Langzeit-Follow-up bei Kindern und Erwachsenen mit angeborenem Herzfehler nach kardialer Resynchronisationstherapie

Hintergrund: Die kardiale Resynchronisationstherapie (CRT) ist eine bewährte Methode zur Behandlung von Herzinsuffizienz bei Erwachsenen. Bei Kindern und Erwachsenen mit angeborenem Herzfehler hat sich die CRT in den letzten Jahren ebenfalls als wichtiges Mittel zur Behandlung von Herzinsuffizienz etabliert. Die Indikationsstellung unterscheidet sich aufgrund der Heterogenität der angeborenen Herzfehler jedoch stark von der erwachsenen Patientenpopulation. Zu dieser Patientenkohorte liegen nur wenige Daten vor und es gibt kaum Langzeitergebnisse. Methodik: Diese retrospektive multizentrische Studie untersucht das Outcome von 105 Kindern und Erwachsenen mit angeborenem Herzfehler nach kardialer Resynchronisationstherapie. Die mediane Follow-up-Zeit betrug 64 Monate (5,3 Jahre). Ergebnisse: Das mediane Alter bei Implantation betrug 19,5 Jahre und reichte von wenigen Monaten bis 69 Jahre. Einen morphologisch linken Systemventrikel wiesen 71,4% (n=75), einen morphologisch rechten Systemventrikel 27,6% (n=29). Zwei Patienten wiesen ein univentrikuläres Herz auf (1,9%). Vor Implantation bestand bei 72,4% (n=76) der Patienten eine vorherige Schrittmachertherapie. Den primären Endpunkt bestehend aus Tod oder Herztransplantation haben 26,7% der Patienten (n=28) erreicht. Davon sind 17,1% Patienten (n=18) gestorben und 9,5% (n=10) wurden herztransplantiert. Es zählten 80 Patienten (76,2%) zu den Respondern, welche als Erhöhung der systemisch ventrikulären Ejektionsfraktion und/oder Verringerung der QRS-Zeit vor und 6 bis 12 Monate nach CRT-Implantation definiert wurde. Die QRS-Zeit verringerte sich von 169,46 ± 31,05ms vor Implantation auf 166,30 ± 34,18ms (p=0,279) zum aktuellen Follow-up. Die Ejektionsfraktion stieg von 32,11 ± 10,01% auf 42,22 ± 14,58% (p=0,003) an. Das NYHA-Stadium verbesserte sich mit einem Median von III (I: 0%; II: 48,5%; III: 43,6%; IV: 7,9%) auf II (I: 27,9%; II: 38,2%; III: 22,1%; IV: 11,8%; p=0,003). Das NT-proBNP sank von 3283,49 ± 5073,14pg/ml auf 3040,97 ± 4637,18pg/ml (p=0,078). Als prädiktiver Parameter für Response konnte in dieser Studie eine QRS-Zeit über 140ms vor CRT-Implantation identifiziert werden (p=0,020). Patienten im Alter von 0 bis 17 Jahren (p=0,010) mit morphologisch linkem Systemventrikel (p=0,039), AV-Block 3. Grades (p=0,011) und einer vorherigen Schrittmachertherapie (p=0,009) erreichten weniger häufig den gemeinsamen Endpunkt bestehend aus Tod oder Herztransplantation. Prädiktive Parameter für das Erreichen des primären Endpunktes galten zum einen ein hohes Alter (p=0,004) und zum anderen keine vorherige Schrittmachertherapie (p=0,007). Schlussfolgerung: In dieser Studie konnte verdeutlicht werden, dass die CRT zu einer Verbesserung der QRS-Zeit, Ejektionsfraktion, NYHA-Stadium und des NT-proBNP-Wertes führt. Insbesondere jüngere Patienten mit einem morphologisch linken Systemventrikel, vorheriger Schrittmachertherapie und langer QRS-Dauer profitierten von einer CRT.Background: Cardiac resynchronization therapy (CRT) is a highly effective treatment of congestive heart failure in adults. In children and adults with congenital heart disease CRT is also an important tool to treat congestive heart failure. However indications differ widely from those of the adult population because of the heterogeneity of the congenital heart diseases. Data in this patient population is rare and especially long-term follow-up is scarce. Methods: This retrospective study examines the outcome of 105 children and adults with congenital heart defects after cardiac resynchronization therapy. The median follow-up time consisted of 64 months (5.3 years). Results: The median age at implantation was 19.5 years and ranged from a few months to 69 years. A systemic left ventricle was present in 71.4% (n=75), a systemic right ventricle in 27.6% (n=29). Two patients had a univentricular heart (1.9%). Before implantation 72.4% (n=76) of the patients had a pacemaker therapy. The primary endpoint consisting of death or heart transplantation was reached by 26.7% (n=28). Of these, 17.1% (n=18) died and 9.5% (n=10) underwent heart transplantation. The QRS duration decreased slightly from 169.46 ± 31.05ms before implantation to 166.30 ± 34.18ms (p=0.279) at the latest follow-up. The ejection fraction increased from 32.11 ± 10.01% to 42.22 ± 14.58% (p=0.003). NYHA stage improved with a median of III (I: 0%; II: 48.5%; III: 43.6%; IV: 7.9%) to II (I: 27.9%; II: 38.2%; III: 22.1%; IV: 11.8%) at the current follow up (p=0.003). NT-proBNP also fell slightly from 3283.49 ± 5073.14pg/ml to 3040.97 ± 4637.18pg/ml (p=0.078). A QRS duration above 140ms before CRT implantation was found to be a predictive parameter for response in this study (p=0,020). Patients aged 0 to 17 years (p=0,010) with a systemic left ventricle (p=0,039), 3rd degree AV block (p=0,011) and previous pacemaker therapy (p=0,009) were less likely to reach the common endpoint. Predictive parameters for reaching the primary endpoint were older age (p=0,004) and no previous pacemaker therapy (p=0,007). Conclusion: This study showed that CRT is a proven method of treating heart failure in children and adults with congenital heart disease and leads to an improvement in QRS duration, NYHA stage, ejection fraction and NT-proBNP value. Younger patients with a systemic left ventricle, previous pacemaker therapy and high QRS duration benefited in particular from CRT

