Medical education during the Covid-19 pandemic long-term experiences of German clinical medical students.

INTRODUCTION: Due to the Covid-19 pandemic and the accompanying hygiene regulations, medical students in Germany faced multiple educational and personal challenges. The challenges included the cancellation and digitalisation of courses, the closing of university institutions such as libraries, a decrease in social contacts, and the risk of a Covid-19 infection. The aim of this study was to understand medical students' pandemic experiences as well as the consequences of these experiences for the students' future work as physicians. MATERIALS AND METHODS: We performed 15 guided, one-on-one interviews with clinical medical students (third to fifth year) at the Otto-von-Guericke-University Magdeburg. Interviews were recorded, transcribed, and anonymised. We performed a qualitative content analysis in accordance with Mayring and thereby formed an inductive category system. The Consolidated Criteria for Reporting Qualitative Research (COREQ) were applied. RESULTS: Five categories were inductively formed: "Changes in the teaching experience", "negative effects on the learning experience", "decrease in personal social contacts", "contact with covid-19", and "pandemic-associated stress increase". The participating students reported higher levels of stress due to isolation and uncertainty regarding their educational future. Furthermore, students welcomed the digitalisation of lectures, developed individual coping strategies, and voluntarily took part in the care of Covid-19 patients. Limitations to social interactions were perceived as the major restrictive factor to their educational structure, their perceived learning success and personal development. CONCLUSION: This study identified social restrictions as well as didactic and academic structural challenges as relevant factors contributing to perceived stress and fear for medical students during the Covid-19 pandemic, especially as regards their learning experience. Students' acceptance of digitalised learning may enable regular interaction with university peers and may facilitate a structured educational life. However, the implementation of digital resources could not provide a sufficient substitute for in-person courses.

Cerebral embolic protection during transcatheter aortic valve replacement: a systematic review and meta-analysis of propensity score matched and randomized controlled trials using the Sentinel cerebral embolic protection device.

BACKGROUND: The Sentinel cerebral embolic protection device (CEP) aims to reduce the risk of stroke during transcatheter aortic valve replacement (TAVR). We performed a systematic review and meta-analysis of propensity score matched (PSM) and randomized controlled trials (RCT) investigating the effect of the Sentinel CEP to prevent strokes during TAVR. METHODS: Eligible trials were searched through PubMed, ISI Web of science databases, Cochrane database, and proceedings of major congresses. Primary outcome was stroke. Secondary outcomes included all-cause mortality, major or life-threatening bleeding, major vascular complications and acute kidney injury at discharge. Fixed and random effect models were used to calculate the pooled risk ratio (RR) with 95% confidence intervals (CI) and absolute risk difference (ARD). RESULTS: A total of 4066 patients from 4 RCTs (3'506 patients) and 1 PSM study (560 patients) were included. Use of Sentinel CEP was successful in 92% of patients and was associated with a significantly lower risk of stroke (RR: 0.67, 95% CI: 0.48-0.95, p = 0.02. ARD: -1.3%, 95% CI: -2.3 - -0.2, p = 0.02, number needed to treat (NNT) = 77), and a reduced risk of disabling stroke (RR: 0.33, 95% CI: 0.17-0.65. ARD: -0.9%, 95% CI: -1.5 - -0.3, p = 0.004, NNT = 111). Use of Sentinel CEP was associated with a lower risk of major or life-threatening bleeding (RR: 0.37, 95% CI: 0.16-0.87, p = 0.02). Risk for nondisabling stroke (RR: 0.93, 95% CI: 0.62-1.40, p = 0.73), all-cause mortality (RR: 0.70, 95% CI: 0.35-1.40, p = 0.31), major vascular complications (RR: 0.74, 95% CI: 0.33-1.67, p = 0.47) and acute kidney injury (RR: 0.74, 95% CI: 0.37-1.50, p = 0.40) were similar. CONCLUSIONS: The use of CEP during TAVR was associated with lower risks of any stroke and disabling stroke with an NNT of 77 and 111, respectively.

An evidence map of systematic reviews on models of outpatient care for patients with chronic heart diseases.

