Comprehensive left atrial flow component analysis reveals abnormal flow patterns in paroxysmal atrial fibrillation.

Left atrial (LA) blood flow plays an important role in diseases such as atrial fibrillation (AF) and atrial cardiomyopathy since alterations in the blood flow might lead to thrombus formation and stroke. Using traditional techniques, such as echocardiography, atrial flow velocities can be measured at the pulmonary veins and the mitral valve, but a comprehensive understanding of the three-dimensional atrial flow field is missing. Previously, ventricular flow has been analyzed using flow component analysis, revealing new insights into ventricular flow and function. Thus, the aim of this project was to develop a comprehensive flow component analysis method for the LA and explore its utility in 21 patients with paroxysmal atrial fibrillation compared with a control group of 8 participants. The flow field was derived from time-resolved CT acquired during sinus rhythm using computational fluid dynamics. Flow components were computed from particle tracking. We identified six atrial flow components: conduit, reservoir, delayed ejection, retained inflow, residual volume, and pulmonary vein backflow. It was shown that conduit flow, defined as blood entering and leaving the LA within the same diastolic phase, exists in most subjects. Although the volume of conduit and reservoir is similar in patients with paroxysmal AF in sinus rhythm and controls, the volume of the other components is increased in paroxysmal AF. Comprehensive quantification of LA flow using flow component analysis makes atrial blood flow quantifiable, thus facilitating investigation of mechanisms underlying atrial dysfunction and can increase understanding of atrial blood flow in disease progression and stroke risk.NEW & NOTEWORTHY We developed a new comprehensive approach to atrial blood component analysis that includes both conduit flow and residual volume and compared the flow components of atrial fibrillation (AF) patients in sinus rhythm with controls. Conduit and reservoir flow were similar between the groups, whereas components with longer residence time in the left atrium were increased in the AF group. This could add to the pathophysiological understanding of atrial diseases and possibly clinical management.

Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease.

BACKGROUND: The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease. METHODS: We conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated-device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality. RESULTS: No patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated-device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated-device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated-device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively). CONCLUSIONS: In this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT02051088.).

Long-term antithrombotic therapy after coronary artery bypass grafting in patients with preoperative atrial fibrillation. A nationwide observational study from the SWEDEHEART registry.

AIMS: To provide data guiding long-term antithrombotic therapy after coronary artery by-pass grafting (CABG) in patients with preoperative atrial fibrillation (AF). METHODS AND RESULTS: From the SWEDEHEART registry, we included all patients, between January 2006 and September 2016, with preoperative AF and CHA2DS2-VASC score ≥2, undergoing CABG. Based on dispensed prescriptions 12 to 18 months after CABG, patients were divided in 3 groups: use of platelet inhibitors (PI) only, oral anticoagulant (OAC) only or a combination of OAC + PI. Outcomes were: Major adverse cardiac and cerebrovascular events (MACCE, [all-cause death, myocardial infarction, or stroke]), net adverse clinical events (NACE, [MACCE or bleeding]) and the individual components of NACE. Inverse probability of treatment weighting was used to adjust for the non-randomized study design. Among 2,564 patients, 1,040 (41%) were treated with PI alone, 1,064 (41%) with OAC alone, and 460 (18%) with PI + OAC. Treatment with PI alone was associated with higher risk for MACCE (adjusted HR 1.43, 95% CI 1.09-1.88), driven by higher risk for stroke and MI, compared with OAC alone. Treatment with PI + OAC, was associated with higher risk for NACE (adjusted HR 1.40, 95% CI 1.06-1.85), driven by higher risk for bleeds, compared with OAC alone. CONCLUSION: In this real-world observational study, a high proportion of patients with AF, undergoing CABG, did not receive a long-term OAC therapy. Treatment with OAC alone was associated with a net clinical benefit, compared with PI alone or PI + OAC.

Predictors of recurrence after catheter ablation and electrical cardioversion of atrial fibrillation: an umbrella review of meta-analyses.

