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Maximal oxygen uptake (VO2max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO2max, and of increases of VO2max in response to exercise training (ΔVO2max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO2max and ΔVO2max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual’s ΔVO2max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans. Plasma proteomic profiles from 650 adult humans are measured before and after a 20-week exercise regimen to determine proteins associated with baseline cardiorespiratory fitness and improvements in response to exercise.

Zusammenfassung Ziel der Studie Zahlreiche Studien weisen auf ein breites Spektrum häufig gleichzeitig auftretender psychischer Störungen wie jene der Generalisierten Angststörung bei der Behandlung von Personen mit Cannabiskonsumstörungen hin (GAD). Bisherige Internet-basierte Studien konnten zwar vereinzelt die Reduktion von Cannabiskonsum zeigen, berücksichtigten aber keine komorbide Störungen. Ziel des E-Coach gestützten Online-Selbsthilfeprogramm CANreduce 2.0 ist die Reduzierung des Cannabiskonsums und der gegebenenfalls vorhandenen GAD. Methodik Sekundäranalyse der in der Allgemeinbevölkerung rekrutierten Cannabiskonsumierenden der CANreduce 2.0 Studie der beiden aktiven Interventionsgruppen (N=367). Für die Analysen wurden diese Teilnehmende aufgrund ihres erreichten Symptomatik-Wertes der General Anxiety Disorder Scale (GAD-7) in 4 Gruppen eingeteilt: Minimale (GAD-7 Werte: 0–4; N=102), Milde (5–9; N=151), Moderate (10–14; N=78) und Schwere (15–21; N=36) Angststörung und anschliessend ihre Behandlungsverläufe mittels Intention-to-Treat Analysen bezüglich ihrer Cannabiskonsumtage und ihrer Werte auf dem Cannabis Use Disorder Identification Test (CUDIT), der Severity of Dependence Scale (SDS), der GAD-7, der Center of Epidemiologic Studies of Depression Scale (CES-D) sowie bezüglich ihrer Adhärenz verglichen. Ergebnisse Alle 4 Gruppen reduzierten unabhängig von ihrer GAD-Symptomatik die Anzahl ihrer Cannabiskonsumtage, ihren CUDIT und SDS Score sowohl 6 Wochen als auch 3 Monate nach der Baselineerhebung. Weiter haben mit Ausnahme von der minimalen GAD-7-Gruppe alle Gruppen eine Reduktion der Angstsymptomatik nach 3 Monaten aufgewiesen. Analog zeigten mit Ausnahme der minimalen GAD-7-Gruppe alle GAD-7-Gruppen eine deutliche Reduktion in der depressiven Symptomatik. Bezüglich der gemessenen Adhärenz zeigten sich keine Unterschiede zwischen den GAD-7-Gruppen. Schlussfolgerungen CANreduce 2.0 scheint sowohl den Cannabiskonsum, die Ausprägung der Cannabiskonsumstörung bzw. die Cannabisabhängigkeit wie auch eine gegebenenfalls vorhandene GAD-Symptomatik zu reduzieren.

ZusammenfassungZiel Untersuchung von Zusammenhängen zwischen der Haptoglobinkonzentration im Blut und dem Auftreten einer Ketose, ausgewählten klinischen Parametern und Lahmheit bei Milchkühen.Material und Methoden Die Datenerhebung fand in 39 bayerischen Milchviehbetrieben über 8 Monate statt. Bei den einbezogenen 712 Fleckvieh- und Braunviehkühen, deren Kalbung 10–30 Tage zurücklag, wurde eine klinische Untersuchung durchgeführt sowie eine Milch- und eine Blutprobe entnommen. Im Blut wurden die Konzentrationen von freien Fettsäuren (non-esterified fatty acids, NEFA), β-Hydroxybutyrat (BHB) und Haptoglobin (Hp) bestimmt, in der Milch die Milchinhaltsstoffe (Fett, Eiweiß, Harnstoff, Laktose, Azeton), BHB, NEFA und die somatische Zellzahl (SCC).Ergebnisse Signifikante Korrelationen ergaben sich zwischen erhöhten Hp-Konzentrationen einerseits und erhöhten NEFA-Konzentrationen in Blut und Milch (p < 0,001), erhöhter SCC (p < 0,001), Lahmheit (p < 0,001), vermindertem Laktosegehalt (p < 0,001) sowie vermindertem Proteingehalt der Milch (p = 0,001) andererseits. In den wärmeren Sommermonaten beprobte Tiere hatten signifikant höhere Hp-Konzentrationen (p < 0,001). Erstkalbinnen wiesen signifikant höhere Hp-Werte auf als multipare Tiere (p < 0,001). Durch die Einteilung der Tiere in 4 Cluster ließ sich ein Hp-Grenzwert bestimmen, der 0,18 mg/ml betrug. Kombiniert mit einem SCC-Grenzwert von 40 500 Zellen/ml Milch konnte der Großteil der subklinisch und klinisch auffälligen Tiere ermittelt werden.Schlussfolgerung und klinische Relevanz Die Messung der Hp-Konzentration im Blut stellt einen praktikablen Ansatz zur Unterstützung des Tiergesundheitsmonitorings im postpartalen Zeitraum dar. Zusammen mit der Auswertung der Milchmenge und der Milchinhaltsstoffe können Abweichungen von physiologischen Zuständen erkannt und betroffene Tiere zeitnah behandelt werden. Haptoglobin kann für die Bewertung des Gesundheitsstatus des Einzeltieres wie auch als Indikator für die Herdengesundheit genutzt werden.

Aims: Modern pharmaceutical product development is a long and complex process associated with significant investments by pharmaceutical companies. The innovative pharmaceutical industry accounts for the vast majority of expenditures in clinical trials of potential new pharmaceuticals and therefore generates economic activity within a country. The aim was to assess the far-reaching economic impact of industry-sponsored clinical-trials (ISCTs) of pharmaceutical products for the healthcare system and the national economy. Materials and methods: The study approach was based on three analytical steps. First, a survey among 15 pharmaceutical companies in Austria was conducted to evaluate the annual number of ISCTs subdivided according to trial phase, therapeutic areas and associated employees. Second, the monetary value of treatments performed in ISCTs was calculated based on a sample of clinical-trial protocols. Finally, the macroeconomic impact, measured in terms of value-added and jobs created by the conducted ISCTs, was calculated using Input–Output analysis by applying an extended Leontief-model. Results: The study demonstrated that €116.22 million spent in ISCTs generated a total value added of €144 million, €74 million direct, in 2018. Each year a medical treatment value of €100 million was financed through 463 ISCTs, with an average value of medical treatment of €37,068 per recruited patient. This represents a significant 0.3% of annual current health-expenditures. In summary, each Euro invested by the pharmaceutical industry in ISCTs generates €1.95 for the Austrian economy. ISCTs also created and secured employment in the extent of 2,021 full-time-equivalents, thus resulting in an employment multiplier of 1.66. Conclusions: In conclusion, conducting clinical-trials by pharmaceutical industry—beside its importance in its own domain—results in tangible benefits and a positive macroeconomic impact that contribute to the sustainability of the Austrian healthcare system by complementing its limited resources. Furthermore, it is a non-negligible factor in locational and industrial policy.

