Randomised, siteless study to compare systematic atrial fibrillation screening using enrichment by a risk prediction model with standard care in a Swedish population aged ≥ 65 years: CONSIDERING-AF study design.

INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia and confers an increased risk of mortality, stroke, heart failure and cognitive decline. There is growing interest in AF screening; however, the most suitable population and device for AF detection remains to be elucidated. Here, we present the design of the CONSIDERING-AF (deteCtiON and Stroke preventIon by moDEl scRreenING for Atrial Fibrillation) study. METHODS AND ANALYSIS: CONSIDERING-AF is a randomised, controlled, siteless, non-blinded diagnostic superiority trial with four parallel groups and a primary endpoint of identifying AF during a 6-month study period set in Region Halland, Sweden. In each group, 740 individuals aged≥65 years will be included. The primary objective is to compare the intervention of AF screening enrichment using a risk prediction model (RPM), followed by 14 days of a continuous ECG patch, with no intervention (standard care). Primary outcome is defined as the incident AF recorded in the Region Halland Information Database after 6 months as compared with standard care. Secondary endpoints include the difference in incident AF between groups enriched or not by the RPM, with and without an invitation to 14 days of continuous ECG recording, and the proportions of oral anticoagulation treatment in the four groups. ETHICS AND DISSEMINATION: This study has ethical approval from the Swedish Ethical Review Authority. Results will be published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: NCT05838781.

Carotid atherosclerosis, changes in tissue remodeling and repair in patients with aortic coarctation.

BACKGROUND AND AIMS: After aortic coarctation (CoA) repair, patients still suffer from cardiovascular complications. The aim of this study was to measure cardiovascular markers, intima-media thickness (IMT) and plaques in controls and patients with CoA. METHODS: Sixty-four patients with CoA (66% male, mean age 48 ± 15 years) and controls (54% men, mean age 47 ± 16 years) underwent ultrasound of their arteries. A multiplex platform to analyze circulating blood levels biomarkers reflecting inflammation, tissue remodeling and repair was used. RESULTS: In men following CoA repair, a significantly increased carotid bulb IMT was observed in comparison to the control group (1.05 [0.72-1.24] vs. 0.67 [0.59-0.95] mm; p = 0.003). Median common carotid artery (CCA) IMT was increased in men compared to controls (0.82 [0.61-0.97] mm vs. 0.58 [0.53-0.76] mm, p < 0.003) and in women compared to controls (0.83 [0.70-0.92] vs. 0.60 [0.55-0.69], p < 0.004). CoA demonstrated an independent association with IMT in both men and women. Men with CoA were also more likely to have a plaque in their carotid arteries (p = 0.010). In women with CoA, we observed significantly lower levels of stem cell factor (SCF, p = 0.004) while in men with CoA we observed significantly lower levels of matrix metalloproteinase-3 (MMP-3, p = 0.048), tumor necrosis factor receptor 1 (TNF-R1, p = 0.032), tumor necrosis factor receptor superfamily member 10B (TRAIL-R2, p = 0.019) and monocyte chemotactic protein 1 (MCP-1, p = 0.015). CONCLUSIONS: This is the first study to show that despite successful CoA repair, patients have more carotid atherosclerosis than can be explained by changes in tissue remodeling and repair.

Bleeding and thromboembolism due to drug-drug interactions with non-vitamin K antagonist oral anticoagulants-a Swedish, register-based cohort study in atrial fibrillation outpatients.