AIMS: The recurrence rates after catheter ablation (CA) and direct current (DC) cardioversion remain high, although they have been established treatments of rhythm control of atrial fibrillation (AF). This umbrella review systematically appraises published meta-analyses of both observational and randomized controlled trials (RCTs) for the association of risk and protective factors for arrhythmia recurrence after CA and DC cardioversion of AF. METHODS AND RESULTS: Three bibliographic databases were searched up to June 2021. Evidence of association was rated as convincing, highly suggestive, suggestive, weak, or not significant with respect to observational studies and as high, moderate, low, or very low with respect to RCTs, according to established criteria. Thirty-one meta-analyses were included. Of the 28 associations between CA and the risk of arrhythmia recurrence, none presented convincing evidence, and only the time from diagnosis to ablation over 1 year provided highly suggestive evidence. The association between hypertension and metabolic profile provided suggestive evidence. The associations of Class IC and III antiarrhythmic drugs use with the recurrence after DC cardioversion were supported by an intermediate level of evidence. CONCLUSION: Although AF is a major health issue, few risk- and protective factors for AF recurrence have been identified. None of these factors examined were supported by convincing evidence, whereas established factors such as female gender and left atrial volume showed only weak association. An early CA strategy combined with treatment of metabolic syndrome and hypertension prior to CA may reduce the risk of arrhythmia recurrence. The use of antiarrhythmics can increase the success rate of DC cardioversion. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number: CRD42021270613.

Comparing efficacy and safety in catheter ablation strategies for atrial fibrillation: a network meta-analysis.

BACKGROUND: There is no consensus on the most efficient catheter ablation (CA) strategy for patients with atrial fibrillation (AF). The objective of this study was to compare the efficacy and safety of different CA strategies for AF ablation through network meta-analysis (NMA). METHODS: A systematic search of PubMed, Web of Science, and CENTRAL was performed up to October 5th, 2020. Randomized controlled trials (RCT) comparing different CA approaches were included. Efficacy was defined as arrhythmia recurrence after CA and safety as any reported complication related to the procedure during a minimum follow-up time of 6 months. RESULTS: In total, 67 RCTs (n = 9871) comparing 19 different CA strategies were included. The risk of recurrence was significantly decreased compared to pulmonary vein isolation (PVI) alone for PVI with renal denervation (RR: 0.60, CI: 0.38-0.94), PVI with ganglia-plexi ablation (RR: 0.62, CI: 0.41-0.94), PVI with additional ablation lines (RR: 0.8, CI: 0.68-0.95) and PVI in combination with bi-atrial modification (RR: 0.32, CI: 0.11-0.88). Strategies including PVI appeared superior to non-PVI strategies such as electrogram-based approaches. No significant differences in safety were observed. CONCLUSIONS: This NMA showed that PVI in combination with additional CA strategies, such as autonomic modulation and additional lines, seem to increase the efficacy of PVI alone. These strategies can be considered in treating patients with AF, since, additionally, no differences in safety were observed. This study provides decision-makers with comprehensive and comparative evidence about the efficacy and safety of different CA strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number: CRD42020169494 .

Clinical decision support for familial hypercholesterolemia (CDS-FH): Rationale and design of a cluster randomized trial in primary care.

BACKGROUND: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder with high risk of premature atherosclerotic cardiovascular disease and death. Clinical decision support (CDS) systems have the potential to aid in the identification and management of patients with FH. Prior studies using computer-based systems to screen patients for FH have shown promising results, but there has been no randomized controlled trial conducted. The aim of the current cluster randomized study is to evaluate if a CDS can increase the identification of FH. METHODS: We have developed a CDS integrated in the electronic health records that will be activated in patients with elevated cholesterol levels (total cholesterol >8 mmol/L or low-density lipoprotein-cholesterol >5.5 mmol/L, adjusted for age, ongoing lipid lowering therapy and presence of premature coronary artery disease) at increased risk for FH. When activated, the CDS will urge the physician to send an automatically generated referral to the local lipid clinic for further evaluation. To evaluate the effects of the CDS, all primary care clinics will be cluster randomized 1:1 to either CDS intervention or standard care in a Swedish region with almost 500,000 inhabitants. The primary endpoint will be the number of patients diagnosed with FH at 30 months. Resource use and long-term health consequences will be estimated to assess the cost-effectiveness of the intervention. CONCLUSION: Despite increasing awareness of FH, the condition remains underdiagnosed and undertreated. The present study will investigate whether a CDS can increase the number of patients being diagnosed with FH.

Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers.