Highlights • Cognitive-behavioural therapy (CBT) and motivational interviewing (MI) can be readily adapted for brief, minimally guided, online interventions. • Minimally guided online treatment is beneficial for hazardous drinking, mood difficulties, and quality of life in the short-term among young adults. • Strategies designed to increase treatment engagement will likely mitigate the risk of attrition in future programs. • Future versions of the Take Care of Me program are still needed to determine long-term effects and differential responses to treatment., Objective Many young adults struggle with comorbid alcohol misuse and emotional problems (i.e., depression and anxiety). However, there is currently a paucity of evidence-based, integrated, accessible treatment options for individuals with these comorbidities. The main goal of this study was to examine efficacy of a novel online, minimally guided, integrated program for comorbid alcohol misuse and emotional problems in young adults. Method: The study was an open-label two-arm RCT. Participants (N = 222, Mage = 24.6, 67.6% female) were randomized to one of two conditions: the Take Care of Me program (an 8-week, online integrated treatment condition consisting of 12 modules), or an online psychoeducational control condition. Intervention modules incorporated content based on principles of cognitive behavioral therapy and motivational interviewing. Participants completed assessment data at baseline, at the end of treatment (i.e., 8 weeks), and at follow-up (i.e., 24 weeks). Data were analyzed using generalized linear mixed models. Results: We observed that participants in the treatment condition showed larger reductions in depression, hazardous drinking, as well as increases in psychological quality of life and confidence at the end of treatment. We did not find group differences on total alcohol use at follow-up, but participants in the treatment group reduced their hazardous drinking and improved their quality of life at 24-week follow-up. Conclusions: Our study provides promising initial evidence for the first iteration of the comorbid alcohol misuse and emotional problems online program.

Background Demographic changes, increased life expectancy and the associated rise in chronic diseases pose challenges to public health care systems. Optimized treatment methods and integrated concepts of care are potential solutions to overcome increasing financial burdens and improve quality of care. In this context modeling is a powerful tool to evaluate potential benefits of different treatment procedures on health outcomes as well as health care budgets. This work presents a novel modeling approach for simulating different treatment procedures of heart failure patients based on extensive data sets from outpatient and inpatient care. Methods Our hybrid heart failure model is based on discrete event and agent based methodologies and facilitates the incorporation of different therapeutic procedures for outpatient and inpatient care on patient individual level. The state of health is modeled with the functional classification of the New York Heart Association (NYHA), strongly affecting discrete state transition probabilities alongside age and gender. Cooperation with Austrian health care and health insurance providers allowed the realization of a detailed model structure based on clinical data of more than 25,000 patients. Results Simulation results of conventional care and a telemonitoring program underline the unfavorable prognosis for heart failure and reveal the correlation of NYHA classes with health and economic outcomes. Average expenses for the treatment of NYHA class IV patients of €10,077 ± €165 were more than doubled compared to other classes. The selected use case of a telemonitoring program demonstrated potential cost savings within two years of application. NYHA classes II and III revealed most potential for additional treatment measures. Conclusion The presented model allows performing extensive simulations of established treatment procedures for heart failure patients and evaluating new holistic methods of care and innovative study designs. This approach offers health care providers a unique, adaptable and comprehensive tool for decision making in the complex and socioeconomically challenging field of cardiovascular diseases.

Due to globalization and the quick development of technology, each government aims to ensure the safety and performance of products brought to their markets to protect its population. The peoples’ health state is of great significance and influenced easily by the quality of medical products. Therefore governments enact laws, directives and regulations to assure that quality. Nevertheless, these regulations can impede innovation and create trade barriers which result in an adverse effect on national economies. Where in some states no regulatory system is installed, others have highly sophisticated registration requirements that must be met. These diversities result in a challenge especially for small and medium sized companies, whose resources are often limited. [1] Manufacturers must control these diverse regulatory requirements by analyzing each market. Therefore an efficient procedure of registration should be defined that streamlines different registration requirements and ensures regulatory compliance. Next to regulatory authorities describing these requirements also harmonization groups play an important role in the design of the global regulatory landscape. Therefore also the most important harmonization groups and their current activities were investigated. The analysis showed that the impact of harmonization groups can be identified easily since new defined or updated regulatory requirements are oriented on their guideline. Still the harmonization of regulatory requirements in the medical device sector is not sufficiently enhanced. Thus the confrontation with each national regulatory system is inevitable.

Background and Aims Despite problematic pornography use (PPU) being prevalent, no previous study has examined the effectiveness of evidence-based interventions for PPU, using rigorous methods. Using a two-armed randomized controlled trial study design, we examined the feasibility and initial effectiveness of a six-week online PPU intervention. Methods We recruited 264 participants (3.8% women, M age = 33.2, SD = 10.6) who were randomized and assigned to either the self-help intervention (n = 123) or waitlist control condition (n = 141), and completed self-report questionnaires at baseline and after the end of the intervention (six-week follow-up). Multivariable linear regression models were generated and tested on a complete case basis to investigate possible treatment effects. Participants provided quantitative and qualitative feedback regarding the intervention’s content and appearance. Results Participants evaluated all modules positively in the intervention in general. There were differential dropout rates (89.4% in intervention vs. 44.7% in control group) with an overall follow-up rate of 34.5%. The intervention group reported significantly lower levels of PPU (P < 0.001, d = 1.32) at the six-week follow-up. Moreover, they reported lower pornography use frequency (P < 0.001, d = 1.65), self-perceived pornography addiction (P = 0.01, d = 0.85), pornography craving (P = 0.02, d = 0.40), and higher pornography avoidance self-efficacy (P = 0.001, d = 0.87) at the six-week follow-up. Discussion and Conclusions The present study was only a first step in rigorous treatment studies for PPU, but the findings are promising and suggest that online interventions for PPU might help reduce PPU in some cases, even without the guidance of therapists, by reducing treatment barriers.