BACKGROUND: Chronic heart disease affects millions of people worldwide and the prevalence is increasing. By now, there is an extensive literature on outpatient care of people with chronic heart disease. We aimed to systematically identify and map models of outpatient care for people with chronic heart disease in terms of the interventions included and the outcomes measured and reported to determine areas in need of further research. METHODS: We created an evidence map of published systematic reviews. PubMed, Cochrane Library (Wiley), Web of Science, and Scopus were searched to identify all relevant articles from January 2000 to June 2021 published in English or German language. From each included systematic review, we abstracted search dates, number and type of included studies, objectives, populations, interventions, and outcomes. Models of care were categorised into six approaches: cardiac rehabilitation, chronic disease management, home-based care, outpatient clinic, telemedicine, and transitional care. Intervention categories were developed inductively. Outcomes were mapped onto the taxonomy developed by the COMET initiative. RESULTS: The systematic literature search identified 8043 potentially relevant publications on models of outpatient care for patients with chronic heart diseases. Finally, 47 systematic reviews met the inclusion criteria, covering 1206 primary studies (including double counting). We identified six different models of care and described which interventions were used and what outcomes were included to measure their effectiveness. Education-related and telemedicine interventions were described in more than 50% of the models of outpatient care. The most frequently used outcome domains were death and life impact. CONCLUSION: Evidence on outpatient care for people with chronic heart diseases is broad. However, comparability is limited due to differences in interventions and outcome measures. Outpatient care for people with coronary heart disease and atrial fibrillation is a less well-studied area compared to heart failure. Our evidence mapping demonstrates the need for a core outcome set and further studies to examine the effects of models of outpatient care or different interventions with adjusted outcome parameters. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42020166330).

DNA-Dependent Protein Kinase Mediates YB-1 (Y-Box Binding Protein)-Induced Double Strand Break Repair.

BACKGROUND: DNA-PK (DNA-dependent protein kinase) is a stress-activated serine/threonine kinase that plays a central role in vascular smooth muscle cell proliferation and vascular proliferative disease processes such as neointimal formation. In this study, we link the activation of DNA-PK to the function of the transcription factor YB-1 (Y-box binding protein). METHODS: To identify YB-1 phosphorylation by DNA-PK, we generated different YB-1-expressing vectors. YB-1 nuclear translocation was investigated using immunoblotting and immunofluorescence staining. For YB-1 activity, luciferase assays were performed. RESULTS: We show by mutational analysis and kinase assay that the transcriptional regulator YB-1 is a substrate of DNA-PK. Blockade of DNA-PK by specific inhibitors revealed its critical involvement in YB-1phosphorylation as demonstrated by inhibition of an overexpressed YB-1 reporter construct. Using DNA-PK-deficient cells, we demonstrate that the shuttling of YB-1 from the cytoplasm to the nucleus is dependent on DNA-PK and that the N-terminal domain of YB-1 is phosphorylated at threonine 89. Point mutation of YB-1 at this residue abrogated the translocation of YB-1 into the nucleus. The phosphorylation of YB-1 by DNA-PK increased cellular DNA repair after exposure to ionizing radiation. Atherosclerotic tissue specimens were analyzed by immunohistochemistry. The DNA-PK subunits and YB-1 phosphorylated at T89 were found colocalized suggesting their in vivo interaction. In mice, the local application of the specific DNA-PK inhibitor NU7026 via thermosensitive Pluronic F-127 gel around dilated arteries significantly reduced the phosphorylation of YB-1. CONCLUSIONS: DNA-PK directly phosphorylates YB-1 and, this way, modulates YB-1 function. This interaction could be demonstrated in vivo, and colocalization in human atherosclerotic plaques suggests clinical relevance of our finding. Phosphorylation of YB-1 by DNA-PK may represent a novel mechanism governing atherosclerotic plaque progression.

The Role of Anticoagulants and Platelet Aggregation Inhibitors in the Treatment of Pseudoaneurysms and Risk of Venous Thrombosis.