INTRODUCTION: Whether detailed genetic information contributes to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. Pathogenic genetic variants in some genes seem to carry a higher risk for arrhythmia and earlier disease onset than others, but comparisons between variants in the same gene have not been done. Combined Annotation Dependent Depletion (CADD) score is a bioinformatics tool that measures the pathogenicity of each genetic variant. We hypothesized that a higher CADD score is associated with arrhythmic events and earlier age at ARVC manifestations in individuals carrying pathogenic or likely pathogenic genetic variants in plakophilin-2 (PKP2). METHODS: CADD scores were calculated using the data from pooled Scandinavian and North American ARVC cohorts, and their association with cardiac events defined as ventricular tachycardia/ventricular fibrillation (VT/VF) or syncope and age at definite ARVC diagnosis were assessed. RESULTS: In total, 33 unique genetic variants were reported in 179 patients (90 males, 71 probands, 96 with definite ARVC diagnosis at a median age of 35 years). Cardiac events were reported in 76 individuals (43%), of whom 53 had sustained VT/VF (35%). The CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p = 0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p = 0.731). CONCLUSION: No correlation was found between CADD scores and clinical manifestations of ARVC, indicating that the score has no additional risk stratification value among carriers of pathogenic or likely pathogenic PKP2 genetic variants.

A decade of catheter ablation of cardiac arrhythmias in Sweden: ablation practices and outcomes.

AIMS: Catheter ablation is considered the treatment of choice for many tachyarrhythmias, but convincing 'real-world' data on efficacy and safety are lacking. Using Swedish national registry data, the ablation spectrum, procedural characteristics, as well as ablation efficacy and reported adverse events are reported. METHODS AND RESULTS: Consecutive patients (≥18 years of age) undergoing catheter ablation in Sweden between 01 January 2006 and 31 December 2015 were included in the study. Follow-up (repeat ablation and vital status) was collected through 31 December 2016. A total of 26 642 patients (57 ± 15 years, 62% men), undergoing a total of 34 428 ablation procedures were included in the study. In total, 4034 accessory pathway/Wolff-Parkinson-White syndrome (12%), 7358 AV-nodal re-entrant tachycardia (21%), 1813 atrial tachycardia (5.2%), 5481 typical atrial flutter (16%), 11 916 atrial fibrillation (AF, 35%), 2415 AV-nodal (7.0%), 581 premature ventricular contraction (PVC, 1.7%), and 964 ventricular tachycardia (VT) ablations (2.8%) were performed. Median follow-up time was 4.7 years (interquartile range 2.7-7.0). The spectrum of treated arrhythmias changed over time, with a gradual increase in AF, VT, and PVC ablation (P < 0.001). Decreasing procedural times and utilization of fluoroscopy with time, were seen for all arrhythmia types. The rates of repeat ablation differed between ablation types, with the highest repeat ablation seen in AF (41% within 3 years). The rate of reported adverse events was low (n = 595, 1.7%). Death in the immediate period following ablation was rare (n = 116, 0.34%). CONCLUSION: Catheter ablations have shifted towards more complex procedures over the past decade. Fluoroscopy time has markedly decreased and the efficacy of catheter ablation seems to improve for AF.

Gender and age differences in symptoms and health-related quality of life in patients with atrial fibrillation referred for catheter ablation.

BACKGROUND: Primary indication for catheter ablation of atrial fibrillation (AF) is to reduce symptoms and improve health-related quality of life (HRQoL). There are data showing differences between the genders and between younger and older patients. To evaluate this, we studied a large Scandinavian cohort of patients referred for catheter ablation of AF. METHODS: Consecutive patients filled out the ASTA questionnaire, assessing symptoms, HRQoL, and perception of arrhythmia, prior to ablation. Patients were recruited from four Swedish and one Danish tertiary center. RESULTS: A total of 2493 patients (72% men) filled out the ASTA questionnaire. Women experienced eight of the nine ASTA scale symptoms more often than men. Patients <65 years reported four symptoms more often, only tiredness was more frequent in those ≥65 years (P = .007). Women and patients <65 years experienced more often palpitations and regarding close to fainting and this was more common among women, no age differences were seen. Women and men scored differently in 10 of the 13 HRQoL items. Only negative impact on sexual life was more common in men (P < .001). Older patients reported more negative influence in four of the HRQoL items and the younger in one; ability to concentrate. CONCLUSIONS: Women experienced a more pronounced symptom burden and were more negatively affected in all HRQoL concerns, except for the negative impact on sexual life, where men reported more influence of AF. Differences between age groups were less pronounced. Disease-specific patient-reported outcomes measures (PROMs) add important information where gender differences should be considered in the care.

A clinical decision support tool for improving adherence to guidelines on anticoagulant therapy in patients with atrial fibrillation at risk of stroke: A cluster-randomized trial in a Swedish primary care setting (the CDS-AF study).

BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity, in particular stroke. Despite good evidence for the reduction of stroke risk with anticoagulant therapy, there remains significant undertreatment. The main aim of the current study was to investigate whether a clinical decision support tool (CDS) for stroke prevention integrated in the electronic health record could improve adherence to guidelines for stroke prevention in patients with AF. METHODS AND FINDINGS: We conducted a cluster-randomized trial where all 43 primary care clinics in the county of Östergötland, Sweden (population 444,347), were randomized to be part of the CDS intervention or to serve as controls. The CDS produced an alert for physicians responsible for patients with AF and at increased risk for thromboembolism (according to the CHA2DS2-VASc algorithm) without anticoagulant therapy. The primary endpoint was adherence to guidelines after 1 year. After randomization, there were 22 and 21 primary care clinics in the CDS and control groups, respectively. There were no significant differences in baseline adherence to guidelines regarding anticoagulant therapy between the 2 groups (CDS group 70.3% [5,186/7,370; 95% CI 62.9%-77.7%], control group 70.0% [4,187/6,009; 95% CI 60.4%-79.6%], p = 0.83). After 12 months, analysis with linear regression with adjustment for primary care clinic size and adherence to guidelines at baseline revealed a significant increase in guideline adherence in the CDS (73.0%, 95% CI 64.6%-81.4%) versus the control group (71.2%, 95% CI 60.8%-81.6%, p = 0.013, with a treatment effect estimate of 0.016 [95% CI 0.003-0.028]; number of patients with AF included in the final analysis 8,292 and 6,508 in the CDS and control group, respectively). Over the study period, there was no difference in the incidence of stroke, transient ischemic attack, or systemic thromboembolism in the CDS group versus the control group (49 [95% CI 43-55] per 1,000 patients with AF in the CDS group compared to 47 [95% CI 39-55] per 1,000 patients with AF in the control group, p = 0.64). Regarding safety, the CDS group had a lower incidence of significant bleeding, with events in 12 (95% CI 9-15) per 1,000 patients with AF compared to 16 (95% CI 12-20) per 1,000 patients with AF in the control group (p = 0.04). Limitations of the study design include that the analysis was carried out in a catchment area with a high baseline adherence rate, and issues regarding reproducibility to other regions. CONCLUSIONS: The present study demonstrates that a CDS can increase guideline adherence for anticoagulant therapy in patients with AF. Even though the observed difference was small, this is the first randomized study to our knowledge indicating beneficial effects with a CDS in patients with AF. TRIAL REGISTRATION: ClinicalTrials.gov NCT02635685.

Formation of Blood Foam in the Air Trap During Hemodialysis Due to Insufficient Automatic Priming of Dialyzers.

We were encouraged to investigate the reasons for large amounts of foam observed in bloodlines during hemodialysis (HD). Foam was visible in the venous air trap within the Artis Gambro dialysis device. Estimates of the extent of foam were graded (0-no foam, 10-extensive foam) by two persons that were blind to the type of dialyzer used. Thirty-seven patients were involved in the dialysis procedures. Consecutive dialyses were graded using dialyzers from Fresenius Medical Care (CorDiax dialyzers that were used for high flux HD-FX80 and FX100, and for hemodiafiltration-FX1000). The extracorporeal circuit was primed automatically by dialysate using Gambro Artis software 8.15 006 (Gambro, Dasco, Medolla Italy, Baxter, Chicago, IL, USA). The priming volume recommended by the manufacturer was 1100 mL, whereas our center uses 1500 mL. Extensive amounts of blood foam were visual in the air traps. Although the manufacturer recommended extension of priming volume up to 3000 mL, this did not eliminate the foam. Microbubble measurement during HD revealed the air to derive from the dialyzers. When changing to PF210H dialyzers (Baxter) and using a priming volume of 1500 mL, the foam was significantly less (P < 0.01). The extent of foam correlated with the size of the FX-dialyzer surface (P = 0.002). The auto-priming program was updated to version 8.21 by the manufacturer and the extent of foam in the air trap using FX dialyzers was now reduced and there was no longer a difference between FX and PF dialyzers, although less foam was still visible in the venous air trap during several dialyses. In conclusion, this study urgently calls attention to blood foam development in the venous air trap when using Artis devices and priming software 8.15 in combination with Fresenius dialyzers. Updated auto-priming software (version 8.21) of Artis should be requested to reduce the extent of foam for the Fresenius dialyzers. Other interactions may also be present. We recommend further studies to clarify these problems. Meanwhile caution is warranted for the combined use of dialysis devices and dialyzers with incompatible automatic priming.

