Remote Kidney and Liver Injury After Transplantation of Lung Allografts in an Allogeneic Mouse Model.

BACKGROUND: Remote organ dysfunction is common after lung transplantation and might negatively affect the outcome. The local anesthetic ropivacaine was previously demonstrated to attenuate acute rejection after allogeneic lung transplantation in mice. We hypothesized that lung transplantation might result in detectable molecular signs of injury in kidneys and liver and that ropivacaine might attenuate this damage. METHODS: Organs from C57BL/6 mice undergoing allogeneic orthotopic single-lung transplantation were procured at postoperative day 5 and analyzed using Western blot and real-time quantitative polymerase chain reaction probing for Src protein tyrosine kinase, STAT3, and bax/bcl-2. During cold ischemia, the allograft had either been flushed with normal saline only or in combination with ropivacaine (1 µM). A nontransplanted group of animals served as the baseline controls. RESULTS: The allogeneic stimulus induced by transplantation led to an increase in Src-phosphorylation and STAT3-expression in the kidneys and livers of lung-transplanted mice compared to nontransplanted animals. Bax/bcl-2 as a marker of cellular apoptosis was not affected by the transplantation. In contrast to the findings in the transplanted lungs, the addition of ropivacaine did not have an effect on the examined markers of inflammation in the remote organs. CONCLUSIONS: The observed increase in the inflammatory signaling provides first insight into a possible mechanism, by which remote organ dysfunction after lung transplantation might occur.

Burden of hospital admissions and resulting patient interhospital transports during the 2020/2021 SARS-CoV-2 pandemic in Saxony, Germany.

Secondary transports of patients from one hospital to another are indicated for medical reasons or to address local constraints in capacity. In particular, interhospital transports of critically ill infectious patients present a logistical challenge and can be key in the effective management of pandemic situations. The state of Saxony in Germany has two characteristics that allow for an extensive evaluation of secondary transports in the pandemic year 2020/2021. First, all secondary transports are centrally coordinated by a single institution. Second, Saxony had the highest SARS-CoV-2 infection rates and the highest COVID-19 associated mortality in Germany. This study evaluates secondary interhospital transports from March 2019 to February 2021 in Saxony with a detailed analysis of transport behaviour during the pandemic phase March 2020 to February 2021. Our analysis includes secondary transports of SARS-CoV-2 patients and compares them to secondary transports of non-infectious patients. In addition, our data show differences in demographics, SARS-CoV-2- incidences, ICU occupancy of COVID-19 patients, and COVID-19 associated mortality in all three regional health clusters in Saxony. In total, 12,282 secondary transports were analysed between March 1st, 2020 and February 28th, 2021, of which 632 were associated with SARS-CoV-2 (5.1%) The total number of secondary transports changed slightly during the study period March 2020 to February 2021. Transport capacities for non-infectious patients were reduced due to in-hospital and out-of-hospital measures and could be used for transport of SARS-CoV-2 patients. Infectious transfers lasted longer despite shorter distance, occurred more frequently on weekends and transported patients were older. Primary transport vehicles were emergency ambulances, transport ambulances and intensive care transport vehicles. Data analysis based on hospital structures showed that secondary transports in correlation to weekly case numbers depend on the hospital type. Maximum care hospitals and specialized hospitals show a maximum of infectious transports approximately 4 weeks after the highest incidences. In contrast, standard care hospitals transfer their patients at the time of highest SARS-CoV-2 case numbers. Two incidence peaks were accompanied by two peaks of increased secondary transport. Our findings show that interhospital transfers of SARS-CoV-2 and non-SARS-CoV-2 patients differ and that different hospital care levels initiated secondary transports at different times during the pandemic.

SARS-CoV-2 Vaccine Breakthrough Infections of Omicron and Delta Variants in Healthcare Workers.

