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Background: Medical smartphone apps and mobile health devices are rapidly entering mainstream use because of the rising number of smartphone users. Consequently, a large amount of consumer-generated data is being collected. Technological advances in innovative sensory systems have enabled data connectivity and aggregation to become cornerstones in developing workable solutions for remote monitoring systems in clinical practice. However, few systems are currently available to handle such data, especially for clinical use., Objective: The aim of this study was to develop and implement the digital health research platform for mobile health (DHARMA) that combines data saved in different formats from a variety of sources into a single integrated digital platform suitable for mobile remote monitoring studies., Methods: DHARMA comprises a smartphone app, a Web-based platform, and custom middleware and has been developed to collect, store, process, and visualize data from different vendor-specific sensors. The middleware is a component-based system with independent building blocks for user authentication, study and patient administration, data handling, questionnaire management, patient files, and reporting., Results: A prototype version of the research platform has been tested and deployed in multiple clinical studies. In this study, we used the platform for the follow-up of pregnant women at risk of developing pre-eclampsia. The patients' blood pressure, weight, and activity were semi-automatically captured at home using different devices. DHARMA automatically collected and stored data from each source and enabled data processing for the end users in terms of study-specific parameters, thresholds, and visualization., Conclusions: The increasing use of mobile health apps and connected medical devices is leading to a large amount of data for collection. There has been limited investment in handling and aggregating data from different sources for use in academic and clinical research focusing on remote monitoring studies. In this study, we created a modular mobile health research platform to collect and integrate data from a variety of third-party devices in several patient populations. The functionality of the platform was demonstrated in a real-life setting among women with high-risk pregnancies., (©Thijs Vandenberk, Valerie Storms, Dorien Lanssens, Hélène De Cannière, Christophe JP Smeets, Inge M Thijs, Tooba Batool, Yves Vanrompay, Pieter M Vandervoort, Lars Grieten. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 29.10.2019.)

Background: European Society of Cardiology guidelines for the treatment of heart failure (HF) prescribe uptitration of angiotensin-converting enzyme inhibitors (ACE-I) and β-blockers to the maximum-tolerated, evidence-based dose. Although HF prognosis can drastically improve when correctly implementing these guidelines, studies have shown that they are insufficiently implemented in clinical practice., Objective: The aim of this study was to verify whether supplementing the usual care with the CardioCoach follow-up tool is feasible and safe, and whether the tool is more efficient in implementing the guideline recommendations for β-blocker and ACE-I., Methods: A total of 25 HF patients were randomly assigned to either the usual care control group (n=10) or CardioCoach intervention group (n=15), and observed for 6 months. The CardioCoach follow-up tool is a two-way communication platform with decision support algorithms for semiautomatic remote medication uptitration. Remote monitoring sensors automatically transmit patient's blood pressure, heart rate, and weight on a daily basis., Results: Patients' satisfaction and adherence for medication intake (10,018/10,825, 92.55%) and vital sign measurements (4504/4758, 94.66%) were excellent. However, the number of technical issues that arose was large, with 831 phone contacts (median 41, IQR 32-65) in total. The semiautomatic remote uptitration was safe, as there were no adverse events and no false positive uptitration proposals. Although no significant differences were found between both groups, a higher number of patients were on guideline-recommended medication dose in both groups compared with previous reports., Conclusions: The CardioCoach follow-up tool for remote uptitration is feasible and safe and was found to be efficient in facilitating information exchange between care providers, with high patient satisfaction and adherence., Trial Registration: ClinicalTrials.gov NCT03294811; https://clinicaltrials.gov/ct2/show/NCT03294811 (Archived by WebCite at http://www.webcitation.org/6xLiWVsgM)., (©Christophe JP Smeets, Valerie Storms, Pieter M Vandervoort, Pauline Dreesen, Julie Vranken, Marita Houbrechts, Hanne Goris, Lars Grieten, Paul Dendale. Originally published in JMIR Cardio (http://cardio.jmir.org), 04.04.2018.)

