Rapid quasi-periodic oscillations in the relativistic jet of BL Lacertae.

Blazars are active galactic nuclei (AGN) with relativistic jets whose non-thermal radiation is extremely variable on various timescales1-3. This variability seems mostly random, although some quasi-periodic oscillations (QPOs), implying systematic processes, have been reported in blazars and other AGN. QPOs with timescales of days or hours are especially rare4 in AGN and their nature is highly debated, explained by emitting plasma moving helically inside the jet5, plasma instabilities6,7 or orbital motion in an accretion disc7,8. Here we report results of intense optical and γ-ray flux monitoring of BL Lacertae (BL Lac) during a dramatic outburst in 2020 (ref. 9). BL Lac, the prototype of a subclass of blazars10, is powered by a 1.7 × 108 MSun (ref. 11) black hole in an elliptical galaxy (distance = 313 megaparsecs (ref. 12)). Our observations show QPOs of optical flux and linear polarization, and γ-ray flux, with cycles as short as approximately 13 h during the highest state of the outburst. The QPO properties match the expectations of current-driven kink instabilities6 near a recollimation shock about 5 parsecs (pc) from the black hole in the wake of an apparent superluminal feature moving down the jet. Such a kink is apparent in a microwave Very Long Baseline Array (VLBA) image.

[Occupational safety in the treatment of COVID-19 patients : Relevant laws and regulations for the treating personnel]. / Arbeitsschutz bei der Versorgung von COVID-19-Patienten : Relevante Gesetze und Regelungen für das versorgende Personal.

The intensive medical care of COVID-19 patients presents the deployed personnel with as yet unknown challenges. For example, protective equipment is now being extensively used, which was otherwise only used in selected situations. Working in such an environment is to be evaluated differently under the aspect of occupational safety than other patient care, especially as more than 1900 suspected cases of a SARS-CoV-19 occupational disease were reported among healthcare workers in Germany. Even in a pandemic, the legal requirements remain valid and personal protective equipment (PPE) has to comply with given standards. The use of FFP3 masks is required in aerosol-forming situations, such as endotracheal intubation or bronchoscopy. In contrast to surgical face masks, there is a maximum wearing time for FFPs masks. Furthermore, in a pandemic there is a basic danger of PPE shortage and recycling of face masks is under discussion. Therefore, usage of non-EU certified PPE may come into effect but this has to follow the requirements defined by European regulations. The aim of this article is to provide an overview of the currently relevant rules and regulations in Germany.

Angiographic and clinical outcomes of patients treated with everolimus-eluting bioresorbable stents in routine clinical practice: Results of the ISAR-ABSORB registry.

OBJECTIVES: We aimed to analyze angiographic and clinical results of patients undergoing BRS implantation in a real-world setting. BACKGROUND: Angiographic and clinical outcome data from patients undergoing implantation of drug-eluting bioresorbable stents (BRS) in routine clinical practice is scant. METHODS: Consecutive patients undergoing implantation of everolimus-eluting BRS at two high-volume centers in Munich, Germany were enrolled. Data were collected prospectively. All patients were scheduled for angiographic surveillance 6-8 months after stent implantation. Quantitative coronary angiographic analysis was performed in a core laboratory. Clinical follow-up was performed to 12 months and events were adjudicated by independent assessors. RESULTS: A total of 419 patients were studied. Mean age was 66.6 ± 10.9 years, 31.5% had diabetes mellitus, 76.1% had multivessel disease, and 39.0% presented with acute coronary syndrome; 49.0% of lesions were AHA/ACC type B2/C, 13.1% had treatment of bifurcation lesions. Mean reference vessel diameter was 2.89 ± 0.46 mm. At angiographic follow-up in-stent late loss was 0.26 ± 0.51 mm, in-segment diameter stenosis was 27.5 ± 16.1, and binary angiographic restenosis was 7.5%. At 12 months, the rate of death, myocardial infarction, or target lesion revascularization was 13.1%. Definite stent thrombosis occurred in 2.6%. CONCLUSIONS: The use of everolimus-eluting BRS in routine clinical practice is associated with high antirestenotic efficacy in patients undergoing angiographic surveillance. Overall clinical outcomes at 12 months are satisfactory though stent thrombosis rates are not insignificant. Further study with longer term follow-up and larger numbers of treated patients is required before we can be sure of the role of these devices in clinical practice.

Restenosis in bare metal and drug-eluting stents: distinct mechanistic insights from histopathology and optical intravascular imaging.

