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.

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.

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.

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.

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.

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.

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.

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.

Cytoprotective activated protein C averts Nlrp3 inflammasome-induced ischemia-reperfusion injury via mTORC1 inhibition.

Cytoprotection by activated protein C (aPC) after ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation, and hence, cell-death forms disjunct from immunologically silent apoptosis are, in theory, more likely to be relevant. Because pyroptosis (ie, cell death resulting from inflammasome activation) is typically observed in IRI, we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRIs. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3A350V mutation abolished the protective effect of aPC, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via proteinase-activated receptor 1 (PAR-1) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Accordingly, inhibiting PAR-1 signaling, but not the anticoagulant properties of aPC, abolished the ability of aPC to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficiently as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression after IRI was corroborated in renal IRI, where the tissue protective effect of aPC was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1-dependent inflammasome activation and that mimicking biased aPC PAR-1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI.

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy.

BACKGROUND: The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. METHODS: The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. RESULTS: Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. CONCLUSIONS: Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).

Do not underestimate the femoral pseudoaneurysm.

In addition to haematoma and arteriovenous fistula, the iatrogenic pseudoaneurysm is a common complication of vascular access that is caused by a perforation in the arterial wall. Iatrogenic pseudoaneurysms can progress in size and lead to rupture and active bleeding. Over the previous few decades, therapeutic methods have evolved from surgical repair to less invasive options, such as ultrasound-guided compression therapy (UGCT) and ultrasound-guided thrombin injection (UGTI). This paper presents an overview of the diagnostic and treatment modalities used in femoral pseudoaneurysms as well as a comprehensive summary of previous studies that analysed the success and complication rates of UGCT and UGTI.

Analysis of cardiovascular mortality, bleeding, vascular and cerebrovascular events in patients with atrial fibrillation vs. sinus rhythm undergoing transfemoral Transcatheter Aortic Valve Implantation (TAVR).

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has been demonstrated to be an established therapy for high-risk, inoperable patients with severe symptomatic aortic valve stenosis. For patients with moderate surgical risk, TAVR is equivalent to conventional aortic valve surgery. However, atrial fibrillation (AF) is also present in many of these patients, thus requiring post-implantation oral anticoagulation therapy in addition to the inhibition of thrombocyte aggregation, which poses the risk of bleeding complications. The aim of our work was to investigate the influence of AF on mortality and the occurrence of bleeding, vascular and cerebrovascular complications related to TAVR according to the VARC-2 criteria. METHODS: Two hundred eighty-three patients who underwent TAVR between March 2010 and April 2016 were retrospectively examined. In total, 257 patients who underwent transfemoral access were included in this study. The mean patient age was 81 ± 6 years, 54.1% of the patients were women, and 42.4% had pre-interventional AF. RESULTS: Compared to patients with sinus rhythm (SR, n = 148), patients with AF (n = 109) had an almost three-fold higher incidence of major vascular complications (AF 14.7% vs. SR 5.4%, p = 0.016) and life-threatening bleeding (AF 11.9% vs. SR 4.1%, p = 0.028) during the first 30 post-procedural days. However, the rate of cerebrovascular complications (AF 3.7% vs. SR 2.7%, p = 0.726) did not significantly differ between the two groups. Overall mortality was significantly higher in patients with AF during the first month (AF 8.3% vs. SR 2.0%, p = 0.032) and the first year (AF 28.4% vs. SR 15.3%; p = 0.020) following TAVR. CONCLUSION: Patients with AF had significantly more severe bleeding complications after TAVR, which were significantly related to mortality. Future prospective randomized studies must clarify the optimal anticoagulation therapy for patients with AF after TAVR. TRIAL REGISTRATION: DRKS00011798 on DRKS (Date 17.03.2017).

CD4+ T cells from human neonates and infants are poised spontaneously to run a nonclassical IL-4 program.

Senescence or biological aging impacts a vast variety of molecular and cellular processes. To date, it is unknown whether CD4(+) Th cells display an age-dependent bias for development into specific subpopulations. In this study, we show the appearance of a distinct CD4(+) T cell subset expressing IL-4 at an early stage of development in infant adenoids and cord blood that is lost during aging. We identified by flow cytometric, fluorescent microscopic, immunoblot, and mass spectrometric analysis a population of CD4(+) T cells that expressed an unglycosylated isoform of IL-4. This T cell subpopulation was found in neonatal but not in adult CD4(+) T cells. Furthermore, we show that the mRNA of the Th2 master transcription factor GATA3 is preferentially expressed in neonatal CD4(+) T cells. The Th2 phenotype of the IL-4(+)CD4(+) T cells could be reinforced in the presence of TGF-ß. Although the IL-4(+)CD4(+) T cells most likely originate from CD31(+)CD4(+) T recent thymic emigrants, CD31 was downregulated prior to secretion of IL-4. Notably, the secretion of IL-4 requires a so far unidentified trigger in neonatal T cells. This emphasizes that cytokine expression and secretion are differentially regulated processes. Our data support the hypothesis of an endogenously poised cytokine profile in neonates and suggest a link between cytokine production and the developmental stage of an organism. The determination of the IL-4 isoform-expressing cells in humans might allow the identification of Th2 precursor cells, which could provide novel intervention strategies directed against Th2-driven immunopathologies such as allergies.