PURPOSE: To study the association between interacting drugs and bleeding or thromboembolism in atrial fibrillation outpatients treated with non-vitamin K antagonist oral anticoagulants (NOACs). METHODS: Population-based cohort study of outpatients treated with NOACs in Sweden from 2008 to 2017. Patients with atrial fibrillation and newly initiated NOAC treatment were identified in the Prescribed Drug Register. Comorbidities and outcome data were retrieved from the Patient Register and the Cause of Death Register. Cox-regression analyses were performed to evaluate the primary endpoints any severe bleed and ischemic stroke/transient ischemic attack/stroke unspecified during the first six months of treatment. Secondary endpoints were gastrointestinal bleeding, intracranial bleeding, ischemic stroke, and venous thromboembolism. RESULTS: Increased risk of any severe bleed was found when NOAC treatment, and drugs with pharmacodynamic effect on bleeding were combined, compared to NOAC only. An increased risk with these combinations was evident for apixaban (hazard ratio (HR) 1.47; 95% CI 1.33-1.63), rivaroxaban (HR 1.7; 95% CI 1.49-1.92), and dabigatran (HR 1.26; 95% CI 1.05-1.52). For apixaban, there was an increased risk of any severe bleed when combined with CYP3A4 and/or P-glycoprotein (P-gp) inhibitors (HR 1.23; 95% CI 1.01-1.5). The use of inducers of CYP3A4 and/or P-gp was low in this cohort, and effects on ischemic stroke/TIA/stroke unspecified could not be established. CONCLUSION: Increased risk of bleeding was seen for pharmacodynamic and pharmacokinetic interactions with NOACs. Prescribers need to be vigilant of the effect of interacting drugs on the risk profile of patients treated with NOACs.

Prevalence of potential drug-drug interactions in Swedish pediatric outpatients.

PURPOSE: To describe the occurrence of potential drug-drug interactions (DDIs) in prescribed drugs, dispensed to pediatric outpatients in Sweden. METHODS: A cross sectional study was conducted based on data from a national register of prescribed drugs, dispensed at pharmacies, to children 0-17 years old. The study period was January 1 to April 30, 2010. Drug dispensing data was linked to the DDI database SFINX. Prevalence and frequencies of potential interactions were investigated, and drugs commonly involved in interactions were identified. The study focused on clinically relevant potential interactions, class D (should be avoided), and class C (can be handled, e.g. by dose adjustment). RESULTS: In the Swedish pediatric population, 0 to 17 years of age, 12% (n = 231 078) of children had at least two dispensed drugs. In this group of patients, 0.14% had potential D-interactions and 1,3% had potential C-interactions. The number of D- and C-interactions that may lead to reduced effects were 181 (52%), and 1224 (32%) respectively. The ten most frequent drugs were involved in 78% and 65% of all potential D-, and C-interactions respectively. Furthermore, 80%, and 58% of the D-, and C-interactions respectively occurred in patients aged 12 to 17. CONCLUSIONS: We identified a limited number of drugs that were represented in the majority of potential interactions. Interactions that can lead to a reduced treatment effect constituted approximately half of D-interactions, and a third of C-interactions. The frequency of potential interactions was higher in older children. The results may contribute to increased prescriber awareness of important potential drug interactions among pediatric outpatients.

Discriminatory ability of right atrial volumes with two- and three-dimensional echocardiography to detect elevated right atrial pressure in pulmonary hypertension.

AIMS: Pulmonary hypertension (PH) patients have high mortality due to right ventricular failure. Predictors of poor prognostic outcome are increased right atrial volume (RAV) and elevated mean right atrial pressure (mRAP). Our aim was to determine whether RAV measured with 2D echocardiography (2DE) and 3D echocardiography (3DE) can detect elevated mRAP in patients evaluated for PH. METHODS: Of 85 patients prospectively evaluated for PH, 44 patients (63 ± 15 years, 57% female) had 2DE, 3DE and right heart catheterization within 48 h and were in sinus rhythm. Maximum (RAVmax ) and minimum (RAVmin ) volumes were measured with 3DE. 2D maximum RAV and RA area, inferior vena cava diameter and collapsibility were measured. Invasive mRAP > 8 mmHg was predefined as elevated. RESULTS: RAVmax and RAVmin correlated with mRAP (r = 0·40 and r = 0·35, P<0·05, for both), and so did 2DE maximum RAV (r = 0·42, P = 0·005) and RA area (r = 0·40, P = 0·008). Area under the curve (AUC) from receiver-operating characteristics curves was for 3DE 0·77 for RAVmax , 0·74 for RAVmin , from 2DE, 0·76 for maximum RAV and 0·75 for RA area to discriminate elevated mRAP (P<0·01 for all). PH patients had larger 3D RAV compared with controls (P<0·01). IVC diameter correlated with mRAP (r = 0·41, P = 0·007), but collapsibility did not (P = 0·078). AUC was neither significant for IVC diameter nor for collapsibility for predicting mRAP>8 mmHg. The optimal threshold was 57 ml m-2 for RAVmax , 31 ml m-2 for RAVmin and 36 ml m-2 for 2DE RAV. CONCLUSIONS: Enlarged RA measures with 2DE and 3DE have better discriminatory ability compared with IVC measures, to detect elevated mRAP in patients evaluated for PH.