Contributions to boundary control of distributed-parameter systems

Eine neuartige Entwurfsmethodik wird für die Regelung von linearen hyperbolischen oder parabolischen partiellen Differentialgleichungen (PDEs) vorgestellt, welche an einem Rand aktuiert und am anderen Rand mit nichtlinearen gewöhnlichen Differentialgleichungen (ODEs) gekoppelt sind. In Anlehnung an die wohlbekannte Backstepping-Methode für lineare Systeme wird eine nichtlineare Zustandstransformation herangezogen, um das System in eine für den Reglerentwurf besonders geeignete Form zu bringen. Das zentrale Ergebnis der vorliegenden Arbeit ist die Konstruktion dieser Zustandstransformation mithilfe der Lösung eines angemessen formulierten Cauchy-Problems. Die Verwendung einer flachheitsbasierten Parametrierung der entsprechenden PDE-Teilsysteme erleichtert diesen Entwurfsschritt. Zudem gestattet die Kombination von Backstepping und flachheitsbasierten Parametrierungen, auf bekannte Ergebnisse aus der bestehenden Literatur aufzubauen. Des Weiteren wird für den Spezialfall linearer Systeme gezeigt, dass der vorgestellte Ansatz sowohl für hyperbolische als auch für parabolische PDE-ODE-Systeme äquivalent zur Backstepping-Methode ist. Die in dieser Arbeit für den Reglerentwurf präsentierte Vorgehensweise bewältigt zuvor ungelöste Probleme und lässt sich aufgrund ihrer Systematik auf eine breitere Systemklasse erweitern. Allerdings sind im Rahmen dessen auch eine Vielzahl an Herausforderungen und interessanten Fragestellungen für weiterführende Untersuchungen entstanden.A novel framework is presented for the late-lumping boundary control of linear hyperbolic or parabolic partial differential equations (PDEs) that are interconnected with nonlinear ordinary differential equations (ODEs) at the unactuated boundary. Inspired by the well-established backstepping method for linear systems, a nonlinear state transformation is utilized to map the plant into a desired target system. The central result of this thesis is the construction of the state transformation through the solution of an appropriately formulated Cauchy problem. This is facilitated by the use of flatness-based parameterizations of the corresponding PDE subsystems. In fact, the combination of backstepping and flatness-based parameterizations allows this work to build upon a substantial body of existing literature. Furthermore, for the special case of linear systems, the approach is shown to be equivalent to the backstepping method for both hyperbolic and parabolic PDE-ODE systems. Although the presented control strategy overcomes previously unsolved problems and enables the systematic development of advanced designs for a broader system class, it has also given rise to numerous challenges and interesting problems for future research

Discovering motifs to fingerprint multi-layer networks: a case study on the connectome of C. Elegans

Motif discovery is a powerful and insightful method to quantify network structures and explore their function. As a case study, we present a comprehensive analysis of regulatory motifs in the connectome of the model organism Caenorhabditis elegans (C. elegans). Leveraging the Efficient Subgraph Counting Algorithmic PackagE (ESCAPE) algorithm, we identify network motifs in the multi-layer nervous system of C. elegans and link them to functional circuits. We further investigate motif enrichment within signal pathways and benchmark our findings with random networks of similar size and link density. Our findings provide valuable insights into the organization of the nerve net of this well-documented organism and can be easily transferred to other species and disciplines alike

