Extracorporeal Life Support in Infarct-Related Cardiogenic Shock.

BACKGROUND: Extracorporeal life support (ECLS) is increasingly used in the treatment of infarct-related cardiogenic shock despite a lack of evidence regarding its effect on mortality. METHODS: In this multicenter trial, patients with acute myocardial infarction complicated by cardiogenic shock for whom early revascularization was planned were randomly assigned to receive early ECLS plus usual medical treatment (ECLS group) or usual medical treatment alone (control group). The primary outcome was death from any cause at 30 days. Safety outcomes included bleeding, stroke, and peripheral vascular complications warranting interventional or surgical therapy. RESULTS: A total of 420 patients underwent randomization, and 417 patients were included in final analyses. At 30 days, death from any cause had occurred in 100 of 209 patients (47.8%) in the ECLS group and in 102 of 208 patients (49.0%) in the control group (relative risk, 0.98; 95% confidence interval [CI], 0.80 to 1.19; P = 0.81). The median duration of mechanical ventilation was 7 days (interquartile range, 4 to 12) in the ECLS group and 5 days (interquartile range, 3 to 9) in the control group (median difference, 1 day; 95% CI, 0 to 2). The safety outcome consisting of moderate or severe bleeding occurred in 23.4% of the patients in the ECLS group and in 9.6% of those in the control group (relative risk, 2.44; 95% CI, 1.50 to 3.95); peripheral vascular complications warranting intervention occurred in 11.0% and 3.8%, respectively (relative risk, 2.86; 95% CI, 1.31 to 6.25). CONCLUSIONS: In patients with acute myocardial infarction complicated by cardiogenic shock with planned early revascularization, the risk of death from any cause at the 30-day follow-up was not lower among the patients who received ECLS therapy than among those who received medical therapy alone. (Funded by the Else Kröner Fresenius Foundation and others; ECLS-SHOCK ClinicalTrials.gov number, NCT03637205.).

Aortic Valve Stenosis Causes Accumulation of Extracellular Hemoglobin and Systemic Endothelial Dysfunction.

BACKGROUND: Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown. METHODS: We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and nitric oxide (NO) consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system. RESULTS: In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb, and increased plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress. CONCLUSIONS: AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT05603520 and NCT01805739.

Routine Extracorporeal Life Support in Infarct-Related Cardiogenic Shock: 1-Year Results of the ECLS-SHOCK Trial.

Extracorporeal life support (ECLS) has been increasingly used in the treatment of severe infarct-related cardiogenic shock in the last decade. The randomised ECLS-SHOCK trial demonstrated no benefit of early routine use on 30-day all-cause death. We herein present mid-term results. At 1-year follow-up, there were no significant differences in all-cause or cardiovascular mortality, neurologic outcome, recurrent myocardial infarction, repeat revascularisation and rehospitalisations for heart failure between ECLS and usual medical care.

Direct access to millions of mutations by whole genome sequencing of an oilseed rape mutant population.

Induced mutations are an essential source of genetic variation in plant breeding. Ethyl methanesulfonate (EMS) mutagenesis has been frequently applied, and mutants have been detected by phenotypic or genotypic screening of large populations. In the present study, a rapeseed M2 population was derived from M1 parent cultivar 'Express' treated with EMS. Whole genomes were sequenced from fourfold (4×) pools of 1988 M2 plants representing 497 M2 families. Detected mutations were not evenly distributed and displayed distinct patterns across the 19 chromosomes with lower mutation rates towards the ends. Mutation frequencies ranged from 32/Mb to 48/Mb. On average, 284 442 single nucleotide polymorphisms (SNPs) per M2 DNA pool were found resulting from EMS mutagenesis. 55% of the SNPs were C → T and G → A transitions, characteristic for EMS induced ('canonical') mutations, whereas the remaining SNPs were 'non-canonical' transitions (15%) or transversions (30%). Additionally, we detected 88 725 high confidence insertions and deletions per pool. On average, each M2 plant carried 39 120 canonical mutations, corresponding to a frequency of one mutation per 23.6 kb. Approximately 82% of such mutations were located either 5 kb upstream or downstream (56%) of gene coding regions or within intergenic regions (26%). The remaining 18% were located within regions coding for genes. All mutations detected by whole genome sequencing could be verified by comparison with known mutations. Furthermore, all sequences are accessible via the online tool 'EMSBrassica' (http://www.emsbrassica.plantbreeding.uni-kiel.de), which enables direct identification of mutations in any target sequence. The sequence resource described here will further add value for functional gene studies in rapeseed breeding.