Understanding SARS-CoV-2 breakthrough infections in vaccinated healthcare workers is of key importance in mitigating the effects of the COVID-19 pandemic in healthcare facilities. An observational prospective cohort study was conducted in vaccinated employees with acute SARS-CoV-2 infection between October 2021 and February 2022. Serological and molecular testing was performed to determine SARS-CoV-2 viral load, lineage, antibody levels, and neutralizing antibody titers. A total of 571 (9.7%) employees experienced SARS-CoV-2 breakthrough infections during the enrolment period, of which 81 were included. The majority (n = 79, 97.5%) were symptomatic and most (n = 75, 92.6%) showed Ct values < 30 in RT-PCR assays. Twenty-four (30%) remained PCR-positive for > 15 days. Neutralizing antibody titers were strongest for the wildtype, intermediate for Delta, and lowest for Omicron variants. Omicron infections occurred at higher anti-RBD-IgG serum levels (p = 0.00001) and showed a trend for higher viral loads (p = 0.14, median Ct difference 4.3, 95% CI [-2.5-10.5]). For both variants, viral loads were significantly higher in participants with lower anti-RBD-IgG serum levels (p = 0.02). In conclusion, while the clinical course of infection with both the Omicron and Delta variants was predominantly mild to moderate in our study population, waning immune response over time and prolonged viral shedding were observed.

Teaching Practical Skills in Anesthesia, Intensive Care, Emergency and Pain Medicine-What Is Really Relevant for Medical Students? Results of a German National Survey of Nearly 3000 Anesthesiologists.

As a part of a major reform of the medical curriculum in Germany, the national catalogue of learning objectives is being revised with the focus shifting from theory-based learning to teaching practical skills. Therefore, we conducted an online survey to answer the question, which practical skills are essential in anesthesia. Participants were asked to rate the relevance of several skills, that medical students should be able to perform at the time of graduation. A total of 2898 questionnaires could be evaluated. The highest ratings were made for "bringing a patient into lateral recumbent position" and "diagnosing a cardiac arrest". All learning objectives regarding regional anesthesia were rated as irrelevant. Furthermore, learning objectives like "performing a bronchoscopy" or "performing a rapid sequence induction" had low ratings. In the subgroup analysis, physicians with advanced training and those who were working at university hospitals rated most skills with higher relevance compared to others. Our survey provides a good prioritization of practical skills for the development of new curricula and assessment frameworks. The results can also help to establish our discipline as a cross-sectional subject in competency-based medical education, thus further increasing the attractiveness for medical students.

Association between Intraoperative Blood Transfusion, Regional Anesthesia and Outcome after Pediatric Tumor Surgery for Nephroblastoma.

BACKGROUND: Recent data suggest that anesthesiologic interventions-e.g., the choice of the anesthetic regimen or the administration of blood products-might play a major role in determining outcome after tumor surgery. In contrast to adult patients, only limited data are available regarding the potential association of anesthesia and outcome in pediatric cancer patients. METHODS: A retrospective multicenter study assessing data from pediatric patients (0-18 years of age) undergoing surgery for nephroblastoma between 2004 and 2018 was conducted at three academic centers in Europe. Overall and recurrence-free survival were the primary outcomes of the study and were evaluated for a potential impact of intraoperative administration of erythrocyte concentrates, the use of regional anesthesia and the choice of the anesthetic regimen. The length of stay on the intensive care unit, the time to hospital discharge after surgery and blood neutrophil-to-lymphocyte ratio were defined as secondary outcomes. RESULTS: In total, data from 65 patients were analyzed. Intraoperative administration of erythrocyte concentrates was associated with a reduction in recurrence-free survival (hazard ratio (HR) 7.59, 95% confidence interval (CI) 1.36-42.2, p = 0.004), whereas overall survival (HR 5.37, 95% CI 0.42-68.4, p = 0.124) was not affected. The use of regional anesthesia and the choice of anesthetic used for maintenance of anesthesia did not demonstrate an effect on the primary outcomes. It was, however, associated with fewer ICU transfers, a shortened time to discharge and a decreased postoperative neutrophil-to-lymphocyte ratio. CONCLUSIONS: The current study provides the first evidence for a possible association between blood transfusion as well as anesthesiologic interventions and outcome after pediatric cancer surgery.

[The cross-sectional field "pain medicine" in medical studies at the University of Leipzig-What has been achieved? : An analysis of self-estimation of students before, during and 5 years after establishment of the cross-sectional field]. / Der Querschnittsbereich 14 "Schmerzmedizin" an der Universität Leipzig ­ was wurde erreicht? : Eine Analyse der Selbsteinschätzung der Studierenden vor, während und fünf Jahre nach Etablierung des Querschnittsbereichs.