Background: Remote monitoring in obstetrics is relatively new; some studies have shown its effectiveness for both mother and child. However, few studies have evaluated the economic impact compared to conventional care, and no cost analysis of a remote monitoring prenatal follow-up program for women diagnosed with gestational hypertensive diseases (GHD) has been published., Objective: The aim of this study was to assess the costs of remote monitoring versus conventional care relative to reported benefits., Methods: Patient data from the Pregnancy Remote Monitoring (PREMOM) study were used. Health care costs were calculated from patient-specific hospital bills of Ziekenhuis Oost-Limburg (Genk, Belgium) in 2015. Cost comparison was made from three perspectives: the Belgian national health care system (HCS), the National Institution for Insurance of Disease and Disability (RIZIV), and costs for individual patients. The calculations were made for four major domains: prenatal follow-up, prenatal admission to the hospital, maternal and neonatal care at and after delivery, and total amount of costs. A simulation exercise was made in which it was calculated how much could be demanded of RIZIV for funding the remote monitoring service., Results: A total of 140 pregnancies were included, of which 43 received remote monitoring (30.7%) and 97 received conventional care (69.2%). From the three perspectives, there were no differences in costs for prenatal follow-up. Compared to conventional care, remote monitoring patients had 34.51% less HCS and 41.72% less RIZIV costs for laboratory test results (HCS: mean €0.00 [SD €55.34] vs mean €38.28 [SD € 44.08], P<.001; RIZIV: mean €21.09 [SD €27.94] vs mean €36.19 [SD €41.36], P<.001) and a reduction of 47.16% in HCS and 48.19% in RIZIV costs for neonatal care (HCS: mean €989.66 [SD €3020.22] vs mean €1872.92 [SD €5058.31], P<.001; RIZIV: mean €872.97 [SD €2761.64] vs mean €1684.86 [SD €4702.20], P<.001). HCS costs for medication were 1.92% lower in remote monitoring than conventional care (mean €209.22 [SD €213.32] vs mean €231.32 [SD 67.09], P=.02), but were 0.69% higher for RIZIV (mean €122.60 [SD €92.02] vs mean €121.78 [SD €20.77], P<.001). Overall HCS costs for remote monitoring were mean €4233.31 (SD €3463.31) per person and mean €4973.69 (SD €5219.00) per person for conventional care (P=.82), a reduction of €740.38 (14.89%) per person, with savings mainly for RIZIV of €848.97 per person (23.18%; mean €2797.42 [SD €2905.18] vs mean €3646.39 [SD €4878.47], P=.19). When an additional fee of €525.07 per month per pregnant woman for funding remote monitoring costs is demanded, remote monitoring is acceptable in their costs for HCS, RIZIV, and individual patients., Conclusions: In the current organization of Belgian health care, a remote monitoring prenatal follow-up of women with GHD is cost saving for the global health care system, mainly via savings for the insurance institution RIZIV., (©Dorien Lanssens, Thijs Vandenberk, Christophe JP Smeets, Hélène De Cannière, Sharona Vonck, Jade Claessens, Yenthel Heyrman, Dominique Vandijck, Valerie Storms, Inge M Thijs, Lars Grieten, Wilfried Gyselaers. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.03.2018.)