Pseudoaneurysms (PSA) are one of the most common complications after arterial punctures. This retrospective study examined whether platelet aggregation inhibitors (APT) or anticoagulants (AC) lower the success rates of PSA treatment. A total of 468 patients with PSA were retrospectively analyzed between 2010 and 2018, and 238 were included in the study. Despite co-medication with APT or AC, thrombin injection (TI) was superior to compression bandage (CB) therapy in treating PSA (TIwAC 79 vs CBwAC 51%; P = .004 and TIwAPT 93 vs CBwAPT 54%; P = .001). There was no decrease in PSA-associated thrombosis in patients requiring anticoagulation after TI. The success rates of the TI and CB groups were compared in patients with and without AC therapy, and the latter was significantly lower. A reduced success rate was not observed in CB therapy patients requiring APT. In contrast, better results were seen in the TI group. Regarding PSA treatment, TI therapy is significantly superior to CB, including in patients requiring concomitant AC or APT therapy. PSA-associated thrombosis also occurs in patients requiring anticoagulation, and sonography should be performed. Concomitant medication use with APT does not significantly influence PSA therapy success or prevention of PSA-associated thrombosis.

Normoxic HIF-1α Stabilization Caused by Local Inflammatory Factors and Its Consequences in Human Coronary Artery Endothelial Cells.

Knowledge about normoxic hypoxia-inducible factor (HIF)-1α stabilization is limited. We investigated normoxic HIF-1α stabilization and its consequences using live cell imaging, immunoblotting, Bio-Plex multiplex immunoassay, immunofluorescence staining, and barrier integrity assays. We demonstrate for the first time that IL-8 and M-CSF caused HIF-1α stabilization and translocation into the nucleus under normoxic conditions in both human coronary endothelial cells (HCAECs) and HIF-1α-mKate2-expressing HEK-293 cells. In line with the current literature, our data show significant normoxic HIF-1α stabilization caused by TNF-α, INF-γ, IL-1ß, and IGF-I in both cell lines, as well. Treatment with a cocktail consisting of TNF-α, INF-γ, and IL-1ß caused significantly stronger HIF-1α stabilization in comparison to single treatments. Interestingly, this cumulative effect was not observed during simultaneous treatment with IL-8, M-CSF, and IGF-I. Furthermore, we identified two different kinetics of HIF-1α stabilization under normoxic conditions. Our data demonstrate elevated protein levels of HIF-1α-related genes known to be involved in the development of atherosclerosis. Moreover, we demonstrate an endothelial barrier dysfunction in HCAECs upon our treatments and during normoxic HIF-1α stabilization comparable to that under hypoxia. This study expands the knowledge of normoxic HIF-1α stabilization and activation and its consequences on the endothelial secretome and barrier function. Our data imply an active role of HIF-1α in vivo in the vasculature in the absence of hypoxia.

Students' perception and learning experience in the first medical clerkship.

BACKGROUND: The German clerkship ("Famulatur") is the first phase in medical education, in which students learn from a physician's perspective. According to the German Licensing Regulations for Physicians, students shall "familiarise" with providing care. However, specific learning objectives for the clerkship are not defined, although the acquisition of different competencies is implicitly demanded. Therefore, an additional understanding of the clerkship students' learning experience is needed. The goal of this study is to explore the student's learning perspective and experiences in the clerkship. METHODS: Twelve guideline-based interviews were conducted with third year medical students. All participants completed their first clerkship. A qualitative content analysis was performed. The inductively identified categories were transferred into a quantitative questionnaire using a 5-point Likert-scale to explore their relevance in a validation cohort. The questionnaire was completed by 222 clinical students of the Otto-von-Guericke-Universität Magdeburg. RESULTS: The qualitative analysis led to 26 individual items assigned to 4 main categories that describe the clerkship experience: 1) "coping with insecurities", 2) "the clerkship as a social arrangement", 3) "the clerkship as a learning opportunity" and 4) "the clerkship as a teaching opportunity". In the quantitative validation cohort, category one yielded a well-balanced result (median 3 = "neither agree nor disagree"; IQR 2-4), items addressed in categories 2-4 were generally supported by the students, predominantly selecting "strongly agree" or "agree" (Median 2; IQR 1-2 for each category). Students rated the role of the clinical team as especially important for their learning success and feared exclusion or negative reactions. CONCLUSIONS: The medical clerkship provides an institutional, professional, and social framework, in which students are learning. Insecurities arose from curricular inconsistencies, a high dependency on the clinical team as well as the absence of specific learning objectives. Therefore, a better curricular integration regarding the semester structure and the learning objectives of the German clerkship is needed.

IKKγ/NEMO Localization into Multivesicular Bodies.

