Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

A multiarm randomized field trial evaluating strategies for udder health improvement in Swiss dairy herds.

The aims of this study were to quantify the effectiveness of specialist advice about udder health in Swiss dairy herds and to compare 3 different udder health improvement strategies against a negative control group. In 2010, 100 Swiss dairy herds with a high (between 200,000 and 300,000 cells/mL) yield-corrected bulk milk somatic cell count (YCBMSCC) were recruited for a 1-yr multiarm randomized field trial. The herds were visited between September and December 2011 to evaluate udder health-management practices and then randomly allocated into 1 of 4 study arms containing 25 herds each. The negative control study arm received neither recommendations for improving udder health nor any active support. The remaining 75 farmers received a herd-specific report with recommendations to improve udder health management. The positive control study arm received no further active support during 2012. The veterinarian study arm received additional support in the form of monthly visits by their herd veterinarian. Finally, the study group study arm received support in the form of bimonthly study group meetings where different topics concerning udder health were discussed. One year later, implementation of recommendations and changes in udder health were assessed. Of the recommendations given, 44.3% were completely implemented, 23.1% partially, and 32.6% were not implemented. No differences in implementation of recommendations were noted between the 3 study arms. At study enrollment, farmers were asked for the study arm of their preference but were subsequently randomly assigned to 1 of the 4 study arms. Farmers that were assigned to the study arm of their preference implemented more recommendations than farmers assigned to a study arm not of their preference. No decrease in the within-herd prevalence of cows that had a high (≥200,000 cells/mL) composite somatic cell count was observed in herds that had a YCBMSCC ≥200,000 cells/mL at the start of intervention. However, the 3 study arms with intervention (positive control, the veterinarian, and the study groups) prevented an increase in the within-herd prevalence of cows that had a high somatic cell count in herds with a low YCBMSCC at the start of the intervention compared with the negative control study arm. In the year after sending the report, herds assigned to the study group study arm had a reduced incidence rate of treated mastitis cases in comparison with the year before sending the report.

Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial

IMPORTANCE High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN54371254.

Neutrophil expression of ICAM1, CXCR1, and VEGFR1 in patients with breast cancer before and after adjuvant chemotherapy

BACKGROUND Distinct populations of neutrophils have been identified based on the expression of intercellular adhesion molecule 1 (ICAM1, CD54) and chemokine receptor 1 (CXCR1, interleukin 8 receptor α). AIM We analyzed the expression of vascular endothelial growth factor receptor 1 (VEGFR1), a physiological negative regulator of angiogenesis, on distinct populations of neutrophils from the blood of patients before and after adjuvant chemotherapy for breast cancer. MATERIALS AND METHODS Neutrophil populations were distinguished as reverse transmigrated (ICAM1(high)/CXCR1(low)), naïve (ICAM1(low)/CXCR1(high)), or tissue-resident neutrophils (ICAM1(low)/CXCR1(low)), and their VEGFR1 expression quantified. RESULTS Reverse transmigrated ICAM1(high)/CXCR1(low) neutrophilic granulocytes decreased significantly after chemotherapy and these were also the cells with highest mean fluorescence intensity for VEGFR1. CONCLUSION Chemotherapy mainly reduces the number of reverse transmigrated long-lived ICAM1(high)/CXCR1(low) VEGFR1-expressing neutrophils. The decrease of antiangiogenic VEGFR1 may have a potential impact on tumour angiogenesis in patients undergoing adjuvant chemotherapy.

Associations between the decrease in bovine clinical mastitis and changes in dairy farmers' attitude, knowledge, and behavior in the Netherlands.

The aim of this study was to associate changes in dairy farmers' self-reported attitude, knowledge, and behavior with the decrease in incidence rate of clinical mastitis (IRCM). Farmer-diagnosed clinical mastitis cases were obtained from two surveys conducted before (July 2004-June 2005) and at the end (2009) of a mastitis control program in the Netherlands. Information on farmers' attitude, knowledge, and behavior was also obtained by sending the farmers the same questionnaire during both surveys. Multivariable linear regression models identified that the herd level 2004 IRCM explained 28% of the variation in the decrease of IRCM. Changes in farmers' attitude and knowledge, and changes in farmers' behavior additionally explained 24% and 5%, respectively. These results suggest that the way management measures are executed may be at least as important as the fact that they are executed. No control group was available for this study because the intervention was applied at the national level. We therefore do not claim any causal relationships.

GOCE: assessment of GPS-only gravity field determination

The GOCE satellite was orbiting the Earth in a Sun-synchronous orbit at a very low altitude for more than 4 years. This low orbit and the availability of high-quality data make it worthwhile to assess the contribution of GOCE GPS data to the recovery of both the static and time-variable gravity fields. We use the kinematic positions of the official GOCE precise science orbit (PSO) product to perform gravity field determination using the Celestial Mechanics Approach. The generated gravity field solutions reveal severe systematic errors centered along the geomagnetic equator. Their size is significantly coupled with the ionospheric density and thus generally increasing over the mission period. The systematic errors may be traced back to the kinematic positions of the PSO product and eventually to the ionosphere-free GPS carrier phase observations used for orbit determination. As they cannot be explained by the current higher order ionospheric correction model recommended by the IERS Conventions 2010, an empirical approach is presented by discarding GPS data affected by large ionospheric changes. Such a measure yields a strong reduction of the systematic errors along the geomagnetic equator in the gravity field recovery, and only marginally reduces the set of useable kinematic positions by at maximum 6 % for severe ionosphere conditions. Eventually it is shown that GOCE gravity field solutions based on kinematic positions have a limited sensitivity to the largest annual signal related to land hydrology.

Childhood cancer survivor cohorts in Europe.