Effects of the Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone on Peripheral Vessel Function and Clinical Parameters in Nondiabetic Patients: A Double-Center, Randomized Controlled Pilot Trial.

OBJECTIVE: Despite the advanced therapy with statins, antithrombotics, and antihypertensive agents, the medical treatment of atherosclerotic disease is less than optimal. Therefore, additional therapeutic antiatherosclerotic options are desirable. This pilot study was performed to assess the potential antiatherogenic effect of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in nondiabetic patients. METHODS: A total of 54 nondiabetic patients were observed in a prospective, double-blind, placebo-controlled study. Patients were randomized to pioglitazone or placebo. The following efficacy parameters were determined by serial analyses: artery pulse wave analysis and carotid-femoral pulse wave velocity (PWV), static and dynamic retinal vessel function, and the common carotid intima-media thickness (IMT). The main secondary endpoint was the change in different biochemical markers. RESULTS: After 9 months, no relevant differences could be determined in the two treatment groups in PWV (pioglitazone 14.3 ± 4.4 m/s vs. placebo 14.2 ± 4.2 m/s), retinal arterial diameter (pioglitazone 112.1 ± 23.3 µm vs. placebo 117.9 ± 21.5 µm) or IMT (pioglitazone 0.85 ± 0.30 mm vs. placebo 0.79 ± 0.15 mm). Additionally, there were no differences in the change in biochemical markers like cholesteryl ester transfer protein, low-density lipoprotein cholesterol, high-sensitivity C-reactive protein or white blood cell count. CONCLUSIONS: Treatment with a peroxisome proliferator-activated receptor-γ agonist in nondiabetic patients did not improve the function of large and small peripheral vessels (PPP Trial, clinicaltrialsregister.eu: 2006-000186-11).

Feasibility of a new method using two-dimensional transesophageal echocardiography for aortic annular sizing in patients undergoing transcatheter aortic valve implantation; a case-control study.

BACKGROUND: Accurate preoperative assessment of the aortic annulus dimension is crucial for successful transcatheter aortic valve implantation (TAVI). In this study we validated a new method using two-dimensional transesophageal echocardiography (2D-TEE) for measurement of the aortic annulus prior to TAVI. METHODS: We analysed 124 patients who underwent successful TAVI using a self-expandable prosthesis, divided equally into two groups; in the study group we used the cross sectional short axis 2D-TEE for measurement of the aortic annulus and in the control group we used the long axis 2D-TEE. RESULTS: Both groups were comparable regarding the clinical parameters. On the other hand, patients in the study group had less left ventricular ejection fraction (38.9 % versus 45.6 %, p = 0.01). The aortic valve annulus was, although not statistically significant, smaller in the study group (21.58 versus 23.28 mm, p = 0.25). Post procedural quantification of the aortic regurgitation revealed that only one patient in both groups had severe aortic regurgitation (AR), in this patient the valve was implanted deep. The incidence of significant AR was higher in the control group (29.0 % versus 12.9 %, p = 0.027). CONCLUSIONS: Sizing of the aortic valve annulus using cross-sectional 2D-TEE offers a safe and plausible method for patients undergoing TAVI using the self-expandable prosthesis and is significantly superior to using long axis 2D-TEE.

Effects of the PPARγ agonist pioglitazone on coronary atherosclerotic plaque composition and plaque progression in non-diabetic patients: a double-center, randomized controlled VH-IVUS pilot-trial.

Despite the advanced therapy with statins, antithrombotics and antihypertensive agents, the medical treatment of coronary artery disease is less than optimal. Therefore, additional therapeutic anti-atherosclerotic options are desirable. This VH-IVUS study (intravascular ultrasonography with virtual histology) was performed to assess the potential anti-atherogenic effect of the PPARγ agonist pioglitazone in non-diabetic patients. A total of 86 non-culprit atherosclerotic lesions in 54 patients with acute coronary syndrome were observed in a 9-month prospective, double-blind, and placebo-controlled IVUS study. Patients were randomized to receive either 30 mg pioglitazone (Pio) or placebo (Plac). As primary efficacy parameter, the change of relative plaque content of necrotic core was determined by serial VH-IVUS analyses. Main secondary endpoint was the change of total plaque volume. In contrast to placebo, in the pioglitazone-treated group, the relative plaque content of necrotic core decreased significantly (Pio -1.3 ± 6.9% vs. Plac +2.6 ± 6.5%, p < 0.01). In comparison to the placebo group, the plaques in pioglitazone-treated patients showed significantly greater reduction of the total plaque volume (Pio -16.1 ± 26.4 mm3 vs. Plac -1.8 ± 30.9 mm3, p = 0.02). Treatment with a PPARγ agonist in non-diabetic patients results in a coronary artery plaque stabilization on top of usual medical care.

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.

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).