The NF-κB pathway is central pathway for inflammatory and immune responses, and IKKγ/NEMO is essential for NF-κB activation. In a previous report, we identified the role of glycogen synthase kinase-3ß (GSK-3ß) in NF-κB activation by regulating IKKγ/NEMO. Here, we show that NEMO phosphorylation by GSK-3ß leads to NEMO localization into multivesicular bodies (MVBs). Using the endosome marker Rab5, we observed localization into endosomes. Using siRNA, we identified the AAA-ATPase Vps4A, which is involved in recycling the ESCRT machinery by facilitating its dissociation from endosomal membranes, which is necessary for NEMO stability and NF-κB activation. Co-immunoprecipitation studies of NEMO and mutated NEMO demonstrated its direct interaction with Vps4A, which requires NEMO phosphorylation. The transfection of cells by a mutated and constitutively active form of Vps4A, Vps4A-E233Q, resulted in the formation of large vacuoles and strong augmentation in NEMO expression compared to GFP-Vps4-WT. In addition, the overexpression of the mutated form of Vps4A led to increased NF-κB activation. The treatment of cells with the pharmacologic V-ATPase inhibitor bafilomycin A led to a dramatic downregulation of NEMO and, in this way, inhibited NF-κB signal transduction. These results reveal an unexpected role for GSK-3ß and V-ATPase in NF-κB signaling activation.

Healthcare professionals' perceptions of impacts of the Covid-19-pandemic on outpatient care in rural areas: a qualitative study.

BACKGROUND: Measures to manage the COVID-19 pandemic have led to impacts on healthcare systems and providers worldwide. Outpatient healthcare professionals (HCPs) provide the majority of patient care. Insight into their experiences during a pandemic is rare. Therefore, we explored how primary and secondary care HCPs in a rural area in Germany experienced their work during the pandemic and what health-related outcomes they perceived in their patients. In this context, we also examined the impact on access to and utilization of healthcare and working conditions. METHODS: We conducted a qualitative interview study with outpatient HCPs. We recruited by e-mail, telephone, professional networks and personal contacts. Data were collected between August 2020 and January 2021. All interviews were audio recorded, transcribed, and analysed using qualitative content analysis. RESULTS: Our sample consisted of 28 HCPs (15 family physicians, 7 cardiologists, and 6 non-physician assistants, 12 female) from Saxony-Anhalt, Germany. HCPs experienced fewer consultations as well as cancellations by hospitals and secondary care physicians, especially at the beginning of the Covid-19-pandemic, while they continued throughout to provide outpatient care. They quickly adopted changes in practice organisation and healthcare provision. There was a shift towards telephone consultations, home visits as well as unconventional consultations e.g. through the practice window. Family physicians used personal relationships to support utilization of healthcare and to avoid health-related effects. Social tension and burden seemed to interact with a perceived lack of preparedness, the pandemic-related changes in their working condition as well as access to and utilization of healthcare. Chronic disease monitoring was postponed, which could have consequences in the course of disease of patients. HCPs experienced effects on patients' psychological well-being. CONCLUSION: Our study demonstrates the impacts of Covid-19-pandemic on outpatient care in rural areas and emphasizes its importance. HCPs experienced impacts on access to and utilization of healthcare, working conditions and health-related outcomes. Health policy should create a framework for healthcare to support outpatient care in rural areas with a looming undersupply of primary and secondary care in order to maintain healthcare and reduce pandemic impacts.

Predictors and prognosis of right ventricular function in pulmonary hypertension due to heart failure with reduced ejection fraction.