Statistical monitoring and dynamic simulation of a wastewater treatment plant: A combined approach to achieve model predictive control.

The on-line monitoring of Chemical oxygen demand (COD) and total phosphorus (TP) restrains wastewater treatment plants to achieve better control of aeration and chemical dosing. In this study, we applied principal components analysis (PCA) to find out significant variables for COD and TP prediction. Multiple regression method applied the variables suggested by PCA to predict influent COD and TP. Moreover, a model of full-scale wastewater treatment plant with moving bed bioreactor (MBBR) and ballasted separation process was developed to simulate the performance of wastewater treatment. The predicted COD and TP data by multiple regression served as model input for dynamic simulation. Besides, the wastewater characteristic of the wastewater treatment plant and MBBR model parameters were given for model calibration. As a result, R2 of predicted COD and TP versus measured data are 81.6% and 77.2%, respectively. The model output in terms of sludge production and effluent COD based on predicted input data fitted measured data well, which provides possibility to enabled model predictive control of aeration and coagulant dosing in practice. This study provide a feasible and economical approach to overcome monitoring and modelling restrictions that limits model predictive control of wastewater treatment plant.

Changes in blood volume shunting in patients with atrial septal defects: assessment of heart function with cardiovascular magnetic resonance during dobutamine stress.

BACKGROUND: The purpose of this study was to determine the effect of stress on left-to-right shunting in patients with atrial septal defect (ASD) and to investigate if the degree of shunting, cardiac output (CO), and right ventricular (RV) volumes are related to exercise capacity. METHODS: Twenty-six patients with a secundum ASD and 16 healthy volunteers were studied with rest/stress cardiac magnetic resonance using 20 µg/kg/min dobutamine and 0.25-0.75 mg atropine to quantify CO, pulmonary to systemic flow ratio (QP/QS), and left ventricular (LV) and RV volumes. Peak oxygen uptake (VO2peak) was determined on ergospirometry. RESULTS: In patients with ASD the QP/QS decreased from 2.0 ± 0.2 at rest to 1.5 ± 0.1 (P < 0.001) during dobutamine stress (n = 20) and shunt volume per heartbeat decreased from 70 ± 9 to 38 ± 9 mL (P < 0.001). However, absolute shunt volume per minute was unchanged (5.1 ± 0.8 vs. 4.5 ± 1.0 L/min, P = 0.32) explained by a higher increase in systemic CO during stress (90 ± 11%) compared with pulmonary CO (43 ± 7%, P < 0.001). In ASD patients, VO2peak correlated with aortic CO during stress (r = 0.77) and QP/QS at rest (r = -0.48) but not during stress (P = 0.09). VO2peak did not correlate with RV volumes in patients. CONCLUSION: Pulmonary to systemic flow ratio and shunt volume per heartbeat decrease during stress in ASD patients. This may be explained by an enhanced LV diastolic function during stress and may have implications to detect disturbances in LV compliance in ASD patients. A high systemic CO during stress is a strong predictor of exercise capacity.

Ecological Effect of Solithromycin on Normal Human Oropharyngeal and Intestinal Microbiota.

