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OBJECTIVES Venoarterial extracorporeal life support (ECLS) has emerged as a potentially life-saving treatment option in therapy-refractory cardiocirculatory failure, but longer-term outcome is poorly defined. Here, we present a comprehensive follow-up analysis covering all major organ systems. METHODS From February 2012 to December 2016, 180 patients were treated with ECLS for therapy-refractory cardiogenic shock or cardiac arrest. The 30-day survival was 43.9%, and 30-day survivors (n = 79) underwent follow-up analysis with the assessment of medium-term survival, quality of life, neuropsychological, cardiopulmonary and end-organ status. RESULTS After a median of 1.9 (1.1–3.6) years (182.4 patient years), 45 of the 79 patients (57.0%) were alive, 35.4% had died and 7.6% were lost to follow-up. Follow-up survival estimates were 78.0% at 1, 61.2% at 3 and 55.1% at 5 years. NYHA class at follow-up was ≤II for 83.3%. The median creatinine was 1.1 (1.0–1.4) mg/dl, and the median bilirubin was 0.8 (0.5–1.0) mg/dl. No patient required dialysis. Overall, 94.4% were free from moderate or severe disability, although 11.1% needed care. Full re-integration into social life was reported by 58.3%, and 39.4% were working. Quality of life was favourable for mental components, but a subset showed deficits in physical aspects. While age was the only peri-implantation parameter significantly predicting medium-term survival, adverse events and functional status at discharge or 30 days were strong predictors. CONCLUSIONS This study demonstrates positive medium-term outcome with high rates of independence in daily life and self-care but a subset of 10–20% suffered from sustained impairments. Our results indicate that peri-implantation parameters lack predictive power but downstream morbidity and functional status at discharge or 30 days can help identify patients at risk for poor recovery.

Treatment with extracorporeal life support (ECLS) in acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) fell short of improving myocardial recovery measured by 30 day ejection fraction in the ECLS-SHOCK trial. However, to date, no data regarding impact of ECLS on long-term outcomes exist. In this randomized, controlled, prospective, open-label trial, 42 patients with CS complicating AMI were randomly assigned to ECLS (ECLS group, n = 21) or no ECLS (control group, n = 21). The primary endpoint was left ventricular ejection fraction (LVEF) after 30 days. Secondary endpoints included mortality and neurological outcome after 12 months. Evaluation of neurological outcome used the modified Rankin Scale. The 12-month all-cause mortality was 19% in the ECLS group versus 38% in the control group (p = 0.31). Only one patient (control group) died after the initial 30 days. Three patients underwent elective percutaneous coronary intervention (PCI) during follow-up (one in the control and two in the ECLS group). Favorable neurological outcome (modified Rankin Score ≤ 2) was seen in 61.9% of patients in the ECLS group versus 57.1% in the control group (p = 1). This pilot study showed that randomized studies with ECLS in CS patients are feasible and safe. Small numbers of included patients impede meaningful conclusions about mortality and neurological outcome. Our findings of numerical differences in mortality and survival with severe neurological impairment give an urgent call for larger multi-centric randomized trials assessing the endpoint of all-cause mortality but also considering the effects on neurological outcome measures.

Lassa virus is endemic in West Africa and can cause severe hemorrhagic fever. The viral L protein transcribes and replicates the RNA genome via its RNA-dependent RNA polymerase activity. Here, we present nine cryo-EM structures of the L protein in the apo-, promoter-bound pre-initiation and active RNA synthesis states. We characterize distinct binding pockets for the conserved 3’ and 5’ promoter RNAs and show how full-promoter binding induces a distinct pre-initiation conformation. In the apo- and early elongation states, the endonuclease is inhibited by two distinct L protein peptides, whereas in the pre-initiation state it is uninhibited. In the early elongation state, a template-product duplex is bound in the active site cavity together with an incoming non-hydrolysable nucleotide and the full C-terminal region of the L protein, including the putative cap-binding domain, is well-ordered. These data advance our mechanistic understanding of how this flexible and multifunctional molecular machine is activated., The L protein of segmented, negative strand RNA viruses contains the RNA-dependent RNA polymerase essential for virus amplification. Here, the authors report cryoEM structures of the Lassa virus L protein in active, RNA-bound states, and provide mechanistic insights.