AIMS: Failure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV-pulmonary artery (PA) coupling, is defined by the ratio of RV end-systolic to PA elastances (Ees/Ea). Using pressure-volume loop (PV-L) technique we aimed to identify an Ees/Ea cut-off predictive for overall survival and to assess hemodynamic and morphologic conditions for adapted RV function in secondary PH due to heart failure with reduced ejection fraction (HFREF). METHODS AND RESULTS: This post hoc analysis is based on 112 patients of the prospective Magdeburger Resynchronization Responder Trial. All patients underwent right and left heart echocardiography and a baseline PV-L and RV catheter measurement. A subgroup of patients (n = 50) without a pre-implanted cardiac device underwent magnetic resonance imaging at baseline. The analysis revealed that 0.68 is an optimal Ees/Ea cut-off (area under the curve: 0.697, P < 0.001) predictive for overall survival (median follow up = 4.7 years, Ees/Ea ≥ 0.68 vs. <0.68, log-rank 8.9, P = 0.003). In patients with PH (n = 76, 68%) multivariate Cox regression demonstrated the independent prognostic value of RV-Ees/Ea in PH patients (hazard ratio 0.2, P < 0.038). Patients without PH (n = 36, 32%) and those with PH but RV-Ees/Ea ≥ 0.68 showed comparable RV-Ees/Ea ratios (0.88 vs. 0.9, P = 0.39), RV size/function, and survival. In contrast, secondary PH with RV-PA coupling ratio Ees/Ea < 0.68 corresponded extremely close to cut-off values that define RV dilatation/remodelling (RV end-diastolic volume >160 mL, RV-mass/volume-ratio ≤0.37 g/mL) and dysfunction (right ventricular ejection fraction <38%, tricuspid annular plane systolic excursion <16 mm, fractional area change <42%, and stroke-volume/end-systolic volume ratio <0.59) and is associated with a dramatically increased short and medium-term all-cause mortality. Independent predictors of prognostically unfavourable RV-PA coupling (Ees/Ea < 0.68) in secondary PH were a pre-existent dilated RV [end-diastolic volume >171 mL, odds ratio (OR) 0.96, P = 0.021], high pulsatile load (PA compliance <2.3 mL/mmHg, OR 8.6, P = 0.003), and advanced systolic left heart failure (left ventricular ejection fraction <30%, OR 1.23, P = 0.028). CONCLUSIONS: The RV-PA coupling ratio Ees/Ea predicts overall survival in PH due to HFREF and is mainly affected by pulsatile load, RV remodelling, and left ventricular dysfunction. Prognostically favourable coupling (RV-Ees/Ea ≥ 0.68) in PH was associated with preserved RV size/function and mid-term survival, comparable with HFREF without PH.

Digitalization of presence events in the COVID-19 pandemia - the lecturers' perspective.

Objective: Due to the COVID-19 pandemic a large part of attendance in medical education became impossible for reasons of disease control. Teachers had to switch to online courses at short notice. The associated developmental push of digital teaching methods, such as online teaching, has anticipated changes, some of which are tantamount to establishment. This study examines the experiences and effects of these changes from the teachers' perspective. Methods: We conducted ten guideline-based anonymized e-mail interviews with lecturers of the Medical Faculty of the Otto-von-Guericke University Magdeburg. Questions were asked on the subject areas of advantages and disadvantages, teaching experience and the future of digital teaching. The qualitative evaluation was based on Mayring. Results: The assessment of the digitization of face-to-face courses could be described by the inductively formed categories "social aspects", "methodological aspects", "institutional aspects", "technical aspects" and "temporal-spatial aspects". These revealed in particular concerns about the lack of personal exchange, temporal-spatial advantages, technical barriers and disagreement about the future role of digital teaching. Conclusion: In the context of the COVID-19 pandemic, face-to-face courses were replaced by online teaching, which is currently an accepted part of the curriculum. The results show, that teachers were able to implement the comprehensive ad-hoc digitization of theoretical courses well, although previously known problem areas were aggravated. Furthermore, a fundamental examination of the future role of digitized courses in medical education must take place.

Inhibition of Platelet Aggregation After Coronary Stenting in Patients Receiving Oral Anticoagulation.

BACKGROUND: Approximately 18% of patients with atrial fibrillation undergo a percutaneous coronary intervention (PCI) to treat coronary heart disease. Pharmacological anticoagulation in patients with atrial fibrillation and PCI involves a trade-off of potential ischemic and hemorrhagic complications. METHODS: This review is based on pertinent publications that were retrieved by a selective literature search, including current guidelines and recommendations. RESULTS: Dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and a P2Y12 inhibitor protects against stent thrombosis, but not against thromboembolic stroke. In contrast, oral anticoagulation does provide effective prevention against stroke during atrial fibrillation. Combining DAPT with oral anticoagulation (triple therapy) over the long term, as has been recommended to date, carries an elevated risk of hemorrhage. In a randomized controlled trial, 44% of patients with atrial fibrillation receiving triple therapy sustained a hemorrhagic event, compared to 19.4% of patients receiving dual therapy. A meta-analysis has shown that clinically relevant hemorrhage is less common under combined treatment with one of the new oral anticoagulants (NOAC) and a single antiplatelet drug than under triple therapy including a vitamin K antagonist (hazard ratio, 0.56; 95% confidence interval 0.39; 0.80]), but no significant difference was found with respect to stent thrombosis, myocardial infarction, or overall mortality. CONCLUSION: After coronary stent implantation, dual therapy with a NOAC and a P2Y12 inhibitor is recommended, subsequent to triple therapy given only during the peri-interventional period.