Solithromycin is a new fluoroketolide. The purpose of the present study was to investigate the effect of orally administered solithromycin on the human oropharyngeal and intestinal microbiota. Thirteen healthy volunteers (median age, 27.3 years) received oral solithromycin at 800 mg on day 1 followed by 400 mg daily on days 2 to 7. Fecal and saliva samples were collected at baseline and on days 2, 5, 7, 9, 14, and 21 for pharmacokinetic and microbiological analyses. Plasma samples were collected predose on days 2, 5, and 7 as proof of exposure, and solithromycin concentration ranges were 21.9 to 258 ng/ml, 18.0 to 386 ng/ml, and 16.9 to 417 ng/ml, respectively. The solithromycin concentrations in feces were 15.8 to 65.4 mg/kg, 24.5 to 82.7 mg/kg, 21.4 to 82.7 mg/kg, 12.1 to 72.4 mg/kg, 0.2 to 25.6 mg/kg, and 0 to 0.5 mg/kg on days 2, 5, 7, 9, 14, and 21, respectively. The numbers of enterobacteria and enterococci decreased and were normalized on day 14. The numbers of lactobacilli and bifidobacteria decreased from day 2 to day 14 and were normalized on day 21. The clostridia decreased on days 2, 7, and 14 and were normalized on day 21. No Clostridium difficile strains or toxins were detected during the study period. The number of Bacteroides strains was not significantly changed. The solithromycin concentrations in saliva were 0 to 1.2 mg/liter, 0 to 0.5 mg/liter, 0 to 0.5 mg/liter, and 0 to 0.1 mg/liter on days 2, 5, 7, and 9, respectively. The numbers of streptococci decreased on day 2 and were normalized on day 5. The numbers of lactobacilli, prevotellae, fusobacteria, and leptotrichiae decreased from day 2 and were normalized on day 21.

[Few drugs dominate among clinically important interactions. Swedish register study lists problem drugs]. / Fåtal läkemedel dominerar bland kliniskt viktiga interaktioner--Svensk registerstudie listar problemläkemedel.

In a recent Swedish register study, a limited number of specific drugs explained a large part of clinically relevant, potential drug-drug interactions (DDI), as defined and detected by the DDI database SFINX. Regarding interactions that should be avoided according to the definition in the database (class D), 15 drug combinations accounted for as much as 80 % of the prevalence in the Swedish population. Ten specific drugs were involved in 94 % of all detected class D interactions. About half of the clinically relevant interactions detected during the four-month study period were associated with an increased risk of adverse drug reactions, whereas the other half has a potential to cause therapeutic failure. An increased awareness among prescribers of these interacting drugs could contribute to safer and more effective drug use.

A limited number of prescribed drugs account for the great majority of drug-drug interactions.

PURPOSE: The purpose of this study was to investigate the prevalence of prescribed combinations of interacting drugs in the Swedish population. METHODS: This study design was retrospective and cross-sectional, based on a national register of dispensed prescription drugs during the period from January 1 to April 30, 2010. Prescription data was linked to the drug-drug interaction database SFINX to yield the prevalence of interacting combinations dispensed in the population. The study focused in particular on C- (clinically relevant interactions that can be handled, e.g. by dose adjustments), and D-interactions (clinically relevant interactions that should be avoided). RESULTS: Thirty-eight and 3.8 % of the population were dispensed combinations of drugs classified as C- or D- interactions, respectively, i.e. clinically relevant, involving all therapeutic areas. Half of the D-interactions were associated with increased risk of adverse drug reactions whereas the other half were considered interactions with a potential to cause therapeutic failure. We identified a top 15 list of D-interactions that included 80 % of the total number of interacting drug combinations. Regarding individual drugs, a group of only ten drugs was involved in as much as 94 % of all D-interactions. CONCLUSIONS: This study reveals that the majority of prescribed interacting drug combinations in Sweden involve a limited number of drugs. The findings may increase the awareness among prescribers of these most common drug interactions in clinical practice and highlight an area for pharmacological education. It may also serve as an inventory of potential interactions within different therapeutic areas for further research.

Risperidone metabolic ratio as a biomarker of individual CYP2D6 genotype in schizophrenic patients.