Background: The use of implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) devices is expanding in the treatment of heart failure. Most of the current devices are equipped with remote monitoring functions, including bioimpedance for fluid status monitoring. The question remains whether bioimpedance measurements positively impact clinical outcome., Objective: The aim of this study was to provide a comprehensive overview of the clinical interventions taken based on remote bioimpedance monitoring alerts and their impact on clinical outcome., Methods: This is a single-center observational study of consecutive ICD and CRT patients (n=282) participating in protocol-driven remote follow-up. Bioimpedance alerts were analyzed with subsequently triggered interventions., Results: A total of 55.0% (155/282) of patients had an ICD or CRT device equipped with a remote bioimpedance algorithm. During 34 (SD 12) months of follow-up, 1751 remote monitoring alarm notifications were received (2.2 per patient-year of follow-up), comprising 2096 unique alerts (2.6 per patient-year of follow-up). Since 591 (28.2%) of all incoming alerts were bioimpedance-related, patients with an ICD or CRT including a bioimpedance algorithm had significantly more alerts (3.4 versus 1.8 alerts per patient-year of follow-up, P<.001). Bioimpedance-only alerts resulted in a phone contact in 91.0% (498/547) of cases, which triggered an actual intervention in 15.9% (87/547) of cases, since in 75.1% (411/547) of cases reenforcing heart failure education sufficed. Overall survival was lower in patients with a cardiovascular implantable electronic device with a bioimpedance algorithm; however, this difference was driven by differences in baseline characteristics (adjusted hazard ratio of 2.118, 95% CI 0.845-5.791). No significant differences between both groups were observed in terms of the number of follow-up visits in the outpatient heart failure clinic, the number of hospital admissions with a primary diagnosis of heart failure, or mean length of hospital stay., Conclusions: Bioimpedance-only alerts constituted a substantial amount of incoming alerts when turned on during remote follow-up and triggered an additional intervention in only 16% of cases since in 75% of cases, providing general heart failure education sufficed. The high frequency of heart failure education that was provided could have contributed to fewer heart failure-related hospitalizations despite significant differences in baseline characteristics., (©Christophe JP Smeets, Julie Vranken, Jo Van der Auwera, Frederik H Verbrugge, Wilfried Mullens, Matthias Dupont, Lars Grieten, Hélène De Cannière, Dorien Lanssens, Thijs Vandenberk, Valerie Storms, Inge M Thijs, Pieter M Vandervoort. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 23.11.2017.)

Background: Photoplethysmography (PPG) is a proven way to measure heart rate (HR). This technology is already available in smartphones, which allows measuring HR only by using the smartphone. Given the widespread availability of smartphones, this creates a scalable way to enable mobile HR monitoring. An essential precondition is that these technologies are as reliable and accurate as the current clinical (gold) standards. At this moment, there is no consensus on a gold standard method for the validation of HR apps. This results in different validation processes that do not always reflect the veracious outcome of comparison., Objective: The aim of this paper was to investigate and describe the necessary elements in validating and comparing HR apps versus standard technology., Methods: The FibriCheck (Qompium) app was used in two separate prospective nonrandomized studies. In the first study, the HR of the FibriCheck app was consecutively compared with 2 different Food and Drug Administration (FDA)-cleared HR devices: the Nonin oximeter and the AliveCor Mobile ECG. In the second study, a next step in validation was performed by comparing the beat-to-beat intervals of the FibriCheck app to a synchronized ECG recording., Results: In the first study, the HR (BPM, beats per minute) of 88 random subjects consecutively measured with the 3 devices showed a correlation coefficient of .834 between FibriCheck and Nonin, .88 between FibriCheck and AliveCor, and .897 between Nonin and AliveCor. A single way analysis of variance (ANOVA; P=.61 was executed to test the hypothesis that there were no significant differences between the HRs as measured by the 3 devices. In the second study, 20,298 (ms) R-R intervals (RRI)-peak-to-peak intervals (PPI) from 229 subjects were analyzed. This resulted in a positive correlation (rs=.993, root mean square deviation [RMSE]=23.04 ms, and normalized root mean square error [NRMSE]=0.012) between the PPI from FibriCheck and the RRI from the wearable ECG. There was no significant difference (P=.92) between these intervals., Conclusions: Our findings suggest that the most suitable method for the validation of an HR app is a simultaneous measurement of the HR by the smartphone app and an ECG system, compared on the basis of beat-to-beat analysis. This approach could lead to more correct assessments of the accuracy of HR apps., (©Thijs Vandenberk, Jelle Stans, Gertjan Van Schelvergem, Caroline Pelckmans, Christophe JP Smeets, Dorien Lanssens, Hélène De Cannière, Valerie Storms, Inge M Thijs, Pieter M Vandervoort. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 25.08.2017.)

