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Copyright of Tijdschrift voor Gezondheidsrecht is the property of Boom uitgevers Den Haag and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BACKGROUND: Drug-eluting stents (DES) are widely used for treatment of coronary artery disease with benefit of reduced restenosis compared to bare metal stents. The XIENCE VEverolimus Eluting Coronary Stent System is a second-generation DES system for better deliverability while maintaining safety and efficacy profiles. The present pharmacokinetic sub-study from the SPIRIT III Randomized and Controlled Trial (RCT) was to evaluate systemic exposure of patients to everolimus and to further demonstrate safety following implantation of XIENCE Vstents with everolimus doses ranging from 53 to 181 microg. METHODS AND RESULTS: Drug concentrations in whole blood were determined at multiple time points using a validated analytical method with a limit of quantification of 0.1 ng/mL. Individual C(max) ranged from 0.17 to 2.40 ng/mL and occurred between 0.07 and 1.88 hours across all dose levels. Both mean and individual C(max) values were below the trough blood concentrations of everolimus (Certican) for inhibition of organ transplant rejection. The last time point at which drug concentrations could be quantified ranged from 12 to 168 hours postimplantation in individual patients. In most cases, the blood levels dropped below the limit of quantification after 72 hours. CONCLUSIONS: This study confirms that the XIENCE Vstent causes a limited and systemic exposure to everolimus. The presumed localized and efficient delivery of everolimus to target vessels coupled with limited and transient systemic drug exposure contributes to the safety and effectiveness of the XIENCE VEECSS in patients of SPIRIT III RCT for longer than 2 years. [ABSTRACT FROM AUTHOR]

Introduction: The genetic risk factors for Coronavirus disease-2019 (COVID19)-associated pulmonary fibrosis (CAPF) are not clearly defined. Mutations in the genes encoding telomerase reverse transcriptase (TERT) and mucin 5B (MUC5B) are well-known genetic risk factors for pulmonary fibrosis. In this study, we aimed to show whether the most common proven mutations of pulmonary fibrosis affect the development of CAPF., Materials and Methods: Forty-eight patients who were matched for age, gender, COVID-19 disease severity, and respiratory support type and needed high flow nasal cannula, non-invasive mechanical ventilator, or invasive mechanical ventilator due to COVID-19 were followed up prospectively. Eighteen patients were excluded from the follow-up due to known structural lung disease, collagen tissue disease, and occupational exposure to fibrosis. The patients were called for follow-up three months after discharge, and CT was performed. Those with fibrosis (n= 15) in the third-month follow-up CT were included in the CAPF group, and those with complete resolution (n= 15) were included in the control group. Blood samples were taken for genetic analysis., Result: TERT gene study revealed that six (40%) of the fibrosis group was normal, while five were heterozygous (33.3%). MUC5B polymorphism was not detected in 10 (66.7%) of the fibrosis group., Conclusions: Individuals with TERT mutations may be at a higher risk for CAPF. Further studies are needed to clarify the genetic risk factors for CAPF.