Clinical decision support for stroke prevention in atrial fibrillation (CDS-AF): Rationale and design of a cluster randomized trial in the primary care setting.

BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity, in particular stroke. Despite good evidence for the reduction of stroke risk with anticoagulant therapy, there remains a significant undertreatment. The main aim of the current study is to investigate whether a clinical decision support tool for stroke prevention (CDS) integrated in the electronic health record can improve adherence to guidelines for stroke prevention in patients with AF. METHODS: We will conduct a cluster randomized trial where 43 primary care clinics in the county of Östergötland, Sweden (population 444,347), will be randomized to be part of the CDS intervention or serve as controls. The CDS will alert responsible physicians of patients with AF and increased risk for thromboembolism according to the CHA2DS2VASc (Congestive heart failure, Hypertension, Age ≥ 74 years, Diabetes mellitus, previous Stroke/TIA/thromboembolism, Vascular disease, Age 65-74 years, Sex category (i.e. female sex)) algorithm without anticoagulant therapy. The primary end point will be adherence to guidelines after 1 year. CONCLUSION: The present study will investigate whether a clinical decision support system integrated in an electronic health record can increase adherence to guidelines regarding anticoagulant therapy in patients with AF.

Oxysterols direct B-cell migration through EBI2.

EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein-Barr-virus infection. Recent studies indicated that this receptor controls follicular B-cell migration and T-cell-dependent antibody production. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism. The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors. Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7α,25-dihydroxycholesterol (OHC), with a dissociation constant of 450 pM for EBI2. In vitro, 7α,25-OHC stimulated the migration of EBI2-expressing mouse B and T cells with half-maximum effective concentration values around 500 pM, but had no effect on EBI2-deficient cells. In vivo, EBI2-deficient B cells or normal B cells desensitized by 7α,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7α,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7α,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T-zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice. Our results show an unexpected causal link between EBI2, an orphan G-protein-coupled receptor controlling B-cell migration, and the known immunological effects of certain oxysterols, thus uncovering a previously unknown role for this class of molecules.

An Ontology-based Context-aware System for Smart Homes: E-care@home.

Smart home environments have a significant potential to provide for long-term monitoring of users with special needs in order to promote the possibility to age at home. Such environments are typically equipped with a number of heterogeneous sensors that monitor both health and environmental parameters. This paper presents a framework called E-care@home, consisting of an IoT infrastructure, which provides information with an unambiguous, shared meaning across IoT devices, end-users, relatives, health and care professionals and organizations. We focus on integrating measurements gathered from heterogeneous sources by using ontologies in order to enable semantic interpretation of events and context awareness. Activities are deduced using an incremental answer set solver for stream reasoning. The paper demonstrates the proposed framework using an instantiation of a smart environment that is able to perform context recognition based on the activities and the events occurring in the home.

Research interest and activity among medical students in Gothenburg, Sweden, a cross-sectional study.

BACKGROUND: The proportion of physicians undertaking doctoral studies is decreasing. Early recruitment of medical students could counteract this trend. This follow-up survey investigated research interest and activity among medical students at the Sahlgrenska Academy, Gothenburg, Sweden. METHODS: A questionnaire was administered to all medical students at the Sahlgrenska Academy, as a follow-up to a 2006 survey. The Mann-Whitney U test was used for ordinal variables and the Fisher exact test for categorical variables. Data from Statistics Sweden was used to analyse the number of PhDs awarded to individuals who earned a medical degree in 2000-2012. RESULTS: Of the students, 16 % were already conducting and another 36 % wanted to conduct research during their studies. The interest was at the same level compared to 2006. The main reasons for conducting research consisted of an interest in scientific problems or the research topic, a wish for personal development or intellectual stimulation. Students engaged in research reported lack of time, increased workload and less time to study as hindering factors. CONCLUSIONS: Recruitment could be improved by offering improved and regular information, clarifying career paths, broadly announcing available projects, and creating new and expanding existing research programmes. The potential for recruitment of Gothenburg medical students to research is substantial, but students are hampered by lack of time, lack of supervisors and lack of information.

Interleukin-15-activated natural killer cells kill autologous osteoclasts via LFA-1, DNAM-1 and TRAIL, and inhibit osteoclast-mediated bone erosion in vitro.