Background: The aims of this study were to investigate the evolution of the transprosthetic pressure gradient and effective orifice area (EOA) during dynamic bicycle exercise in bileaflet mechanical heart valves and to explore the relationship with exercise capacity., Methods: Patients with bileaflet aortic valve replacement (n = 23) and mitral valve replacement (MVR; n = 16) prospectively underwent symptom-limited supine bicycle exercise testing with Doppler echocardiography and respiratory gas analysis. Transprosthetic flow rate, peak and mean transprosthetic gradient, EOA, and systolic pulmonary artery pressure were assessed at different stages of exercise., Results: EOA at rest, midexercise, and peak exercise was 1.66 ± 0.23, 1.56 ± 0.30, and 1.61 ± 0.28 cm 2 , respectively (P = .004), in aortic valve replacement patients and 1.40 ± 0.21, 1.46 ± 0.27, and 1.48 ± 0.25 cm 2 , respectively (P = .160), in MVR patients. During exercise, the mean transprosthetic gradient and the square of transprosthetic flow rate were strongly correlated (r = 0.65 [P < .001] and r = 0.84 [P < .001] for aortic valve replacement and MVR, respectively), conforming to fundamental hydraulic principles for fixed orifices. Indexed EOA at rest was correlated with exercise capacity in MVR patients only (Spearman ρ = 0.68, P = .004). In the latter group, systolic pulmonary artery pressures during exercise were strongly correlated with the peak transmitral gradient (ρ = 0.72, P < .001)., Conclusions: In bileaflet mechanical valve prostheses, there is no clinically relevant increase in EOA during dynamic exercise. Transprosthetic gradients during exercise closely adhere to the fundamental pressure-flow relationship. Indexed EOA at rest is a strong predictor of exercise capacity in MVR patients. This should be taken into account in therapeutic decision making and prosthesis selection in young and dynamic patients., (Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Although remote monitoring (RM) has proven its added value in various health care domains, little is known about the remote follow-up of pregnant women diagnosed with a gestational hypertensive disorders (GHD)., Objective: The aim of this study was to evaluate the added value of a remote follow-up program for pregnant women diagnosed with GHD., Methods: A 1-year retrospective study was performed in the outpatient clinic of a 2nd level prenatal center where pregnant women with GHD received RM or conventional care (CC). Primary study endpoints include number of prenatal visits and admissions to the prenatal observation ward. Secondary outcomes include gestational outcome, mode of delivery, neonatal outcome, and admission to neonatal intensive care (NIC). Differences in continuous and categorical variables in maternal demographics and characteristics were tested using Unpaired Student's two sampled t test or Mann-Whitney U test and the chi-square test. Both a univariate and multivariate analysis were performed for analyzing prenatal follow-up and gestational outcomes. All statistical analyses were done at nominal level, Cronbach alpha=.05., Results: Of the 166 patients diagnosed with GHD, 53 received RM and 113 CC. After excluding 5 patients in the RM group and 15 in the CC group because of the missing data, 48 patients in RM group and 98 in CC group were taken into final analysis. The RM group had more women diagnosed with gestational hypertension, but less with preeclampsia when compared with CC (81.25% vs 42.86% and 14.58% vs 43.87%). Compared with CC, univariate analysis in RM showed less induction, more spontaneous labors, and less maternal and neonatal hospitalizations (48.98% vs 25.00%; 31.63% vs 60.42%; 74.49% vs 56.25%; and 27.55% vs 10.42%). This was also true in multivariate analysis, except for hospitalizations., Conclusions: An RM follow-up of women with GHD is a promising tool in the prenatal care. It opens the perspectives to reverse the current evolution of antenatal interventions leading to more interventions and as such to ever increasing medicalized antenatal care., (©Dorien Lanssens, Thijs Vandenberk, Christophe JP Smeets, Hélène De Cannière, Geert Molenberghs, Anne Van Moerbeke, Anne van den Hoogen, Tiziana Robijns, Sharona Vonck, Anneleen Staelens, Valerie Storms, Inge M Thijs, Lars Grieten, Wilfried Gyselaers. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 09.03.2017.)