PURPOSE: The purpose of the present study was to investigate the predictive value of the risperidone metabolic ratio for the individual CYP2D6 genotype. METHODS: The determination of risperidone, 9-hydroxyrisperidone, and CYP2D6 genotype was performed in 89 schizophrenic patients. The receiver operator characteristic (ROC) method and the area under the ROC curve (AUC) were used to illustrate the predictive value of risperidone metabolic ratio for the individual CYP2D6 genotype. The area under the ROC curve (AUC) was used as a global measure of this predictive value. To evaluate the proposed cutoff levels of >1 and <0.1 to identify individuals with a poor or ultrarapid CYP2D6 genotype the sensitivity, specificity, positive predictive value and negative predictive were calculated. RESULTS: The area under the ROC curve (AUC) for poor and ultrarapid metabolisers was 0.85 and 0.86, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of a risperidone/9-OH-risperidone ratio >1 to CYP2D6 poor metaboliser genotype were 75 %, 95 %, 60 % and 97 %, respectively. The corresponding measures for a metabolic ratio < 0.1 to predict ultrarapid metabolisers were 80 %, 77 %, 18 % and 98 %. CONCLUSIONS: A metabolic ratio > 1 or < 0.1 may be a useful therapeutic biomarker to recommend CYP2D6 genetic testing to guide the present or future treatment of patients in need of psychotropic drugs.

Manual correction of semi-automatic three-dimensional echocardiography is needed for right ventricular assessment in adults; validation with cardiac magnetic resonance.

BACKGROUND: Three-dimensional echocardiography (3DE) and semi-automatic right ventricular delineation has been proposed as an appropriate method for right ventricle (RV) evaluation. We aimed to examine how manual correction of semi-automatic delineation influences the accuracy of 3DE for RV volumes and function in a clinical adult setting using cardiac magnetic resonance (CMR) as the reference method. We also examined the feasibility of RV visualization with 3DE. METHODS: 62 non-selected patients were examined with 3DE (Sonos 7500 and iE33) and with CMR (1.5T). Endocardial RV contours of 3DE-images were semi-automatically assessed and manually corrected in all patients. End-diastolic (EDV), end-systolic (ESV) volumes, stroke volume (SV) and ejection fraction (EF) were computed. RESULTS: 53 patients (85%) had 3DE-images feasible for examination. Correlation coefficients and Bland Altman biases between 3DE with manual correction and CMR were r = 0.78, -22 ± 27 mL for EDV, r = 0.83, -7 ± 16 mL for ESV, r = 0.60, -12 ± 18 mL for SV and r = 0.60, -2 ± 8% for EF (p < 0.001 for all r-values). Without manual correction r-values were 0.77, 0.77, 0.70 and 0.49 for EDV, ESV, SV and EF, respectively (p < 0.001 for all r-values) and biases were larger for EDV, SV and EF (-32 ± 26 mL, -21 ± 15 mL and - 6 ± 9%, p ≤ 0.01 for all) compared to manual correction. CONCLUSION: Manual correction of the 3DE semi-automatic RV delineation decreases the bias and is needed for acceptable clinical accuracy. 3DE is highly feasible for visualizing the RV in an adult clinical setting.

Comparison of different views with three-dimensional echocardiography: apical views offer superior visualization compared with parasternal and subcostal views.

Studies seeking to validate real-time three-dimensional echocardiography (3DE) with regard to cardiac function and dimensions have almost exclusively used apical views. However, it has never been examined whether apical views are preferable to parasternal or subcostal views. In the present study, we compared the feasibility of 3DE volumetric measurements of the four heart chambers in three different views. We included 40 patients planned for a routine two-dimensional transthoracic echocardiography examination (2DE). All patients were scanned with both 2DE and 3DE (Sonos 7500; Philips Medical Systems Andover, MA, USA). Parasternal, apical and subcostal views were used for 3DE. Volumes were calculated using manual tracing in 16 planes. 2DE was performed in parasternal longaxis, subcostal and apical four- and two-chamber views. Manual tracing was used for area calculations. To be judged fully traceable, 5/6 (85%) or more of the ventricular and atrial walls had to be adequately visualized in each plane. The left ventricle and left atrium were adequately visualized in the 3DE apical view in 34 (85%) and 40 (100%) patients, respectively. Visualization of the right atrium was adequate in 31 (78%) patients, whereas the right ventricle was adequately visualized in only 12 (30%) patients. The apical view of 3DE provided superior visualization of all four heart chambers compared with the parasternal and subcostal views, when applying a slight off-axis approach for both ventricles when needed. Thus, in the present study, there was no incremental value of assessment of chamber volumes in the parasternal and subcostal views.