The emergence of the B.1.617.2 (Delta) variant of the severe acute syndrome coronavirus (SARS-CoV-2) that emerged in 2019 (COVID-19), resulted in a surge of cases in India and has expanded and been detected across the world, including in the United States. The B.1.617.2 (Delta) variant has been seen to be twice more transmissible coupled with potential increases in disease severity and immune escape. As a result, case numbers and hospitalisations are once again on the rise in the USA. On 16 July 2021, the Centers for Disease Control and Prevention (CDC) reported a 7-day average 69.3% increase in new cases and a 35% increase in hospitalisations. Although the gold standard for SARS-CoV-2 variants identification remains genomic sequencing, this approach is not accessible to many clinical laboratories. The main goal of this study was to validate and implement the detection of the B.1.617.2 (Delta) variant utilising an open reverse transcription polymerase chain reaction (RT-PCR) platform by explicitly detecting the S-gene target failure (SGTF) corresponding to the deletion of two amino acids (ΔE156/ΔF157) characteristic of B.1.617.2 (Delta) variant. This approach was conceived as a rapid screening of B.1.617.2 (Delta) variant in conjunction with CDC's recommended N1 (nucleocapsid gene), N2, and RP (human RNase P) genes, as a pre-screening tool prior to viral genomic sequencing. We assessed 4,937 samples from 5 July to 5 September 2021. We identified the B.1.617.2 (Delta) variant in 435 of 495 positive samples (87.8%); the additional positive samples (7 samples, 1.4%) were found to belong to the B.1.1.7 (Alpha, UK) lineage and the remaining 53 samples (10.7%) were reported as 'other' lineages. Whole genome sequencing of 46 randomly selected samples validated the strains identified as positive and negative for the B.1.617.2 (Delta) variant and confirmed the S gene deletion in addition to B.1.617.2 characteristic mutations including L452R, T478K, P681R and D950N located in the spike protein. This modality has been used as routine testing at the Riverside University System Health (RUHS) Medical Center as a method for detection of B.1.617.2 (Delta) to pre-screen samples before genome sequencing. The assay can be easily implemented in clinical laboratories, most notably those with limited economic resources and access to genomic platforms., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Survivors of Head and Neck Cancer experience specific problems in functional performance. The aim of this study was to obtain the test-retest reliability of measurements on Maximal Mouth Opening (MMO), shoulder and neck function, lower and upper body strength, level of mobility and walking ability., Materials and Methods: Test-retest study design. Measurements on MMO (intra- and extra orally), Active range of motion of shoulders and neck, 30 Seconds Chair Stand Test, Grip Strength, Timed Up and Go test, and Six Minute Walk test., Results: In total 50 participants were included. The mean age was 68.6. ± 9.9 years and median time since end of treatment was 3.0 years (Q1-Q3: 1.0-5.25 years). We found good to excellent test-retest reliability on the core set of measurements (Intraclass Correlation Coefficient (ICC) 0.77 to 0.98). Measurement of MMO with cardboard card, forward flexion shoulder and Six Minute Walk test had a relatively small measurement error (Smallest Detectable Change (SDC) % 5.4% - 15.1%). Measurement of MMO with a caliper, shoulder abduction, shoulder external rotation, later flexion and rotation of the neck, grip strength, 30 Seconds Chair Stand Test, and Timed up and Go test had a relatively large measurement error (SDC% 19.8% - 44.7%)., Conclusion: This core set of measurements on physical performance is found reliable and therefore able to differentiate in physical performance. The reported measurement errors should be taken into consideration when interpreting the results of repeated measurements., Implications for Cancer Survivors: A core set of physical measurements can be used to measure physical performance in survivors of Head and Neck Cancer., Competing Interests: The authors have declared that no competing interests exist.

Directive 2010/63/EU introduced requirements for the classification of the severity of procedures to be applied during the project authorisation process to use animals in scientific procedures and also to report actual severity experienced by each animal used in such procedures. These requirements offer opportunities during the design, conduct and reporting of procedures to consider the adverse effects of procedures and how these can be reduced to minimize the welfare consequences for the animals. Better recording and reporting of adverse effects should also help in highlighting priorities for refinement of future similar procedures and benchmarking good practice. Reporting of actual severity should help inform the public of the relative severity of different areas of scientific research and, over time, may show trends regarding refinement. Consistency of assignment of severity categories across Member States is a key requirement, particularly if re-use is considered, or the safeguard clause is to be invoked. The examples of severity classification given in Annex VIII are limited in number, and have little descriptive power to aid assignment. Additionally, the examples given often relate to the procedure and do not attempt to assess the outcome, such as adverse effects that may occur. The aim of this report is to deliver guidance on the assignment of severity, both prospectively and at the end of a procedure. A number of animal models, in current use, have been used to illustrate the severity assessment process from inception of the project, through monitoring during the course of the procedure to the final assessment of actual severity at the end of the procedure (Appendix 1).

Background: Sarcoidosis is an inflammatory granulomatous disease of unknown etiology that involves multiple organ systems. Many studies have shown a strong relationship between inflammation and atherosclerosis. The aim of this study is to investigate the relationship between elastic properties of the aorta and the duration of the disease in patients with sarcoidosis., Method: The study population included 52 patients with sarcoidosis (22 men, mean age = 42.7 ± 10.7 years, and mean disease duration = 38.8 ± 10.8 months) and 50 healthy control subjects (18 men, and mean age = 42.0 ± 8.0 years). Aortic stiffness (β) index, aortic strain (AoS) and aortic distensibility (AoD) were calculated from the aortic diameters measured by transthoracic echocardiography and blood pressure obtained by sphygmomanometer. Cardiac functions were determined by using routine echocardiographic evaluation consist of standard two-dimensional and conventional Doppler and tissue Doppler imaging., Results: The conventional echocardiographic parameters were similar between patients and controls. There were significant differences between the control and the patient groups in β index (1.63 ± 0.55 vs 2.44 ± 1.54, p = 0.001), AoS (15.61 ± 5.69 vs 10.93 ± 4.11%, p < 0.001) and AoD (6.35 ± 2.64 vs 4.66 ± 1.98, 10 (-6) cm(2)/dyn, p = 0.001). There were statistically significant negative correlations between the disease duration and AoD (r = -0.46, p = 0.01) and AoS (r= -0.44, p = 0.002), whereas there was a positive correlation between the disease duration and β index (r = 0.37, p = 0.01). In multivariate analysis, disease duration was significantly related with AoD, AoS and β index (respectively, RR = 3.28, p = 0.002; RR = 3.03, p = 0.004; RR = 2.39, p = 0.02)., Conclusion: We observed that elastic properties of the aorta alter in patients with sarcoidosis. We also have demonstrated a statistically significant correlation between aortic elastic properties and the disease duration.