BACKGROUND: The field of pain medicine was established as an obligatory subject area of medical schools in Germany in 2016. No prior study has evaluated the effects of this curricular change on students' competences in the field of pain medicine. OBJECTIVE: The aim of this study was to find out to what extent the introduction of the additional subject "pain medicine" positively influenced the students' acquisition of competences measured via a self-assessment. MATERIAL AND METHODS: A longitudinal and interdisciplinary curriculum for pain medicine was developed according to the current recommendations for curriculum development for medical education. In parallel, a questionnaire was created for the students' self-assessment of their own level of knowledge and the importance of pain medicine teaching content on a 5-stage Likert scale. The surveys were conducted before the implementation of the curriculum (2014), directly after the first cohort finished (2016) and 5 years after the implementation (2019) and compared by Kruskal-Wallis test. RESULTS: The implementation of the curriculum has led to significant improvement in relevant aspects. For example, students now feel better prepared overall for the treatment of pain patients (2.67 in 2014 vs. 3.18 in 2019). Individual sub-aspects such as taking a pain history (3.63 vs. 4.10) or drawing up an analgesia scheme (3.56 vs. 4.14) are now also subjectively better mastered. CONCLUSION: Even though the results are encouraging, there is further potential for improvement in some sub-areas. For example, the students' rating regarding the question about their preparation for treating patients in pain is not yet satisfactory. Therefore, the curriculum should be developed further with a focus on competence orientation. Digital teaching formats can be integrated as well as interprofessional units and simulated patients. Additionally, the examination formats should be further developed towards standardized practical examinations.

Role of the lectin-like domain of thrombomodulin in septic cardiomyopathy.

AIMS: Septic cardiomyopathy is a severe complication of sepsis and septic shock. This study aimed to evaluate the role of thrombomodulin and its lectin-like domain (LLD-TM) in the development of septic cardiomyopathy and the link between LLD-TM, HMGB-1, and toll-like receptors 2/4 (TLR 2/4) to intracellular mechanisms resulting in reduced cardiac function. MATERIALS AND METHODS: Sepsis was induced using a polymicrobial peritoneal infection model in wildtype and mice lacking the lectin-like domain of thrombomodulin (TMLeD/LeD), and severity of disease and cardiac function was compared. Cell cultures of cardiomyocytes were prepared from hearts harvested from wildtype and TMLeD/LeD mice. Cultures of neonatal cardiomyocytes were transfected with complete human thrombomodulin or human thrombomodulin deficient of LLD-TM and when TLR-2 and/or TLR-4 were blocked. All cultures were challenged with inflammatory stimuli. KEY FINDINGS: Lack of the LLD-TM results in a significant increase in severity of disease, decreased survival and impaired cardiac function in septic mice. In vivo and in vitro analyses of cardiomyocytes displayed high levels of inflammatory cytokines causing cardio-depression. In vitro results showed a strong correlation between elevated HMGB-1 levels and elevated troponin-1 levels. No connection was found between HMGB-1 and TLR-2 and/or -4 signalling pathways. Phospholamban mediated dysregulation of calcium homeostasis resulted in a general impairment after sepsis induction, but showed no connection to LLD-TM. SIGNIFICANCE: Lack of LLD-TM results in an increase in general severity of disease, decreased survival and impaired cardiac function in sepsis. TLR-2 and TLR 4 do not participate as mediating factors in the development of septic cardiomyopathy.

Development and consensus of entrustable professional activities for final-year medical students in anaesthesiology.