An increasing body of evidence points to the existence of important differences in the processes of restenosis following drug-eluting stent (DES) as compared to bare metal stent implantation. Preclinical investigation and human autopsy studies have shown that the high efficacy of DES in comparison with bare metal stents in preventing restenosis is achieved at the collateral cost of a delay in healing of the stented arterial segment. Moreover bare metal stent restenosis is typically characterised by a homogeneous tissue rich in smooth muscle cells; whereas DES restenosis is more often hypocellular and proteoglycan-rich. In addition, in-stent neoatherosclerosis appears to have an accelerated course in DES. Angiographic surveillance studies show that while neointimal formation peaks six months after bare metal stenting, neointimal formation after DES therapy is temporally right shifted and remains a dynamic ongoing process (late luminal loss creep) even out to five years. The widespread availability of high resolution optical coherence tomography (OCT) is affording better understanding of the pathophysiology of in-stent restenosis. While bare metal stent restenosis is characterized by predominantly homogenous high-signal tissue echogenicity, layered pattern or heterogeneous tissue composition is more common in DES restenosis. Moreover, preliminary data suggests that tissue attenuation may increase in a time-dependent manner. Nevertheless, the paucity of direct histopathological correlation studies means that the tissue composition of these lesions remains speculative. Data from specifically designed imaging-pathology correlation studies in suitable preclinical models of restenosis and in autopsy specimens is eagerly awaited. Furthermore, although long-term longitudinal clinical follow-up is necessary to define the clinical relevance of optical imaging findings, the nature of restenosis as a disease entity means that its natural history is often altered by a mandate for repeat intervention directly following data acquisition.

From bench to bedside: initial experience with the Primus drug-coated balloon catheter.

AIM: Drug-coated balloon (DCB) technology has emerged as a promising therapy particularly in the treatment of coronary in-stent restenosis. Although a variety of devices are available for clinical use, clinical outcomes have been variable and scope for significant improvement exists. METHODS: In a preclinical study, a total of 10 juvenile healthy farm pigs underwent catheter-based DCB deployment in coronary arteries with angiographic and pathological follow-up at 7 or 28 days. Animals were randomly allocated to the PRIMUS or Dior® DCB (N.=10 per group) and evaluated by histopathology and morphometric analysis. In a first-in-man clinical study a total of 19 consecutive patients presenting with restenosis within drug-eluting stents were treated with the PRIMUS DCB. Clinical follow-up was performed out to 6 months. RESULTS: Neointimal thickness was similar between the PRIMUS and Dior® DCB groups, while fibrin deposition and inflammation were more sustained in the PRIMUS group at 28 days. In 19 consecutive patients presenting with in-stent restenosis of drug-eluting stents, treatment with the PRIMUS DCB catheter resulted in high procedural efficacy. There were no adverse clinical events observed out to 6 months. CONCLUSION: The PRIMUS DCB demonstrates high preclinical safety and excellent acute performance and safety. Further studies are needed to delineate the relative merits of this novel DCB compared to other devices.

Polymer coatings and delayed arterial healing following drug-eluting stent implantation.

The antirestenotic efficacy of drug-eluting stent (DES) technology is based on the local delivery and modulated release of cytotoxic drugs targeted at inhibition of neointimal hyperplasia. Control of drug-release kinetics is a critical component of device efficacy. To date this has been most effectively performed by stent coatings comprised of non-erodable (permanent) polymer which facilitate drug loading and delay elution of the active drug. In fact all 4 of the systems currently approved by the Food and Drug Administration (FDA) use a permanent polymer-based drug release system. Balancing the need for lipophilicity (to bind active drug) with hydrophilicity (which offers superior biocompatibility) is a key challenge in polymer technology. Delayed arterial healing (DAH) following DES implantation has been demonstrated in human autopsy studies and animal models and is implicated in late thrombotic occlusion and delayed loss of antirestenotic efficacy. It is characterised by 1) persistent fibrin deposition; 2) delayed endothelialization; 3) chronic inflammation; and 4) persistent platelet activation. Within segment heterogeneity in degree of healing is typical. Inflammatory response to polymer residue plays an important role and may be non-specific (monocyte-macrophage predominant) or hypersensitivity related. Failure of early preclinical models to sufficiently predict DAH in man was an important problem. Second generation DES attempt to address the issue of DAH by using thinner stent struts, lower drug load and more biocompatible polymer. At present the focus of development is towards biodegradable polymer coatings which offer the attractive prospect of controlled drug-release without the potential for late polymer-associated adverse effects. This review highlights the role of polymer coatings in determination of DES efficacy, summarises the preclinical and clinical evidence linking polymer coatings with DAH and evaluates the promise of third generation polymer-free and biodegradable polymer DES.

Optical coherence tomography surveillance following drug-eluting stent implantation.