Background Acute chest syndrome (ACS) is a leading cause of morbidity and mortality among children with sickle cell disease (SCD). Preventing hypoxemia by optimizing lung aeration during sleep remains a challenge. Objectives To explore safety, feasibility, and tolerability of noninvasive, bi-level positive airway pressure ventilation (BiPAP) as preventative, supportive care for hospitalized, medically stable children with SCD on a general pediatric inpatient unit. Methods Retrospective chart review of patients ≤22 years of age with SCD admitted to the general pediatric inpatient unit from February 1, 2017 to March 1, 2020 for whom BiPAP was recommended as supportive care. Hospitalizations were excluded if patients were admitted to the pediatric intensive care unit (PICU), required BiPAP for respiratory failure, or used BiPAP at home for obstructive sleep apnea. Results Twenty-three patients had 53 hospitalizations in which BiPAP was recommended. Fifty-two (98%) hospitalizations included acute SCD pain. Indications for BiPAP included prior ACS (94%), chest or back pain (79%), and/or oxygen desaturation (66%). On 17 occasions, patients already had mild to moderate ACS but were stable when BiPAP was recommended. BiPAP was used successfully during 75% of hospitalizations for a median of two nights. There were no adverse effects associated with BiPAP. PICU transfer for respiratory support occurred during three hospitalizations. In 26 hospitalizations of children at risk for ACS who tolerated BiPAP, 23 (88%) did not develop ACS. Conclusions BiPAP is safe, feasible, and well tolerated as supportive care for hospitalized children with SCD. Next steps include an intervention trial to further assess the efficacy of BiPAP on ACS prevention.

Controversy exists regarding the threshold of recipient twin polyhydramnios required to diagnose twin-twin transfusion syndrome at a gestational age of ≥20 weeks. One criterion set (Quintero staging) requires the amniotic fluid maximum vertical pocket for the recipient twin to measure ≥8 cm, whereas another (European) system uses a maximum vertical pocket for the recipient twin of ≥10 cm.This study aimed to characterize the patients with twin-twin transfusion syndrome who were treated with laser surgery and would be excluded from laser surgery according to the European criteria.A total of 366 monochorionic diamniotic twins diagnosed with twin-twin transfusion syndrome from 20 to 26 weeks' gestation who underwent laser surgery at our center were studied. A maximum vertical pocket for the recipient twin of ≥8 cm was used to diagnose twin-twin transfusion syndrome. Patients were retrospectively divided into the following 2 groups: group A with a maximum vertical pocket for the recipient twin of ≥8 cm and10 cm and group B with a maximum vertical pocket for the recipient twin of ≥10 cm. The association of each of the groups with the survivorship outcomes was tested. Bivariate associations between the patient characteristics and the 30-day donor twin and dual survivorship outcomes were evaluated. Tests used in the analysis were chi-square or Fisher exact tests as appropriate for categorical variables and Kruskal-Wallis tests for continuous variables. Multiple logistic regression models for each of the survivorship outcomes were then assessed. The results are reported as mean±standard deviation.Of the 366 studied patients, 53 (14.5%) had a maximum vertical pocket for the recipient twin of ≥8 and10 cm (group A) and 313 (85.5%) had a maximum vertical pocket for the recipient twin of ≥10 cm (group B). Groups A and B did not differ in the Quintero stage. Notably, 60.4% (32 of 53) of group A patients were stage III or IV. When compared with group B, group A was diagnosed with twin-twin transfusion syndrome at an earlier gestational age (21.7±1.6 vs 22.3±1.6 weeks; P=.0037) and had a higher prevalence of donor growth restriction (81.1% [43 of 53] vs 65.5% [205 of 313]; P=.0260). Rates of at least 1 twin and dual twin survival between group A and B were similar (98.1% [52 of 53] vs 95.8% [300 of 313]; P=.7023, and 79.2% [42 of 53] vs 83.4% [261 of 313]; P=.4369, respectively). Logistic regression models adjusted for perioperative characteristics showed no difference in the outcomes between the groups (group B as reference) (donor twin survival odds ratio, 0.64; 95% confidence interval, 0.29-1.42; P=.2753; and dual survivor odds ratio, 0.90; 95% confidence interval, 0.42-1.91; P=.7757).Restriction of the definition of twin-twin transfusion syndrome to a maximum vertical pocket for the recipient of ≥10 cm beyond 20 weeks gestational age would potentially exclude 14.5% of patients from laser surgery, the majority of whom had advanced stage twin-twin transfusion syndrome. A unifying criterion of a maximum vertical pocket for the recipient of ≥8 cm regardless of gestational age would allow inclusion of these patients and access to surgical management.