Background Gambling and tobacco smoking are highly comorbid among North American adults. However, there is a paucity of treatment options that are integrated (i.e. targeting both gambling and tobacco smoking simultaneously), accessible, and evidence based. Methods The aim of this two-arm open-label randomized controlled trial is to examine the effectiveness of an online, self-guided integrated treatment for problem gambling and tobacco smoking. A target sample of 214 participants will be recruited and be randomized into either an 8-week integrated or gambling only control condition. Both conditions will consist of seven online modules following cognitive behavioural therapy and motivational interviewing principles. Our three primary outcomes are (1) the number of days gambled, (2) money spent on gambling activities, and (3) time spent in gambling activities. Secondary outcomes include gambling disorder symptoms, cigarette use, and nicotine dependence symptoms. Assessments will be completed at baseline, at completion (i.e. 8 weeks from baseline), and at follow-up (i.e. 24 weeks from baseline). Generalized linear mixed modelling will be used to evaluate our primary and secondary outcomes. We expect that participants receiving online integrated treatment will show larger reductions in gambling relative to those receiving a control gambling only intervention. We further hypothesize that reductions in smoking will mediate these group differences. Discussion The rates of problem gambling and tobacco smoking are high in North America; yet, the treatment options for both are limited, with no integrated treatments available. If supported, our pilot study will be a cost-effective and accessible way to improve treatments for co-occurring problem gambling and tobacco use. Trial registration ClinicalTrials.gov NCT03614884. Registered on August 3, 2019

Lung cancer is still a leading cause of death worldwide. In recent years, knowledge has been obtained of the mechanisms modulating ion channel kinetics and thus of cell bioelectric properties, which is promising for oncological biomarkers and targets. The complex interplay of channel expression and its consequences on malignant processes, however, is still insufficiently understood. We here introduce the first approach of an in-silico whole-cell ion current model of a cancer cell, in particular of the A549 human lung adenocarcinoma, including the main functionally expressed ion channels in the plasma membrane as so far known. This hidden Markov-based model represents the electrophysiology behind proliferation of the A549 cell, describing its rhythmic oscillation of the membrane potential able to trigger the transition between cell cycle phases, and it predicts membrane potential changes over the cell cycle provoked by targeted ion channel modulation. This first A549 in-silico cell model opens up a deeper insight and understanding of possible ion channel interactions in tumor development and progression, and is a valuable tool for simulating altered ion channel function in lung cancer electrophysiology., Author summary Advances in the understanding of functional alterations at genetic, epigenetic or protein expression and the expanding knowledge in mechanisms modulating ion channel kinetics and thus the cells’ bioelectric properties have arisen as promising cancer biomarkers and oncological targets. Our hidden Markov-based in-silico cell model represents the electrophysiology behind proliferation of the A549 cell line, explaining the cell’s rhythmic oscillation from hyperpolarized to depolarized states of the membrane potential, able to trigger the transition between cell cycle phases. The model enables the prediction of membrane potential changes over the cell cycle provoked by targeted modulation of specific ion channels, leading to cell cycle promotion or interruption. We are encouraged that the availability of this first cancer cell model will provide profound insight into possible roles and interactions of ion channels in tumor development and progression, and may aid in the testing of research hypotheses in lung cancer electrophysiology.

There is recent experimental evidence that sarcomere strain behavior is highly heterogeneous across and between muscle structures. Hence, considering the hierarchical architecture of muscles, also the behavior of all acting muscle substructures is effected. However, typical investigations are limited to ex-vivo experiments or pose serious limitations for in-vivo studies. In this work, we investigate in-vivo length changes in human muscle fascicles by means of non-invasive ultrafast ultrasound. To this end, we employ a research ultrasound system and a linear array transducer to image, in plane-wave mode, medial gastrocnemius muscles during electrically-stimulated contractions. The ultrasound-based approach presented in this study allows to measure strain distributions within muscle fascicles during contractions, where the sub-fascicle structures exhibit heterogeneous behaviors.

Until now direct localization of motor endplates for any arbitrary muscle structure was reserved to cadaver studies or restricted to specific muscles in-vivo. Utilizing ultrafast ultrasound we report a versatile in-vivo method for the detection of motor endplate zones. To achieve this goal, we employ a research ultrasound system with a linear array transducer probe to record ultrasound images of electrically-stimulated medial gastrocnemius muscles. An optical flow speckle tracking algorithm is used to track the points along a single fascicle. We localize motor endplates at intersection points where mechanical contraction waves diverge bidirectionally towards the fiber ends. Contrary to common experimental methods, our proposed ultrafast ultrasound-based approach allows to localize motor endplates also in deep and pennate muscles in-vivo. These results open up new applications for ultrasound in neuromuscular research.

Along with increasing enthusiasm for sports comes an increase of sport related injuries. One of the most common injuries in the human knee is the tear of the anterior cruciate ligament (ACL). The selection of a graft fixation device is an important factor that determines the outcome of an anterior cruciate ligament reconstruction. Before the healing process is completed, the graft is dependent on tibial and femoral fixation devices to maintain normal ACL graft tension. Among various devices, the use of an adjustable loop suspensory fixation device (ALD) in soft-tissue graft reconstruction attracts current interest. An advantage of the ALD is the ability to draw the graft to the depth of the bone tunnel to achieve adequate graft tension while minimizing the empty space in the tunnel. In this study a comprehensive controlled laboratory investigation is performed to examine the biomechanical properties of commonly used cortical fixation devices, with the aim of implementing a standard testing procedure for adjustable loop devices. The procedure consists of three test series, a loop shortening test and two different stability test series (singe device and tendon device test). Those test series are used to compare the performance of a new ALD from Arthrex (Naples, USA) with five competitor devices already on the market. In order to obtain representative results eight samples of each device are tested. In comparison to the previously performed studies, a complete unloading is applied in the stability tests, which allows for a detailed examination of the ALDs locking mechanisms in dynamically loaded test situations. Furthermore, the performed loop shortening tests reveal important aspects, such as the shortening accuracy and settling effects of the loops, that are not found in previous studies. Therefore, the used test protocol can be recommended for further testing.