Spinocerebellar ataxia type 23 (SCA23) is caused by missense mutations in prodynorphin, encoding the precursor protein for the opioid neuropeptides α-neoendorphin, Dynorphin (Dyn) A and Dyn B, leading to neurotoxic elevated mutant Dyn A levels. Dyn A acts on opioid receptors to reduce pain in the spinal cord, but its cerebellar function remains largely unknown. Increased concentration of or prolonged exposure to Dyn A is neurotoxic and these deleterious effects are very likely caused by an N-methyl-d-aspartate-mediated non-opioid mechanism as Dyn A peptides were shown to bind NMDA receptors and potentiate their glutamate-evoked currents. In the present study, we investigated the cellular mechanisms underlying SCA23-mutant Dyn A neurotoxicity. We show that SCA23 mutations in the Dyn A-coding region disrupted peptide secondary structure leading to a loss of the N-terminal α-helix associated with decreased κ-opioid receptor affinity. Additionally, the altered secondary structure led to increased peptide stability of R6W and R9C Dyn A, as these peptides showed marked degradation resistance, which coincided with decreased peptide solubility. Notably, L5S Dyn A displayed increased degradation and no aggregation. R6W and wt Dyn A peptides were most toxic to primary cerebellar neurons. For R6W Dyn A, this is likely because of a switch from opioid to NMDA- receptor signalling, while for wt Dyn A, this switch was not observed. We propose that the pathology of SCA23 results from converging mechanisms of loss of opioid-mediated neuroprotection and NMDA-mediated excitotoxicity., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The spinocerebellar ataxias (SCAs) form an ever-growing group of neurodegenerative disorders causing dysfunction of the cerebellum and loss of motor control in patients. Currently, 41 different genetic causes have been identified, with each mutation affecting a different gene. Interestingly, these diverse genetic causes all disrupt cerebellar function and produce similar symptoms in patients. In order to understand the disease better, and define possible therapeutic targets for multiple SCAs, the field has been searching for common ground among the SCAs. In this review, we discuss the physiology of climbing fibers and the possibility that climbing fiber dysfunction is a point of convergence for at least a subset of SCAs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Spinocerebellar ataxia type 23 is caused by mutations in PDYN, which encodes the opioid neuropeptide precursor protein, prodynorphin. Prodynorphin is processed into the opioid peptides, α-neoendorphin, and dynorphins A and B, that normally exhibit opioid-receptor mediated actions in pain signalling and addiction. Dynorphin A is likely a mutational hotspot for spinocerebellar ataxia type 23 mutations, and in vitro data suggested that dynorphin A mutations lead to persistently elevated mutant peptide levels that are cytotoxic and may thus play a crucial role in the pathogenesis of spinocerebellar ataxia type 23. To further test this and study spinocerebellar ataxia type 23 in more detail, we generated a mouse carrying the spinocerebellar ataxia type 23 mutation R212W in PDYN. Analysis of peptide levels using a radioimmunoassay shows that these PDYN(R212W) mice display markedly elevated levels of mutant dynorphin A, which are associated with climber fibre retraction and Purkinje cell loss, visualized with immunohistochemical stainings. The PDYN(R212W) mice reproduced many of the clinical features of spinocerebellar ataxia type 23, with gait deficits starting at 3 months of age revealed by footprint pattern analysis, and progressive loss of motor coordination and balance at the age of 12 months demonstrated by declining performances on the accelerating Rotarod. The pathologically elevated mutant dynorphin A levels in the cerebellum coincided with transcriptionally dysregulated ionotropic and metabotropic glutamate receptors and glutamate transporters, and altered neuronal excitability. In conclusion, the PDYN(R212W) mouse is the first animal model of spinocerebellar ataxia type 23 and our work indicates that the elevated mutant dynorphin A peptide levels are likely responsible for the initiation and progression of the disease, affecting glutamatergic signalling, neuronal excitability, and motor performance. Our novel mouse model defines a critical role for opioid neuropeptides in spinocerebellar ataxia, and suggests that restoring the elevated mutant neuropeptide levels can be explored as a therapeutic intervention., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The dominantly inherited cerebellar ataxias are a heterogeneous group of neurodegenerative disorders caused by Purkinje cell loss in the cerebellum. Recently, we identified loss-of-function mutations in the KCND3 gene as the cause of spinocerebellar ataxia type 19/22 (SCA19/22), revealing a previously unknown role for the voltage-gated potassium channel, Kv4.3, in Purkinje cell survival. However, how mutant Kv4.3 affects wild-type Kv4.3 channel functioning remains unknown. We provide evidence that SCA19/22-mutant Kv4.3 exerts a dominant negative effect on the trafficking and surface expression of wild-type Kv4.3 in the absence of its regulatory subunit, KChIP2. Notably, this dominant negative effect can be rescued by the presence of KChIP2. We also found that all SCA19/22-mutant subunits either suppress wild-type Kv4.3 current amplitude or alter channel gating in a dominant manner. Our findings suggest that altered Kv4.3 channel localization and/or functioning resulting from SCA19/22 mutations may lead to Purkinje cell loss, neurodegeneration and ataxia.

