Lead and generator dysfunction in children and adolescents with epicardial pacemaker and implantable cardioverter defibrillator systems: The challenge of early recognition.

BACKGROUND: A major issue of cardiac implantable electronic device therapy in pediatric patients is the high incidence of lead dysfunctions and associated reinterventions. This study aims to analyze the timing and mode of generator and lead dysfunction. METHODS: Retrospective single-center analysis of 283 children and young adults with an epicardial pacemaker or implantable cardioverter defibrillator therapy from 1998 to 2018. RESULTS: Mean age at implant was 6.1 years (SD ± 5.8 years) and median follow-up 6.4 years (IQR, 3.4-10.4 years) with a total of 1998.1 patient-years of cardiac device therapy. A total of 120 lead-related complications were observed in 82 patients (29.0%). They were detected by device interrogation (n = 86), symptoms (n = 13), intraoperative findings (n = 7), routine chest radiography (n = 5), routine ECG (n = 4), patient alert sound by device (n = 3), and physical examination (n = 2). It was possible to find the date of the event on the device memory in 21 out of 120 lead dysfunctions (18%) with a median time interval between occurrence and detection of 1.3 months (IQR, 0.2-5.0 months). Moreover, 20 generator-related complications were found in 13 patients. CONCLUSIONS: Early recognition of lead and generator dysfunction remains challenging in pediatric patients. As symptoms are relatively rare conditions in the context of PM and ICD dysfunction, close patient monitoring is mandatory, even in asymptomatic patients with a good clinical course. To further improve the safety of pediatric pacing systems, more durable epicardial electrodes are desirable.

The accelerated waning of immunity and reduced effect of booster in patients treated with bDMARD and tsDMARD after SARS-CoV-2 mRNA vaccination.

Objectives: This study aimed to assess the duration of humoral responses after two doses of SARS-CoV-2 mRNA vaccines in patients with inflammatory joint diseases and IBD and booster vaccination compared with healthy controls. It also aimed to analyze factors influencing the quantity and quality of the immune response. Methods: We enrolled 41 patients with rheumatoid arthritis (RA), 35 with seronegative spondyloarthritis (SpA), and 41 suffering from inflammatory bowel disease (IBD), excluding those receiving B-cell-depleting therapies. We assessed total anti-SARS-CoV-2 spike antibodies (Abs) and neutralizing Ab titers 6 months after two and then after three doses of mRNA vaccines compared with healthy controls. We analyzed the influence of therapies on the humoral response. Results: Patients receiving biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) showed reduced anti-SARS-CoV-2 S Abs and neutralizing Ab titers compared with HC or patients receiving conventional synthetic (cs)DMARDs 6 months after the first two vaccination doses. Anti-SARS-CoV-2 S titers of patients with b/tsDMARDs declined more rapidly, leading to a significant reduction in the duration of vaccination-induced immunity after two doses of SARS-CoV-2 mRNA vaccines. While 23% of HC and 19% of patients receiving csDMARDs were without detectable neutralizing Abs 6 months after the first two vaccination doses, this number was 62% in patients receiving b/tsDMARDs and 52% in patients receiving a combination of csDMARDs and b/tsDMARDs. Booster vaccination led to increased anti-SARS-CoV-2 S Abs in all HC and patients. However, anti-SARS-CoV-2 S Abs after booster vaccination was diminished in patients receiving b/tsDMARDs, either alone or in combination with csDMARDs compared to HC. Conclusion: Patients receiving b/tsDMARDs have significantly reduced Abs and neutralizing Ab titers 6 months after mRNA vaccination against SARS-CoV-2. This was due to a faster decline in Ab levels, indicating a significantly reduced duration of vaccination-induced immunity compared with HC or patients receiving csDMARDs. In addition, they display a reduced response to a booster vaccination, warranting earlier booster vaccination strategies in patients under b/tsDMARD therapy, according to their specific Ab levels.

Combined use of magnetic microbeads for endothelial cell isolation and enhanced cell engraftment in myocardial repair.