BACKGROUND Survival rates of out-of-hospital cardiac arrest remain poor. Bystander cardiopulmonary resuscitation (CPR) is crucial for survival and feedback devices could improve its quality. OBJECTIVE We investigated quality of chest compression when using the Cardio First AngelTM (CFA) feedback device compared to standard basic life support (BLS). The analysis focused on laymen. METHODS Laymen without (n= 43) and with (n= 96) explanation of the device, medical students (n= 128) and medical staff (n= 27) performed 60 seconds of standard versus assisted chest compression using the CFA on a resuscitation manikin. Compression frequency, depth and position were analyzed according to current guidelines. RESULTS Laymen showed significantly better success rates regarding correct compression depth when using the CFA (23.3% vs. 55.8%, p= 0.004 and 25.0% vs. 52.1%, p< 0.001, laymen without and with explanation of the device, respectively). Medical students likewise improved (22.7% vs. 42.2%, p= 0.004). Hand positioning was 100% correct in all groups with the device. Improvement in frequency yielded by the CFA was more pronounced for probands with fears of contact (p= 0.02). The benefit of using the device did not differ significantly in laymen with or without explanation. CONCLUSIONS Chest compression as performed by laymen was significantly improved with regard to compression depth when using the CFA for guidance and feedback. With the device, no cases of incorrect hand positioning occurred in any group.

Despite multimodal treatment of patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI), the outcome remains poor. Large retrospective analyses and animal models suggest that extracorporeal life support (ECLS) in CS-complicating AMI improves outcome [(1)][1]. However, to

Assessing the platelets’ functional status during surgery on cardiopulmonary bypass is challenging. This study used multiple electrode impedance aggregometry (Multiplate®) to create a timeline of platelet aggregation changes as induced by cardiopulmonary bypass in antiplatelet-naive patients undergoing elective surgery for mitral valve regurgitation. We performed six consecutive measurements (T1: pre-operatively, T2: after heparinization, T3: 3 min after establishment of cardiopulmonary bypass, T4: immediately after administration of cardioplegia, T5: 5 min after administration of cardioplegia, and T6: 45 min after administration of cardioplegia). Platelet aggregation was determined after stimulation with 3.2-μg/mL collagen, 6.4-μM adenosine diphosphate, and 32-μM thrombin receptor activating peptide. Five patients were included (age: 64 ± 10 years, one female). We observed a decrease in hematocrit levels by −17.1% ± 3.7% (T1 vs T6) with a drop after establishment of cardiopulmonary bypass (T2 vs T3) and slightly decreasing platelet counts by −6.2% ± 7.7% (T1 vs T6). Immediately after establishment of cardiopulmonary bypass (T2 vs T3), we observed reduced platelet aggregation responses for stimulation with adenosine diphosphate (−19.7% ± 12.8%) and thrombin receptor activating peptide (−19.3% ± 6.3%). Interestingly, we found augmented platelet aggregation for all stimuli 45 min after administration of cardioplegia (T5 vs T6) with the strongest increase for collagen (+83.4% ± 42.8%; adenosine diphosphate: +39.0% ± 37.2%; thrombin receptor activating peptide: +34.5% ± 18.5%). Thus, after an initial drop due to hemodilution upon establishment of cardiopulmonary bypass, platelet reactivity increased over time which was not outweighed by decreasing platelet counts due to mechanical platelet destruction and absorption. These findings have implications for rational transfusion, peri-operative antiplatelet therapy, and for the management of patients on other extracorporeal support, such as extracorporeal life support or extracorporeal membrane oxygenation.