Background Given the scarcity of alcohol prevention and use disorder treatments in many low- and middle-income countries (LMICs), the World Health Organization has launched an eHealth portal that includes the web-based self-help program “Alcohol e-Health.” Objective We aimed to test the effectiveness of the Alcohol e-Health program in a randomized controlled trial. Methods This was a two-arm, individually randomized, and controlled trial across four LMICs comparing the self-help program and a psychoeducation and internet access as usual waiting list. Participants were broadly recruited from community samples in Belarus, Brazil, India, and Mexico from January 2016 through January 2019. The primary outcome measure was change in the Alcohol Use Disorders Identification Test (AUDIT) score with a time frame of 6 months between baseline and follow-up. Secondary outcomes included self-reported numbers of standard drinks over the previous week and cessation of harmful or hazardous drinking (AUDIT score Results For this study, we recruited 1400 predominantly male (n=982, 70.1%) at least harmful or hazardous alcohol drinkers. The mean age was 37.6 years (SD 10.5). The participants were recruited from Brazil (n=587), Mexico (n=509), India (n=212), and Belarus (n=92). Overall, complete case analysis identified higher AUDIT changes in the intervention group (B=−4.18, 95% CI −5.42 to −2.93, P Conclusions The expansion of the Alcohol e-Health program to other LMICs with underdeveloped alcohol prevention and treatment systems for alcohol use disorders should be considered after successful replication of the present results. Trial Registration ISRCTN ISRCTN14037475; https://www.isrctn.com/ISRCTN14037475 International Registered Report Identifier (IRRID) RR2-10.1111/add.14034

Background Depression and harmful alcohol use are two of the top five leading causes of years of life lost to disability in high-income countries. Integrated treatment targeting both at the same time is often considered more complicated and difficult and, therefore, more expensive. Consequently, integrated internet-based interventions could be a valuable addition to traditional care. Methods A three-arm randomized controlled trial was conducted comparing the effectiveness of (1) an integrated, minimal-guidance, adherence-focused self-help intervention designed to reduce both alcohol use and depression symptoms (AFGE-AD); (2) a similar intervention designed to reduce alcohol use only (AFGE-AO), and (3) internet access as usual (IAU) as a control condition, in at least moderately depressed alcohol misusers from February 2016—March 2020. We recruited 689 alcohol misusers (51.6 % males, mean age = 42.8 years) with at least moderate depression symptoms not otherwise in treatment from the general population. Six months after baseline, 288 subjects (41.8 %) were reachable for the final assessment. Results All interventions yielded reduced alcohol-use after six months (AFGE-AD: -16.6; AFGE-AO: -19.8; IAU: -13.2). Those who undertook active-interventions reported significantly fewer standard drinks than controls (AFGE-AD: p = .048, d=0.10; AFGE-AO: p = .004, d=0.20). The two active-intervention groups also reported significantly less severe depression symptoms than controls (AFGE-AD: p = .006, d=0.41; AFGE-AO: p = .008, d=0.43). Testing revealed noninferiority between the two interventions. Conclusions This study documented sustained effectiveness of the first integrated, fully internet-based self-help intervention developed for the reduction of both alcohol use and depression symptoms in at least moderately depressed adult alcohol misusers recruited from the general population.

Identification of the best CMR technique for quantitative assessment of myocardial salvage using a systematic comparison.

Background and AimsThe past-year prevalence of problematic pornography use (PPU) was 1–6% in adult populations. As a result of treatment obstacles and barriers, such as unaffordable treatments, only a minority of problematic pornography users may seek treatment. Having a free, online, self-help program may overcome treatment barriers and may help those individuals who cannot receive traditional or offline treatment for PPU. Although the effectiveness of such online programs reducing substance use and problematic gambling have been reported, no prior study has examined the efficacy of an online self-help intervention aiming to reduce PPU.MethodsThis two-armed randomized controlled trial (RCT) will examine the effectiveness of an online self-help program (Hands-off) to reduce PPU, while also considering psychopathological comorbidities. The six-week intervention condition includes six core modules developed to reduce PPU based on motivational interviewing, cognitive behavioral therapy, mindfulness, and wise social-psychological intervention techniques. The target sample size is 242 participants. Self-report questionnaires will be administered at baseline, right after the end of the intervention, at one-month, and three-month follow-ups after the end of the intervention. The primary outcome will be the level of PPU. Secondary outcomes will include pornography use frequency, pornography craving, pornography use-avoidance self-efficacy, sex mindset, sexual satisfaction, negative and positive emotions, and life satisfaction. Data will be analyzed on an intention-to-treat basis using linear mixed models.ResultsResults will be reported at conferences and published in a scientific peer-reviewed journal. The participants will be sent a lay-person-friendly summary of the results via e-mail.

Recording muscle tendon junction displacements during movement, allows separate investigation of the muscle and tendon behaviour, respectively. In order to provide a fully-automatic tracking method, we employ a novel deep learning approach to detect the position of the muscle tendon junction in ultrasound images. We utilize the attention mechanism to enable the network to focus on relevant regions and to obtain a better interpretation of the results. Our data set consists of a large cohort of 79 healthy subjects and 28 subjects with movement limitations performing passive full range of motion and maximum contraction movements. Our trained network shows robust detection of the muscle tendon junction on a diverse data set of varying quality with a mean absolute error of 2.55$\pm$1 mm. We show that our approach can be applied for various subjects and can be operated in real-time. The complete software package is available for open-source use via: https://github.com/luuleitner/deepMTJ, Comment: Accepted version to be published in 2020, 42nd Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Montreal, Canada

Recent studies show that vestibular implants have the potential to compensate the loss of functionality of the organ of equilibrium. The objective of this study was the development of a simulation framework which estimates the capability of various electrode arrangements and stimulation waveforms to selectively excite the ampullary nerves in the vestibular system. The choice of electrode configuration and stimulation waveform shows a significant influence in resulting selectivity, energy expenditure and injected charge in our simulations. This simulation environment could be beneficial in the development of safe and selective stimulation electrode designs.

Objective Most preventable adverse drug events and medication errors occur during medication ordering. Medication order entry and clinical decision support are available on paper or as computerized systems. In this post-hoc analysis we investigated frequency and clinical impact of blood glucose (BG) documentation- and user-related calculation errors as well as workflow deviations in diabetes management. We aimed to compare a paper-based protocol to a computerized medication management system combined with clinical workflow and decision support. Methods Seventy-nine hospitalized patients with type 2 diabetes mellitus were treated with an algorithm driven basal-bolus insulin regimen. BG measurements, which were the basis for insulin dose calculations, were manually entered either into the paper-based workflow protocol (PaperG: 37 patients) or into GlucoTab ® —a mobile tablet PC based system (CompG: 42 patients). We used BG values from the laboratory information system as a reference. A workflow simulator was used to determine user calculation errors as well as workflow deviations and to estimate the effect of errors on insulin doses. The clinical impact of insulin dosing errors and workflow deviations on hypo- and hyperglycemia was investigated. Results The BG documentation error rate was similar for PaperG (4.9%) and CompG group (4.0%). In PaperG group, 11.1% of manual insulin dose calculations were erroneous and the odds ratio (OR) of a hypoglycemic event following an insulin dosing error was 3.1 (95% CI: 1.4–6.8). The number of BG values influenced by insulin dosing errors was eightfold higher than in the CompG group. In the CompG group, workflow deviations occurred in 5.0% of the tasks which led to an increased likelihood of hyperglycemia, OR 2.2 (95% CI: 1.1–4.6). Discussion Manual insulin dose calculations were the major source of error and had a particularly strong influence on hypoglycemia. By using GlucoTab ® , user calculation errors were entirely excluded. The immediate availability and automated handling of BG values from medical devices directly at the point of care has a high potential to reduce errors. Computerized systems facilitate the safe use of more complex insulin dosing algorithms without compromising usability. In CompG group, missed or delayed tasks had a significant effect on hyperglycemia, while in PaperG group insufficient precision of documentation times limited analysis. The use of old BG measurements was clinically less relevant. Conclusion Insulin dosing errors and workflow deviations led to measurable changes in clinical outcome. Diabetes management systems including decision support should address nurses as well as physicians in a computerized way. Our analysis shows that such systems reduce the frequency of errors and therefore decrease the probability of hypo- and hyperglycemia.

