Implantable loop recorders in patients with unexplained syncope: Clinical predictors of pacemaker implantation

Background: Implantable loop recorders (ILR) are a valuable tool for the investigation of unexplained syncopal episodes. The aim of this retrospective single center study was to identify predictive factors for pacemaker implantation in patients with unexplained syncope who underwent ILR insertion. Methods: One hundred six patients were retrospectively analyzed (mean age 59.1 years; 47.2% male) with unexplained syncope and negative conventional testing who underwent ILR implantation. The pri- mary study endpoint was detection of symptomatic or asymptomatic bradycardia requiring pacemaker implantation.  Results: The average follow-up period after ILR implantation was 20 ± 15 months. Pacemaker im- plantation according to current guidelines was necessary in 22 (20.8%) patients, mean duration until index bradycardia was 81 ± 88 (2–350) days. Ten (45.5%) patients received a pacemaker due to sinus arrest, 7 (31.8%) patients due to third-degree atrioventricular block, 2 (9.1%) patients due to second- degree atrioventricular block and 1 (4.5%) patient due to atrial fibrillation with a slow ventricular rate. Three factors remained significant in multivariate analysis: obesity, which defined by a body mass index above 30 kg/m2 (OR: 7.39, p = 0.014), a right bundle branch block (OR: 9.40, p = 0.023) and chronic renal failure as defined by a glomerular filtration rate of less than 60 mL/min (OR: 6.42, p = 0.035). Conclusions: Bradycardia is a frequent finding in patients undergoing ILR implantation due to un- explained syncope. Obesity, right bundle branch block and chronic renal failure are independent clinical predictors of pacemaker implantation

The PompeQoL questionnaire: Development and validation of a new measure for children and adolescents with Pompe disease

Genetic disorders pose great challenges for affected individuals and their families, as they must cope with the irreversible nature of the disease and a life‐long dependence on medical assistance and treatment. Children and adolescents dealing with Pompe disease (PD) often struggle to keep up with their peers in physical activities. To gain valuable insights into their subjective experiences and better understand their perception and coping related to daily challenges linked to their condition and treatment, the use of standardized questionnaires is crucial. This study introduces the novel PompeQoL 1.0 questionnaire for children and adolescents with PD, designed for comprehensive assessment of both disease‐specific FDH and HRQoL through self‐ and proxy reports. Content validity was ensured through patients' and parents' involvement at the initial stages of development and in subsequent cognitive debriefing process. Participants found the questionnaire easy to understand, answerable, relevant, and comprehensive. Adjustments based on feedback from patients and their parents improved its utility as a patient‐ and observer‐reported outcome measure. After careful item examination, 52 items were selected, demonstrating moderate to excellent test–retest reliability for most scales and initial evidence for satisfactory construct validity. The PompeQoL questionnaire stands as a valuable screening instrument for both clinical and research purposes. Future research should prioritize additional revisions and larger validation studies, focusing on testing the questionnaire in clinical practice and trials. Nevertheless, the PompeQoL 1.0 stands out as the first standardized measure providing insights into disease‐specific FDH and HRQoL among children and adolescents with various forms of PD

A Cross-Organizational Process Mining Framework for Obtaining Insights from Software Products: Accurate Comparison Challenges

Software vendors offer various software products to large numbers of enterprises to support their organization, in particular Enterprise Resource Planning (ERP) software. Each of these enterprises use the same product for similar goals, albeit with different processes and configurations. Therefore, software vendors want to obtain insights into how the enterprises use the software product, what the differences are in usage between enterprises, and the reasons behind these differences. Cross-organizational process mining is a possible solution to address these needs, as it aims at comparing enterprises based on their usage. In this paper, we present a novel Cross-Organizational Process Mining Framework which takes as input, besides event log, semantics (meaning of terms in an enterprise) and organizational context (characteristics of an enterprise). The framework provides reasoning capabilities to determine what to compare and how. Besides, the framework enables one to create a catalog of metrics by deducing diagnostics from the usage. By using this catalog, the framework can monitor the (positive) effects of changes on processes. An enterprise operating in a similar context might also benefit from the same changes. To accommodate these improvement suggestions, the framework creates an improvement catalog of observed changes. Later, we provide a set of challenges which have to be met in order to obtain the inputs from current products to show the feasibility of the framework. Next to this, we provide preliminary results showing they can be met and illustrate an example application of the framework in cooperation with an ERP software vendor