Leaf and shoot apical meristem transcriptomes of quinoa (Chenopodium quinoa Willd.) in response to photoperiod and plant development.

Understanding the regulation of flowering time is crucial for adaptation of crops to new environment. In this study, we examined the timing of floral transition and analysed transcriptomes in leaf and shoot apical meristems of photoperiod-sensitive and -insensitive quinoa accessions. Histological analysis showed that floral transition in quinoa initiates 2-3 weeks after sowing. We found four groups of differentially expressed genes in quinoa genome that responded to plant development and floral transition: (i) 222 genes responsive to photoperiod in leaves, (ii) 1812 genes differentially expressed between accessions under long-day conditions in leaves, (iii) 57 genes responding to developmental changes under short-day conditions in leaves and (iv) 911 genes responding to floral transition within the shoot apical meristem. Interestingly, among numerous candidate genes, two putative FT orthologs together with other genes (e.g. SOC1, COL, AP1) were previously reported as key regulators of flowering time in other species. Additionally, we used coexpression networks to associate novel transcripts to a putative biological process based on the annotated genes within the same coexpression cluster. The candidate genes in this study would benefit quinoa breeding by identifying and integrating their beneficial haplotypes in crossing programs to develop adapted cultivars to diverse environmental conditions.

Assessing the potential for precision medicine in body weight reduction with regard to type 2 diabetes mellitus therapies: A meta-regression analysis of 120 randomized controlled trials.

AIMS: To assess the potential for precision medicine in type 2 diabetes by quantifying the variability of body weight as response to pharmacological treatment and to identify predictors which could explain this variability. METHODS: We used randomized clinical trials (RCTs) comparing glucose-lowering drugs (including but not limited to sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and thiazolidinediones) to placebo from four recent systematic reviews. RCTs reporting on body weight after treatment to allow for calculation of its logarithmic standard deviation (log[SD], i.e., treatment response heterogeneity) in verum (i.e., treatment) and placebo groups were included. Meta-regression analyses were performed with respect to variability of body weight after treatment and potential predictors. RESULTS: A total of 120 RCTs with a total of 43 663 participants were analysed. A slightly larger treatment response heterogeneity was shown in the verum groups, with a median log(SD) of 2.83 compared to 2.79 from placebo. After full adjustment in the meta-regression model, the difference in body weight log(SD) was -0.026 (95% confidence interval -0.044; 0.008), with greater variability in the placebo groups. Scatterplots did not show any slope divergence (i.e., interaction) between clinical predictors and the respective treatment (verum or placebo). CONCLUSIONS: We found no major treatment response heterogeneity in RCTs of glucose-lowering drugs for body weight reduction in type 2 diabetes. The precision medicine approach may thus be of limited value in this setting.

The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients.