BACKGROUND: Alcohol misuse and emotional problems (ie, depression and anxiety) are highly comorbid among Canadian young adults. However, there is a lack of integrated, accessible, and evidence-based treatment options for these young adults.OBJECTIVE: The main goal of this study is to develop and test the efficacy of an integrated, online self-help program designed to target both alcohol misuse and emotional problems.METHODS: A two-arm randomized controlled trial design will be used to compare the efficacy of the online integrated treatment to a psychoeducational control group. A target sample of 214 participants will be recruited and randomly assigned to either condition. The integrated treatment will last 8 weeks, and participants will work through 12 modules. Modules will incorporate content based on principles of cognitive behavioral therapy and motivational interviewing. Participants in the control group will receive links to psychoeducational resources and will have access to the full treatment after follow-up. The primary outcome will be the number of Canadian standard drinks consumed in the week leading up the assessment. Secondary outcomes of interest include symptoms of depression, anxiety, alcohol-related problems, quality of life, and use of other drugs. Assessments will be completed at 3 time-points: at baseline, at the end of treatment (ie, 8 weeks), and at follow-up (ie, 24 weeks). Upon completion, data will be analyzed using generalized linear mixed models.RESULTS: Data collection began in June 2018 and will continue until January 2020. Final study results will be submitted for publication by July 2020.CONCLUSIONS: Currently, there are no integrated treatments designed to target alcohol misuse and the range of emotional problems experienced by young adults. This research stands to provide an effective, accessible (ie, Web-based), and feasible option to treat the many struggling young adults in this country.TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03406039; https://clinicaltrials.gov/ct2/show/NCT03406039 (Archived by WebCite at http://www.webcitation.org/72fDefnrh).REGISTERED REPORT IDENTIFIER: PRR1-10.2196/11298.

A dysfunctional vestibular system can be a severe detriment to the quality of life of a patient. Recent studies have shown the feasibility for a vestibular implant to restore rotational sensation via electrical stimulation of vestibular ampullary nerves. However, the optimal stimulation site for selective elicitation of the desired nerve is still unknown. We realized a finite element model on the basis of μCT scans of a human inner ear and incorporated naturally distributed, artificial neural trajectories. A well-validated neuron model of myelinated fibers was incorporated to predict nerve responses to electrical stimulation. Several virtual electrodes were placed in locations of interest inside the bony labyrinth (intra-labyrinthine) and inside the temporal bone, near the target nerves (extra-labyrinthine), to determine preferred stimulation sites and electrode insertion depths. We investigated various monopolar and bipolar electrode configurations as well as different pulse waveform shapes for their ability to selectively stimulate the target nerve and for their energy consumption. The selectivity was evaluated with an objective measure of the fiber recruitment. Considerable differences of required energy and achievable selectivity between the configurations were observed. Bipolar, intra-labyrinthine electrodes provided the best selectivities but also consumed the highest amount of energy. Bipolar, extra-labyrinthine configurations did not offer any advantages compared to the monopolar approach. No selective stimulation could be performed with the monopolar, intra-labyrinthine approach. The monopolar, extra-labyrinthine electrodes required the least energy for satisfactory selectivities, making it the most promising approach for functional vestibular implants. Different pulse waveform shapes did not affect the achieved selectivity considerably but shorter pulse durations showed consistently a more selective activation of the target nerves. A cathodic, centered triangular waveform shape was identified as the most energy-efficient of the tested shapes. Based on these simulations we are able to recommend the monopolar, extra-labyrinthine stimulation approach with cathodic, centered triangular pulses as good trade-off between selectivity and energy consumption. Future implant designs could benefit from the findings presented here.

Usability of medical devices is one of the main determining factors in preventing use errors in treatment and strongly correlates to patient safety and quality of treatment. This thesis demonstrates the usability testing and evaluation of a prototype for locomotor therapy of infants. Therefore, based on the normative requirements of the EN 62366, a concept combined of evaluation procedures and assessing methods was created to enable extensive testing and analysis of the different aspects of usability. On the basis of gathered information weak points were identified and appropriate measures were presented to increase the usability and operating safety of the locomotor prototype. The overall outcome showed an usability value of 77.4% and an evaluation score of 6.99, which can be interpreted as “satisfactory”.

The aim of this work was to analyse the medication process and the potential for errors during the process steps. For this purpose, a literature review was conducted and a questionnaire was developed to compare the results from the literature with the current medication process in Styrian hospitals. The questionnaire was divided into four different parts with a total of 29 questions. For the survey all 37 Styrian hospitals were contacted whereas 11 filled out the questionnaire. The survey showed that there is no standardized medication process defined and that the rate of medication errors is generally underestimated. In addition, technical solutions may help to reduce errors but are expected to be hardly used in clinical practice.

Our sense of balance and spatial orientation strongly depends on the correct functionality of our vestibular system. Vestibular dysfunction can lead to blurred vision and impaired balance and spatial orientation, causing a significant decrease in quality of life. Recent studies have shown that vestibular implants offer a possible treatment for patients with vestibular dysfunction. The close proximity of the vestibular nerve bundles, the facial nerve and the cochlear nerve poses a major challenge to targeted stimulation of the vestibular system. Modeling the electrical stimulation of the vestibular system allows for an efficient analysis of stimulation scenarios previous to time and cost intensive in vivo experiments. Current models are based on animal data or CAD models of human anatomy. In this work, a (semi-)automatic modular workflow is presented for the stepwise transformation of segmented vestibular anatomy data of human vestibular specimens to an electrical model and subsequently analyzed. The steps of this workflow include (i) the transformation of labeled datasets to a tetrahedra mesh, (ii) nerve fiber anisotropy and fiber computation as a basis for neuron models, (iii) inclusion of arbitrary electrode designs, (iv) simulation of quasistationary potential distributions, and (v) analysis of stimulus waveforms on the stimulation outcome. Results obtained by the workflow based on human datasets and the average shape of a statistical model revealed a high qualitative agreement and a quantitatively comparable range compared to data from literature, respectively. Based on our workflow, a detailed analysis of intra- and extra-labyrinthine electrode configurations with various stimulation waveforms and electrode designs can be performed on patient specific anatomy, making this framework a valuable tool for current optimization questions concerning vestibular implants in humans.