Drug-eluting stents are currently used in the majority of percutaneous coronary interventions. Preclinical investigations and human autopsy studies have shown that the high efficacy of drug-eluting stents (DES) in preventing restenosis is achieved at the expense of a delay in healing. Optical coherence tomography (OCT) represents a novel intracoronary imaging tool to evaluate vascular healing response after stent implantation. Owing to its outstanding resolution in the catheter near-field, quantitative morphometric measures were complemented by more qualitative description of neointimal tissue characterization. Clinical imaging studies employing these methodologies gained valuable insights into vascular healing responses after DES implantation and are reported in this review. However, an important limitation of OCT imaging analysis, despite its high resolution, remains the inability to assess the precise cellular composition and functional capability of the neointimal tissue, especially of the endothelium. Future long-term clinical studies are warranted to determine the clinical relevance of surrogate parameters derived from preliminary OCT surveillance studies.

A novel "pro-healing" approach: the COMBO™ dual therapy stent from a pathological view.

Current generations of monotherapy drug-eluting stents only inhibit neointimal hyperplasia. However, these stent designs have other drawbacks such as delayed arterial healing, hypersensitivity, late stent thrombosis, and neoatherosclerosis, creating a need for a new generation of safer devices. The novel 'pro-healing' COMBOTM dual therapy stent aims to address these issues by reducing neointimal hyperplasia via an abluminal bioabsorbable polymer eluting sirolimus, and by simultaneously capturing circulating endothelial progenitor cells via luminally immobilized anti-CD34+ antibodies. Short-term preclinical data shows promising results as compared to 1st generation and 2nd generation drug-eluting stents; however long-term literature remains unavailable until now. This review aims to evaluate, histopathologically, drawbacks of the current era of stents at autopsy, review short-term preclinical and clinical data from the REMEDEE trial, and present original long-term preclinical data. To date, preclinical data shows good performance of the COMBOTM stent comparable with the safety profile of bare metal stents with minimal inflammation, increased endothelialization, and acceptable neointimal hyperplasia with no statistical evidence of late catch-up. Clinical data from the REMEDEE trial at 12 months shows non-inferiority to paclitaxel drug-eluting stents, no evidence of late stent thrombosis, and a low rate of adverse clinical events.

Pathophysiology of superficial femoral artery in-stent restenosis.

Peripheral artery disease (PAD) is an emerging problem especially with aging population and increase in the incidence of diabetes and metabolic syndrome. The disease is histologically characterized by the presence of moderate to severe calcification and fibrous plaques as compared to coronary and carotid atherosclerotic disease, which are richer in necrotic core. Endovascular therapy for the superficial femoral artery (SFA), at least in the United States, has been largely limited to balloon angioplasty and stenting and these are considered safe and relatively effective therapies. However, the patency rates remain low even at one year and restenosis is a growing and challenging problem. Recently the development of newer devices, i.e., drug-eluting stent, and drug coated balloon are showing greater efficacy and are being adopted into daily practice. In this review, we will present the morphologic characteristics of the underlying SFA atherosclerotic disease and discuss in-stent restenosis and the mechanisms that may be involved in the induction of excessive smooth muscle cell proliferation and deposition of proteoglycans and collagen, that lead to restenosis.

Comparative assessment of drug-eluting balloons in an advanced porcine model of coronary restenosis.

The advent of drug-eluting balloon (DEB) therapy has represented an important development in interventional cardiology. Nevertheless, preclinical data with this technology remain scant, and comparative studies have not previously been published. Bare metal stents were implanted in the coronary arteries of 15 pigs followed by balloon angioplasty. Animals were allocated to treatment with a 60-second inflation of one of four different balloon catheters: a conventional untreated plain angioplasty balloon (PBA, Biotronik AG), the Pantera Lux DEB (3.0 µg/mm2 paclitaxel; BTHC excipient, Biotronik AG), the Elutax DEB (2.0 µg/mm2 paclitaxel; no excipient; Aachen Resonance), or the SeQuent Please DEB (3.0 µg/mm2 paclitaxel; iopromide excipient: B. Braun). Twenty-eight days following balloon deployment, animals underwent repeat angiography for quantitative coronary angiography analysis and euthanasia for histopathologic assessment. By histology, the mean neointimal thickness was 0.44 ± 0.19 mm with PBA, 0.35 ± 0.13 mm with Pantera Lux , 0.61 ± 0.20 mm with Elutax , and 0.47 ± 0.21 mm with SeQuent Please DEB (p=0.02). In comparison with PBA, deployment of the Pantera Lux or the SeQuent Please DEB resulted in delayed healing characterised by significant increases in fibrin, neointimal cell vacuity and delayed re-endothelialisation. In conclusion, investigation of comparative DEB performance in a porcine model of advanced coronary restenosis reveals significant heterogeneity of neointimal suppression between the devices tested with numerically lowest values seen in the Pantera Lux group. On the other hand, evidence of delayed healing was observed in the most effective DEB groups.