With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia - PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCareSurFup and PanCareLIFE. Overall goal. The overall goal of these large cohort studies is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers.

Mycoplasma bovis infections in Swiss dairy cattle: a clinical investigation

Mycoplasma bovis causes mastitis in dairy cows and is associated with pneumonia and polyarthritis in cattle. The present investigation included a retrospective case–control study to identify potential herd-level risk factors for M. bovis associated disease, and a prospective cohort study to evaluate the course of clinical disease in M. bovis infected dairy cattle herds in Switzerland. Eighteen herds with confirmed M. bovis cases were visited twice within an average interval of 75 d. One control herd with no history of clinical mycoplasmosis, matched for herd size, was randomly selected within a 10 km range for each case herd. Animal health data, production data, information on milking and feeding-management, housing and presence of potential stress- factors were collected. Composite quarter milk samples were aseptically collected from all lactating cows and 5% of all animals within each herd were sampled by nasal swabs. Organ samples of culled diseased cows were collected when logistically possible. All samples were analyzed by real-time polymerase chain reaction (PCR). In case herds, incidence risk of pneumonia, arthritis and clinical mastitis prior to the first visit and incidence rates of clinical mastitis and clinical pneumonia between the two visits was estimated. Logistic regression was used to identify potential herd-level risk factors for M. bovis infection. In case herds, incidence risk of M. bovis mastitis prior to the first visit ranged from 2 to 15%, whereas 2 to 35% of the cows suffered from clinical pneumonia within the 12 months prior to the first herd visit. The incidence rates of mycoplasmal mastitis and clinical pneumonia between the two herd visits were low in case herds (0–0.1 per animal year at risk and 0.1-0.6 per animal year at risk, respectively). In the retrospective-case-control study high mean milk production, appropriate stimulation until milk-let-down, fore-stripping, animal movements (cattle shows and trade), presence of stress-factors, and use of a specific brand of milking equipment, were identified as potential herd-level risk factors. The prospective cohort study revealed a decreased incidence of clinical disease within three months and prolonged colonization of the nasal cavity by M. bovis in young stock.

Early developmental, temperamental and educational problems in ‘substance use disorder’ patients with and without ADHD. Does ADHD make a difference?

Introduction: The prevalence of ADHD among patients with substance use disorder (SUD) is substantial. This study addressed the following research questions: Are early developmental, temperamental and educational problems overrepresented among SUD patients with ADHD compared to SUD patients without ADHD? Do this comorbid group receive early help for their ADHD, and are there signs of self-medicating with illicit central stimulants? Method: An international, multi-centre cross-sectional study was carried out involving seven European countries, with 1205 patients in treatment for SUD. The mean age was 40 years and 27% of the sample was female. All par- ticipants were interviewed with the Mini International Neuropsychiatric Interview Plus and the Conners' Adult ADHD Diagnostic Interview for DSM-IV. Results: SUD patients with ADHD (n = 196; 16.3% of the total sample) had a significantly slower infant develop- ment than SUD patients without ADHD (n = 1,009; 83.4%), had greater problems controlling their temperament, and had lower educational attainment. Only 24 (12%) of the current ADHD positive patients had been diagnosed and treated during childhood and/or adolescence. Finally, SUD patients with ADHD were more likely to have central stimulants or cannabis as their primary substance of abuse, whereas alcohol use was more likely to be the primary substance of abuse in SUD patients without ADHD. Conclusion: The results emphasize the importance of early identification of ADHD and targeted interventions in the health and school system, as well as in the addiction field.

Risk factors for borderline personality disorder in treatment seeking patients with a substance use disorder: an international multicenter study

Borderline personality disorder (BPD) and substance use disorders (SUDs) often co-occur, partly because they share risk factors. In this international multicenter study, risk factors for BPD were examined for SUD patients. In total, 1,205 patients were comprehensively examined by standardized interviews and questionnaires on psychiatric diagnosis and risk factors, and it was found that 1,033 (85.7%) had SUDs without BPD (SUD) and 172 (14.3%) had SUD with BPD (SUD + BPD). SUD + BPD patients were significantly younger, more often females and more often diagnosed with comorbid adult attention deficit/hyperactivity disorder. SUD + BPD patients did not differ from SUD patients on most risk factors typical for SUD such as maternal use of drugs during pregnancy or parents having any SUD. However, SUD + BPD patients did have a higher risk of having experienced emotional and physical abuse, neglect, or family violence in childhood compared to SUD patients, suggesting that child abuse and family violence are BPD-specific risk factors in patients with SUDs. © 2015 S. Karger AG, Basel.

Mobility and Bandwidth Prediction as a Service in Virtualized LTE Systems

Recently telecommunication industry benefits from infrastructure sharing, one of the most fundamental enablers of cloud computing, leading to emergence of the Mobile Virtual Network Operator (MVNO) concept. The most momentous intents by this approach are the support of on-demand provisioning and elasticity of virtualized mobile network components, based on data traffic load. To realize it, during operation and management procedures, the virtualized services need be triggered in order to scale-up/down or scale-out/in an instance. In this paper we propose an architecture called MOBaaS (Mobility and Bandwidth Availability Prediction as a Service), comprising two algorithms in order to predict user(s) mobility and network link bandwidth availability, that can be implemented in cloud based mobile network structure and can be used as a support service by any other virtualized mobile network services. MOBaaS can provide prediction information in order to generate required triggers for on-demand deploying, provisioning, disposing of virtualized network components. This information can be used for self-adaptation procedures and optimal network function configuration during run-time operation, as well. Through the preliminary experiments with the prototype implementation on the OpenStack platform, we evaluated and confirmed the feasibility and the effectiveness of the prediction algorithms and the proposed architecture.