OBJECTIVE This study was meant to analyse the centre experience of the Munich Lung Transplant Group in lung transplantation of patients with severe pulmonary hypertension. Outcome data focus on survival and right heart remodelling. METHODS All patients receiving a lung transplant between 10/2010 and 08/2016 were retrospectively analysed (n = 343). Patients were categorised into individuals with or without severe pre-operative pulmonary hypertension (PH; mPAP ≥ 35 mm Hg or mPAP ≥ 25 mm Hg with cardiac index

Background Surgical treatment of constrictive pericarditis (CP) is particularly challenging because of the increased risk of right heart failure. The necessity of postoperative extracorporeal life support (ECLS) can result in mortality rates of 100%. Preemptive implantation of ECLS may improve postoperative outcomes; however, no data are currently available on its use. We conducted a retrospective study to evaluate the feasibility of our strategy. Methods Between September 2012 and June 2016, ECLS was established percutaneously through the groin vessels in 12 individually selected patients with high-risk CP immediately before pericardiectomy in the operating theater as part of the surgical strategy. Prolonged weaning was performed in the intensive care unit. Demographic characteristics, perioperative data, and survival were analyzed. Results The median patient age was 61.5 years (first quartile, third quartile: 51.3, 68.5 years), with a preoperative central venous pressure of 24 mm Hg (first quartile, third quartile: 21, 28 mm Hg). Furthermore, the pulmonary artery pressure was greater than 60 mm Hg in 50% of patients and a dip plateau sign existed in 75% before surgery. The median duration of ECLS therapy was 132 hours (first quartile, third quartile: 96, 168 hours) with a length of stay on the intensive care unit of 10 days (first quartile, third quartile: 7.0, 16.8 days). There was no intraoperative death. The cumulative 30-day, 1-year, and 5-year survival rates were 83% ± 11%, 75% ± 13%, and 75% ± 13%, respectively. Conclusions From our real-world data, preemptive use of perioperative ECLS, assigned by individual team decision in selected patients with severe CP, is a feasible and safe strategy.

End-stage heart failure is associated with significant morbidity and mortality. Heart transplantation has the potential to offer a return to daily activities for critically ill patients and is the gold standard therapy. However, heart transplantations are decreasing yearly with a historic low in Germany in 2017. By striking contrast, both waiting list numbers and waiting time have increased owing to a lack of acceptable donor organs. Ventricular assist devices (VAD) represent a reasonable therapeutic alternative for patients on heart transplantation waiting lists. Patients ineligible for transplantation may undergo VAD implantation as a destination therapy. However, the necessity for life-long anticoagulation must be weighed against bleeding complications in potential VAD candidates. VAD-dependent patients also face risks of driveline infections, in addition to restricted activities of daily living owing to limited battery capacities. Given Germany's low transplantation rate, VAD implantation may serve as a middle ground. With the recent events in transplantation medicine, trust among the German population has declined. Transplant centers must ensure graft quality and ongoing care, define minimum caseload for accreditation, and implement specialty care units in heart failure. Furthermore, the legislation shift from extended consent to dissent solution has the potential to end donor organ shortage.

Objectives Diagnosis of prosthetic graft infection after cardiac and proximal aortic surgery is a challenge. Besides technical considerations, redo surgery is associated with substantial morbidity and mortality. Therefore, an accurate diagnosis is mandatory. We report on our experience with hybrid 18-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET)/computed tomography (CT) imaging, which is increasingly used to diagnose infections in the detection of graft infection after cardiac surgery. Methods Twenty-six patients who underwent (18)F-FDG PET/CT imaging after cardiac surgery between February 2010 and September 2014 for suspected graft infection were retrospectively analysed (81% male, age 54.3 ± 13.7 years). PET/CT imaging was performed 36.5 ± 70.5 (0.5-300) months after surgery. 2 patients (8%) had undergone aortic valve replacement (concomitant ascending and proximal arch replacement in 1), 1 (4%) aortic root reconstruction, 9 (35%) aortic root replacement (concomitant partial arch in 4, arch replacement and postoperative TEVAR in 1), 2 (8%) ascending aortic and partial arch replacement and 2 (8%) ascending aortic replacement along with frozen elephant trunk. In 10 (38%), more than one previous cardiac surgical procedure had been performed. Maximum standardized uptake values (SUVmax) were obtained for all patients. If the patients were reoperated on, the final diagnosis was derived from intraoperative findings and/or microbiological results. Otherwise, the longest clinical follow-up available served as a reference. Results Conventional CT was positive for infection in 13 cases (50%). In 22 (85%), PET was indicative of infection (SUVmax 10.5 ± 4.1). PET did not only confirm true-positive CT results in all but 1 case; in almost 30%, it provided substantial additional diagnostic information in comparison with CT alone. Receiver operating characteristic analysis identified an SUVmax of 7.25 to achieve maximum sensitivity (89%) and specificity (100%) in prediction of infection. Twelve patients (46%) required redo surgery for graft infection; in 1 additional patient (4%), sternal re-fixation was necessary. Furthermore, 2 patients had to be reoperated on for torn-out anastomosis and paraprosthetic perfusion (8%). Conclusions PET provides functional data, confirms a CT diagnosis and may even increase diagnostic sensitivity in comparison with CT alone in selected cases. Specificity can be compromised by postoperative changes or chronic inflammatory reactions induced by the graft. CT and/or echocardiography should remain the first diagnostic step in case of a suspected infection because of their broad and fast availability. If confirmation is needed or diagnosis is not achievable using conventional methods, PET might be chosen as the next modality to gain additional information in experienced centres.