BACKGROUND: The transfer of classic concepts of competency-based medical education into clinical practice has been proven to be difficult in the past, being described as partially fragmented, misleading and inadequate. At the beginning of training, novice doctors commonly feel overwhelmed, overloaded and exposed to extreme time pressure. The discrepancy between expected and actual clinical competence of doctors at the start of their speciality training jeopardizes patient safety. The framework of Entrustable Professional Activities (EPAs) is a promising instrument to effectively integrate competency-based training into clinical practice and may help to close this gap and consequently to improve patient safety. METHODS: For anaesthesiology, we developed 5 EPAs for final-year medical students. The EPAs comprised the following seven categories: 1. Title, 2. Specifications, 3. Limitations, 4. Competency domains, 5. Knowledge, abilities and skills, professional attitudes, 6. Assessment and 7. Entrustment. Based on a modified, online-based Delphi study, we further developed and refined these EPAs. Education experts were recruited from the alumni network of the Master of Medical Education (MME) degree course from the University of Heidelberg, Germany. RESULTS: 28 data sets were evaluated in three Delphi rounds. 82% of study participants had previous experience with EPAs. Qualitative and quantitative data formed the basis during the iterative process and resulted in complete descriptions of 5 EPAs for final-year medical students in anaesthesiology. CONCLUSIONS: Our study including the associated description of 5 EPAs represent a further step and starting point for EPA-based curricula in medical training in Germany linking undergraduate training, to residency training and continuous medical education.

Regional responsibility and coordination of appropriate inpatient care capacities for patients with COVID-19 - the German DISPENSE model.

As of late 2019, the COVID-19 pandemic has been a challenge to health care systems worldwide. Rapidly rising local COVID-19 incidence rates, result in demand for high hospital and intensive care bed capacities on short notice. A detailed up-to-date regional surveillance of the dynamics of the pandemic, precise prediction of required inpatient capacities of care as well as a centralized coordination of the distribution of regional patient fluxes is needed to ensure optimal patient care. In March 2020, the German federal state of Saxony established three COVID-19 coordination centers located at each of its maximum care hospitals, namely the University Hospitals Dresden and Leipzig and the hospital Chemnitz. Each center has coordinated inpatient care facilities for the three regions East, Northwest and Southwest Saxony with 36, 18 and 29 hospital sites, respectively. Fed by daily data flows from local public health authorities capturing the dynamics of the pandemic as well as daily reports on regional inpatient care capacities, we established the information and prognosis tool DISPENSE. It provides a regional overview of the current pandemic situation combined with daily prognoses for up to seven days as well as outlooks for up to 14 days of bed requirements. The prognosis precision varies from 21% and 38% to 12% and 15% relative errors in normal ward and ICU bed demand, respectively, depending on the considered time period. The deployment of DISPENSE has had a major positive impact to stay alert for the second wave of the COVID-19 pandemic and to allocate resources as needed. The application of a mathematical model to forecast required bed capacities enabled concerted actions for patient allocation and strategic planning. The ad-hoc implementation of these tools substantiates the need of a detailed data basis that enables appropriate responses, both on regional scales in terms of clinic resource planning and on larger scales concerning political reactions to pandemic situations.

[COVID-19: a chance for digitalization of teaching? : Report of experiences and results of a survey on digitalized teaching in the fields of anesthesiology, intensive care, emergency, pain and palliative medicine at the University of Leipzig]. / COVID-19: eine Chance zur Digitalisierung der Lehre? : Erfahrungsbericht und Ergebnisse einer Umfrage zur digitalen Lehre im Bereich Anästhesiologie, Intensiv-, Notfall-, Schmerz- und Palliativmedizin an der Universität Leipzig.

BACKGROUND: The SARS-CoV­2 pandemic has been a major challenge for graduate education. Teaching had to be digitalized within a very short time. This also affected the areas of anesthesiology, intensive care, emergency, pain and palliative care at the Department of Anesthesiology and Intensive Care Medicine at the University of Leipzig. OBJECTIVE: The aim of this questionnaire-based survey was to find out which courses can be digitalized from the students' point of view and which forms of teaching are associated with obstacles. In addition, we examined which technical infrastructure supports digitalization best. MATERIAL AND METHODS: In the course of digitalization the lecture series in the areas of palliative care and pain medicine had to be revised but also digital alternatives for seminars, simulation courses and bedside teaching had to be created. Video podcasts, digital learning material, educational films and video conferences were used for the digital implementation of the courses. Depending on the course, different digital methods were combined. In addition, a discussion forum for the exchange between faculty and students was established. An online evaluation was then carried out to assess the content. RESULTS: A total of 82 4th and 5th year medical students took part in the survey. More than 60% of students rated the learning effect of digital courses as "high" or "very high". Video podcasts of the lectures (45.1%) and digital bedside teaching (34.1%) were rated as the most effective ways of imparting knowledge. In particular, 92.7% of the surveyed students believed that the lectures could be replaced digitally on a permanent basis. For bedside teaching (3.7%) and emergency simulation course (1.2%) this is far less the case. In the majority of cases (56.1%), students needed 30-90 min daily for the preparation and post-processing of the contents. Just under 90% gave the digital courses offered by the hospital an overall grade of 1 or 2 (on a scale from 1 = best to 6 = worst). CONCLUSION: The SARS-CoV­2 pandemic posed major challenges for graduate teaching. At the same time, however, it also helped to overcome often long-standing hurdles to the digitalization of teaching. In the course of the digital semester, different teaching formats could be digitalized to varying degrees: Lectures can be digitally reproduced particularly well from the students' perspective, whereas the digitalization of bedside teaching has not been possible in most cases.