Skeletal muscle remodelling and contractile dysfunction occur through both acute and chronic disease processes. These include the accumulation of insoluble aggregates of misfolded amyloid proteins that is a pathological feature of Huntington's disease (HD). While HD has been described primarily as a neurological disease, HD patients' exhibit pronounced skeletal muscle atrophy. Given that huntingtin is a ubiquitously expressed protein, skeletal muscle fibres may be at risk of a cell autonomous HD-related dysfunction. However the mechanism leading to skeletal muscle abnormalities in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that symptomatic animals developed a progressive impairment of the contractile characteristics of the hind limb muscles tibialis anterior (TA) and extensor digitorum longus (EDL), accompanied by a significant loss of motor units in the EDL. In symptomatic animals, these pronounced functional changes were accompanied by an aberrant deregulation of contractile protein transcripts and their up-stream transcriptional regulators. In addition, HD mouse models develop a significant reduction in muscle force, possibly as a result of a deterioration in energy metabolism and decreased oxidation that is accompanied by the re-expression of the HDAC4-DACH2-myogenin axis. These results show that muscle dysfunction is a key pathological feature of HD.

Purpose: Echocardiography is increasingly important in the guidance and follow-up of percutaneous transcatheter device closures. It was recently shown that the Amplatzer left atrial appendage occluder frequently presents as a figure-of-eight artifact due to interaction of device mesh and ultrasound waves. It remains unknown whether this can be translated to other types of disc occluders. Furthermore, the morphology of this figure-of-eight artifact appears to be different in the transesophageal and transthoracic image of the same device. The aim of this study was to evaluate the echocardiographic appearance of different types of disc occluders, and to clarify differences in morphology of the figure-of-eight artifact., Methods: A mathematical model of an epitrochoid curve was used for numerical simulation of disc occluder appearance at various imaging depths. In addition, an in vitro setup was used for echocardiographic analysis of different types of disc occluders at adjustable imaging depth and position., Results: Mathematically, decreasing the imaging depth resulted in a more asymmetric figure-of-eight, i.e. with small upper part and wide lower part. In vitro results were in close agreement with the mathematical results. In addition, in vitro a figure-of-eight artifact was obtained in all different types of disc occluder devices., Conclusions: Different types of percutaneous disc occluders all present as a figure-of-eight artifact on echocardiography when imaged from a coronal imaging position. The morphology of the artifact depends on the imaging depth, with a more asymmetric figure-of-eight morphology at smaller probe-to-device distance. This clarifies the differences observed between transesophageal and transthoracic imaging., (© 2014, Wiley Periodicals, Inc.)