No guidelines for mechanical circulatory support in patients with therapy-refractory cardiogenic shock and multiorgan failure including ongoing cardiopulmonary resuscitation (CPR) exist. To achieve immediate cardiopulmonary stabilization, we established an interdisciplinary concept with on-site percutaneous extracorporeal life support (ECLS) implantation. From February 2012 to November 2014, 96 patients were deemed eligible for ECLS implantation. Establishing ECLS was successful in 87 patients (mean age 54 +/- 13 years, 16% female, initial flow 4.4 +/- 0.9 l/min). Aetiologies included acute coronary syndromes (n = 52, 60%), cardiomyopathies (n = 25, 29%) and other pathologies. Fifty-nine patients (68%) had been resuscitated, and in 27 (31%), implantation was performed during CPR;11 patients (13%) were awake at implantation and 20 (23%) underwent implantation in the referring hospital. Metabolic parameters differed in non-survivors versus survivors before ECLS implantation (pH 7.15 +/- 0.23 vs. 7.27 +/- 0.18, P = 0.007;lactate levels 10.90 +/- 6.00 mmol/l vs. 8.79 +/- 5.78 mmol/l, P = 0.091) and 6 h postimplantation (pH 7.27 +/- 0.11 vs. 7.37 +/- 0.11, P < 0.001;lactate levels 10.19 +/- 5.52 mmol/l vs. 5.52 +/- 4.17 mmol/l, P < 0.001). Altogether 44 patients could be weaned, and 9 were bridged to assist device implantation and 1 to heart transplantation. The mean time of support was 6 days, and the 30-day survival rate was 47% (n = 41). ECLS serves as a bridge-to-decision and bridge-to-treatment device. Our interdisciplinary ECLS programme achieved acceptable survival of critically ill patients despite a substantial percentage of patients having been resuscitated and no absolute exclusion criteria. Further studies defining inclusion- and exclusion criteria might additionally improve outcome.

A significant subset of Veterans residing in in VA Community Living Centers (CLCs) demonstrate challenging dementia-related behaviors that affect their quality of life, stress the caregiving staff, and interfere with successful placement in the community. The Behavioral Recovery Outreach (BRO) team was created at the VA Central Iowa Healthcare System to: (1) treat challenging dementia-related behaviors while Veterans reside in the CLC, and (2) ensure successful placements post-discharge. This team, comprised of a psychologist, nurse, social worker, and recreational therapist, facilitates successful placements by communicating effective behavior plans at discharge, providing on-site visits at 1, 3, 6, and 12 months post-discharge, and providing as-needed consultation. The team, working with 66 Veterans to date, has demonstrated 89% success in community placements. The BRO team implementation process and outcomes will be discussed.

The reattachment of the supra-aortic vessels during hybrid arch repair using a branched prosthesis is time consuming and sometimes technically challenging. Here, we describe the surgical technique of bridging the end-to-end anastomoses between the graft branches and the supra-aortic vessels by self-expanding covered stents to reduce suturing time, avoid anastomotic bleeding, enhance true lumen remodeling, and improve vessel alignment to the hybrid graft.