ECMO use in Germany: An analysis of 29,929 ECMO runs.

BACKGROUND: Extracorporeal Membrane Oxygenation (ECMO) use is increasing despite limited evidence. The aim of this study was to demonstrate heterogeneity of ECMO use and its association with hospital size and annual frequency in Germany. METHODS: This is a database analysis of all ECMO cases in Germany from 2010 to 2016 using the German Diagnosis Related Groups (DRG) coding system for ECMO. RESULTS: During the study period, 510 hospitals performed 29,929 ECMO runs (12,572 vvECMO, 11,504 vaECMO, 1993 pECLA) with an increase over time. Mortality ranged between 58% and 66% for vaECMO cases and 66% and 53% for vvECMO cases. 304 (61%) hospitals performed only one ECMO per year. 78%% of all ECMO runs were performed in centres with more than 20 cases per year and more than half of all ECMO runs were performed in hospitals with >1.000 beds. Mortality for vv and vaECMO was highest in very small hospitals (< 200 beds; 70%; 74%) and very large hospitals (>1000 beds; 60%; 62%). CONCLUSIONS: Use of ECMO is still increasing and a substantial proportion of hospitals performs very few ECMO runs. Small hospitals had a significantly higher mortality, but dependence on hospital size and ECMO mortality was irregular.

Mitochondrial-cell cycle cross-talk drives endoreplication in heart disease.

Endoreplication, duplication of the nuclear genome without cell division, occurs in disease to drive morphologic growth, cell fate, and function. Despite its criticality, the metabolic underpinnings of disease-induced endoreplication and its link to morphologic growth are unknown. Heart disease is characterized by endoreplication preceding cardiac hypertrophy. We identify ATP synthase as a central control node and determinant of cardiac endoreplication and hypertrophy by rechanneling free mitochondrial ADP to methylenetetrahydrofolate dehydrogenase 1 L (MTHFD1L), a mitochondrial localized rate-limiting enzyme of formate and de novo nucleotide biosynthesis. Concomitant activation of the adenosine monophosphate­activated protein kinase (AMPK)­retinoblastoma protein (Rb)-E2F axis co-opts metabolic products of MTHFD1L function to support DNA endoreplication and pathologic growth. Gain- and loss-of-function studies in genetic and surgical mouse heart disease models and correlation in individuals confirm direct coupling of deregulated energetics with endoreplication and pathologic overgrowth. Together, we identify cardiometabolic endoreplication as a hitherto unknown mechanism dictating pathologic growth progression in the failing myocardium.

Percutaneous hepatic melphalan perfusion: Single center experience of procedural characteristics, hemodynamic response, complications, and postoperative recovery.

BACKGROUND: Percutaneous hepatic melphalan perfusion (PHMP) for the selective treatment of hepatic metastases is known to be associated with procedural hypotension and coagulation disorders. Studies on anesthetic management, perioperative course, complications, and postoperative recovery in the intensive care unit (ICU) have not been published. METHODS: In a retrospective observational study, we analyzed consecutive patients who were admitted for PHMP over a 6-year period (2016-2021). Analyses included demographic, treatment, and outcome data with regard to short-term complications until ICU discharge. RESULTS: Fifty-three PHMP procedures of 16 patients were analyzed. In all of the cases, procedure-related hypotension required the median (range) highest noradrenaline infusion rate of 0.5 (0.17-2.1) µg kg min-1 and fluid resuscitation volume of 5 (3-14) liters. Eighty-four PHMP-related complications were observed in 33 cases (62%), of which 9 cases (27%) involved grade III and IV complications. Complications included airway constriction (requiring difficult airway management), vascular catheterization issues (which resulted in the premature termination of PHMP, as well as to the postponement of PHMP and to the performance of endovascular bleeding control after PHMP), and renal failure that required hemodialysis. Discharge from the ICU was possible after one day in most cases (n = 45; 85%); however, in 12 cases (23%), prolonged mechanical ventilation was required. There were no procedure-related fatalities. CONCLUSIONS: PHMP is frequently associated with challenging cardiovascular conditions and complications that require profound anesthetic skills. For safety reasons, PHMP should only be performed in specialized centers that provide high-level hospital infrastructures and interdisciplinary expertise.