Background: The regenerative potential of the heart after injury is limited. Therefore, cell replacement strategies have been developed. However, the engraftment of transplanted cells in the myocardium is very inefficient. In addition, the use of heterogeneous cell populations precludes the reproducibility of the outcome. Methods: To address both issues, in this proof of principle study, we applied magnetic microbeads for combined isolation of eGFP+ embryonic cardiac endothelial cells (CECs) by antigen-specific magnet-associated cell sorting (MACS) and improved engraftment of these cells in myocardial infarction by magnetic fields. Results: MACS provided CECs of high purity decorated with magnetic microbeads. In vitro experiments revealed that the angiogenic potential of microbead-labeled CECs was preserved and the magnetic moment of the cells was strong enough for site-specific positioning by a magnetic field. After myocardial infarction in mice, intramyocardial CEC injection in the presence of a magnet resulted in a strong improvement of cell engraftment and eGFP+ vascular network formation in the hearts. Hemodynamic and morphometric analysis demonstrated augmented heart function and reduced infarct size only when a magnetic field was applied. Conclusion: Thus, the combined use of magnetic microbeads for cell isolation and enhanced cell engraftment in the presence of a magnetic field is a powerful approach to improve cell transplantation strategies in the heart.

Immune Response after mRNA COVID-19 Vaccination in Lung Transplant Recipients: A 6-Month Follow-Up.

BACKGROUND AND OBJECTIVE: This prospective cohort study analyzed the immune response to COVID-19 mRNA vaccines in lung transplant recipients (LuTRs) compared to healthy controls (HCs) at a 6-month follow-up. METHODS: After the first two doses of either BNT162b2 or mRNA-1273, SARS-CoV-2 antibodies were measured in LuTRs (n = 57) and sex- and age-matched HCs (n = 57). Antibody kinetics during a 6-month follow-up and the effect of a third vaccine dose were evaluated. Humoral responses were assessed using the Elecsys® Anti-SARS-CoV-2 S immunoassay. In 16 LuTRs, SARS-CoV-2-specific T cell responses were quantified using IFN-γ ELISpot assays. RESULTS: Seroconversion rates were 94% and 100% after the first and second vaccine dose, respectively, in HCs, while only 19% and 56% of LuTRs developed antibodies. Furthermore, 22 of 24 LuTRs who received the third vaccine dose showed seroconversion (five of seven primary non-responders and 17 of 17 primary responders). A T cell response against SARS-CoV-2-spike S1 and/or S2 was detected in 100% (16/16) of HCs and 50% (8/16) of LuTRs. CONCLUSIONS: The data suggest that LuTRs have reduced humoral and cellular immune responses after two doses of COVID-19 mRNA vaccination when compared to HCs. A third dose may be of substantial benefit.

SARS-CoV-2 Vaccine Response in Patients With Autoimmune Hepatitis.

Patients suffering from autoimmune hepatitis, a chronic immune-mediated liver disease with an incidence of 0.9 to 2 per 100,000 population per year in Europe, are considered to have a particularly increased risk for coronavirus disease 2019 (Covid-19)-associated hospitalization and death.1,2 Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination provides an essential tool to reduce morbidity and mortality in this cohort. However, a large multicenter study in China has shown a lower immunogenic response to inactivated whole-virion SARS-CoV-2 vaccines of chronic liver disease patients in comparison with the healthy population.3 Furthermore, reports from inflammatory bowel diseases or rheumatic disorders showed a reduced serologic response in patients taking glucocorticoids or thiopurine.4,5 The decrease in vaccine-induced antibodies over time, as well as the emergence of variants of concern, led to the recommendation of an additional vaccination in immunocompromised patients.

Immunogenicity of COVID-19 Vaccinations in Hematological Patients: 6-Month Follow-Up and Evaluation of a 3rd Vaccination.