The use of autonomous contracting randomly grown cardiomyocyte monolayers cultivated on microelectrode arrays (MEAs) represents an accepted experimental setting for preclinical experimental research in the field of cardiac electrophysiology. A dominant pacemaker forces a monolayer to adhere to a regular and synchronized contraction. Randomly distributed multiple pacemakers interfere with this dominant center, resulting in more or less frequent changes of propagation direction. This study aims to characterize the impact of changing propagation directions at single electrodes of the MEA on the four intrinsic parameters of registered field potentials (FPs) FPrise, FPMIN, FPpre, and FPdur and conduction velocity (CV) under normal and hypothermal conditions. Primary cultures of chicken cardiomyocytes ( n = 18) were plated directly onto MEAs and FPs were recorded in a temperature range between 37 and 29°C. The number and spatiotemporal distribution of biological and artificial pacemakers of each cell layer inside and outside of the MEA registration area were evaluated using an algorithm developed in-house. In almost every second myocardial cell layer, interfering autonomous pacemakers were detected at stable temperatures, showing random spatial distributions with similar beating rates. Additionally, a temperature-dependent change of the dominant pacemaker center was observed in n = 16 experiments. A significant spread-direction-dependent variation of CV, FPrise, FPMIN, and FPpre up to 14% could be measured between different endogenous pacemakers. In conclusion, based on our results, disregarding the spatial origin of excitation may lead to misinterpretations and erroneous conclusions of FP parameters in the verification of research hypotheses in cellular electrocardiology.

Movement science investigating muscle and tendon functions during locomotion utilizes commercial ultrasound imagers built for medical applications. These limit biomechanics research due to their form factor, range of view, and spatio-temporal resolution. This review systematically investigates the technical aspects of applying ultrasound as a research tool to investigate human and animal locomotion. It provides an overview on the ultrasound systems used and of their operating parameters. We present measured fascicle velocities and discuss the results with respect to operating frame rates during recording. Furthermore, we derive why muscle and tendon functions should be recorded with a frame rate of at least 150 Hz and a range of view of 250 mm. Moreover, we analyze why and how the development of better ultrasound observation devices at the hierarchical level of muscles and tendons can support biomechanics research. Additionally, we present recent technological advances and their possible application. We provide a list of recommendations for the development of a more advanced ultrasound sensor system class targeting biomechanical applications. Looking to the future, mobile, ultrafast ultrasound hardware technologies create immense opportunities to expand the existing knowledge of human and animal movement., Sensors, 19 (19), ISSN:1424-8220

Hypothermia has a profound impact on the electrophysiological mechanisms of the heart. Experimental investigations provide a better understanding of electrophysiological alterations associated with cooling. However, there is a lack of computer models suitable for simulating the effects of hypothermia in cardio-electrophysiology. In this work, we propose a model that describes the cooling-induced electrophysiological alterations in ventricular tissue in a temperature range from 27°C to 37°C. To model the electrophysiological conditions in a 3D left ventricular tissue block it was essential to consider the following anatomical and physiological parameters in the model: the different cell types (endocardial, M, epicardial), the heterogeneous conductivities in longitudinal, transversal and transmural direction depending on the prevailing temperature, the distinct fiber orientations and the transmural repolarization sequences. Cooling-induced alterations on the morphology of the action potential (AP) of single myocardial cells thereby are described by an extension of the selected Bueno-Orovio model for human ventricular tissue using Q10 temperature coefficients. To evaluate alterations on tissue level, the corresponding pseudo electrocardiogram (pECG) was calculated. Simulations show that cooling-induced AP and pECG-related parameters, i.e. AP duration, morphology of the notch of epicardial AP, maximum AP upstroke velocity, AP rise time, QT interval, QRS duration and J wave formation are in good accordance with literature and our experimental data. The proposed model enables us to further enhance our knowledge of cooling-induced electrophysiological alterations from cellular to tissue level in the heart and may help to better understand electrophysiological mechanisms, e.g. in arrhythmias, during hypothermia.

Cardiac cryoablation applied for treating cardiac arrhythmias has shown promising results after intervention, particularly for the creation of elongated lesions. A model for simulating and assessing cryoablation interventions was developed, evaluated and validated with animal experiments. We employed two simulations of different freezing outlet settings for a loop shaped cryocatheter, applying Pennes heat equation for cardiac tissue. Our experiments demonstrated that an equidistantly spaced freezing outlet distribution of 5mm led to an improved formation of lesions, i.e., elongated lesions were observed throughout the transmural cardiac volume and on the epicardial structure. A complete transmural frozen lesion was not achieved with a freezing outlet distance of 10mm. These simulation results could be experimentally verified by morphological and histological examinations. Using our simulation model we were able to optimize the intervention procedure by predicting and assessing the freezing process. This should further increase the success rate of cardiac cryoablation in clinical interventions.

Motivation: The discovery of new and unexpected biomarkers in cardiovascular disease is a highly data-driven process that requires the complementary power of modern metabolite profiling technologies, bioinformatics and biostatistics. Clinical biomarkers of early myocardial injury are lacking. A prospective biomarker cohort study was carried out to identify, categorize and profile kinetic patterns of early metabolic biomarkers of planned myocardial infarction (PMI) and spontaneous (SMI) myocardial infarction. We applied a targeted mass spectrometry (MS)-based metabolite profiling platform to serial blood samples drawn from carefully phenotyped patients undergoing alcohol septal ablation for hypertrophic obstructive cardiomyopathy serving as a human model of PMI. Patients with SMI and patients undergoing catheterization without induction of myocardial infarction served as positive and negative controls to assess generalizability of markers identified in PMI. Results: To identify metabolites of high predictive value in tandem mass spectrometry data, we introduced a new feature selection method for the categorization of metabolic signatures into three classes of weak, moderate and strong predictors, which can be easily applied to both paired and unpaired samples. Our paradigm outperformed standard null-hypothesis significance testing and other popular methods for feature selection in terms of the area under the receiver operating curve and the product of sensitivity and specificity. Our results emphasize that this new method was able to identify, classify and validate alterations of levels in multiple metabolites participating in pathways associated with myocardial injury as early as 10 min after PMI. Availability: The algorithm as well as supplementary material is available for download at: www.umit.at/page.cfm?vpath=departments/technik/iebe/tools/bi Contact: christian.baumgartner@umit.at Supplementary information: Supplementary data are available at Bioinformatics online.