Background: Restrictive mitral valve annuloplasty (RMA) for secondary mitral regurgitation might cause functional mitral stenosis, yet its clinical impact and underlying pathophysiological mechanisms remain debated., Objectives: The purpose of our study was to assess the hemodynamic and clinical impact of effective orifice area (EOA) after RMA and its relationship with diastolic anterior leaflet (AL) tethering at rest and during exercise., Methods: Consecutive RMA patients (n = 39) underwent a symptom-limited supine bicycle exercise test with Doppler echocardiography and respiratory gas analysis. EOA, transmitral flow rate, mean transmitral gradient, and systolic pulmonary arterial pressure were assessed at different stages of exercise. AL opening angles were measured at rest and peak exercise. Mortality and heart failure readmission data were collected for at least 20 months after surgery., Results: EOA and AL opening angle were 1.5 ± 0.4 cm(2) and 68 ± 10°, respectively, at rest (r = 0.4; p = 0.014). EOA increased significantly to 2.0 ± 0.5 cm(2) at peak exercise (p < 0.001), showing an improved correlation with AL opening angle (r = 0.6; p < 0.001). Indexed EOA (EOAi) at peak exercise was an independent predictor of exercise capacity (maximal oxygen uptake, p = 0.004) and was independently associated with freedom from all-cause mortality or hospital admission for heart failure (p = 0.034). Patients with exercise EOAi <0.9 cm(2)/m(2) (n = 14) compared with ≥0.9 cm(2)/m(2) (n = 25) had a significantly worse outcome (p = 0.048). In multivariate analysis, AL opening angle at peak exercise (p = 0.037) was the strongest predictor of exercise EOAi., Conclusions: In RMA patients, EOA increases during exercise despite fixed annular size. Diastolic AL tethering plays a key role in this dynamic process, with increasing AL opening during exercise being associated with higher exercise EOA. EOAi at peak exercise is a strong and independent predictor of exercise capacity and is associated with clinical outcome. Our findings stress the importance of maximizing AL opening by targeting the subvalvular apparatus in future repair algorithms for secondary mitral regurgitation., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Detection of intermittent atrial fibrillation (AF) is done using a 24-h Holter. Holter recordings are powerful but lack the comfort and have limited recording times resulting in under diagnosing of intermittent AF., Objective: Within this work we evaluated and compared a novel miniaturized three-channel ECG monitoring patch versus a 24-h Holter system., Methods: Both patients with a chronic AF rhythm (n=5) as well as patients with an AF rhythm that underwent electrical reconversion (n = 5) were equipped with both a 24-h Holter and ECG patch., Results: Alignment of raw data of both ECG systems allowed cross-correlation analysis. Overall good correlations of up to 85% were obtained. RR-interval analysis of both systems resulted in very high correlations of 99% and higher. AF analysis showed correct identification of AF on both ECG systems., Conclusions: The performance of our ECG patch matches that of the 24-h Holter and could provide a suitable tool for long-term monitoring applications., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cerebellar ataxias are progressive neurodegenerative disorders characterized by atrophy of the cerebellum leading to motor dysfunction, balance problems, and limb and gait ataxia. These include among others, the dominantly inherited spinocerebellar ataxias, recessive cerebellar ataxias such as Friedreich's ataxia, and X-linked cerebellar ataxias. Since all cerebellar ataxias display considerable overlap in their disease phenotypes, common pathological pathways must underlie the selective cerebellar neurodegeneration. Therefore, it is important to identify the molecular mechanisms and routes to neurodegeneration that cause cerebellar ataxia. In this review, we discuss the use of functional genomic approaches including whole-exome sequencing, genome-wide gene expression profiling, miRNA profiling, epigenetic profiling, and genetic modifier screens to reveal the underlying pathogenesis of various cerebellar ataxias. These approaches have resulted in the identification of many disease genes, modifier genes, and biomarkers correlating with specific stages of the disease. This article is part of a Special Issue entitled: From Genome to Function., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: Restrictive mitral valve annuloplasty combined with coronary artery bypass grafting is the treatment of choice for ischemic mitral regurgitation. Postoperative functional mitral stenosis and its potential impact on functional capacity remain the object of debate. The aim of this study was to assess functional and hemodynamic outcome at rest and during exercise in a population with ischemic mitral regurgitation after a standardized restrictive mitral valve annuloplasty., Methods: A total of 23 patients with ischemic mitral regurgitation who were previously treated with coronary artery bypass grafting and restrictive mitral valve annuloplasty underwent a semi-supine (bicycle) exercise test with Doppler echocardiography and ergospirometry. The surgical technique was identical in all patients, using a complete semi-rigid ring downsized by 2 sizes after measuring the height of the anterior mitral leaflet, to achieve a coaptation length of at least 8 