Osteoclasts reside on bone and are the main bone resorbing cells playing an important role in bone homeostasis, while natural killer (NK) cells are bone-marrow-derived cells known to play a crucial role in immune defence against viral infections. Although mature NK cells traffic through bone marrow as well as to inflammatory sites associated with enhanced bone erosion, including the joints of patients with rheumatoid arthritis, little is known about the impact NK cells may have on mature osteoclasts and bone erosion. We studied the interaction between human NK cells and autologous monocyte-derived osteoclasts from healthy donors in vitro. We show that osteoclasts express numerous ligands for receptors present on activated NK cells. Co-culture experiments revealed that interleukin-15-activated, but not resting, NK cells trigger osteoclast apoptosis in a dose-dependent manner, resulting in drastically decreased bone erosion. Suppression of bone erosion requires contact between NK cells and osteoclasts, but soluble factors also play a minor role. Antibodies masking leucocyte function-associated antigen-1, DNAX accessory molecule-1 or tumour necrosis factor-related apoptosis-inducing ligand enhance osteoclast survival when co-cultured with activated NK cells and restore the capacity of osteoclasts to erode bone. These results suggest that interleukin-15-activated NK cells may directly affect bone erosion under physiological and pathological conditions.

Clinical and preclinical characterization of the histamine H(4) receptor antagonist JNJ-39758979.

The histamine H4 receptor (H(4)R) has been shown to have preclinical involvement in both inflammatory and pruritic responses. JNJ-39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine] is a potent and selective H(4)R antagonist with a Ki at the human receptor of 12.5 ± 2.6 nM and greater than 80-fold selectivity over other histamine receptors. The compound also exhibited excellent selectivity versus other targets. JNJ-39758979 showed dose-dependent activity in models of asthma and dermatitis consistent with other H(4)R antagonists. Preclinical toxicity studies of up to 6 months in rats and 9 months in monkeys indicated an excellent safety profile, supporting the clinical testing of the compound. An oral formulation of JNJ-39758979 was studied in a phase 1 human volunteer study to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated, with the exception of dose-dependent nausea, and no safety issues were noted in the phase 1 study. JNJ-39758979 exhibited good pharmacokinetics upon oral dosing with a plasma half-life of 124-157 hours after a single oral dose. In addition, dose-dependent inhibition of histamine-induced eosinophil shape change was detected, suggesting that the H4R was inhibited in vivo. In conclusion, JNJ-39758979 is a potent and selective H(4)R antagonist that exhibited good preclinical and phase 1 safety in healthy volunteers with evidence of a pharmacodynamics effect in humans.

Sensor network infrastructure for a home care monitoring system.

This paper presents the sensor network infrastructure for a home care system that allows long-term monitoring of physiological data and everyday activities. The aim of the proposed system is to allow the elderly to live longer in their home without compromising safety and ensuring the detection of health problems. The system offers the possibility of a virtual visit via a teleoperated robot. During the visit, physiological data and activities occurring during a period of time can be discussed. These data are collected from physiological sensors (e.g., temperature, blood pressure, glucose) and environmental sensors (e.g., motion, bed/chair occupancy, electrical usage). The system can also give alarms if sudden problems occur, like a fall, and warnings based on more long-term trends, such as the deterioration of health being detected. It has been implemented and tested in a test environment and has been deployed in six real homes for a year-long evaluation. The key contribution of the paper is the presentation of an implemented system for ambient assisted living (AAL) tested in a real environment, combining the acquisition of sensor data, a flexible and adaptable middleware compliant with the OSGistandard and a context recognition application. The system has been developed in a European project called GiraffPlus.

[Improved information in Medical School may increase recruitment of physician-scientists]. / Information på läkarprogrammet viktig för rekrytering till forskning.

The proportion of physicians undertaking doctoral studies has decreased progressively over the last years both in Sweden and internationally. To counteract this trend, it is important to investigate and improve the recruitment of medical students to research. In the fall of 2012, a questionnaire study investigating interest and involvement in research was conducted among all medical students at Sahlgrenska Academy, Gothenburg University in Sweden. The proportion of students involved in research (16 %) was unchanged from a previous similar study in 2006, and participating in a research project was considered to contribute positively to medical studies.  A large number of students (36 %) were interested in conducting research during the semesters, and the main disincentives included lack of time, lack of information, and lack of project and research group.  Research stimulating projects such as the 'Amanuensis Program' had a positive impact on research interest in general. For increased and early recruitment of medical students, efforts should be made to offer improved and regular information about conducting research, to publish available research projects and research groups, and to create and expand research programs for motivated medical students. Along with improved conditions and financial resources, we propose that these measures would help to accommodate the growing need for recruitment of medical students and physicians to research.