Objective Extracorporeal life support (ECLS) emerges as a salvage option in therapy refractory cardiogenic shock but is limited to highly specialized tertiary care centers. Critically ill patients are often too unstable for conventional transport. Mobile ECLS programs for remote implantation and subsequent air or ground-based transport for patient retrieval could solve this dilemma and make full-spectrum advanced cardiac care available to patients in remote hospitals in whom shock otherwise might be fatal. Methods From December 2012 to March 2016, 40 patients underwent venoarterial ECLS implantation in remote hospitals with subsequent transport to our center and were retrospectively analyzed. The mobile ECLS team was available 24/7, implantation was performed percutaneously bedside, and compact support systems designed for transport were used. Results Twenty percent of the patients were female; the mean age was 55 ± 10 years, and the mean Interagency Registry for Mechanically Assisted Circulatory Support score was 1.3 ± 0.5. Patient retrieval was accomplished via ground-based (n = 29, 72.5%, mean distance = 27.9 ± 29.7 km [range, 5.6-107.1 km]) or air (n = 11, mean distance = 62.4 ± 27.2 km [range, 38.9-116.4 km]) transport. No ECLS-related complications occurred during transport. The ECLS system could be explanted in 65.0% (n = 26) of patients, and the 30-day survival rate was 52.5% (n = 21). Conclusion Remote ECLS implantation and interfacility transport on ECLS are feasible and effective. Interdisciplinary teams and full-spectrum cardiac care are essential to achieve optimal outcomes. Rapid-response ECLS networks have the potential to substantially increase the survival of cardiogenic shock patients.

The major task in most autopsies is the evaluation of circumstances and cause of a person's death. The quantification of edema, primarily in certain brain regions, is a promising marker to distinguish between certain causes of death. This is especially important if there is no visible reason, for example, in the case of distinguishing Sudden Infant Death Syndrome from Shaken Impact Syndrome. However, until now there is no standardized procedure in forensic medicine for the quantification of edema in parenchymatous organs. Therefore, the aim of our work is to develop a fast low-cost measuring system that fits into the procedure of an autopsy. One approach for an exact quantification of edema is to determine the humidity content in the tissue with the so-called oven dry method, which we used as a reference. The approach presented here is the determination of the humidity content via a measurement of the relative permittivity of the tissue. We use two different setups: a transmission and a reflection measurement. Thereby a linear regression between the humidity content and the relative permittivity was found with excellent regression coefficients of R = 0.98 for the transmission measurement and R = 0.97 for the reflection measurement. We compare the results of the used methods regarding accuracy and measuring time.

Objectives Different revascularization strategies for patients with acute myocardial infarction (AMI) exist. It remains unclear whether ventricular unloading using cardiopulmonary bypass (CPB) or extracorporeal life support (ECLS) has an impact on early postischaemic ventricular function. Here, we report on the results of an approach using a miniaturized CPB in a well-established animal model of AMI. Methods In a randomized fashion, 30 male Wistar rats were assigned to temporary left anterior descending (LAD) ligation (30 min) followed by 180 min of reperfusion either with or without 60 min of CPB (70 ml/min, 36°C). The CPB circuit consisted of a venous reservoir, a peristaltic roller pump and a membrane oxygenator with heat exchanger. Cardiac function was measured at 60 and 120 min after reperfusion (F60, F120) using a conductance catheter. Results The mortality rate was 37% (11/30). Thus, 19 animals could be included into the analysis (8 CPB). The mean cardiac output did not differ between the groups at F60 [63 ± 29 vs 54 ± 25 ml/min (CPB), P = 0.56] and F120 [73 ± 27 vs 53 ± 24 ml/min (CPB), P = 0.21]. During reperfusion, the mean left ventricular ejection fraction (LVEF) was stable in both the control (F60 37 ± 5% vs F120 33 ± 8%, P = 0.42) and the CPB groups (F60 52 ± 11% vs F120 51 ± 13%, P = 0.71). CPB animals had a significantly better LVEF after reperfusion (F60 P = 0.007, F120 P = 0.01). Conclusions In this animal model of AMI, the establishment of CPB resulted in a significantly better LVEF in comparison with conventional reperfusion only. This beneficial effect may have an impact on revascularization strategies and timing in patients presenting with AMI in the future.