Here we analyzed SARS-CoV-2-specific antibodies and T-cell responses after two coronavirus disease 2019 vaccinations over a six-month period in patients with hematological malignancies and assessed the effect of a third vaccination in a subgroup. Sixty-six patients and 66 healthy controls were included. After two vaccinations seroconversion was seen in 52% and a T-cell-specific response in 59% of patients compared with 100% in controls (p = 0.001). Risk factors for a poor serological response were age (<65a), history of anti-CD20 therapy within the year preceding vaccination, CD19+ B-cells < 110/µL, and CD4+ T-cells > 310/µL. The magnitude of T-cell response was higher in patients <65a and with CD19+ B-cells < 110/µL. Patients and healthy controls demonstrated a significant decrease in SARS-CoV-2 S antibody levels over the period of six months (p < 0.001). A third vaccination demonstrated a strong serological response in patients who had responded to the previous doses (p < 0.001). The third vaccination yielded seroconversion in three out of 19 patients in those without serological response. We conclude that both humoral and cellular responses after SARS-CoV-2 immunization are impaired in patients with hematological malignancies. A third vaccination enhanced B-cell response in patients who previously responded to the second vaccination but may be of limited benefit in patients without prior seroconversion.

Response to SARS-CoV-2 vaccination in systemic autoimmune rheumatic disease depends on immunosuppressive regimen: a matched, prospective cohort study.

OBJECTIVE: To assess the humoral response to messenger RNA (mRNA) vaccine of patients with systemic autoimmune rheumatic disease (SARD) and the effect of immunosuppressive medication in a matched cohort study. METHODS: Patients with SARD were enrolled and matched 1:1 for sex and age with healthy control (HC) subjects. Differences in humoral response to two doses of an mRNA vaccine in terms of seroconversion rate (SCR) and SARS-CoV-2 antibody level between the two groups and the impact of treatment within patients with SARD were assessed. RESULTS: We enrolled 82 patients with SARD and 82 matched HC. SCR after the first dose was lower among the patient group than that of HC (65% compared with 100% in HC, p<0.0001) but levelled up after the second dose (94% vs 100%). After the second dose, SCR was lower for patients on combination disease-modifying antirheumatic drug (DMARD) therapy compared with all other groups (81% compared with 95% for monotherapy, p=0.01; 100% for both no DMARD therapy and HC, both p<0.0001). In addition, antibody levels after both doses were lower in patients compared with HC. We found that vaccination response was determined primarily by the number of DMARDs and/or glucocorticoids received, with patients receiving combination therapy (dual and triple therapy) showing the poorest response. CONCLUSIONS: Patients with SARD showed a good response after the second vaccination with an mRNA vaccine. However, the choice of immunosuppressive medication has a marked effect on both SCR and overall antibody level, and the number of different immunomodulatory therapies determines vaccination response.

Importance of the second SARS-CoV-2 vaccination dose for achieving serological response in patients with rheumatoid arthritis and seronegative spondyloarthritis.

OBJECTIVES: To assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response. METHODS: We enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response. RESULTS: Samples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC. CONCLUSIONS: Patients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy.

Direct measurement of electrostatic potentials at the atomic scale: A conceptual comparison between electron holography and scanning transmission electron microscopy.

Off-axis electron holography and first moment STEM are sensitive to electromagnetic potentials or fields, respectively. In this work, we investigate in what sense the results obtained from both techniques are equivalent and work out the major differences. The analysis is focused on electrostatic (Coulomb) potentials at atomic spatial resolution. It is shown that the probe-forming/objective aperture strongly affects the reconstructed electrostatic potentials and that, as a result of the different illumination setups, dynamical diffraction effects show a specific response with increasing specimen thickness. It is shown that thermal diffuse scattering is negligible for a wide range of specimen thicknesses, when evaluating the first moment of diffraction patterns.

Comparison of first moment STEM with conventional differential phase contrast and the dependence on electron dose.

This study addresses the comparison of scanning transmission electron microscopy (STEM) measurements of momentum transfers using the first moment approach and the established method that uses segmented annular detectors. Using an ultrafast pixelated detector to acquire four-dimensional, momentum-resolved STEM signals, both the first moment calculation and the calculation of the differential phase contrast (DPC) signals are done for the same experimental data. In particular, we investigate the ability to correct the segment-based signal to yield a suitable approximation of the first moment for cases beyond the weak phase object approximation. It is found that the measurement of momentum transfers using segmented detectors can approach the first moment measurement as close as 0.13 h/nm in terms of a root mean square (rms) difference in 10 nm thick SrTiO3 for a detector with 16 segments. This amounts to 35% of the rms of the momentum transfers. In addition, we present a statistical analysis of the precision of first moment STEM as a function of dose. For typical experimental settings with recent hardware such as a Medipix3 Merlin camera attached to a probe-corrected STEM, we find that the precision of the measurement of momentum transfers stagnates above certain doses. This means that other instabilities such as specimen drift or scan noise have to be taken into account seriously for measurements that target, e.g., the detection of bonding effects in the charge density.