BACKGROUND: Norepinephrine (NE) is a cornerstone drug in the management of septic shock, with its dose being used clinically as a marker of disease severity and as mortality predictor. However, variations in NE dose reporting either as salt formulations or base molecule may lead to misinterpretation of mortality risks and hinder the process of care. METHODS: We conducted a retrospective analysis of the MIMIC-IV database to assess the impact of NE dose reporting heterogeneity on mortality prediction in a cohort of septic shock patients. NE doses were converted from the base molecule to equivalent salt doses, and their ability to predict 28-day mortality at common severity dose cut-offs was compared. RESULTS: 4086 eligible patients with septic shock were identified, with a median age of 68 [57-78] years, an admission SOFA score of 7 [6-10], and lactate at diagnosis of 3.2 [2.4-5.1] mmol/L. Median peak NE dose at day 1 was 0.24 [0.12-0.42] µg/kg/min, with a 28-day mortality of 39.3%. The NE dose showed significant heterogeneity in mortality prediction depending on which formulation was reported, with doses reported as bitartrate and tartrate presenting 65 (95% CI 79-43)% and 67 (95% CI 80-47)% lower ORs than base molecule, respectively. This divergence in prediction widened at increasing NE doses. When using a 1 µg/kg/min threshold, predicted mortality was 54 (95% CI 52-56)% and 83 (95% CI 80-87)% for tartrate formulation and base molecule, respectively. CONCLUSIONS: Heterogeneous reporting of NE doses significantly affects mortality prediction in septic shock. Standardizing NE dose reporting as base molecule could enhance risk stratification and improve processes of care. These findings underscore the importance of consistent NE dose reporting practices in critical care settings.

The INTOXICATE study: methodology and preliminary results of a prospective observational study.

BACKGROUND: There is currently no practice-based, multicenter database of poisoned patients admitted to intensive care units (ICUs). The INTOXICATE study, endorsed by the ESICM and EAPCCT, aimed to determine the rate of eventful admissions among acutely intoxicated adult ICU patients. METHODS: Ethical approval was obtained for this multicenter, prospective observational study, and data-sharing agreements were signed with each participating center. An electronic case report form was used to collect data on patient demographics, exposure, clinical characteristics, investigations, treatment, and in-hospital mortality data. The primary outcome, 'eventful admission', was a composite outcome defined as the rate of patients who received any of the following treatments in the first 24 h after the ICU admission: oxygen supplementation with a FiO2 > 40%, mechanical ventilation, vasopressors, renal replacement therapy (RRT), cardiopulmonary resuscitation, antidotes, active cooling, fluid resuscitation (> 1.5 L of intravenous fluid of any kind), sedation, or who died in the hospital. RESULTS: Seventy-eight ICUs, mainly from Europe, but also from Australia and the Eastern Mediterranean, participated. A total of 2,273 patients were enrolled between November 2020 and June 2023. The median age of the patients was 41 years, 72% were exposed to intoxicating drugs. The observed rate of patients with an eventful ICU admission was 68% (n = 1546/2273 patients). The hospital mortality was 4.5% (n = 103/2273). CONCLUSIONS: The vast majority of patients survive, and approximately one third of patients do not receive any ICU-specific interventions after admission in an intensive care unit for acute intoxication. High-quality detailed clinical data have been collected from a large cohort of acutely intoxicated ICU patients, providing information on the pattern of severe acute poisoning requiring intensive care admission and the outcomes of these patients. TRIAL REGISTRATION: OSF registration ID: osf.io/7e5uy.

30-Day Mortality among Very Old Patients Admitted to European Intensive Care Units for Major Trauma.

INTRODUCTION: Cases of major trauma in the very old (over 80 years) are increasingly common in the intensive care unit (ICU). Predicting outcome is challenging in this group of patients as chronological age is a poor marker of health and poor predictor of outcome. Increasingly, decisions are guided by the use of organ dysfunction scores of both acute conditions (e.g., sequential organ failure assessment [SOFA] score) and chronic health issues (e.g., clinical frailty scale [CFS]). Recent work suggests that increased CFS is associated with a worse outcome in elderly major trauma patients. We aimed to test whether this association held true in the very old (over 80) or whether SOFA had a stronger association with 30-day outcome. METHODS: Data from the very elderly intensive care patient (VIP)-1 and VIP-2 studies for patients over 80 years old with major trauma admissions were merged. These participants were recruited from 20 countries across Europe. Baseline characteristics, level of care provided, and outcome (ICU and 30-day mortality) were summarised. Uni- and multivariable regression analyses were undertaken to determine associations between CFS and SOFA score in the first 24 h, type of major trauma, and outcomes. RESULTS: Of the 8,062 acute patients recruited to the two VIP studies, 498 patients were admitted to intensive care because of major trauma. Median age was 84 years, median SOFA score was 6 (IQR 3, 9), and median CFS was 3 (IQR 2, 5). Survival for 30 days was 54%. Median and interquartile range of CFS were the same for survivors and non-survivors. In the logistic regression analysis, CFS was not associated with increased mortality. SOFA score (p < 0.001) and trauma with head injury (p < 0.01) were associated with increased mortality. CONCLUSIONS: Major trauma admissions in the very old are not uncommon, and 30-day mortality is high. We found that CFS was not a helpful predictor of mortality. SOFA and trauma with head injury were associated with worse outcomes in this patient group.