Objective: The purpose of the present study was to analyse the evolution of the Spanish population's global and regional adherence to the Mediterranean diet (MD) since 1987., Design: A cross-sectional study was conducted analysing food consumption from the Spanish Household Consumption Surveys administered by the Spanish Ministry of Agriculture, Fisheries and Food., Setting: The Mediterranean Adequacy Index (MAI) was applied to measure the adherence to the MD. The significance of the MAI trend was evaluated using a regression model., Subjects: The sample comprises a household consumption data set, which consisted of 2500 households in 1987 and increased to 6200 in 2005., Results: There was a significant decrease in the MAI (P=0.001) during the past two decades in Spanish households. From 1987 to 1997, MD adherence significantly decreased, but since 1998 it appears to have stabilised. In recent years, the daily household availability of several of the food components of the MD has increased. The MAI was observed to be significantly higher during the entire period in some Mediterranean regions, such as Andalusia, and significantly lower in more inland regions, such as Castile-Leon., Conclusions: During the past two decades, Spain has experienced a significant downward trend in adherence to the predominant dietary pattern, likely as a result of numerous socio-economic changes. However, a stabilisation and a recent slight recovery have been observed during the past decade.

Objectives: Sarcoidosis is an inflammatory granulomatous disease of unknown cause that involves multiple organ systems. Myocardial involvement is usually associated with poor prognosis, but diagnosis of cardiac sarcoidosis is frequently difficult. The aim of this study was to investigate the atrial conduction time in patients with sarcoidosis by using high-usefulness tissue Doppler echocardiography., Methods: The study population included 49 patients with sarcoidosis (19 men; mean age, 40.5 ± 9.8 years; mean disease duration, 35.7 ± 15.3 months) and 45 healthy control subjects (17 men; mean age, 40.7 ± 7.2 years). From the 12-lead electrocardiogram, P wave dispersion (PWD) was calculated. The timing of atrial contractions (PA) was measured as the intervals between the onset of P wave on electrocardiogram and the beginning of A-wave on TDI, and atrial electromechanical delay (EMD) was calculated from the lateral (PA lateral) and septal (PA septal) mitral annulus and lateral tricuspid annulus (PA tricuspid)., Results: Both PA lateral and PA septal were significantly longer in patients with sarcoidosis than control subjects (67.9 ± 16.1 vs 56.3 ± 13.1, P < 0.001; and 54.8 ± 15.2 vs 45.1 ± 14.2 ms, P = 0.002, respectively). Intra-atrial (PA septal-PA tricuspid) and interatrial (PA lateral-PA tricuspid) EMD were significantly higher in sarcoidosis groups (12.6 ± 7.5 vs 8.0 ± 7.1, P = 0.003; and 25.7 ± 9.8 vs 19.3 ± 7.7 ms, P = 0.001, respectively). Similarly, maximum P-wave duration and PWD were significantly longer in patients with sarcoidosis than control subjects (105.2 ± 11.8 vs 96.7 ± 15.4, P = 0.004 and 24.7 ± 5.6 vs 19.7 ± 7.1 ms, P = 0.001, respectively). There were significant positive correlations between the disease duration and interatrial EMD (r = 0.56, P < 0.001) and intra-atrial EMD (r = 0.66, P < 0.001). Positive correlation also was present between the disease duration and PWD (r = .62, P < 0.001)., Conclusions: Atrial EMD was found prolonged in patients with sarcoidosis. We also have demonstrated that PWD, interatrial and intra-atrial EMD were significantly correlated with disease duration. This study calls attention to measurement of atrial conduction time that may be clinically helpful in the recognition of cardiac involvement.

Recently, a study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made. Here, we assessed the feasibility of combining docetaxel with intravenously (i.v.) administered R101933, and determined the disposition of docetaxel with and without the P-gp inhibitor. Patients received i.v. R101933 alone at a dose escalated from 250 to 500 mg on day 1 (cycle 0), docetaxel 100 mg/m(2) as a 1-h infusion on day 8 (cycle 1) and the combination every 3 weeks thereafter (cycle 2 and further cycles). 12 patients were entered into the study, of whom 9 received the combination treatment. Single treatment with i.v. R101933 was associated with minimal toxicity consisting of temporary drowsiness and somnolence. Dose-limiting toxicity consisting of neutropenic fever was seen in cycles 1 and 2 or in further cycles at both dose levels. The plasma pharmacokinetics of docetaxel were not changed by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 22.5+/-6.2 l/h/m(2) and 24.2+/-7.4 l/h/m(2) (P=0.38) in cycles 1 and 2, respectively. However, the faecal excretion of unchanged docetaxel decreased significantly after the combination treatment from 2.5+/-2.1% to less than 1% of the administered dose of docetaxel, most likely due to inhibition of the intestinal P-gp by R101933. Plasma concentrations of R101933 were not different in cycles 0 or 2 and the concentrations achieved in the first 12-h period after i.v. infusion were capable of inhibiting P-gp in an ex vivo assay. We conclude that the combination of 100 mg/m(2) i.v. docetaxel and 500 mg i.v. R101933 is feasible, lacks pharmacokinetic interaction in plasma, and shows evidence of P-gp inhibition both in an ex vivo assay and in vivo as indicated by the inhibition of intestinal P-gp.