Background: The evaluation of comorbidity is of increasing importance in patients with hematologic disorders. Patients and methods: In the present study, the influence of comorbidity on survival and acute myeloid leukemia (AML) evolution was analyzed retrospectively in 419 patients with de novo myelodysplastic syndromes (MDS) (observation period: 1985-2007). The median age was 71 years (range 24-91 years). Two different scoring systems, the hematopoietic stem-cell transplantation-specific comorbidity index (HCT-CI) and the Charlson comorbidity index (CCI) were applied. Results: The HCT-CI was found to be a significant prognostic factor for overall survival (OS, P < 0.05) as well as event-free survival (EFS, P < 0.05) in our patients, whereas the CCI was of prognostic significance for OS (P < 0.05), but not for EFS. For AML-free survival, neither the HCT-CI nor the CCI were of predictive value. A multivariate analysis including age, lactate dehydrogenase, ferritin, karyotype, number of cytopenias, French-American-British groups, and comorbidity was applied. Comorbidity was found to be an independent prognostic factor in patients with low- or int-1-risk MDS (P < 0.05) regarding OS and EFS. Conclusions: Together, our data show that comorbidity is an important risk factor for OS and EFS in patients with MDS.

Background Transfusion-related morbidity is an emerging problem in chronically transfused patients with myelodysplastic syndromes (MDS). Although several iron-chelating drugs are available, the optimal way of treatment of iron-overload remains uncertain. A major disadvantage of deferoxamine is that the drug has to be applied as continuous subcutaneous infusion. Therefore, novel oral agents have been developed. One of these drugs is deferasirox (Exjade®). Materials and methods We report on 14 MDS patients who were treated with deferasirox (500–1500 mg daily) for up to 24 months. In these patients, treatment responses were recorded by determining serum ferritin levels before and during therapy and by applying recently established response criteria. Results In all patients except one, ferritin levels decreased during therapy. Four patients showed a complete response, one a minor response and five a stable iron load. In the responding patients, initially elevated liver enzymes decreased substantially. No substantial change in transferrin saturation or transfusion frequency was recorded. Side effects were mild and tolerable in most patients. In one patient, treatment with deferasirox was stopped because of impaired kidney function. Conclusion Our data show that treatment with deferasirox is a reasonable approach to counteract iron overload in patients with MDS.

Motivation: Alcoholic fatty liver disease (AFLD) and non-AFLD (NAFLD) can progress to severe liver diseases such as steatohepatitis, cirrhosis and cancer. Thus, the detection of early liver disease is essential; however, minimal invasive diagnostic methods in clinical hepatology still lack specificity. Results: Ion molecule reaction mass spectrometry (IMR-MS) was applied to a total of 126 human breath gas samples comprising 91 cases (AFLD, NAFLD and cirrhosis) and 35 healthy controls. A new feature selection modality termed Stacked Feature Ranking (SFR) was developed to identify potential liver disease marker candidates in breath gas samples, relying on the combination of different entropy- and correlation-based feature ranking methods including statistical hypothesis testing using a two-level architecture with a suggestion and a decision layer. We benchmarked SFR against four single feature selection methods, a wrapper and a recently described ensemble method, indicating a significantly higher discriminatory ability of up to 10–15% for the SFR selected gas compounds expressed by the area under the ROC curve (AUC) of 0.85–0.95. Using this approach, we were able to identify unexpected breath gas marker candidates in liver disease of high predictive value. A literature study further supports top-ranked markers to be associated with liver disease. We propose SFR as a powerful tool for biomarker search in breath gas and other biological samples using mass spectrometry. Availability: The algorithm SFR and IMR-MS datasets are available under http://biomed.umit.at/page.cfm?pageid=526 Contact: michalel.netzer@umit.at; christian.baumgartner@umit.at

Specific inhibitors of PI3K isoforms are currently evaluated for their therapeutic potential in leukemia. We found that BCR/ABL+ human leukemic cells express PI3Kδ and therefore explored its impact on leukemia development. Using PI3Kδ-deficient mice, we define a dual role of PI3Kδ in leukemia. We observed a growth-promoting effect in tumor cells and an essential function in natural killer (NK) cell–mediated tumor surveillance: Abelson-transformed PI3Kδ-deficient cells induced leukemia in RAG2-deficient mice with an increased latency, indicating that PI3Kδ accelerated leukemia progression in vivo. However, the absence of PI3Kδ also affected NK cell–mediated tumor surveillance. PI3Kδ-deficient NK cells failed to lyse a large variety of target cells because of defective degranulation, as also documented by capacitance recordings. Accordingly, transplanted leukemic cells killed PI3Kδ-deficient animals more rapidly. As a net effect, no difference in disease latency in vivo was detected if both leukemic cells and NK cells lack PI3Kδ. Other tumor models confirmed that PI3Kδ-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3Kδ in the NK compartment is as relevant to survival of the mice as the delayed tumor progression. This dual function must be taken into account when using PI3Kδ inhibitors as antileukemic agents in clinical trials.

The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.

Objective Chronic eosinophilic leukemia (CEL) is a myeloproliferative disorder characterized by molecular and/or cytogenetic evidence of clonality of eosinophils, marked eosinophilia, and organ damage. In many patients, the transforming mutation FIP1L1-PDGFRα and the related CHIC2 deletion are found. The respective oncoprotein, FIP1L1-PDGFRα, is considered to play a major role in malignant cell growth in CEL. The tyrosine kinase (TK) inhibitor imatinib (STI571) has been described to counteract the TK activity of FIP1L1-PDGFRα in most patients. However, not all patients with CEL show a response to imatinib. Therefore, several attempts have been made to identify other TK inhibitors that counteract growth of neoplastic eosinophils. Materials and Methods We provide evidence that dasatinib, a multi-targeted kinase inhibitor, blocks the growth and survival of EOL-1, an eosinophil leukemia cell line carrying FIP1L1-PDGFRα. Results The effects of dasatinib on proliferation of EOL-1 cells were dose-dependent, with an IC 50 of 0.5 to 1nM, which was found to be in the same range when compared to IC 50 values produced with imatinib. Dasatinib was also found to induce apoptosis in EOL-1 cells in a dose-dependent manner (IC 50 : 1–10 nM). The apoptosis-inducing effects of dasatinib on EOL-1 cells were demonstrable by light microscopy, flow cytometry, and in a TUNEL assay. In Western blot experiments, dasatinib completely blocked the phosphorylation of FIP1L1-PDGFRα in EOL-1 cells. Conclusions Dasatinib inhibits the growth of leukemic eosinophils through targeting of the disease-related oncoprotein FIP1L1-PDGFRα. Based on this observation, dasatinib may be considered as a new interesting treatment option for patients with CEL.