Multicenter exploration of specialist palliative care in patients with left ventricular assist devices - a retrospective study.

BACKGROUND: The number of advanced heart failure patients with left ventricular assist devices (LVAD) is increasing. Despite guideline-recommendations, little is known about specialist palliative care involvement in LVAD-patients, especially in Europe. This study aims to investigate timing and setting of specialist palliative care in LVAD-patients. METHODS: We conducted a retrospective multicenter study in 2022. Specialist palliative care services in German LVAD-centers were identified and invited to participate. Forty adult LVAD-patients (mean age 65 years (SD 7.9), 90% male) from seven centers that received a specialist palliative care consultation during hospitalization were included. RESULTS: In 37 (67.3%) of the 55 LVAD-centers, specialist palliative care was available. The median duration between LVAD-implantation and first specialist palliative care contact was 17 months (IQR 6.3-50.3 months). Median duration between consultation and death was seven days (IQR 3-28 days). 65% of consults took place in an intensive/intermediate care unit with half of the patients having a Do-Not-Resuscitate order. Care planning significantly increased during involvement (advance directives before: n = 15, after: n = 19, p < 0.001; DNR before: n = 20, after: n = 28, p < 0.001). Symptom burden as assessed at first specialist palliative care contact was higher compared to the consultation requests (request: median 3 symptoms (IQR 3-6); first contact: median 9 (IQR 6-10); p < 0.001) with a focus on weakness, anxiety, overburdening of next-of-kin and dyspnea. More than 70% of patients died during index hospitalization, one third of these in a palliative care unit. CONCLUSIONS: This largest European multicenter investigation of LVAD-patients receiving specialist palliative care shows a late integration and high physical and psychosocial symptom burden. This study highlights the urgent need for earlier integration to identify and address poorly controlled symptoms. Further studies and educational efforts are needed to close the gap between guideline-recommendations and the current status quo.

Merging virtual and physical experiences: extended realities in cardiovascular medicine.

Technological advancement and the COVID-19 pandemic have brought virtual learning and working into our daily lives. Extended realities (XR), an umbrella term for all the immersive technologies that merge virtual and physical experiences, will undoubtedly be an indispensable part of future clinical practice. The intuitive and three-dimensional nature of XR has great potential to benefit healthcare providers and empower patients and physicians. In the past decade, the implementation of XR into cardiovascular medicine has flourished such that it is now integrated into medical training, patient education, pre-procedural planning, intra-procedural visualization, and post-procedural care. This review article discussed how XR could provide innovative care and complement traditional practice, as well as addressing its limitations and considering its future perspectives.

Importance of pseudoaneurysms after TAVI - a retrospective analysis of 2063 patients.