Sex and gender differences in the molecular etiology of Parkinson's disease: considerations for study design and data analysis

Parkinson’s disease (PD) is more prevalent in men than women, and presents with different clinical features in each sex. Despite widespread recognition of these differences, females are under-represented in clinical and experimental studies of PD, and much remains to be elucidated regarding the biological underpinnings of sex differences in PD. In this review, we summarize known contributors to sex differences in PD etiology across the life course, with a focus on neurological development and gene regulation. Sex differences that are established at conception and heightened during adolescence and midlife may partially embed future PD risk, due to the complex interactions between gonadal hormones, gene regulation, lifestyle factors, and aging. While the neuroprotective properties of estrogen are strongly implicated in reduced prevalence of PD in women, interactions with genotype and gender-biased lifestyle factors are incompletely understood. Consideration of sex and genderrelated factors in study design, data analysis, and interpretation have the power to expedite our knowledge of the etiology of PD in men and in women, and to inform prevention and therapeutic strategies tailored to each sex. Plain english summary Parkinson’s disease (PD) more commonly affects men, and is known to have different symptoms in men and women. While this is in part due to the protective effects of estrogen in women, our understanding of why there is a sex difference in PD, and how it develops in each sex, is currently incomplete. This article provides an overview of factors throughout the lifespan that contribute to the differences between men and women in brain health and risk for PD, with a focus on hormones, gene regulation, and their intersections with lifestyle factors. We also discuss how researchers can consider sex and gender in future studies to enhance our understanding of how PD develops, and potentially develop sex-tailored prevention and treatment strategies. Highlights • Genetic risk for PD is similar between men and women. • Transcriptomic and epigenetic differences in men and women with PD have been reported, particularly in substantia nigra tissue. • Emerging evidence suggests interactions between gene regulation, sex hormones, and lifestyle factors contribute to disease pathogenesis in each sex. • Statistical approaches can be used to balance sex ratios and explore sex as a contributor to PD etiology, rather than a confounder. • Increasing representation of women in PD clinical studies is a priority for future research endeavors

A screening setup to streamline in vitro engineered living material cultures with the host

Engineered living materials (ELMs), which usually comprise bacteria, fungi, or animal cells entrapped in polymeric matrices, offer limitless possibilities in fields like drug delivery or biosensing. Determining the conditions that sustain ELM performance while ensuring compatibility with ELM hosts is essential before testing them in vivo. This is critical to reduce animal experimentation and can be achieved through in vitro investigations. Currently, there are no standards that ensure ELM compatibility with host tissues. Towards this goal, we designed a 96-well plate-based screening method to streamline ELM growth across culture conditions and determine their compatibility potential in vitro. We showed proliferation of three bacterial species encapsulated in hydrogels over time and screened six different cell culture media. We fabricated ELMs in bilayer and monolayer formats and tracked bacterial leakage as a measure of ELM biocontainment. After screening, an appropriate medium was selected that sustained growth of an ELM, and it was used to study cytocompatibility in vitro. ELM cytotoxicity on murine fibroblasts and human monocytes was studied by adding ELM supernatants and measuring cell membrane integrity and live/dead staining, respectively, proving ELM cytocompatibility. Our work illustrates a simple setup to streamline the screening of compatible environmental conditions of ELMs with the host

Revolutionizing MASLD: How Artificial Intelligence Is Shaping the Future of Liver Care

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as a leading cause of chronic liver disease. In recent years, artificial intelligence (AI) has attracted significant attention in healthcare, particularly in diagnostics, patient management, and drug development, demonstrating immense potential for application and implementation. In the field of MASLD, substantial research has explored the application of AI in various areas, including patient counseling, improved patient stratification, enhanced diagnostic accuracy, drug development, and prognosis prediction. However, the integration of AI in hepatology is not without challenges. Key issues include data management and privacy, algorithmic bias, and the risk of AI-generated inaccuracies, commonly referred to as “hallucinations”. This review aims to provide a comprehensive overview of the applications of AI in hepatology, with a focus on MASLD, highlighting both its transformative potential and its inherent limitations

Plasticity of metallic glasses dictated by their state at the fragile-to-strong transition temperature