The pharmacodynamic (PD) interaction between the benzodiazepine agonist midazolam and the alpha(2)-adrenergic agonist dexmedetomidine was characterized for defined measures of anesthetic action and cardiovascular and ventilatory side effects in 33 rats. For various combinations of constant plasma concentrations of midazolam (0.1-20 microg/ml) and dexmedetomidine (0.3-19 ng/ml) obtained by target-controlled infusion, the whisker reflex (WR), righting reflex (RR), startle reflex to noise (SR), tail clamp response (TC), and corneal reflex (CR) were assessed. EEG (power in 0.5-3.5-Hz frequency band), mean arterial pressure, and heart rate were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The nature and extent of PD interaction was quantified by the model parameter synergy (SYN < 0, antagonism; SYN = 0, additivity; and SYN > 0, synergy). With increasing drug concentrations WR was lost first, followed by RR, SR, TC, and CR. These effects were accompanied by an increase of the EEG measure. The drug interaction was synergistic for all stimulus-response measures and the degree of synergy increased with deeper levels of central nervous system depression (SYN was 7.3, 145, 560, 374, and 1490 for WR, RR, SR, TC, and CR, respectively). The cardiovascular side effects of dexmedetomidine, evaluated at similar PD endpoints, were reduced in the presence of midazolam. Ventilatory side effects were minor for all drug combinations. The nature and extent of the PD interactions were not reflected in the EEG measure.

This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics.

This study characterizes the anesthetic profile of dexmedetomidine on the basis of steady-state plasma concentrations using defined stimulus-response, ventilatory, and continuous electroencephalographic (EEG) and cardiovascular effect measures in rats. At constant plasma concentrations of dexmedetomidine (range, 0.5-19 ng/ml), targeted and maintained by target-controlled infusion, the whisker reflex, righting reflex, startle reflex (to noise), tail clamp response, hot water tail-flick latency, and attenuation of heart rate (HR) increase associated with tail-flick (sympathoadrenal block) and corneal reflex, were assessed in 22 rats. EEG (power in 0.5- to 3.5-Hz frequency band), mean arterial pressure, and HR were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The following steady-state plasma EC(50) values of dexmedetomidine (mean +/- S.E. nanograms per milliliter) were estimated: HR decrease (0.51 +/- 0.04), EEG (1.02 +/- 0.08), whisker reflex (1.09 +/- 0.10), sympathoadrenal block (1.85 +/- 0.80), mean arterial blood pressure increase (1.99 +/- 0.44), righting reflex (2.13 +/- 0.15), tail-flick latency (3.65 +/- 0.87), startle reflex (3.75 +/- 0.64), tail clamp (5.49 +/- 1.34), and corneal reflex (24.5 +/- 12.3). At the EC(50) value of tail clamp, ventilatory depression was minor. In rats, dexmedetomidine creates bradycardia, sedation/hypnosis, sympathoadrenal blocking effects, and blood pressure-increasing effects at plasma concentrations below 2.5 ng/ml. Higher plasma concentrations are needed to loose the startle reflex, tail-flick, tail clamp, and corneal reflex responses. Ventilatory depressant effects are minor. The applied EEG measure seems to reflect sedation/hypnosis but seems to have limited value to predict the deeper levels of analgesia and anesthesia of dexmedetomidine.

This paper describes the development and implementation of a sensitive radioreceptor assay (RRA) for determining concentrations of dexmedetomidine, an alpha-2 adrenergic agonist with anesthetic properties, in rat plasma. Calf retina membranes were selected as the alpha-2 adrenergic receptor source, and the alpha-2 antagonist [3H]RX821002 and the alpha-2 agonist [3H]clonidine were evaluated as radioligands. We optimized the binding conditions for both radioligands and chose a radioligand for implementation in the RRA based on the characteristics of the inhibition binding curves with dexmedetomidine. The final method is based on competition between the radioligand [3H]clonidine and dexmedetomidine for high-affinity binding sites present in calf retina membranes. The assay has a coefficient of variation of 8% in the range 23.7-592 pg for 0.2 mL of plasma. This assay can be applied to pharmacokinetic-pharmacodynamic studies of dexmedetomidine.