Image-based consensus molecular subtyping in rectal cancer biopsies and response to neoadjuvant chemoradiotherapy

The development of deep learning (DL) models to predict the consensus molecular subtypes (CMS) from histopathology images (imCMS) is a promising and cost-effective strategy to support patient stratification. Here, we investigate whether imCMS calls generated from whole slide histopathology images (WSIs) of rectal cancer (RC) pre-treatment biopsies are associated with pathological complete response (pCR) to neoadjuvant long course chemoradiotherapy (LCRT) with single agent fluoropyrimidine. DL models were trained to classify WSIs of colorectal cancers stained with hematoxylin and eosin into one of the four CMS classes using a multi-centric dataset of resection and biopsy specimens (n = 1057 WSIs) with paired transcriptional data. Classifiers were tested on a held out RC biopsy cohort (ARISTOTLE) and correlated with pCR to LCRT in an independent dataset merging two RC cohorts (ARISTOTLE, n = 114 and SALZBURG, n = 55 patients). DL models predicted CMS with high classification performance in multiple comparative analyses. In the independent cohorts (ARISTOTLE, SALZBURG), cases with WSIs classified as imCMS1 had a significantly higher likelihood of achieving pCR (OR = 2.69, 95% CI 1.01–7.17, p = 0.048). Conversely, imCMS4 was associated with lack of pCR (OR = 0.25, 95% CI 0.07–0.88, p = 0.031). Classification maps demonstrated pathologist-interpretable associations with high stromal content in imCMS4 cases, associated with poor outcome. No significant association was found in imCMS2 or imCMS3. imCMS classification of pre-treatment biopsies is a fast and inexpensive solution to identify patient groups that could benefit from neoadjuvant LCRT. The significant associations between imCMS1/imCMS4 with pCR suggest the existence of predictive morphological features that could enhance standard pathological assessment

Postauthorization safety study of betaine anhydrous

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013–2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0–9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation

Baseline Absolute Lymphocyte Count and ECOG Performance Score Are Associated with Survival in Advanced Non-Small Cell Lung Cancer Undergoing PD-1/PD-L1 Blockade

Immune-checkpoint blockade in front-line or second-line treatment improves survival in advanced non-small cell lung cancer (aNSCLC) when compared with chemotherapy alone. However, easily applicable predictive parameters are necessary to guide immune-checkpoint inhibition in clinical practice. In this retrospective bi-centric analysis, we investigated the impact of baseline patient and tumor characteristics on clinical outcome in aNSCLC patients treated with programmed cell death protein 1(PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors. Between May 2015 and January 2018, 142 unselected consecutive NSCLC patients received PD-1/PD-L1 inhibitors during the course of disease. In multivariate analysis, we identified the Eastern Cooperative Oncology Group (ECOG) performance status (ECOG &gt; 1 versus ECOG &le; 1, HR: 3.23, 95%CI: 1.58&ndash;6.60, P = 0.001), baseline absolute lymphocyte count (ALC; high: &gt;0.93 &times; 109/L versus low: &le; 0.93 &times; 109/L, HR: 0.38, 95%CI: 0.23&ndash;0.62, P &lt; 0.001), prior or concomitant anti-vascular endothelial growth factor (VEGF) targeting therapy (yes versus no, HR: 2.18, 95%CI: 1.15&ndash;4.14, P = 0.017) and TNM stage (IV versus III, HR: 4.18, 95%CI: 1.01&ndash;17.36, P = 0.049) as the most relevant parameters for survival. Neither antibiotic exposure (antibiotic-positive versus antibiotic-negative, HR: 0.90, 95%CI: 0.56&ndash;1.45, P = 0.675), nor PD-L1 expression on tumor cells (&ge;1% versus &lt;1%, HR: 0.68, 95%CI: 0.41&ndash;1.13, P = 0.140) was associated with survival. Baseline ECOG performance status and ALC were associated with survival in aNSCLC patients treated with PD-1/PD-L1 inhibitors and assessment of these parameters could be suitable in clinical practice