mm., Results: At a mean follow-up of 28 ± 15 months, mean transmitral gradients at rest and maximal exercise were 4.4 ± 1.8 mm Hg and 8.2 ± 4.2 mm Hg, respectively (P < .001). Transmitral gradients did not correlate with exercise capacity (maximal oxygen uptake) or pulmonary artery pressures. Patients with a resting mean gradient of 5 mm Hg or greater (n = 9) reached a significantly higher maximal oxygen uptake; however, they had a better ejection fraction and cardiac output at rest and reached a higher cardiac output at peak exercise., Conclusions: Transmitral gradients after restrictive mitral valve annuloplasty for ischemic mitral regurgitation did not correlate with functional capacity as measured by maximal oxygen uptake during semi-supine bicycle testing. Functional capacity and transmitral gradients are determined not only by the severity of mitral stenosis but also by hemodynamic factors, such as ejection fraction and cardiac output. Transmitral gradients should be interpreted with respect to patient hemodynamics and not necessarily be considered as detrimental for functional capacity., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

The case is reported of a 38-year-old male patient with pulmonary homograft acute infective endocarditis and aortic root dilation that occurred 13 years after a Ross procedure for bicuspid aortic valve regurgitation. Aortic and pulmonary root replacements were performed, using a Freestyle stentless aortic root bioprosthesis in both cases, with excellent hemodynamics on postoperative echocardiography. In addition, preoperative systemic septic embolization had occurred despite an absence of left-sided endocarditis, presumably due to an intrapulmonary shunt. This case report demonstrates the feasibility of a double stentless bioprosthesis approach, and stresses the need to remain vigilant for septic embolization even in isolated right-sided endocarditis.

We assess the effect of enhanced basal sliding on the flow and mass budget of the Greenland ice sheet, using a newly developed parameterization of the relation between meltwater runoff and ice flow. A wide range of observations suggest that water generated by melt at the surface of the ice sheet reaches its bed by both fracture and drainage through moulins. Once at the bed, this water is likely to affect lubrication, although current observations are insufficient to determine whether changes in subglacial hydraulics will limit the potential for the speedup of flow. An uncertainty analysis based on our best-fit parameterization admits both possibilities: continuously increasing or bounded lubrication. We apply the parameterization to four higher-order ice-sheet models in a series of experiments forced by changes in both lubrication and surface mass budget and determine the additional mass loss brought about by lubrication in comparison with experiments forced only by changes in surface mass balance. We use forcing from a regional climate model, itself forced by output from the European Centre Hamburg Model (ECHAM5) global climate model run under scenario A1B. Although changes in lubrication generate widespread effects on the flow and form of the ice sheet, they do not affect substantial net mass loss; increase in the ice sheet's contribution to sea-level rise from basal lubrication is projected by all models to be no more than 5% of the contribution from surface mass budget forcing alone.

Continuous Global Positioning System observations reveal rapid and large ice velocity fluctuations in the western ablation zone of the Greenland Ice Sheet. Within days, ice velocity reacts to increased meltwater production and increases by a factor of 4. Such a response is much stronger and much faster than previously reported. Over a longer period of 17 years, annual ice velocities have decreased slightly, which suggests that the englacial hydraulic system adjusts constantly to the variable meltwater input, which results in a more or less constant ice flux over the years. The positive-feedback mechanism between melt rate and ice velocity appears to be a seasonal process that may have only a limited effect on the response of the ice sheet to climate warming over the next decades.

N,N',N" -triethylenethiophosphoramide (thioTEPA) is a trifunctional alkylating agent with a broad spectrum of antitumour activity developed in the 1950s. The drug is now experiencing renewed interest as it appears to be one of the most effective anticancer drugs in high dose regimens. Despite many years of experience with thioTEPA, pharmacologic data are incomplete and controversy remains with respect to the dose-dependent pharmacokinetics of thioTEPA. In recent years greater insight has been obtained into the metabolism of thioTEPA, but there is still a gap between the total urinary excretion of thioTEPA and metabolites and the alkylating activity. In vivo and in vitro studies show that alkylation of DNA by thioTEPA can follow two pathways, but it remains unclear which pathway represents the precise mechanism of action. The currently available sensitive analytical methods for thioTEPA and its metabolites can be used to elucidate the many questions that still exist even so many years after its introduction. An overview is given of the chemistry, pharmacology, clinical use and toxicity of thioTEPA as well as its pharmacokinetics and analytical methods for thioTEPA and its metabolites., (Copyright 2000 Harcourt Publishers Ltd.)