Motivation: Prostate cancer is the most prevalent tumor in males and its incidence is expected to increase as the population ages. Prostate cancer is treatable by excision if detected at an early enough stage. The challenges of early diagnosis require the discovery of novel biomarkers and tools for prostate cancer management. Results: We developed a novel feature selection algorithm termed as associative voting (AV) for identifying biomarker candidates in prostate cancer data measured via targeted metabolite profiling MS/MS analysis. We benchmarked our algorithm against two standard entropy-based and correlation-based feature selection methods [Information Gain (IG) and ReliefF (RF)] and observed that, on a variety of classification tasks in prostate cancer diagnosis, our algorithm identified subsets of biomarker candidates that are both smaller and show higher discriminatory power than the subsets identified by IG and RF. A literature study confirms that the highest ranked biomarker candidates identified by AV have independently been identified as important factors in prostate cancer development. Availability: The algorithm can be downloaded from the following http://biomed.umit.at/page.cfm?pageid=516 Contact: melanie.osl@umit.at

Dasatinib is a multitargeted drug that blocks several tyrosine kinases. Apart from its well-known antileukemic activity, the drug has attracted attention because of potential immunosuppressive and anti-inflammatory effects. We report that dasatinib at 1 μM completely blocks anti-IgE–induced histamine release in blood basophils in healthy donors, and allergen-induced release of histamine in sensitized individuals. In addition, dasatinib inhibited FcϵRI-mediated release of IL-4 and IgE-mediated up-regulation of CD13, CD63, CD164, and CD203c in basophils. The effects of dasatinib were dose-dependent (IC50: 50-500 nM) and specific for FcϵRI activation in that the drug failed to inhibit C5a-induced or Ca-ionophore–induced histamine release. Interestingly, at lower concentrations, dasatinib even promoted FcϵRI-dependent histamine release in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several FcϵRI downstream targets in basophils, in-cluding Btk. Correspondingly, FcϵRI-mediated histamine secretion in basophils was markedly reduced in Btk knockout mice and in a patient with Btk deficiency. However, the remaining “low-level” mediator secretion in Btk-deficient cells was fully blocked down again by 1 μM dasatinib. Together, these data suggest that dasatinib inhibits FcϵRI-mediated activation of basophils through multiple signaling molecules including Btk. Dasatinib may be an interesting agent for immunologic disorders involving Btk-dependent responses or/and FcϵRI activation of basophils.

SummaryThis article is part of a For-Discussion-Section of Methods of Information in Medicine about the paper “Computational Electrocardiography: Revisiting Holter ECG Monitoring” written by Thomas M. Deserno and Nikolaus Marx. It is introduced by an editorial. This article contains the combined commentaries invited to independently comment on the paper of Deserno and Marx. In subsequent issues the discussion can continue through letters to the editor.

Background Cardiac cryoablation is a minimally invasive procedure to treat cardiac arrhythmias by cooling cardiac tissues responsible for the cardiac arrhythmia to freezing temperatures. Although cardiac cryoablation offers a gentler treatment than radiofrequency ablation, longer interventions and higher recurrence rates reduce the clinical acceptance of this technique. Computer models of ablation scenarios allow for a closer examination of temperature distributions in the myocardium and evaluation of specific effects of applied freeze-thaw protocols in a controlled environment. Methods In this work multiple intervention scenarios with two freeze-thaw cycles were simulated with varying durations and starting times of the interim thawing phase using a finite element model verified by in-vivo measurements and data from literature. To evaluate the effects of different protocols, transmural temperature distributions and iceball dimensions were compared over time. Cryoadhesion durations of the applicator were estimated in the interim thawing phase with varying thawing phase starting times. In addition, the increase of cooling rates was compared between the freezing phases, and the thawing rates of interim thawing phases were analyzed over transmural depth. Results It could be shown that the increase of cooling rate, the regions undergoing additional phase changes and depths of selected temperatures depend on the chosen ablation protocol. Only small differences of the estimated cryoadhesion duration were found for ablation scenarios with interim thawing phase start after 90 s freezing. Conclusions By the presented model a quantification of effects responsible for cell death is possible, allowing for the analysis and optimization of cryoablation scenarios which contribute to a higher clinical acceptance of cardiac cryoablation.

SummaryObjectives: Cardiovascular diseases are the most frequent cause of death in industrialized countries. Non-adherence with prescribed medication and recommended lifestyle changes significantly increases the risk of major cardiovascular events. The telemonitoring programme MyCor (Myokardinfarkt und Koronarstent Programm in Tirol) is a multi-modal intervention programme to improve lifestyle and medication management of patients with coronary heart disease (CHD). It includes patient education, self-monitoring with goal-setting and feedback, and regular clinical visits. We evaluated the MyCor telemonitoring programme regarding technical feasibility, user acceptance, patient adherence, change in health status, and change in quality of life.Methods: A 4½-month study was conducted with two telemonitoring phases and one interim phase. The study comprised patient surveys, standardized assessment of quality of life using the MacNew questionnaire at study entry and after 4 and 18 weeks, analysis of adherence to medication and physical activity during the two telemonitoring phases, and analysis of reached goals regarding health conditions during the telemonitoring phases.Results: Twenty-five patients (mean age: 63 years) participated in the study. Patients showed a high acceptance of the MyCor tele-monitoring programme. Patients reported feelings of self-control, motivation for lifestyle changes, and improved quality of life. Adherence to daily measurements was high with 86% and 77% in the two telemonitoring phases. Adherence to medication was also high with up to 87% and 80%. Pre-defined goals for physical activity were reached in up to 86% and 73% of days, respectively. Quality of life improved from 5.5 at study entry to 6.3 at the end (p< 0.01; MacNew questionnaire). Reductions in blood pressure and heart rate or an improvement in reaching defined goals could not be observed.Conclusions: The MyCor telemonitoring programme Tirol for CHD patients has a high rate of acceptance among included patients. Critical evaluation revealed subjective benefits regarding quality of life and health status as well as high adherence rates to medication and lifestyle changes. Achieving long-term adherence and verifying clinical outcomes, however, remains an open issue. Our findings will promote further studies, addressing different strategies for an optimal mix of patient education, telemonitoring, feedback, and clinical follow-ups.