High incidence of deep vein thrombosis during the treatment of pseudoaneurysms - a retrospective nonrandomized study.

Background: Pseudoaneurysms (PSAs) are concerning complications after arterial invasive interventions. Therapeutic options include manual ultrasound-assisted compression, pressure dressings, surgical intervention and thrombin injection. Compression of neighboring veins is obvious. However, the incidence of deep vein thrombosis (DVT) in patients with PSA has not previously been investigated. Patients and methods: In this retrospective, nonrandomized study 238 patients with PSA were analyzed from 2013 to 2018. In 149 patients, all of the parameters were complete for participating. PSAs were treated according to the local standard therapy with either ultrasound-guided compression followed by compression bandage or thrombin injection. Treatment success was evaluated 24 hours later, and the venous system was examined for the presence of DVT. Results: Peripheral DVT was found in 25.4% patients after ultrasound-assisted compression and subsequent pressure bandages, but only 6.4% of patients had DVT after thrombin injection (p = 0.013). Lower leg veins, particularly veins of the crural muscles, were primarily affected. Significantly more PSAs were successfully treated without the occurrence of DVT in the thrombin injection group compared to the compression group (93.6 vs. 69.0%; p = 0.001). Conclusions: Our study revealed that the use of thrombin injections resulted in a significantly lower rate of postinterventional DVT and a higher total number of successfully treated PSAs compared to compression therapy.

Different DOACs Control Inflammation in Cardiac Ischemia-Reperfusion Differently.

RATIONALE: While thrombin is the key protease in thrombus formation, other coagulation proteases, such as fXa (factor Xa) or aPC (activated protein C), independently modulate intracellular signaling via partially distinct receptors. OBJECTIVES: To study the differential effects of fXa or fIIa (factor IIa) inhibition on gene expression and inflammation in myocardial ischemia-reperfusion injury. METHODS AND RESULTS: Mice were treated with a direct fIIa inhibitor (fIIai) or direct fXa inhibitor (fXai) at doses that induced comparable anticoagulant effects ex vivo and in vivo (tail-bleeding assay and FeCl3-induced thrombosis). Myocardial ischemia-reperfusion injury was induced via left anterior descending ligation. We determined infarct size and in vivo aPC generation, analyzed gene expression by RNA sequencing, and performed immunoblotting and ELISA. The signaling-only 3K3A-aPC variant and inhibitory antibodies that blocked all or only the anticoagulant function of aPC were used to determine the role of aPC. Doses of fIIai and fXai that induced comparable anticoagulant effects resulted in a comparable reduction in infarct size. However, unbiased gene expression analyses revealed marked differences, including pathways related to sterile inflammation and inflammasome regulation. fXai but not fIIai inhibited sterile inflammation by reducing the expression of proinflammatory cytokines (IL [interleukin]-1ß, IL-6, and TNFα [tumor necrosis factor alpha]), as well as NF-κB (nuclear factor kappa B) and inflammasome activation. This anti-inflammatory effect was associated with reduced myocardial fibrosis 28 days post-myocardial ischemia-reperfusion injury. Mechanistically, in vivo aPC generation was higher with fXai than with fIIai. Inhibition of the anticoagulant and signaling properties of aPC abolished the anti-inflammatory effect associated with fXai, while inhibiting only the anticoagulant function of aPC had no effect. Combining 3K3A-aPC with fIIai reduced the inflammatory response, mimicking the fXai-associated effect. CONCLUSIONS: We showed that specific inhibition of coagulation via direct oral anticoagulants had differential effects on gene expression and inflammation, despite comparable anticoagulant effects and infarct sizes. Targeting individual coagulation proteases induces specific cellular responses unrelated to their anticoagulant effect.