PECAM/eGFP transgenic mice for monitoring of angiogenesis in health and disease.

For the monitoring of vascular growth as well as adaptive or therapeutic (re)vascularization endothelial-specific reporter mouse models are valuable tools. However, currently available mouse models have limitations, because not all endothelial cells express the reporter in all developmental stages. We have generated PECAM/eGFP embryonic stem (ES) cell and mouse lines where the reporter gene labels PECAM+ endothelial cells and vessels with high specificity. Native eGFP expression and PECAM staining were highly co-localized in vessels of various organs at embryonic stages E9.5, E15.5 and in adult mice. Expression was found in large and small arteries, capillaries and in veins but not in lymphatic vessels. Also in the bone marrow arteries and sinusoidal vessel were labeled, moreover, we could detect eGFP in some CD45+ hematopoietic cells. We also demonstrate that this labeling is very useful to monitor sprouting in an aortic ring assay as well as vascular remodeling in a murine injury model of myocardial infarction. Thus, PECAM/eGFP transgenic ES cells and mice greatly facilitate the monitoring and quantification of endothelial cells ex vivo and in vivo during development and injury.

Absolute Scale Quantitative Off-Axis Electron Holography at Atomic Resolution.

An absolute scale match between experiment and simulation in atomic-resolution off-axis electron holography is demonstrated, with unknown experimental parameters determined directly from the recorded electron wave function using an automated numerical algorithm. We show that the local thickness and tilt of a pristine thin WSe_{2} flake can be measured uniquely, whereas some electron optical aberrations cannot be determined unambiguously for a periodic object. The ability to determine local specimen and imaging parameters directly from electron wave functions is of great importance for quantitative studies of electrostatic potentials in nanoscale materials, in particular when performing in situ experiments and considering that aberrations change over time.

Fine electron biprism on a Si-on-insulator chip for off-axis electron holography.

Off-axis electron holography allows both the amplitude and the phase shift of an electron wavefield propagating through a specimen in a transmission electron microscope to be recovered. The technique requires the use of an electron biprism to deflect an object wave and a reference wave to form an interference pattern. Here, we introduce an approach based on semiconductor processing technology to fabricate fine electron biprisms with rectangular cross-sections. By performing electrostatic calculations and preliminary experiments, we demonstrate that such biprisms promise improved performance for electron holography experiments.

Long-term outcome of epicardial implantable cardioverter-defibrillator systems in children: results justify its preference in paediatric patients.

Aims: The question of whether transvenous or epicardial implantable cardioverter defibrillator (ICD) system is more beneficial in children and adolescents is controversially discussed. We sought to analyse the long-term outcome after implantation of ICDs using epicardial pacing/sensing and pleural shock leads. Methods and results: Retrospective analysis of 31 consecutive patients undergoing a total of 55 implantations of epicardial/pleural ICD systems below 20 years of age. Median age at implantation was 11.4 years (range 2.2-20) and median follow-up 57 months (range 0.4-127). The ICDs were implanted for primary (n = 17) and for secondary prevention (n = 14). The first defibrillation threshold at implantation was ≤25 J in 94% of the implant procedures. Appropriate shocks occurred in 6 of 31 patients. Inappropriate shocks occurred in 4 of 31 patients triggered by lead fracture, T-wave oversensing, sinus tachycardia, and atrial fibrillation. Freedom from first ICD discharge was 81, 71, and 71% at 3, 6, and 9 years, respectively. Reoperation was indicated in 16 of 31 patients for lead failure (n=11), end of battery life (n=10), generator migration (n=1) and recall (n=1); freedom from reoperation was 74 and 55% at 3 and 6 years. Conclusion: Paediatric epicardial/pleural ICD therapy is feasible, effective, and safe both in the short-term as well as in the long-term perspective at the price of relatively frequent surgical revisions. They do not generally result in an increased burden of inappropriate shocks. This ICD system meets the needs of the paediatric population and can be recommended as a first choice in this age group.