e14297 Background: The induction of powerful CD8+ T cell immunity to tumor associated self-antigens (TAAs) represents a critical yet challenging goal. Here we report on the development of an arenavirus-based delivery platform meeting this challenge. Previously we have shown that genetically engineered replication-attenuated lymphocytic choriomeningitis virus (LCMV) vectors, TheraT(LCMV), induce strong TAA-specific CD8 T cell immunity, but these responses can not be substantially augmented upon TheraT(LCMV) readministration. Counter to expectations, vector-neutralizing antibodies were not accountable for limited homologous prime-boosting capacity. Instead, dominant viral backbone-reactive CD8+ T cells competed against subdominant TAA-specific responses, limiting their magnitude. Methods: Herein we engineered and characterized delivery systems based on the arenaviruses Mopeia, Candid#1 and Pichinde (TheraT(MOP), TheraT(CAND), TheraT(PIC)). Results: We demonstrate that heterologous TheraT(CAND) – TheraT(LCMV) and TheraT(PIC)-TheraT(LCMV) prime-boost substantially augment TAA-specific CD8 T cell responses by rendering them immunodominant. Accordingly, intravenous administration of mice triggered up to 50% TAA epitope-specific CD8+ T cells and cured established tumors. Conversely, TheraT(MOP) – TheraT(LCMV) prime-boost was poorly immunogenic owing to cross-reactive T cell epitopes in the respective viral backbones. Conclusions: These findings establish heterologous arenavirus prime-boost combinations as a powerful new modality in tumor immunotherapy and highlight CD8 T cell epitope dominance as a significant hurdle to overcome in the vectored delivery of TAAs.

OBJECTIVES: Therapy refractory cardiogenic shock is associated with dismal outcome. Percutaneous implantation of an extracorporeal life support (ECLS) system achieves immediate cardiopulmonary stabilization, sufficient end-organ perfusion and reduction of subsequent multiorgan failure (MOF). METHODS: Forty-one patients undergoing percutaneous ECLS implantation for cardiogenic shock from February 2012 until August 2013 were retrospectively analysed. Mean age was 52 ± 13 years, 6 (15%) were female. Mean pH values obtained before ECLS implantation were 7.15 ± 0.24, mean lactate concentration was 11.7 ± 6.4 mmol/l. Levels obtained 6 h after ECLS implantation were 7.30 ± 0.14 and 8.7 ± 5.0 mmol/l, respectively. In 23 patients (56%) cardiogenic shock resulted from an acute coronary syndrome in 13 (32%) from cardiomyopathy, in 5 (12%) from other causes. Twenty-seven (66%) had been resuscitated, in 14 (34%) implantation was performed under ongoing cardiopulmonary resuscitation (CPR). Of note, 97% of the acute coronary syndrome patients underwent percutaneous coronary intervention (PCI) either before ECLS implantation or under ECLS support. Extracorporeal life support implantation was performed on scene (Emergency Department, Cath Lab, Intensive Care Unit) by a senior cardiac surgeon and a trained perfusionist, in 8 cases (20%) in the referring hospital. RESULTS: Thirty-day mortality was 51% [21 patients, due to MOF (n= 14), cerebral complications (n= 6) and heart failure (n= 1)]. Logistic regression analysis identified 6-h pH values as an independent risk factor of 30-day mortality (P< 0.001, OR = 0.000, 95% CI 0.000–0.042). Neither CPR nor implantation under ongoing CPR resulted in significant differences. In 26 cases (63%), the ECLS system could be explanted, after mean support of 169 ± 67 h. Seven of these patients received cardiac surgery [ventricular assist device implantation (n= 4), heart transplantation (n= 1), other procedures (n= 2)]. CONCLUSIONS: Due to the evolution of transportable ECLS systems and percutaneous techniques implantation on scene is feasible. Extracorporeal life support may serve as a bridge-to-decision and bridge-to-treatment device. Neurological evaluation before ventricular assist device implantation and PCI under stable conditions are possible. Despite substantial mortality, ECLS implantation in selected patients by an experienced team offers additional support to conventional therapy as well as CPR and allows survival in patients that otherwise most likely would have died. This concept has to be implemented in cardiac survival networks in the future.