Pressure-volume loop validation of TAPSE/PASP for right ventricular arterial coupling in heart failure with pulmonary hypertension.

AIMS: The aim of this study was to validate the tricuspid annular plane systolic excursion/systolic pulmonary artery (PA) pressure (TAPSE/PASP) ratio with the invasive pressure-volume (PV) loop-derived end-systolic right ventricular (RV) elastance/PA elastance (Ees/Ea) ratio in patients with heart failure with reduced ejection fraction (HFREF) and secondary pulmonary hypertension (PH). METHODS AND RESULTS: The relationship of TAPSE and TAPSE/PASP with RV-PV loop (single-beat)-derived contractility Ees, afterload Ea, and Ees/Ea was assessed in 110 patients with HFREF with and without secondary PH. The results were compared with other surrogate parameters such as the fractional area change/PASP ratio. The association of the surrogates with all-cause mortality was evaluated. In patients with PH (n = 74, 67%), TAPSE significantly correlated with Ees (r = 0.356), inverse with Ea (r = -0.514) but was most closely associated with Ees/Ea (r = 0.77). Placing TAPSE in a ratio with PASP slightly reduced the relationship to Ees/Ea (r = 0.71) but was more closely related to the parameters of PA vascular load, diastolic RV function, and RV energetics. The area under the curve of TAPSE/PASP and TAPSE for discriminating overall survival in receiver operating characteristic analysis was not different (P = 0.78. Prognostic relevant cut-offs were 17 mm for TAPSE and 0.38 mm/mmHg for TAPSE/PASP. Both parameters in multivariate cox regression remained independently prognostically relevant. CONCLUSION: TAPSE is an easily and reliably obtainable and valid surrogate parameter for RV-PA coupling in PH due to HFREF. Putting TAPSE into a ratio with PASP did not further improve the coupling information or prognostic assessment. TRIAL IDENTIFIER: DRKS-German Clinical Trials Register (DRKS00011133; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011133).

DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation.

The transcription factors of the nuclear factor κB (NF-κB) family play a pivotal role in the cellular response to DNA damage. Genotoxic stress-induced activation of NF-κB differs from the classical canonical pathway by shuttling of the NF-κB Essential Modifier (IKKγ/NEMO) subunit through the nucleus. Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR). Blockade of DNA-PK by a specific shRNA or by DNA-PKcs-deficient cells abrogated NEMO entry into the nucleus, as well. Accordingly, SUMOylation of NEMO, a prerequisite of nuclear NEMO, was abolished. Based on these observations, we propose a model in which NEMO phosphorylation by DNA-PK provides the first step in the nucleocytoplasmic trafficking of NEMO.

Impact of aspirin on takotsubo syndrome: a propensity score-based analysis of the InterTAK Registry.

AIMS: The aim of the present study was to investigate the impact of aspirin on prognosis in takotsubo syndrome (TTS). METHODS AND RESULTS: Patients from the International Takotsubo (InterTAK) Registry were categorized into two groups based on aspirin prescription at discharge. A comparison of clinical outcomes between groups was performed using an adjusted analysis with propensity score (PS) stratification; results from the unadjusted analysis were also reported to note the effect of the PS adjustment. Major adverse cardiac and cerebrovascular events (MACCE: a composite of death, myocardial infarction, TTS recurrence, stroke or transient ischaemic attack) were assessed at 30-day and 5-year follow-up. A total of 1533 TTS patients with known status regarding aspirin prescription at discharge were included. According to the adjusted analysis based on PS stratification, aspirin was not associated with a lower hazard of MACCE at 30-day [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.50-3.04, P = 0.64] or 5-year follow-up (HR 1.11, 95% CI 0.78-1.58, P = 0.58). These results were confirmed by sensitivity analyses performed with alternative PS-based methods, i.e. covariate adjustment and inverse probability of treatment weighting. CONCLUSION: In the present study, no association was found between aspirin use in TTS patients and a reduced risk of MACCE at 30-day and 5-year follow-up. These findings should be confirmed in adequately powered randomized controlled trials. ClinicalTrials.gov Identifier: NCT01947621.

Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.

AIMS: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS). METHODS AND RESULTS: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission. CONCLUSIONS: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.