Background: Bifemoral arterial access is common in patients undergoing transcatheter aortic valve implantation (TAVI), with a primary treatment access (TAVI access) and a secondary non-TAVI access. Pseudoaneurysm (PSA) is an important complication of femoral arterial puncture. Major vascular complications after TAVI are well described, but little is known about PSA. Patients and methods: A total of 2063 patients underwent transfemoral TAVI between January 2014 and January 2020. Vascular ultrasound of the common femoral artery was assessed before and after TAVI. We compared patient characteristics, periprocedural risk scores, procedural characteristics, and access site bleeding events according to Valve Academic Research Consortium 3 (VARC-3) criteria, length of stay (LOS), and all-cause mortality at one year between patients with (46) and without (2017) PSA. Results: The incidence of PSA after TAVI was 2.2% (46/2063). All PSA were successfully treated with ultrasound-guided manual compression (UGMC) or thrombin injection (UGTI) without complications. Patients with PSA had lower platelet counts (210×1000/µl vs. 234×1000/µl; p<0.05), more heart failure symptoms on admission (91% vs. 25%; p<0.05), were more often treated with (N)OACs for atrial fibrillation (AF; 54% vs. 38%; p <0.05), and were less often treated with aspirin (35% vs. 51%; p<0.03). Multivariate analysis identified secondary access site (odds ratio [OR] 8.11; p<0.001) and (N)OAC therapy (OR 1.31; p = 0.037) as risk factors for PSA development. PSA is associated with VARC-3 type 1-3 access site bleeding and longer LOS (15.2 ± 11.3 d vs. 11.6 ± 8.9 d; p<0.01), but this did not affect one year mortality (17% vs. 14%; p = 0.53). Conclusions: Pseudoaneurysms are an important complication after TAVI and are associated with access site bleeding and prolonged hospital stay. (N)OAC therapy and secondary access are important risk factors. Pseudoaneurysms can be safely and effectively treated with thrombin injection and do not affect one-year mortality.

Targeted Interleukin-9 delivery in pulmonary hypertension: Comparison of immunocytokine formats and effector cell study.

AIMS: Pulmonary hypertension (PH) is accompanied by pulmonary vascular remodelling. By targeted delivery of Interleukin-9 (IL9) via the immunocytokine F8IL9, beneficial effects could be demonstrated in a mouse model of PH. This study aimed to compare two immunocytokine formats (single-chain Fv and full IgG) and to identify potential target cells of IL9. METHODS: The Monocrotaline mouse model of PH (PH, n = 12) was chosen to evaluate the treatment effects of F8IL9F8 (n = 12) and F8IgGIL9 (n = 6) compared with sham-induced animals (control, n = 10), the dual endothelin receptor antagonist Macitentan (MAC, n = 12) or IL9-based immunocytokines with irrelevant antigen specificity (KSFIL9KSF, n = 12; KSFIgGIL9 n = 6). Besides comparative validation of treatment effects, the study was focused on the detection and quantification of mast cells (MCs) and regulatory T cells (Tregs). RESULTS: There was a significantly elevated systolic right ventricular pressure (104 ± 36 vs. 45 ± 17 mmHg) and an impairment of right ventricular echocardiographic parameters (RVbasal: 2.52 ± 0.25 vs. 1.94 ± 0.13 mm) in untreated PH compared with controls (p < 0.05). Only the groups treated with F8IL9, irrespective of the format, showed consistent beneficial effects (p < 0.05). Moreover, F8IL9F8 but not F8IgGIL9 treatment significantly reduced lung tissue damage compared with untreated PH mice (p < 0.05). There was a significant increase in Tregs in F8IL9-treated compared with control animals, the untreated PH and the MAC group (p < 0.05). CONCLUSIONS: Beneficial treatment effects of targeted IL9 delivery in a preclinical model of PH could be convincingly validated. IL9-mediated recruitment of Tregs into lung tissue might play a crucial role in the induction of anti-inflammatory and anti-proliferative mechanisms potentially contributing to a novel disease-modifying concept.

Diabetes mellitus is associated with 90-day mortality in old critically ill COVID-19 patients: a multicenter prospective observational cohort study.