Hormonal Blood Pressure Regulationduring General Anesthesia Usinga Standardized Propofol Dosagein Children and Adolescents SeemsNot to Be Affected by Body Weight.

Obesity in pediatric surgical patients is a challenge for the anesthesiologist. Despite potentially beneficial properties, propofol might also induce hypotension. This study examined whether a dose adjustment in overweight children could avoid hypotension and if there would be differences regarding hormonal regulation in children under anesthesia. Fifty-nine children undergoing surgery under general anesthesia were enrolled in this prospective observational trial. Participants were allocated into two groups according to their BMI. The induction of anesthesia was conducted using propofol ("overweight": 2 mg/kgBW, "regular": 3.2 mg/kgBW). The maintenance of anesthesia was conducted as total intravenous anesthesia. Hormone levels of renin, angiotensin II, aldosterone, copeptin, norepinephrine and epinephrine were assessed at different timepoints. Blood pressure dropped after the administration of propofol in both groups, with a nadir 2 min after administration-but without a significant difference in the strength of reduction between the two groups. As a reaction, an increase in the plasma levels of renin, angiotensin and aldosterone was observed, while levels of epinephrine, norepinephrine and copeptin dropped. By adjusting the propofol dosage in overweight children, the rate of preincision hypotension could be reduced to the level of normal-weight patients with a non-modified propofol dose. The hormonal counter regulation was comparable in both groups. The release of catecholamines and copeptin as an indicator of arginine vasopressin seemed to be inhibited by propofol.

Detection of posttraumatic pneumothorax using electrical impedance tomography-An observer-blinded study in pigs with blunt chest trauma.

INTRODUCTION: Posttraumatic pneumothorax (PTX) is often overseen in anteroposterior chest X-ray. Chest sonography and Electrical Impedance Tomography (EIT) can both be used at the bedside and may provide complementary information. We evaluated the performance of EIT for diagnosing posttraumatic PTX in a pig model. METHODS: This study used images from an existing database of images acquired from 17 mechanically ventilated pigs, which had sustained standardized blunt chest trauma and had undergone repeated thoracic CT and EIT. 100 corresponding EIT/CT datasets were randomly chosen from the database and anonymized. Two independent and blinded observers analyzed the EIT data for presence and location of PTX. Analysis of the corresponding CTs by a radiologist served as reference. RESULTS: 87/100 cases had at least one PTX detected by CT. Fourty-two cases showed a PTX > 20% of the sternovertebral diameter (PTXtrans20), whereas 52/100 PTX showed a PTX>3 cm in the craniocaudal diameter (PTXcc3), with 20 cases showing both a PTXtranscc and a PTXcc3. We found a very low agreement between both EIT observers considering the classification overall PTX/noPTX (κ = 0.09, p = 0.183). For PTXtrans20, sensitivity was 59% for observer 1 and 17% for observer 2, with a specificity of 48% and 50%, respectively. For PTXcc3, observer 1 showed a sensitivity of 60% with a specificity of 51% while the sensitivity of observer 2 was 17%, with a specificity of 89%. By programming a semi-automatized detection algorithm, we significantly improved the detection rate of PTXcc3, with a sensitivity of 73% and a specificity of 70%. However, detection of PTXtranscc was not improved. CONCLUSION: In our analysis, visual interpretation of EIT without specific image processing or comparison with baseline data did not allow clinically useful diagnosis of posttraumatic PTX. Multimodal imaging approaches, technical improvements and image postprocessing algorithms might improve the performance of EIT for diagnosing PTX in the future.

