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Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holier electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holier ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 +/- 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses >= 3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holier ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder.
Practical quantum communication between remote quantum memories rely on single photons at telecom wavelengths. Although spin-photon entanglement has been demonstrated in atomic and solid-state qubit systems, the produced single photons at short wavelengths and with polarization encoding are not suitable for long-distance communication, because they suffer from high propagation loss and depolarization in optical fibres. Establishing entanglement between remote quantum nodes would further require the photons generated from separate nodes to be indistinguishable. Here, we report the observation of correlations between a quantum-dot spin and a telecom single photon across a 2-km fibre channel based on time-bin encoding and background-free frequency downconversion. The downconverted photon at telecom wavelengths exhibits two-photon interference with another photon from an independent source, achieving a mean wavepacket overlap of greater than 0.89 despite their original wavelength mismatch (900 and 911 nm). The quantum-networking operations that we demonstrate will enable practical communication between solid-state spin qubits across long distances.
Background
Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region.
Methods
The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals.
Results
Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31%), mainly in secondary stroke prevention; b) improvement over time (44%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period.
Conclusion
The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.
Well-developed phonological awareness skills are a core prerequisite for early literacy development. Although effective phonological awareness training programs exist, children at risk often do not reach similar levels of phonological awareness after the intervention as children with normally developed skills. Based on theoretical considerations and first promising results the present study explores effects of an early musical training in combination with a conventional phonological training in children with weak phonological awareness skills. Using a quasi-experimental pretest-posttest control group design and measurements across a period of 2 years, we tested the effects of two interventions: a consecutive combination of a musical and a phonological training and a phonological training alone. The design made it possible to disentangle effects of the musical training alone as well the effects of its combination with the phonological training. The outcome measures of these groups were compared with the control group with multivariate analyses, controlling for a number of background variables. The sample included N = 424 German-speaking children aged 4–5 years at the beginning of the study. We found a positive relationship between musical abilities and phonological awareness. Yet, whereas the well-established phonological training produced the expected effects, adding a musical training did not contribute significantly to phonological awareness development. Training effects were partly dependent on the initial level of phonological awareness. Possible reasons for the lack of training effects in the musical part of the combination condition as well as practical implications for early literacy education are discussed.
Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.
SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, we described the acid ceramidase as an additional target of fluoxetine. To discover these effects, we synthesized an ASM-independent fluoxetine derivative, AKS466. High-resolution SARS-CoV-2–RNA FISH and RTqPCR analyses demonstrate that AKS466 down-regulates viral gene expression. It is shown that SARS-CoV-2 deacidifies the lysosomal pH using the ORF3 protein. However, treatment with AKS488 or fluoxetine lowers the lysosomal pH. Our biochemical results show that AKS466 localizes to the endo-lysosomal replication compartments of infected cells, and demonstrate the enrichment of the viral genomic, minus-stranded RNA and mRNAs there. Both fluoxetine and AKS466 inhibit the acid ceramidase activity, cause endo-lysosomal ceramide elevation, and interfere with viral replication. Furthermore, Ceranib-2, a specific acid ceramidase inhibitor, reduces SARS-CoV-2 replication and, most importantly, the exogenous supplementation of C6-ceramide interferes with viral replication. These results support the hypotheses that the acid ceramidase is a SARS-CoV-2 host factor.
Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development.
Solid-state cavity quantum electrodynamics is a rapidly advancing field, which explores the frontiers of light–matter coupling. Metal-based approaches are of particular interest in this field, as they carry the potential to squeeze optical modes to spaces significantly below the diffraction limit. Transition metal dichalcogenides are ideally suited as the active material in cavity quantum electrodynamics, as they interact strongly with light at the ultimate monolayer limit. Here, we implement a Tamm-plasmon-polariton structure and study the coupling to a monolayer of WSe\(_{2}\), hosting highly stable excitons. Exciton-polariton formation at room temperature is manifested in the characteristic energy–momentum dispersion relation studied in photoluminescence, featuring an anti-crossing between the exciton and photon modes with a Rabi-splitting of 23.5 meV. Creating polaritonic quasiparticles in monolithic, compact architectures with atomic monolayers under ambient conditions is a crucial step towards the exploration of nonlinearities, macroscopic coherence and advanced spinor physics with novel, low-mass bosons.
Evaluation von Defekten des triangulären fibrokartilaginären Komplexes (TFCC) und der intrinsischen Bänder des Handgelenkes mit der direkten MR-Arthrographie im Vergleich zur diagnostischen Arthroskopie unter besonderer Berücksichtigung von Partialdefekten. Material und Methoden: 75 direkte MR-Arthrographien des Handgelenkes (intraartikuläre Injektion eines Gemisches aus Gadoliniumchelaten und Iotrolan) wurden von zwei erfahrenen Radiologen im Konsens ausgewertet. Es wurden T1-gewichtete Spin-Echo(SE)-Sequenzen in frontaler und sagittaler sowie Fast low angle shot (FLASH) 3D-Sequenzen in frontaler Schichtung akquiriert. Läsionen des skapholunären Bandes wurden entsprechend den Leitlinien der Deutschen Gesellschaft für Handchirurgie (DGH), Läsionen des lunatotriquetralen Bandes nach Hempfling, Läsionen des TFCC nach Palmer eingeteilt. Anschließend wurden die Befunde mit der Arthroskopie als Referenzstandard korreliert. Ergebnisse: Für die Verletzungen der intrinsischen Bänder und des TFCC waren die Sensitivitäten und Spezifitäten für Komplettrupturen 96% und 99,6% (T1-SE) bzw. 92% und 100% (FLASH 3D), für Partialdefekte 68,1% und 93,3% (T1-SE) bzw. 63% und 96,1% (FLASH 3D). Die T1-SE-Sequenz eignete sich für die Einschätzung skapholunärer Banddefekte besser als die FLASH 3D-Sequenz (p < 0,05). Für Partialdefekte das skapholunären Bandes wurde mit der T1-SE-Sequenz eine Sensitivität von 83,3%, mit der FLASH 3D-Sequenz von 64,7% erreicht. Schlussfolgerung: Die direkte MR-Arthrographie ist bei der Einschätzung von Komplettrupturen der intrinsischen Bänder und des TFCC der diagnostischen Arthroskopie gleichwertig. Mit der T1-SE-Sequenz sind Partialdefekte des skapholunären Bandes im Vergleich zur Arthroskopie mit ausreichender Sicherheit erkennbar. Die T1-SE-Sequenz war hierfür der FLASH 3D-Sequenz überlegen (p < 0,05) und sollte bei der Einschätzung skapholunärer Partialdefekte bevorzugt werden. Die Einschätzung des lunatotriquetralen Bandes gelingt nicht zuverlässig.
Highly efficient single-photon sources (SPS) can increase the secure key rate of quantum key distribution (QKD) systems compared to conventional attenuated laser systems. Here we report on a free space QKD test using an electrically driven quantum dot single-photon source (QD SPS) that does not require a separate laser setup for optical pumping and thus allows for a simple and compact SPS QKD system. We describe its implementation in our 500 m free space QKD system in downtown Munich. Emulating a BB84 protocol operating at a repetition rate of 125 MHz, we could achieve sifted key rates of 5-17 kHz with error ratios of 6-9% and g((2))(0)-values of 0.39-0.76.