Intracardiac thrombus in adults with the Fontan circulation.

OBJECTIVES: To determine the treatment and outcomes of a cohort of adults with the Fontan circulation diagnosed with intracardiac thrombus. BACKGROUND: Formation of thrombus is common after the Fontan operation, albeit little has been published on the treatment and outcomes of these patients once they have developed an intracardiac thrombus. METHODS: We identified all patients who had been converted to the Fontan circulation from the cardiology database at the Toronto Congenital Cardiac Centre for Adults, Toronto, and The Royal Brompton Hospital, London, studying the period from 1981 to 2003. We then reviewed the relevant echocardiograms and medical records. RESULTS: Intracardiac thrombus was identified in 28 of 235 patients with the Fontan circulation, the patients having an average age of 27 plus or minus 9 years. Of the patients, 21 were initially medically treated, 19 with heparin or warfarin, and 2 with thrombolysis, whereas 7 patients underwent immediate surgical removal of the clot. Overall mortality was 18%, with residual clots seen in 39% of surviving patients at 1 year of follow up. At presentation, the haemodynamic stability of each patient with intracardiac thrombus dictated initial strategies for management, with 17% of those with stable presentations undergoing immediate surgical treatment, as opposed to 75% of those with unstable presentations (p-value equals 0.04), as well as correlating with ultimate clinical outcome. The rate of death was 8% in haemodynamically stable patients, versus 75% in haemodynamically unstable patients (p value equals 0.01). CONCLUSION: Formation of intracardiac thrombus is not rare in adults with the Fontan circulation, and carries a significant risk of death, especially in clinically unstable patients. Emphasis on prevention of formation of the clot is warranted.

Comparison of echocardiographic and cardiac magnetic resonance imaging for assessing right ventricular function in adults with repaired tetralogy of fallot.

Adults with repaired tetralogy of Fallot and significant chronic pulmonary regurgitation are at risk for progressive right ventricular (RV) dilatation and dysfunction. The assessment of RV function is important in the management in these patients. There is still a lack of an adequate geometric model to quantify RV function by echocardiography. The myocardial performance index (MPI) is a nonvolumetric method to quantify global ventricular function. In this study, the accuracy of MPI obtained by echocardiography to quantify RV function was assessed in 57 adults with repaired tetralogy of Fallot. The MPI measurement was compared with the RV ejection fraction (EF) derived by cardiac magnetic resonance imaging. There was a negative linear correlation between the MPI and the RVEF (r = 0.73, p <0.001). A MPI cutoff of > or =0.40 had a sensitivity of 81% and a specificity of 85% to diagnose a RVEF <35%. A MPI cutoff of <0.25 had a sensitivity of 70% and a specificity of 89% to identify patients with RVEFs > or =0.50. In a multivariate regression model, the MPI was not affected by the degree of pulmonary regurgitation, the presence of tricuspid regurgitation, or the QRS duration. In conclusion, the Doppler-derived MPI is a simple and reliable method for the evaluation of RV systolic function in adults with repaired tetralogy of Fallot.

Topography characterization of a deep grating using near-field imaging.

Using near-field optical microscopy at the wavelength of 633 nm, we image light intensity distributions at several distances above an approximately 2-microm-deep and a 1-microm-period glass grating illuminated from below under the condition of total internal reflection. The intensity distributions are numerically modeled, and an inversion procedure based on a least-squares-fit optimization is employed to extract the grating geometry from the optical images.