Highlights ► EVA is a globally available virus collection serving academia, public health and industry. ► EVA is a unique, networked, quality-controlled non-profit virus archive that benefits science. ► EVA provides wide-ranging access to virus collections held in laboratories worldwide. ► Laboratories in developing countries contribute to the pool of quality-controlled reagents., The European Virus Archive (EVA) was conceived as a direct response to the need for a coordinated and readily accessible collection of viruses that could be made available to academia, public health organisations and industry, initially within Europe, but ultimately throughout the world. Although scientists worldwide have accumulated virus collections since the early twentieth century, the quality of the collections and the viruses collected may vary according to the personal interests and agenda of the scientists. Moreover, when laboratories are re-organised or closed, collections are no longer maintained and gradually cease to exist. The tragedy of 9/11 and other disruptive activities have also meant that some previously available biological reagents are no longer openly exchanged between countries. In 2008, funding under the FP7–EU infrastructure programme enabled the initiation of the EVA. Within three years, it has developed from a consortium of nine European laboratories to encompass associated partners in Africa, Russia, China, Turkey, Germany and Italy. There is every reason to believe that EVA will continue to expand and ultimately exist as a globally networked, quality-controlled non-profit archive for the benefit of science. Organizations or individuals who would like to be considered as contributors are invited to contact the EVA coordinator, Jean–Louis Romette, at jean-louis.romette@univmed.fr.

Testicular germ cell tumours (GCTs) of adolescents and adults can be subdivided into seminomas (referred to as dysgerminomas of the ovary) and non-seminomas, all referred to as type II GCTs. They originate from carcinoma in situ (CIS), being the malignant counterparts of primordial germ cells (PGCs)/gonocytes. The invasive components mimic embryogenesis, including the stem cell component embryonal carcinoma (EC), the somatic lineage teratoma (TE), and the extra-embryonic tissues yolk sac tumour (YST) and choriocarcinoma (CH). The other type is the so-called spermatocytic seminomas (SS, type III GCT), composed of neoplastic primary spermatocytes. We reported previously that the miRNAs hsa-miR 371-373 cluster is involved in overruling cellular senescence induced by oncogenic stress, allowing cells to become malignant. Here we report the first high-throughput screen of 156 microRNAs in a series of type II and III GCTs (n = 69, in duplicate) using a quantitative PCR-based approach. After normalization to allow inter-sample analysis, the technical replicates clustered together, and the previous hsa-miRNA 371-373 cluster finding was confirmed. Unsupervised cluster analysis demonstrated that the cell lines are different from the in vivo samples. The in vivo samples, both normal and malignant, clustered predominantly based on their maturation status. This parallels normal embryogenesis, rather than chromosomal anomalies in the tumours. miRNAs within a single cluster showed a similar expression pattern, implying common regulatory mechanisms. Normal testicular tissue expressed most discriminating miRNAs at a higher level than SE and SS. Moreover, differentiated non-seminomas showed overexpression of discriminating miRNAs. These results support the model that miRNAs are involved in regulating differentiation of stem cells, retained in GCTs.

Background This retrospective single-center study aimed to analyze transfusion requirements, coagulation parameters, and outcome parameters in patients undergoing lung transplantation (LuTx) with intraoperative extracorporeal circulatory support, comparing cardiopulmonary bypass (CPB), and extracorporeal membrane oxygenation (ECMO). Methods Over a 3-year period, 49 of a total of 188 LuTx recipients were identified being set intraoperatively on either conventional CPB (n = 22) or ECMO (n = 27). Intra- and postoperative transfusion and coagulation factor requirements as well as early outcome parameters were analyzed. Results LuTx patients on CPB had significantly higher intraoperative transfusion requirements when compared with ECMO patients, that is, packed red cells (9 units [5–18] vs. 6 units [4–8], p = 0.011), platelets (3.5 units [2–4] vs. 2 units [0–3], p = 0.034), fibrinogen (5 g [4–6] vs. 0 g [0–4], p = 0.013), prothrombin complex concentrate (3 iU [2–5] vs. 0 iU [0–2], p = 0.001), and tranexamic acid (2.5 mg [2–5] vs. 2.0 mg [1–3], p = 0.002). Also, ventilator support requirements (21days [7–31] vs. 5 days [3–21], p = 0.013) and lengths of ICU stays (36 days [14–62] vs. 15 days [6–44], p = 0.030) were markedly longer in CPB patients. There were no differences in 30-day and 1-year mortality rates. Conclusion These data indicate a perioperative advantage of ECMO usage with low-dose heparinization over conventional CPB for extracorporeal circulatory support during LuTx. Long-term outcome is not affected.