The effect of cooling on the plasticity of glasses in general, and bulk metallic glasses (BMGs) in particular, is usually studied with continuously varying cooling rates; slower cooling rates lead to stiffer, harder, and more brittle glasses than higher cooling rates. These protocols obscure any potential discontinuity that a glass might experience, depending on whether its microstructure resembles that of a fragile or a strong glass-forming liquid. Here, we use large-scale molecular dynamics to simulate the nanoindentation behavior of model BMGs (Zr0.6Cu0.3Al0.1) obtained by rapidly quenching equilibrium melts from temperatures above and below the fragile-to-strong transition temperature fst, leading to fragile and strong glasses, respectively. While the contact modulus deduced from the indentation simulation evolves smoothly with the temperature q from which the equilibrium melt is quenched, the plastic response changes quasi-discontinuously as q passes through fst. In particular, strong glasses develop highly asymmetric flow profiles with mature shear bands, unlike fragile glasses. Differences are most evident in the von Mises strain localization parameter, which, after shearband formation, takes similar values for all fragile samples and distinct values for strong samples. Moreover, seemingly erratic flow profiles for our indentation geometry produced surprisingly reproducible and, thus, deterministic features. It remains to be determined to what extent other classes of glass formers follow our observation that plastic behavior is significantly influenced by whether the melt is fragile or strong when it falls out of equilibrium during cooling

Emergent complex phases in a discrete flocking model with reciprocal and non-reciprocal interactions

There is growing interest in multi-species active matter systems with reciprocal and non-reciprocal interactions. While such interactions have been explored in continuous symmetry models, less is known about multi-species discrete-symmetry systems. To address this, we study the two-species active Ising model (TSAIM), a discrete counterpart of the two-species Vicsek model. Our investigation explores both inter-species reciprocal and non-reciprocal interactions, along with the possibility of species interconversion. In the reciprocal TSAIM, we observe the emergence of a high-density parallel flocking state, a feature not seen in previous flocking models. With species interconversion, the TSAIM corresponds to an active extension of the Ashkin-Teller model and exhibits rich state diagrams. In the non-reciprocal TSAIM, a run-and-chase dynamics emerge. We also find that the system is metastable due to droplet excitation and exhibits spontaneous motility-induced interface pinning. A hydrodynamic theory validates our numerical simulations and confirms the phase diagrams

Adapting Energy Conservation Building Code-2023 for the Diverse Climates of Pakistan: A Path to Affordable Energy Efficiency and Sustainable Living

In Pakistan and most other developing nations, the residential building sector is one of the highest energy-consuming domains. The residential sector has the highest share of 50% of final electricity use of the country. Though Energy Conservation Building Codes (ECBC-2023) provide structured energy guidelines, no work has been performed to quantify the actual energy-saving potential of code-compliant retrofits in residential buildings. This study investigates the performance of ECBC-compliant retrofitting strategies for residential buildings under Pakistan’s diverse climatic conditions. The Passive House Planning Package (PHPP), a validated simulation tool, was used to assess energy performance improvements through building envelope interventions such as thermal insulation, solar shading, window glazing, and optimal orientation. Field data were collected from three representative cities, Multan (hot desert), Taxila (humid subtropical), and Quetta (cold semi-arid), to simulate both conventional and energy-efficient building scenarios. The results showed substantial seasonal energy savings in all three climates. During the heating period, energy savings were 48%, 50%, and 60% for Taxila, Multan, and Quetta, respectively. Similarly, energy savings during the cooling season were 44%, 33%, and 16%. Life cycle economic analysis revealed that these retrofits yielded Net Present Values (NPVs) of USD 752 (Taxila), USD 1226 (Multan), and USD 1670 (Quetta) over a 30-year period, with discounted payback periods ranging from 6 to 10 years. Furthermore, a life cycle assessment demonstrated that retrofitted buildings yielded up to 26% reduction in overall carbon emissions, combining both embodied and operational sources. The findings highlight that ECBC-2023 is not only a technically viable solution for energy savings but also financially attractive in residential retrofitting. By incorporating localized climate responsiveness into ECBC-compliant building design, the study provides a practical roadmap for achieving Pakistan’s energy efficiency goals. Additionally, the outcomes serve as a basis for informing policy initiatives, supporting building code adaptation, and raising public awareness of sustainable housing practices

Functional Microendoscopy Reveals Calcium Responses of Single Cells in Tracheal Tuft Cells and Kidney Podocytes

Microendoscopy, a crucial technology for minimally invasive investigations of organs, facilitates studies within confined cavities. However, conventional microendoscopy is often limited by probe size and the constraint of using a single excitation wavelength. In response to these constraints, a multichannel microendoscope with a slender profile of only 360 µm is engineered. Functional signals both in situ and in vivo are successfully captured from individual single cells, employing a specially developed software suite for image processing, and exhibiting an effective resolution of 4.6 µm, allowing for the resolution of subcellular neuronal structures. This system enabled the first examination of calcium dynamics in vivo in murine tracheal tuft cells (formerly named brush cells) and in situ in kidney podocytes. Additionally, it recorded ratiometric redox reactions in various biological settings, including intact explanted organs and pancreatic islet cultures. The flexibility and streamlined operation of the microendoscopic technique open new avenues for conducting in vivo research, allowing for studies of tissue and organ function at cellular resolution