Quantitative measurement of mean inner potential and specimen thickness from high-resolution off-axis electron holograms of ultra-thin layered WSe2.

The phase and amplitude of the electron wavefunction that has passed through ultra-thin flakes of WSe2 is measured from high-resolution off-axis electron holograms. Both the experimental measurements and corresponding computer simulations are used to show that, as a result of dynamical diffraction, the spatially averaged phase does not increase linearly with specimen thickness close to an [001] zone axis orientation even when the specimen has a thickness of only a few layers. It is then not possible to infer the local specimen thickness of the WSe2 from either the phase or the amplitude alone. Instead, we show that the combined analysis of phase and amplitude from experimental measurements and simulations allows an accurate determination of the local specimen thickness. The relationship between phase and projected potential is shown to be approximately linear for extremely thin specimens that are tilted by several degrees in certain directions from the [001] zone axis. A knowledge of the specimen thickness then allows the electrostatic potential to be determined from the measured phase. By using this combined approach, we determine a value for the mean inner potential of WSe2 of 18.9±0.8V, which is 12% lower than the value calculated from neutral atom scattering factors.

Combined Computational Approach Based on Density Functional Theory and Artificial Neural Networks for Predicting The Solubility Parameters of Fullerenes.

The solubility of organic semiconductors in environmentally benign solvents is an important prerequisite for the widespread adoption of organic electronic appliances. Solubility can be determined by considering the cohesive forces in a liquid via Hansen solubility parameters (HSP). We report a numerical approach to determine the HSP of fullerenes using a mathematical tool based on artificial neural networks (ANN). ANN transforms the molecular surface charge density distribution (σ-profile) as determined by density functional theory (DFT) calculations within the framework of a continuum solvation model into solubility parameters. We validate our model with experimentally determined HSP of the fullerenes C60, PC61BM, bisPC61BM, ICMA, ICBA, and PC71BM and through comparison with previously reported molecular dynamics calculations. Most excitingly, the ANN is able to correctly predict the dispersive contributions to the solubility parameters of the fullerenes although no explicit information on the van der Waals forces is present in the σ-profile. The presented theoretical DFT calculation in combination with the ANN mathematical tool can be easily extended to other π-conjugated, electronic material classes and offers a fast and reliable toolbox for future pathways that may include the design of green ink formulations for solution-processed optoelectronic devices.

Anterior fixation in the osteoporotic spine: cut-out and pullout characteristics of implants.

A new concept for the anchorage of anterior fixation implants in the osteoporotic thoracic and lumbar spine is presented. The SpiralBlade has been proposed as a suitable device for use in the osteoporotic spine, due to its broad, flat surface, which should provide resistance against cut-out of the implant through the vertebral body under dynamic loading. The cut-out and pullout characteristics of this implant were tested. The SpiralBlade was tested with and without a supplementary insertion guide screw. Two other commercial implants were tested for comparison: the VentroFix and the MACS-TL HMA (hollow monoaxial) screw. All implants were tested in osteoporotic human cadaveric vertebrae, using a modified in vitro testing protocol which simulated a full corpectomy model. Dynamic cyclic loading of 100 N, 200 N and 400 N was applied to the implant for 1000 cycles at each load level, and the subsidence of the vertebral body relative to the implant was measured. Following cyclic testing, the pullout strength of the implant was measured. No significant differences were found in the cut-out performance between the SpiralBlade with guide screw and the VentroFix. The SpiralBlade inserted without a guide screw was prone to cutting-out and a substantial loss of angular alignment of the vertebral body. Cut-out of the HMA screw was significantly greater than with the other implants. Two HMA screws fractured during testing. The VentroFix, with an average pullout force of 1166 N, has a significantly higher resistance to pullout than the SpiralBlade with guide screw (417 N), the SpiralBlade (332 N) and the Aesculap HMA screw (298 N). The SpiralBlade may be an alternative to anterior screw fixation in the osteoporotic spine, offering the same cut-out resistance with one implant rather than two screws.