch-Down Bearings (TDB) loads generated during a rotor drop event is analysed. When unexpected Active Magnetic Bearings (AMB) shut down occurs, the rotor drops onto TDB, providing a non-linear transient motion that can lead to unexpected responses. In this paper, the influences of TDB characteristics is assessed aiming at providing better drop characteristics in terms of loads

Efficacy of ivabradine in heart failure patients with a high-risk profile (analysis from the SHIFT trial)

Aims Early start and patient profile-oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) < 110 mmHg, resting heart rate (RHR) ≥ 75 b.p.m., left ventricular ejection fraction (LVEF) ≤ 25%, New York Heart Association (NYHA) Class III/IV, and their combination. Methods and results The SHIFT trial enrolled 6505 patients (LVEF ≤ 35% and RHR ≥ 70 b.p.m.), randomized to ivabradine or placebo on the background of guideline-defined standard care. Compared with placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint (cardiovascular death or HF hospitalization) in patients with SBP < 110 and ≥110 mmHg [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.74–1.08 vs. HR 0.80, 95% CI 0.72–0.89, P interaction = 0.34], LVEF ≤ 25% and >25% (HR 0.85, 95% CI 0.72–1.01 vs. HR 0.80, 95% CI 0.71–0.90, P interaction = 0.53), and NYHA III–IV and II (HR 0.83, 95% CI 0.74–0.94 vs. HR 0.81, 95% CI 0.69–0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with <75 (HR 0.76, 95% CI 0.68–0.85 vs. HR 0.97, 95% CI 0.81–0.1.16, P interaction = 0.02). When combining these profiling parameters, treatment with ivabradine was also associated with risk reductions comparable with patients with low-risk profiles for the primary endpoint (relative risk reduction 29%), cardiovascular death (11%), HF death (49%), and HF hospitalization (38%; all P values for interaction: 0.40). No safety concerns were observed between study groups. Conclusions Our analysis shows that RHR reduction with ivabradine is effective and improves clinical outcomes in HF patients across various risk indicators such as low SBP, high RHR, low LVEF, and high NYHA class to a similar extent and without safety concern

Multicolour correlative imaging using phosphor probes

Correlative light and electron microscopy exploits the advantages of optical methods, such as multicolour probes and their use in hydrated live biological samples, to locate functional units, which are then correlated with structural details that can be revealed by the superior resolution of electron microscopes. One difficulty is locating the area imaged by the electron beam in the much larger optical field of view. Multifunctional probes that can be imaged in both modalities and thus register the two images are required. Phosphor materials give cathodoluminescence (CL) optical emissions under electron excitation. Lanthanum phosphate containing thulium or terbium or europium emits narrow bands in the blue, green and red regions of the CL spectrum; they may be synthesised with very uniform-sized crystals in the 10- to 50-nm range. Such crystals can be imaged by CL in the electron microscope, at resolutions limited by the particle size, and with colour discrimination to identify different probes. These materials also give emissions in the optical microscope, by multiphoton excitation. They have been deposited on the surface of glioblastoma cells and imaged by CL. Gadolinium oxysulphide doped with terbium emits green photons by either ultraviolet or electron excitation. Sixty-nanometre crystals of this phosphor have been imaged in the atmospheric scanning electron microscope (JEOL ClairScope). This probe and microscope combination allow correlative imaging in hydrated samples. Phosphor probes should prove to be very useful in correlative light and electron microscopy, as fiducial markers to assist in image registration, and in high/super resolution imaging studies

Sex differences in arterial hypertension.

There is strong evidence that sex chromosomes and sex hormones influence blood pressure (BP) regulation, distribution of cardiovascular (CV) risk factors and co-morbidities differentially in females and males with essential arterial hypertension. The risk for CV disease increases at a lower BP level in females than in males, suggesting that sex-specific thresholds for diagnosis of hypertension may be reasonable. However, due to paucity of data, in particularly from specifically designed clinical trials, it is not yet known whether hypertension should be differently managed in females and males, including treatment goals and choice and dosages of antihypertensive drugs. Accordingly, this consensus document was conceived to provide a comprehensive overview of current knowledge on sex differences in essential hypertension including BP development over the life course, development of hypertension, pathophysiologic mechanisms regulating BP, interaction of BP with CV risk factors and co-morbidities, hypertension-mediated organ damage in the heart and the arteries, impact on incident CV disease, and differences in the effect of antihypertensive treatment. The consensus document also highlights areas where focused research is needed to advance sex-specific prevention and management of hypertension