BACKGROUND: Several studies have found an association between diabetes mellitus, disease severity and outcome in COVID-19 patients. Old critically ill patients are particularly at risk. This study aimed to investigate the impact of diabetes mellitus on 90-day mortality in a high-risk cohort of critically ill patients over 70 years of age. METHODS: This multicentre international prospective cohort study was performed in 151 ICUs across 26 countries. We included patients ≥ 70 years of age with a confirmed SARS-CoV-2 infection admitted to the intensive care unit from 19th March 2020 through 15th July 2021. Patients were categorized into two groups according to the presence of diabetes mellitus. Primary outcome was 90-day mortality. Kaplan-Meier overall survival curves until day 90 were analysed and compared using the log-rank test. Mixed-effect Weibull regression models were computed to investigate the influence of diabetes mellitus on 90-day mortality. RESULTS: This study included 3420 patients with a median age of 76 years were included. Among these, 37.3% (n = 1277) had a history of diabetes mellitus. Patients with diabetes showed higher rates of frailty (32% vs. 18%) and several comorbidities including chronic heart failure (20% vs. 11%), hypertension (79% vs. 59%) and chronic kidney disease (25% vs. 11%), but not of pulmonary comorbidities (22% vs. 22%). The 90-day mortality was significantly higher in patients with diabetes than those without diabetes (64% vs. 56%, p < 0.001). The association of diabetes and 90-day mortality remained significant (HR 1.18 [1.06-1.31], p = 0.003) after adjustment for age, sex, SOFA-score and other comorbidities in a Weibull regression analysis. CONCLUSION: Diabetes mellitus was a relevant risk factor for 90-day mortality in old critically ill patients with COVID-19. STUDY REGISTRATION: NCT04321265, registered March 19th, 2020.

The impact of ethnic background on ICU care and outcome in sepsis and septic shock - A retrospective multicenter analysis on 17,949 patients.

BACKGROUND: Previous studies have been inconclusive about racial disparities in sepsis. This study evaluated the impact of ethnic background on management and outcome in sepsis and septic shock. METHODS: This analysis included 17,146 patients suffering from sepsis and septic shock from the multicenter eICU Collaborative Research Database. Generalized estimated equation (GEE) population-averaged models were used to fit three sequential regression models for the binary primary outcome of hospital mortality. RESULTS: Non-Hispanic whites were the predominant group (n = 14,124), followed by African Americans (n = 1,852), Hispanics (n = 717), Asian Americans (n = 280), Native Americans (n = 146) and others (n = 830). Overall, the intensive care treatment and hospital mortality were similar between all ethnic groups. This finding was concordant in patients with septic shock and persisted after adjusting for patient-level variables (age, sex, mechanical ventilation, vasopressor use and comorbidities) and hospital variables (teaching hospital status, number of beds in the hospital). CONCLUSION: We could not detect ethnic disparities in the management and outcomes of critically ill septic patients and patients suffering from septic shock. Disparate outcomes among critically ill septic patients of different ethnicities are a public health, rather than a critical care challenge.

The Sequential Organ Failure Assessment (SOFA) Score: has the time come for an update?

The Sequential Organ Failure Assessment (SOFA) score was developed more than 25 years ago to provide a simple method of assessing and monitoring organ dysfunction in critically ill patients. Changes in clinical practice over the last few decades, with new interventions and a greater focus on non-invasive monitoring systems, mean it is time to update the SOFA score. As a first step in this process, we propose some possible new variables that could be included in a SOFA 2.0. By so doing, we hope to stimulate debate and discussion to move toward a new, properly validated score that will be fit for modern practice.