Inhibition of the Hypoxia-Inducible Factor 1α-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease.

BACKGROUND: Enhancers are genomic regulatory elements conferring spatiotemporal and signal-dependent control of gene expression. Recent evidence suggests that enhancers can generate noncoding enhancer RNAs, but their (patho)biological functions remain largely elusive. METHODS: We performed chromatin immunoprecipitation-coupled sequencing of histone marks combined with RNA sequencing of left ventricular biopsies from experimental and genetic mouse models of human cardiac hypertrophy to identify transcripts revealing enhancer localization, conservation with the human genome, and hypoxia-inducible factor 1α dependence. The most promising candidate, hypoxia-inducible enhancer RNA ( HERNA)1, was further examined by investigating its capacity to modulate neighboring coding gene expression by binding to their gene promoters by using chromatin isolation by RNA purification and λN-BoxB tethering-based reporter assays. The role of HERNA1 and its neighboring genes for pathological stress-induced growth and contractile dysfunction, and the therapeutic potential of HERNA1 inhibition was studied in gapmer-mediated loss-of-function studies in vitro using human induced pluripotent stem cell-derived cardiomyocytes and various in vivo models of human pathological cardiac hypertrophy. RESULTS: HERNA1 is robustly induced on pathological stress. Production of HERNA1 is initiated by direct hypoxia-inducible factor 1α binding to a hypoxia-response element in the histoneH3-lysine27acetylation marks-enriched promoter of the enhancer and confers hypoxia responsiveness to nearby genes including synaptotagmin XVII, a member of the family of membrane-trafficking and Ca2+-sensing proteins and SMG1, encoding a phosphatidylinositol 3-kinase-related kinase. Consequently, a substrate of SMG1, ATP-dependent RNA helicase upframeshift 1, is hyperphoshorylated in a HERNA1- and SMG1-dependent manner. In vitro and in vivo inactivation of SMG1 and SYT17 revealed overlapping and distinct roles in modulating cardiac hypertrophy. Finally, in vivo administration of antisense oligonucleotides targeting HERNA1 protected mice from stress-induced pathological hypertrophy. The inhibition of HERNA1 postdisease development reversed left ventricular growth and dysfunction, resulting in increased overall survival. CONCLUSIONS: HERNA1 is a novel heart-specific noncoding RNA with key regulatory functions in modulating the growth, metabolic, and contractile gene program in disease, and reveals a molecular target amenable to therapeutic exploitation.

Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery - a sub-analysis of the RIPHeart-Study.

BACKGROUND: The aim of our study was the identification of genetic variants associated with postoperative complications after cardiac surgery. METHODS: We conducted a prospective, double-blind, multicenter, randomized trial (RIPHeart). We performed a genome-wide association study (GWAS) in 1170 patients of both genders (871 males, 299 females) from the RIPHeart-Study cohort. Patients undergoing non-emergent cardiac surgery were included. Primary endpoint comprises a binary composite complication rate covering atrial fibrillation, delirium, non-fatal myocardial infarction, acute renal failure and/or any new stroke until hospital discharge with a maximum of fourteen days after surgery. RESULTS: A total of 547,644 genotyped markers were available for analysis. Following quality control and adjustment for clinical covariate, one SNP reached genome-wide significance (PHLPP2, rs78064607, p = 3.77 × 10- 8) and 139 (adjusted for all other outcomes) SNPs showed promising association with p < 1 × 10- 5 from the GWAS. CONCLUSIONS: We identified several potential loci, in particular PHLPP2, BBS9, RyR2, DUSP4 and HSPA8, associated with new-onset of atrial fibrillation, delirium, myocardial infarction, acute kidney injury and stroke after cardiac surgery. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov NCT01067703, prospectively registered on 11 Feb 2010.

Clinical consequences of chest tube malposition in trauma resuscitation: single-center experience.