Fault-tolerant delay-insensitive codes

Abweichender Titel nach Übersetzung der Verfasserin/des VerfassersZusammenfassung in deutscher SpracheMit ihrer Robustheit gegen Signallaufzeitschwankungen bieten asynchrone delay-insensitive (DI) Übertragungsstrecken vorteilhafte Eigenschaften im Vergleich zu synchronen Lösungen. Dabei ist allerdings zu beachten, dass dafür spezielle DI Codes notwendig sind. Diese Codes sind aber in der Regel sehr anfällig für transiente Fehler, die während einer Übertragung auftreten können, da bei vielen dieser Codes bereits ein einzelner Fehler (im schlimmsten Fall) eine völlige Änderung des Nachrichteninhaltes zur Folge haben kann. Wenn dem Empfänger einer solchen Nachricht keine zusätzlichen Informationen zur Verfügung gestellt werden, hat dieser keine Möglichkeit, diese Übertragungsfehler zu erkennen, was natürlich schwerwiegende Konsequenzen für ein System an sich sowie dessen Umgebung haben kann. In dieser Arbeit werden daher Möglichkeiten zur Absicherung von DI Kommunikation untersucht. Darüber hinaus wird ein neuartiges, zweistufiges Kodierungsverfahren vorgestellt, das auf der Kombination von fehlererkennenden und DI Codes basiert. Diese Lösung nützt dabei die inhärente Fehlerwiderstandsfähigkeit von DI Codes aus und erreicht damit eine gute Kodierungseffizienz bei gleichzeitig niedrigem Implementierungsaufwand. Um die Fehleranfälligkeit der Codes zu analysieren und um gültige Lösungen zu ermitteln, kommen Methoden der Graphentheorie zum Einsatz. Im Vergleich zu existierenden Lösungen wird hier sehr genau darauf geachtet, keine Annahmen über das Signallaufzeitverhalten zu treffen. Die vorgeschlagene Lösung ist sehr generisch und kann prinzipiell mit jedem vierphasigen DI Code verwendet werden. Mittels einer repräsentativen Auswahl von m-aus-n Codes wird gezeigt, wie das Kodierungsverfahren angewendet wird und welche Kodierungseffizienz dabei zu erwarten ist. Zusätzlich wird eine Metrik eingeführt, die es erlaubt geeignete Codes für gegebene Anforderungen an fehlertolerante Übertragungsstrecken zu identifizieren. Weiters stellen wir eine Reihe von Sender- und Empfängerschaltungen vor, die verwendet werden können, um das neue Kodierungsverfahren zu implementieren. Zwei detaillierte Implementierungsbeispiele auf Gatterebene für Vertreter der m-aus-n Codeklasse demonstrieren dabei die Machbarkeit des Lösungsansatzes und geben einen Einblick in die zu erwartenden Implementierungskosten.Compared to synchronous approaches, asynchronous delay-insensitive (DI) communication links have very interesting and desirable properties with respect to their robustness against timing variations and delay assumptions required to implement them. However, special DI codes have to be used to encode the data being transmitted. These codes are usually prone to transient faults occurring during an ongoing transmission, since, in the worst case, even a single transient fault is sufficient to completely change the contents of a message. Unless further redundant information is provided, the receiver has no means to detect such an erroneous transmission. This can, of course, have severe consequences on a system and the environment depending on it. In this thesis we therefore investigate existing approaches to secure DI communication against transient faults and propose a novel two-step data encoding scheme that combines DI and error detecting codes. Our solution exploits the inherent fault resilience of DI codes to achieve a low overhead and hence good coding efficiency. We use methods from graph theory to analyze this fault resilience and identify appropriate solutions. In contrast to existing approaches we carefully avoid the introduction of timing assumptions to mask faults. The proposed coding scheme is generic and can, in principle, be used with any 4-phase DI code. We give examples on how to apply it to selected representatives of the important class of m-of-n codes and analyze the resulting coding efficiency. Additionally, we provide a metric that allows to identify which codes are well suited for fault-tolerant communication. We, furthermore, provide a range of transmitter and receiver circuit variants that implement the presented coding scheme. In particular, we give detailed gate-level implementation examples for two m-of-n codes, that demonstrate the feasibility of our approach and give some insight into the required implementation overhead.8