SYSTEMI - systemic organ communication in STEMI: design and rationale of a cohort study of patients with ST-segment elevation myocardial infarction.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) still causes significant mortality and morbidity despite best-practice revascularization and adjunct medical strategies. Within the STEMI population, there is a spectrum of higher and lower risk patients with respect to major adverse cardiovascular and cerebral events (MACCE) or re-hospitalization due to heart failure. Myocardial and systemic metabolic disorders modulate patient risk in STEMI. Systematic cardiocirculatory and metabolic phenotyping to assess the bidirectional interaction of cardiac and systemic metabolism in myocardial ischemia is lacking. METHODS: Systemic organ communication in STEMI (SYSTEMI) is an all-comer open-end prospective study in STEMI patients > 18 years of age to assess the interaction of cardiac and systemic metabolism in STEMI by systematically collecting data on a regional and systemic level. Primary endpoint will be myocardial function, left ventricular remodelling, myocardial texture and coronary patency at 6 month after STEMI. Secondary endpoint will be all-cause death, MACCE, and re-hospitalisation due to heart failure or revascularisation assessed 12 month after STEMI. The objective of SYSTEMI is to identify metabolic systemic and myocardial master switches that determine primary and secondary endpoints. In SYSTEMI 150-200 patients are expected to be recruited per year. Patient data will be collected at the index event, within 24 h, 5 days as well as 6 and 12 months after STEMI. Data acquisition will be performed in multilayer approaches. Myocardial function will be assessed by using serial cardiac imaging with cineventriculography, echocardiography and cardiovascular magnetic resonance. Myocardial metabolism will be analysed by multi-nuclei magnetic resonance spectroscopy. Systemic metabolism will be approached by serial liquid biopsies and analysed with respect to glucose and lipid metabolism as well as oxygen transport. In summary, SYSTEMI enables a comprehensive data analysis on the levels of organ structure and function alongside hemodynamic, genomic and transcriptomic information to assess cardiac and systemic metabolism. DISCUSSION: SYSTEMI aims to identify novel metabolic patterns and master-switches in the interaction of cardiac and systemic metabolism to improve diagnostic and therapeutic algorithms in myocardial ischemia for patient-risk assessment and tailored therapy. TRIAL REGISTRATION: Trial Registration Number: NCT03539133.

Corrigendum: The genome of Chenopodium quinoa.

This corrects the article DOI: 10.1038/nature21370.

The genome of Chenopodium quinoa.

Chenopodium quinoa (quinoa) is a highly nutritious grain identified as an important crop to improve world food security. Unfortunately, few resources are available to facilitate its genetic improvement. Here we report the assembly of a high-quality, chromosome-scale reference genome sequence for quinoa, which was produced using single-molecule real-time sequencing in combination with optical, chromosome-contact and genetic maps. We also report the sequencing of two diploids from the ancestral gene pools of quinoa, which enables the identification of sub-genomes in quinoa, and reduced-coverage genome sequences for 22 other samples of the allotetraploid goosefoot complex. The genome sequence facilitated the identification of the transcription factor likely to control the production of anti-nutritional triterpenoid saponins found in quinoa seeds, including a mutation that appears to cause alternative splicing and a premature stop codon in sweet quinoa strains. These genomic resources are an important first step towards the genetic improvement of quinoa.

Contribution of information about acute and geriatric characteristics to decisions about life-sustaining treatment for old patients in intensive care.

BACKGROUND: Life-sustaining treatment (LST) in the intensive care unit (ICU) is withheld or withdrawn when there is no reasonable expectation of beneficial outcome. This is especially relevant in old patients where further functional decline might be detrimental for the self-perceived quality of life. However, there still is substantial uncertainty involved in decisions about LST. We used the framework of information theory to assess that uncertainty by measuring information processed during decision-making. METHODS: Datasets from two multicentre studies (VIP1, VIP2) with a total of 7488 ICU patients aged 80 years or older were analysed concerning the contribution of information about the acute illness, age, gender, frailty and other geriatric characteristics to decisions about LST. The role of these characteristics in the decision-making process was quantified by the entropy of likelihood distributions and the Kullback-Leibler divergence with regard to withholding or withdrawing decisions. RESULTS: Decisions to withhold or withdraw LST were made in 2186 and 1110 patients, respectively. Both in VIP1 and VIP2, information about the acute illness had the lowest entropy and largest Kullback-Leibler divergence with respect to decisions about withdrawing LST. Age, gender and geriatric characteristics contributed to that decision only to a smaller degree. CONCLUSIONS: Information about the severity of the acute illness and, thereby, short-term prognosis dominated decisions about LST in old ICU patients. The smaller contribution of geriatric features suggests persistent uncertainty about the importance of functional outcome. There still remains a gap to fully explain decision-making about LST and further research involving contextual information is required. TRIAL REGISTRATION: VIP1 study: NCT03134807 (1 May 2017), VIP2 study: NCT03370692 (12 December 2017).