PURPOSE: Evaluation of trauma patients with chest tube malposition using initial emergency computed tomography (CT) and assessment of outcomes and the need for chest tube replacement. METHODS: Patients with an injury severity score > 15, admitted directly from the scene, and requiring chest tube insertion prior to initial emergency CT were retrospectively reviewed. Injury severity, outcomes, and the positions of chest tubes were analyzed with respect to the need for replacement after CT. RESULTS: One hundred seven chest tubes of 78 patients met the inclusion criteria. Chest tubes were in the pleural space in 58% of cases. Malposition included intrafissural positions (27%), intraparenchymal positions (11%) and extrapleural positions (4%). Injury severity and outcomes were comparable in patients with and without malposition. Replacement due to malfunction was required at similar rates when comparing intrapleural positions with both intrafissural or intraparenchymal positions (11 vs. 23%, p = 0.072). Chest tubes not reaching the target position (e.g., pneumothorax) required replacement more often than targeted tubes (75 vs. 45%, p = 0.027). Out-of-hospital insertions required higher replacement rates than resuscitation room insertions (29 vs. 10%, p = 0.016). Body mass index, chest wall thickness, injury severity, insertion side and intercostal space did not predict the need for replacement. CONCLUSIONS: Patients with malposition of emergency chest tubes according to CT were not associated with worse outcomes compared to patients with correctly positioned tubes. Early emergency chest CT in the initial evaluation of severely injured patients allows precise detection of possible malposition of chest tubes that may require immediate intervention.

Mechanical complications and outcomes following invasive emergency procedures in severely injured trauma patients.

This study aimes to determine the complication rates, possible risk factors and outcomes of emergency procedures performed during resuscitation of severely injured patients. The medical records of patients with an injury severity score (ISS) >15 admitted to the University Hospital Leipzig from 2010 to 2015 were reviewed. Within the first 24 hours of treatment, 526 patients had an overall mechanical complication rate of 26.2%. Multivariate analysis revealed out-of-hospital airway management (OR 3.140; 95% CI 1.963-5.023; p < 0.001) and ISS (per ISS point: OR 1.024; 95% CI 1.003-1.045; p = 0.027) as independent predictors of any mechanical complications. Airway management complications (13.2%) and central venous catheter complications (11.4%) were associated with ISS >32.5 (p < 0.001) and ISS >33.5 (p = 0.005), respectively. Chest tube complications (15.8%) were associated with out-of-hospital insertion (p = 0.002) and out-of-hospital tracheal intubation (p = 0.033). Arterial line complications (9.4%) were associated with admission serum lactate >4.95 mmol/L (p = 0.001) and base excess <-4.05 mmol/L (p = 0.008). In multivariate analysis, complications were associated with an increased length of stay in the intensive care unit (p = 0.019) but not with 24 hour mortality (p = 0.930). Increasing injury severity may contribute to higher complexity of the individual emergency treatment and is thus associated with higher mechanical complication rates providing potential for further harm.

RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study: Myocardial Dysfunction, Postoperative Neurocognitive Dysfunction, and 1 Year Follow-Up.

BACKGROUND: Remote ischemic preconditioning (RIPC) has been suggested to protect against certain forms of organ injury after cardiac surgery. Previously, we reported the main results of RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study, a multicenter trial randomizing 1403 cardiac surgery patients receiving either RIPC or sham-RIPC. METHODS AND RESULTS: In this follow-up paper, we present 1-year follow-up of the composite primary end point and its individual components (all-cause mortality, myocardial infarction, stroke and acute renal failure), in a sub-group of patients, intraoperative myocardial dysfunction assessed by transesophageal echocardiography and the incidence of postoperative neurocognitive dysfunction 5 to 7 days and 3 months after surgery. RIPC neither showed any beneficial effect on the 1-year composite primary end point (RIPC versus sham-RIPC 16.4% versus 16.9%) and its individual components (all-cause mortality [3.4% versus 2.5%], myocardial infarction [7.0% versus 9.4%], stroke [2.2% versus 3.1%], acute renal failure [7.0% versus 5.7%]) nor improved intraoperative myocardial dysfunction or incidence of postoperative neurocognitive dysfunction 5 to 7 days (67 [47.5%] versus 71 [53.8%] patients) and 3 months after surgery (17 [27.9%] versus 18 [27.7%] patients), respectively. CONCLUSIONS: Similar to our main study, RIPC had no effect on intraoperative myocardial dysfunction, neurocognitive function and long-term outcome in cardiac surgery patients undergoing propofol anesthesia. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01067703.